Vidaza (azacitidine)

Azacitidine, a synthetic pyrimidine nucleoside analog of cytidine, is an antineoplastic agent.

Azacitidine, a synthetic pyrimidine nucleoside analog of cytidine, is an antineoplastic agent. Following cellular uptake and bioenzymatic transformation to nucleotide triphosphates, azacitidine is incorporated into DNA and RNA. The drug appears to exert its antineoplastic effect by inhibiting DNA methyltransferase (the enzyme responsible for methylating newly synthesized DNA in mammalian cells), thereby causing hypomethylation of DNA, and by direct cytotoxic effect on abnormal hematopoietic cells in the bone marrow.

Azacitidine also decreases RNA stability and protein synthesis. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not appear to cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for cellular differentiation and proliferation.

The cytotoxic effects of azacitidine may cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Nonproliferating cells, however, are relatively insensitive to azacitidine. In vitro, the antileukemic activity of azaciditine was demonstrated by the induction of acute myeloid leukemia (AML) cell line apoptosis and reduced cell viability.

During the first treatment cycle in pediatric patients with juvenile myelomonocytic leukemia (JMML), reduced global DNA methylation scores were observed in bone marrow granulocytes after treatment with azacitidine. Global DNA methylation was reduced to a greater extent with higher azaciditine plasma exposures in adult patients with AML who received oral azacitidine for 14 days out of a 28-day cycle.

Azaciditine is rapidly absorbed following subcutaneous administration, and peak plasma concentrations are achieved 30 minutes after administration. Based on the area under the serum concentration time-curve (AUC), approximately 89% of subcutaneous azacitidine is bioavailable relative to azacitidine administered intravenously. In adult patients with cancer, AUC and peak plasma concentrations of subcutaneous azacitidine are approximately dose proportional over the dosage range of 25--100 mg/m2.

Administration of multiple IV or subcutaneous doses at the recommended dosage does not result in accumulation of the drug. Systemic exposure of oral azacitidine is approximately dose proportional over the dosage range of 120--600 mg once daily (0.4 to 2 times the recommended dosage). Following repeated administration of oral azacitidine at a dosage of 300 mg once daily, accumulation of the drug does not occur.

Relative to subcutaneous administration, the mean oral biovailability of azacitidine is 11%. Following oral administration of azacitidine, peak plasma concentrations are attained in a median of 1 hour. Administration of oral azacitidine with a high-fat, high calorie meal (approximately 800--1000 Kcal, 50% from fat), does not affect the total systemic exposure of azacitidine, but reduces peak plasma concentrations by 21%.

Azacitidine is not metabolized by cytochrome P450 (CYP) isoenzymes; azacitidine undergoes spontaneous hydrolysis and deamination by cytidine deaminase. Azaciditine and its metabolites primarily undergo elimination via urinary excretion. Following IV administration of a radiolabeled dose of azacitidine, cumulative excretion in the urine was 85% of the radiolabeled dose; less than 1% of the radiolabeled dose was recovered in the feces over a 3-day period.

Following subcutaneous administration of radiolabeled azacitidine, the mean urinary excretion of radioactivity was 50%. Based on total radioactivity after intravenous and subcutaneous administration, the mean elimination half-lives of azacitidine (and its metabolites) between routes were similar, and were approximately 4 hours. The mean elimination half-life of oral azacitidine is approximately 30 minutes.

After administration of oral azacitidine at the recommended dosage of 300 mg once daily, less than 2% of the dose is recovered in the urine as unchanged drug. Based on population pharmacokinetic analysis, following IV administration of either a 75 mg/m2 or 2.5 mg/kg dose of injectable azacitidine in pediatric patients with JMML, the mean geometric half-life of azaciditine is 0.3 hours. Based on a population pharmacokinetic analysis of adult and pediatric patients, no clinically meaningful differences were detected in the pharmacokinetics of IV azacitidine based on sex or tumor type (myelodysplastic syndrome (MDS), JMML, AML).

Increased clearance of injectable azaciditine in adult and pediatric patients was associated with an increased baseline body weight ranging from 4.6--102 kg; however, dosing based on body surface area (BSA) or body weight resulted in consistent plasma concentrations in pediatric patients with JMML across body weights from 4.6--18.5 kg and ages of 0.2--6.9 years. The pharmacokinetics of injectable azaciditine have not been evaluated based on hepatic impairment, race/ethnicity, or gender. Following single and multiple dose subcutaneous administrations of azacitidine in patients with severe renal impairment, exposure was increased by approximately 70% and 41%, respectively.

No clinically meaningful differences in the pharmacokinetics of oral azacitidine have been detected based on age (46--93 years), sex, body weight (39.3--129 kg), mild hepatic impairment (total bilirubin less than or equal to the upper limit of normal (ULN), or total bilirubin 1--1.5 times ULN with any AST level) , and mild to moderate renal impairment (creatinine clearance 30--89 mL/minute). The effects of race/ethnicity, moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN and any AST) or severe renal impairment (creatinine clearance 15--29 mL/minute) on the pharmacokinetics of oral azacitidine are not known.

USES: This medication is used to treat certain types of blood cancers in which the bone marrow does not produce enough healthy blood cells. People with these disorders usually have problems such as infections, anemia, and easy bleeding/bruising. Azacitidine works by helping your bone marrow make healthy blood cells.

It also kills abnormal blood cells that have grown too fast and do not work properly. This form of azacitidine should not be used in place of the form taken by mouth.

Generic name: azacitidine
Pronunciation: (AY-za-SYE-ti-deen)

The following indications are listed for Vidaza:

• Chronic Myelomonocytic Leukemia
• Juvenile Myelomonocytic Leukemia
• Myelodysplastic Syndrome

Also known as: Preleukemia.

No ICD codes are available for this drug.