Included as part of the PRECAUTIONS section.

Anemia, Neutropenia and Thrombocytopenia

Treatment with VIDAZA is associated with anemia, neutropenia and thrombocytopenia. Complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle. After administration of the recommended dosage for the first cycle, dosage for subsequent cycles should be reduced or delayed based on nadir counts and hematologic response [see DOSAGE AND ADMINISTRATION].

Severe Pre-existing Hepatic Impairment

Because azacitidine is potentially hepatotoxic in patients with severe pre-existing hepatic impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have been reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline albumin < 30 g/L. Azacitidine is contraindicated in patients with advanced malignant hepatic tumors [see CONTRAINDICATIONS].

Safety and effectiveness of VIDAZA in patients with MDS and hepatic impairment have not been studied as these patients were excluded from the clinical trials.

Renal Abnormalities

Renal abnormalities ranging from elevated serum creatinine to renal failure and death have been reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for nonMDS conditions. In addition, renal tubular acidosis, defined as a fall in serum bicarbonate to < 20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium < 3 mEq/L) developed in 5 patients with CML treated with azacitidine and etoposide. If unexplained reductions in serum bicarbonate < 20 mEq/L or elevations of BUN or serum creatinine occur, the dosage should be reduced or held [see DOSAGE AND ADMINISTRATION].

Patients with renal impairment should be closely monitored for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys [see DOSAGE AND ADMINISTRATION].

Safety and effectiveness of VIDAZA in patients with MDS and renal impairment have not been studied as these patients were excluded from the clinical trials.

Monitoring Laboratory Tests

Complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each cycle. Liver chemistries and serum creatinine should be obtained prior to initiation of therapy.

Use in Pregnancy

VIDAZA may cause fetal harm when administered to a pregnant woman. Azacitidine caused congenital malformations in animals. Women of childbearing potential should be advised to avoid pregnancy during treatment with VIDAZA. There are no adequate and well-controlled studies in pregnant women using VIDAZA. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use In Specific Populations].

Use in Males

Men should be advised to not father a child while receiving treatment with VIDAZA. In animal studies, pre-conception treatment of male mice and rats resulted in increased embryofetal loss in mated females [see Nonclinical Toxicology].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m², approximately 8% the recommended human daily dose on a mg/m² basis) administered IP three times per week for 52 weeks. An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine IP at 2.0 mg/kg (6.0 mg/m², approximately 8% the recommended human daily dose on a mg/m² basis) once a week for 50 weeks. A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m² (approximately 20-80% the recommended human daily dose on a mg/m² basis) revealed an increased incidence of testicular tumors compared with controls.

The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems Salmonella typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Pro, WP3103P, WP3104P, and CC103; in in vitro forward gene mutation assay in mouse lymphoma cells and human lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells.

Administration of azacitidine to male mice at 9.9 mg/m² (approximately 9% the recommended human daily dose on a mg/m² basis) daily for 3 days prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats 3 times per week for 11 or 16 weeks at doses of 15-30 mg/m² (approximately 20-40%, the recommended human daily dose on a mg/m² basis) resulted in decreased weight of the testes and epididymides, and decreased sperm counts accompanied by decreased pregnancy rates and increased loss of embryos in mated females. In a related study, male rats treated for 16 weeks at 24 mg/m² resulted in an increase in abnormal embryos in mated females when examined on day 2 of gestation.

Use In Specific Populations

Pregnancy

Pregnancy Category D [see WARNING AND PRECAUTIONS]

VIDAZA may cause fetal harm when administered to a pregnant woman. Azacitidine was teratogenic in animals. There are no adequate and well controlled studies with Vidaza in pregnant women. Women of childbearing potential should be advised to avoid pregnancy during treatment with VIDAZA. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Female partners of male patients receiving VIDAZA should not become pregnant [see Nonclinical Toxicology].

Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single IP (intraperitoneal) injection of 6 mg/m² (approximately 8% of the recommended human daily dose on a mg/m² basis) azacitidine on gestation day 10. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3-12 mg/m² (approximately 4%-16% the recommended human daily dose on a mg/m² basis).

In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4-8 (postimplantation) at a dose of 6 mg/m² (approximately 8% of the recommended human daily dose on a mg/m² basis), although treatment in the preimplantation period (on gestation days 1-3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after a single IP dose of 3 to 12 mg/m² (approximately 8% the recommended human daily dose on a mg/m² basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused fetal death when administered at 3-12 mg/m² on gestation days 9 and 10; average live animals per litter was reduced to 9% of control at the highest dose on gestation day 9. Fetal anomalies included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, edema, and rib abnormalities).

Nursing Mothers

It is not known whether azacitidine or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for azacitidine in animal studies and the potential for serious adverse reactions in nursing infants from Vidaza, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into consideration the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the total number of patients in Studies 1, 2 and 3, 62% were 65 years and older and 21% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In addition there were no relevant differences in the frequency of adverse reactions observed in patients 65 years and older compared to younger patients.

Of the 179 patients randomized to azacitidine in Study 4, 68% were 65 years and older and 21% were 75 years and older. Survival data for patients 65 years and older were consistent with overall survival results. The majority of adverse reactions occurred at similar frequencies in patients < 65 years of age and patients 65 years of age and older.

Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Gender

There were no clinically relevant differences in safety and efficacy based on gender.

Race

Greater than 90% of all patients in all trials were Caucasian. Therefore, no comparisons between Caucasians and non-Caucasians were possible.

Last reviewed on RxList: 1/10/2013
This monograph has been modified to include the generic and brand name in many instances.