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Use in Males: Men should be advised to not father a child while receiving treatment with azacitidine. (See NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, Impairment of Fertility for discussion of premating effects of azacitidine exposure on male fertility and embryonic viability.)
Anemia, Neutropenia and Thrombocytopenia: Treatment with azacitidine 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 as described in DOSAGE & ADMINISTRATION.
Severe Preexisting Hepatic Impairment: Because azacitidine is potentially hepatotoxic in patients with severe preexisting hepatic impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have been rarely 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 azacitidine 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 rarely in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for non-MDS 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 as described in DOSAGE & ADMINISTRATION.
Patients with renal impairment should be closely monitored for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys. (See DOSAGE & ADMINISTRATION.)
Safety and effectiveness of azacitidine in patients with MDS and renal impairment have not been studied as these patients were excluded from the clinical trials.
Information for Patients: Patients should inform their physician about any underlying liver and renal disease.
Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with azacitidine. For nursing mothers, 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.
Men should be advised to not father a child while receiving treatment with azacitidine.
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.
Renal Impairment: Severe renal impairment (Clcr < 30 ml/min) has no major effect on the exposure of azacitidine after multiple SC administrations. Therefore, azacitidine can be administered to patients with renal impairment without Cycle 1 dose adjustment.
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.
Use in Pregnancy: Teratogenic Effects: Pregnancy Category D.
Azacitidine may cause fetal harm when administered to pregnant woman. 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 an mg/m2 basis) azacitidine on gestation day 10. Developmental abnormalities 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 (micromedia, club foot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, edema, and rib abnormalities).
There are no adequate and well-controlled studies in pregnant women using azacitidine. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with azacitidine.
Use in Children: Safety and effectiveness in pediatric patients have not been established.
Use in the Elderly: Of the total number of patients in studies 1,2 and 3 described in Pharmacology: CLINICAL STUDIES under Actions, 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 events 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 toxic 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.
