Azacitidine - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS • Risks of Substitution with Other Azacitidine Products: Do not substitute VIDAZA for oral azacitidine ( 2.1 , 5.1 ). • Anemia, Neutropenia and Thrombocytopenia: Monitor complete blood counts (CBC) frequently . • Hepatotoxicity: Patients with severe preexisting hepatic impairment are at higher risk for toxicity . • Renal Toxicity: Monitor patients with renal impairment for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys . • Tumor Lysis Syndrome: VIDAZA may cause fatal or serious tumor lysis syndrome, including in patients with MDS.

Assess baseline risk and monitor and treat as appropriate . • Embryo-Fetal Toxicity: VIDAZA can cause fetal harm.

Advise female patients and male patients with female partners of reproductive potential of the potential risk to a fetus and to use effective contraception .

5.1 Risks of Substitution with Other Azacitidine Products Due to substantial differences in the pharmacokinetic parameters [see Clinical Pharmacology ] , the recommended dose and schedule for VIDAZA are different from those of oral azacitidine products.

Treatment of patients using VIDAZA at the recommended dosage of oral azacitidine may result in a fatal adverse reaction.

Treatment of patients using oral azacitidine at the doses recommended for VIDAZA may not be effective.

Do not substitute VIDAZA for oral azacitidine [see Dosage and Administration ] .

5.2 Anemia, Neutropenia and Thrombocytopenia VIDAZA causes anemia, neutropenia and thrombocytopenia in adult patients with MDS and in pediatric patients with JMML.

Monitor complete blood counts frequently for response and/or toxicity, at a minimum, prior to each dosing cycle.

In adult patients with MDS, after administration of the recommended dosage for the first cycle, adjust dosage for subsequent cycles based on nadir counts and hematologic response [see Dosage and Administration ] .

In pediatric patients with JMML, dose reductions due to hematological toxicity are not recommended within the first 3 cycles as hematological toxicity will be difficult to assess and to differentiate from the natural course of the underlying disorder [see Dosage and Administration ] .

5.3 Hepatotoxicity in Patients with 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 ].

Monitor liver chemistries prior to initiation of therapy and with each cycle.

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

5.4 Renal Toxicity Renal toxicity 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 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.

Monitor serum creatinine and electrolytes prior to initiation of therapy and with each cycle.

If unexplained reductions in serum bicarbonate <20 mEq/L or elevations of BUN or serum creatinine occur, reduce or hold the dose [see Dosage and Administration ] .

Patients with renal impairment may be at increased risk for renal toxicity.

Also, azacitidine and its metabolites are primarily excreted by the kidney.

Therefore, monitor these patients closely for toxicity [see Dosage and Administration ( 2.6 , 2.7 )] .

Patients with MDS or pediatric patients with JMML and renal impairment were excluded from the clinical studies.

5.5 Tumor Lysis Syndrome VIDAZA may cause fatal or serious tumor lysis syndrome, including in patients with MDS.