Azacitidine for injection is a nucleoside metabolic inhibitor indicated for the treatment of patients with the following FAB myelodysplastic syndrome (MDS) subtypes: Refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).
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1.1Myelodysplastic Syndromes (MDS) Azacitidine
for injection is indicated for treatment of patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).
Contraindications
Advanced Malignant Hepatic Tumors ( 4.1 ). Hypersensitivity to Azacitidine or Mannitol ( 4.2 ).
4.1Advanced Malignant Hepatic Tumors Azacitidine
for injection is contraindicated in patients with advanced malignant hepatic tumors [see Warnings and Precautions (5.2) ] .
4.2Hypersensitivity to Azacitidine or Mannitol Azacitidine
for injection is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol.
Warnings and precautions
Anemia, Neutropenia and Thrombocytopenia: Monitor complete blood counts (CBC) frequently ( 5.1 ). Hepatotoxicity: Patients with severe preexisting hepatic impairment are at higher risk for toxicity ( 5.2 ). Renal Toxicity: Monitor patients with renal impairment for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys ( 5.3 ). Tumor Lysis Syndrome: Azacitidine for injection may cause fatal or serious tumor lysis syndrome, including in patients with MDS.
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Assess baseline risk and monitor and treat as appropriate ( 5.4 ). Embryo-Fetal Risk: Azacitidine for injection can cause fetal harm. Advise females with reproductive potential of the potential risk to a fetus and to avoid pregnancy ( 5.5 ).
5.1Anemia, Neutropenia and Thrombocytopenia
Azacitidine causes anemia, neutropenia and thrombocytopenia. Monitor complete blood counts frequently for response and/or toxicity, at a minimum, prior to each dosing cycle. 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 (2.3) ] .
5.2Hepatotoxicity 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 (4.1) ] .
Monitor liver chemistries prior to initiation of therapy and with each cycle. 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.
5.3Renal 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 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.
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 (2.4) ] . 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 (2.4 , 2.5) ] .
Patients with MDS and renal impairment were excluded from the clinical studies.
5.4Tumor Lysis Syndrome Azacitidine
for injection may cause fatal or serious tumor lysis syndrome, including in patients with MDS. Tumor lysis syndrome may occur despite concomitant use of allopurinol. Assess baseline risk and monitor and treat as appropriate.
5.5 Embryo-Fetal Risk Based on the mechanism of action and findings in animals, azacitidine for injection can cause fetal harm when administered to a pregnant woman. Azacitidine administered to pregnant rats via a single intraperitoneal (IP) dose approximating 8% of the recommended human daily dose caused fetal death and anomalies [see Use in Specific Populations (8.1) ] . Advise females with reproductive potential to avoid pregnancy during treatment with azacitidine for injection [see Use in Specific Populations (8.3) ] .
Men should be advised to not father a child while receiving treatment with azacitidine for injection.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Based
on its mechanism of action and findings in animals, azacitidine can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no data on the use of azacitidine in pregnant women. Azacitidine was teratogenic and caused embryo-fetal lethality in animals at doses lower than the recommended human daily dose (see Data ) . Advise pregnant women of the potential risk to the fetus.
The background rate of major birth defects and miscarriage is unknown for the indicated population. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data Animal Data Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single IP (intraperitoneal) injection of 6 mg/m 2 (approximately 8% of the recommended human daily dose on a mg/m 2 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/m 2 (approximately 4%-16% the recommended human daily dose on a mg/m 2 basis). In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4-8 (postimplantation) at a dose of 6 mg/m 2 (approximately 8% of the recommended human daily dose on a mg/m 2 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/m 2 (approximately 8% the recommended human daily dose on a mg/m 2 basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused fetal death when administered at 3-12 mg/m 2 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).
Adverse reactions
The following adverse reactions are described in other labeling sections: Anemia, Neutropenia and Thrombocytopenia [see Warnings and Precautions (5.1) ] Hepatotoxicity in Patients with Severe Pre-existing Hepatic Impairment [see Warnings and Precautions (5.2) ] Renal Toxicity [see Warnings and Precautions (5.3) ] Tumor Lysis Syndrome [see Warnings and Precautions (5.4) ] Embryo-Fetal Risk [see Warnings and Precautions (5.5) ] Most Commonly Occurring Adverse Reactions (Subcutaneous or Intravenous Route): nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, ecchymosis.
The most common adverse reactions by intravenous route also included petechiae, rigors, weakness and hypokalemia. Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (Subcutaneous or Intravenous Route): Discontinuation: leukopenia, thrombocytopenia, neutropenia. Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia. Dose Reduced: leukopenia, neutropenia, thrombocytopenia.
Most common adverse reactions (>30%) by subcutaneous route are: nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia and ecchymosis. Most common adverse reactions by intravenous route also included petechiae, rigors, weakness and hypokalemia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Adverse Reactions in Clinical Trials
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to azacitidine in 443 MDS patients from 4 clinical studies. Study 1 was a supportive-care controlled trial (subcutaneous administration), Studies 2 and 3 were single arm studies (one with subcutaneous administration and one with intravenous administration), and Study 4 was an international randomized trial (subcutaneous administration) [see Clinical Studies (14) ] .
In Studies 1, 2 and 3, a total of 268 patients were exposed to azacitidine, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one year). Azacitidine was studied primarily in supportive-care controlled and uncontrolled trials (n=150 and n=118, respectively). The population in the subcutaneous studies (n=220) was 23 to 92 years old (mean 66.4 years), 68% male, and 94% white, and had MDS or AML.
The population in the intravenous study (n=48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white. Most patients received average daily doses between 50 and 100 mg/m 2 . In Study 4, a total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed to azacitidine. Of these patients, 119 were exposed for 6 or more cycles, and 63 for at least 12 cycles. The mean age of this population was 68.1 years (ranging from 42 to 83 years), 74% were male, and 99% were white.
Most patients received daily azacitidine doses of 75 mg/m 2 . Table 1 presents adverse reactions occurring in at least 5% of patients treated with azacitidine (subcutaneous) in Studies 1 and 2. It is important to note that duration of exposure was longer for the azacitidine-treated group than for the observation group: patients received azacitidine for injection for a mean of 11.4 months while mean time in the observation arm was 6.1 months.
Table 1: Most Frequently Observed Adverse Reactions (≥ 5.0% in All Subcutaneous Azacitidine Treated Patients; Studies 1 and 2) Number (%) of Patients System Organ Class Preferred Term Multiple terms of the same preferred terms for a patient are only counted once within each treatment group. All Azacitidine for Injection Includes adverse reactions from all patients exposed to azacitidine, including patients after crossing over from observations.
Similar to Studies 1 and 2 described above, duration of exposure to treatment with azacitidine was longer (mean 12.2 months) compared with best supportive care (mean 7.5 months). Table 2: Most Frequently Observed Adverse Reactions (≥ 5.0% in the Azacitidine Treated Patients and the Percentage with NCI CTC Grade 3/4 Reactions; Study 4) Number (%) of Patients Any Grade Grade 3/4 System Organ Class Preferred Term Multiple reports of the same preferred term from a patient were only counted once within each treatment.
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