Azacitidine for Injection is a nucleoside metabolic inhibitor indicated for the treatment of adult 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) ( 1 ).
1.1 Myelodysplastic Syndromes (MDS) Azacitidine for Injection is indicated for treatment of adult 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).
Pediatric use information is approved for Celgene Corporation’s Vidaza ® (azacitidine for injection). However due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that information.
Contraindications
Azacitidine for Injection is contraindicated in patients with advanced malignant hepatic tumors [ see Warnings and Precautions (5.3) ]. a known hypersensitivity to azacitidine. Advanced malignant hepatic tumors ( 4 ). Hypersensitivity to azacitidine ( 4 ).
Warnings and precautions
Risks of Substitution with Other Azacitidine Products : Do not substitute Azacitidine for Injection for oral azacitidine ( 2.1 , 5.1 ). Anemia, Neutropenia and Thrombocytopenia: Monitor complete blood counts (CBC) frequently ( 5.2 ). Hepatotoxicity : Patients with severe preexisting hepatic impairment are at higher risk for toxicity ( 5.3 ). Renal Toxicity : Monitor patients with renal impairment for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys ( 5.4 ).
Tumor Lysis Syndrome : Azacitidine for Injection may cause fatal or serious tumor lysis syndrome, including in patients with MDS. Assess baseline risk and monitor and treat as appropriate ( 5.5 ). Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception ( 5.6 , 8.1 , 8.3 ).
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5.1Risks of Substitution with Other Azacitidine Products Due
to substantial differences in the pharmacokinetic parameters [ see Clinical Pharmacology ( 12.3 )], the recommended dose and schedule for Azacitidine for Injection are different from those of oral azacitidine products. Treatment of patients using Azacitidine for Injection 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 Azacitidine for Injection may not be effective.
Do not substitute Azacitidine for Injection for oral azacitidine [ see Dosage and Administration (2.1) ].
5.2 Anemia, Neutropenia and Thrombocytopenia Azacitidine for Injection 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 (2.4) ] .
Pediatric use information is approved for Celgene Corporation’s Vidaza ® (azacitidine for injection). However due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that information.
5.3 Hepatic Toxicity in Patients with Severe Pre-existing Hepatic Impairment Because Azacitidine for Injection 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 less than 30 g/L.
Azacitidine for Injection is contraindicated in patients with advanced malignant hepatic tumors [ see Contraindications (4) ] . Monitor liver chemistries prior to initiation of therapy and with each cycle. Safety and effectiveness of Azacitidine for Injection in patients with MDS and hepatic impairment have not been studied as these patients were excluded from the clinical trials. Pediatric use information is approved for Celgene Corporation’s Vidaza ® (azacitidine for injection).
However due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that information.
5.4Renal 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 less than 20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium less than 3 mEq/L) developed in 5 patients with CML (an unapproved use) 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 less than 20 mEq/L or elevations of BUN or serum creatinine occur, reduce or hold the dose [ see Dosage and Administration (2.5) ] . 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 ( 2.5 , 2.6 )] . Patients with MDS and renal impairment were excluded from the clinical studies. Pediatric use information is approved for Celgene Corporation’s Vidaza ® (azacitidine for injection). However due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that information.
5.5 Tumor 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.
5.6 Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, Azacitidine for Injection can cause fetal harm when administered to a pregnant woman. In animal studies, azacitidine caused adverse developmental outcomes when administered to mice and rats at doses of 3 to 12 mg/m 2 and 6 mg/m 2 (approximately 4% to 16% and 8%) of the recommended human daily dose of 75 mg/m 2 , respectively. Advise pregnant women of the potential risk to a fetus .
Advise females of reproductive potential to use effective contraception during treatment with Azacitidine for Injection and for 6 months following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Azacitidine for Injection and for 3 months following the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .
Adverse reactions
The following clinically significant adverse reactions are described elsewhere in labeling: Anemia, Neutropenia and Thrombocytopenia [ see Warnings and Precautions (5.2) ] Hepatotoxicity in Patients with Severe Pre-existing Hepatic Impairment [ see Warnings and Precautions (5.3) ] Renal Toxicity [ see Warnings and Precautions (5.4) ] Tumor Lysis Syndrome [ see Warnings and Precautions (5.5) ] Most common adverse reactions (> 30%) in adult patients with MDS 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 Actavis at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience
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 . Most Commonly Occurring Adverse Reactions (Subcutaneous or Intravenous Route) in Adult Patients with MDS : 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 (Greater Than 2%) Resulting in Clinical Intervention (Subcutaneous or Intravenous Route) in Adult Patients with MDS : Discontinuation : leukopenia, thrombocytopenia, neutropenia. Dose Held : leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia. Dose Reduced : leukopenia, neutropenia, thrombocytopenia. 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 a mean of 11.4 months while mean time in the observation arm was 6.1 months. Table 1: Most Frequently Observed Adverse Reactions (Greater Than or Equal To 5% in All Subcutaneous Azacitidine-Treated Patients; Studies 1 and 2) Number (%) of Patients Body System Adverse Reaction a All Azacitidine b Observation c (N=220) (N=92) a Multiple terms of the same preferred terms for a patient are only counted once within each treatment group. b Includes adverse reactions from all patients exposed to azacitidine, including patients after crossing over from observations. c Includes adverse reactions from observation period only; excludes any adverse events after crossover to azacitidine.
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 (Greater Than or Equal To 5% 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 Body System Adverse Reactions a Azacitidine (N=175) Best Supportive Care Only (N= 102) Azacitidine (N=175) Best Supportive Care Only (N= 102) a Multiple reports of the same preferred term from a patient were only counted once within each treatment.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
