Azacitid IV/SC Injection

Azacitid 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).

Azacitidine is a pyrimidine nucleoside analog of cytidine that inhibits DNA/RNA methyltransferases. Azacitidine is incorporated into DNA and RNA following cellular uptake and enzymatic biotransformation to nucleotide triphosphates. Incorporation of Azacitidine into the DNA of cancer cells in vitro, including acute myeloid leukemia cells, inhibited DNA methyltransferases, reduced DNA methylation and altered gene expression, including re-expression of genes regulating tumor suppression and cell differentiation. Incorporation of Azacitidine into the RNA of cancer cells, including leukemic cells, inhibited RNA methyltransferases, reduced RNA methylation, decreased RNA stability and decreased protein synthesis. Antileukemic activity of Azacitidine was demonstrated by reduction of cell viability and induction of apoptosis in AML cell lines in vitro. Azacitidine decreased tumor burden and increased survival in leukemic tumor models in vivo.

Do not substitute Azacitidine for intravenous or subcutaneous Azacitidine. The indications and dosing regimen for Azacitidine differ from that of intravenous or subcutaneous Azacitidine.

Recommended Dosage: The recommended dosage of Azacitidine is 300 mg orally once daily with or without food on Days 1 through 14 of each 28-day cycle. Continue Azacitidine until disease progression or unacceptable toxicity. Administer an antiemetic 30 minutes prior to each dose of Azacitidine for the first 2 cycles. Antiemetic prophylaxis may be omitted after 2 cycles if there has been no nausea and vomiting. If the absolute neutrophil count (ANC) is less than 0.5 Gi/L on Day 1 of a cycle, do not administer Azacitidine (Azacitidine). Delay the start of the cycle until the ANC is 0.5 Gi/L or more.

Instruct patients on the following:

• Do not split, crush, or chew Azacitidine tablets.
• Take a dose about the same time each day.
• If a dose of Azacitidine is missed, or not taken at the usual time, take the dose as soon as possible on the same day, and resume the normal schedule the following day. Do not take 2 doses on the same day.
• If a dose is vomited, do not take another dose on the same day. Resume the normal schedule the following day. Azacitidine is a hazardous drug. Follow applicable special handling and disposal procedures.

Monitoring and Dosage Modifications for Adverse Reactions: Monitor complete blood count every other week for the first 2 cycles and prior to the start of each cycle thereafter. Increase monitoring to every other week for the 2 cycles after any dose reduction for myelosuppression.

Azacitidine is contraindicated in patients with known severe hypersensitivity to Azacitidine.

The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression. The following adverse reactions have been identified during postapproval use of intravenous or subcutaneous
Azacitid. Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Hypersensitivity reaction
• Interstitial lung disease
• Tumor lysis syndrome
• Sweet’s syndrome (acute febrile neutrophilic dermatosis)
• Necrotizing fasciitis (including fatal cases)
• Differentiation syndrome

Pregnancy: Based on its mechanism of action and findings in animals, Azacitidine can cause fetal harm when administered to a pregnant woman. There are no available data on Azacitidine use in pregnant women to evaluate for a drug associated risk. Azacitidine was teratogenic and caused embryo-fetal lethality in animals at doses less than the recommended human daily dose of oral Azacitidine on a mg/m2 basis. Advise pregnant women of the potential risk to the fetus. The estimated background of major birth defects and miscarriage for the indicated population is unknown. 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% to 4% and 15% to 20%, respectively.

Lactation: There are no data regarding the presence of Azacitidine in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with Azacitidine and for 1 week after the last dose.

Risks of Substitution with Other Azacitid Products: Due to substantial differences in the pharmacokinetic parameters, the recommended dose and schedule for Azacitid are different from those for the intravenous or subcutaneous Azacitid products. Treatment of patients using intravenous or subcutaneous Azacitid at the recommended dosage of Azacitidmay result in a fatal adverse reaction. Treatment of patients using Azacitid at the doses recommended for intravenous or subcutaneous Azacitid may not be effective. Do not substitute Azacitid for intravenous or subcutaneous Azacitid.

Myelosuppression: New or worsening Grade 3 or 4 neutropenia and thrombocytopenia occurred in 49% and 22% of patients who received Azacitid, respectively. Febrile neutropenia occurred in 12%. A dose reduction was required for 7% and 2% of patients due to neutropenia and thrombocytopenia, respectively. Less than 1% of patients discontinued Azacitid due to either neutropenia or thrombocytopenia. Monitor complete blood counts and modify the dosage as recommended. Provide standard supportive care, including hematopoietic growth factors, if myelosuppression occurs.

Increased Early Mortality in Patients with Myelodysplastic Syndromes: In AZA-MDS-003 (NCT01566695), 216 patients with red blood cell transfusion-dependent anemia and thrombocytopenia due to myelodysplastic syndromes were randomized to Azacitid or placebo. One hundred and seven patients received a median of 5 cycles of Azacitid 300 mg daily for 21 days of a 28-day cycle. Enrollment was discontinued early due to a higher incidence of early fatal and/or serious adverse reactions in patients who received Azacitid compared with placebo. The most frequent fatal adverse reaction was sepsis. The safety and effectiveness of Azacitid for treatment of myelodysplastic syndromes have not been established. Treatment of patients with myelodysplastic syndromes with Azacitid is not recommended outside of controlled trials.

Embryo-Fetal Toxicity: Based on the mechanism of action and findings in animals, Azacitid can cause fetal harm when administered to a pregnant woman. Azacitid administered to pregnant rats via a single intraperitoneal dose less than the recommended human daily dose of oral Azacitid on a mg/m2 basis caused fetal death and anomalies. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Azacitid and for at
least 6 months after the last dose. Advise males with female partners of reproductive potential to use effective
contraception during treatment with Azacitid and for at least 3 months after the last dose.

Pediatric Use: The safety and effectiveness of Azacitid in pediatric patients have not been established

Geriatric Use: Of the 238 patients in QUAZAR who received Azacitid, 72% were 65 years of age or older, while 12% were 75 years of age or older. No overall differences in safety or effectiveness of Azacitid were observed between these patients and younger patients

Renal Impairment: Monitor patients with severe renal impairment (creatinine clearance 15 to 29 mL/min calculated by Cockcroft-Gault formula) more frequently for adverse reactions and modify the Azacitid dosage for adverse reactions. No dose adjustment of Azacitid is recommended for patients with mild to severe renal impairment (CrCl 15 to 89 mL/min).

Hepatic Impairment: Azacitid has not been studied in patients with pre-existing severe hepatic impairment (total bilirubin >3 × ULN). A recommended dosage of Azacitid has not been established for patients with moderate hepatic impairment (total bilirubin >1.5 to 3 × ULN). No dose adjustment of Azacitid is recommended for patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 × ULN and any AST).

One case of overdose with Azacitid was reported during clinical trials. A patient experienced diarrhea, nausea, and vomiting after receiving a single IV dose of approximately 290 mg/m2, almost 4 times the recommended starting dose. The events resolved without sequelae, and the correct dose was resumed the following day. In the event of overdosage, the patient should be monitored with appropriate blood counts and should receive supportive treatment, as necessary. There is no known specific antidote for Azacitid overdosage.

Cytotoxic Chemotherapy

Store below 25°C, in a cool and dry place. Keep away from light. Keep out of the reach of children.