azacitidine 300 MG Oral Tablet

INDICATIONS & USAGE Azacitidine for injection (Azacitidine), 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) 1.1 Myelodysplastic Syndromes (MDS) Azacitidine for injection (Azacitidine), 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 Bristol-Myers Squibb’s Vidaza (azacitidine for injection). However, due to Bristol-Myers Squibb’s marketing exclusivity rights, this drug product is not labeled with that information.

DOSAGE AND ADMINISTRATION Do not substitute azacitidine for injection for oral azacitidine. The indications and dosing regimen for azacitidine for injection differ from that of oral azacitidine ( 2.1 , 5.1 ). MDS: The recommended starting dosage for the first treatment cycle, for all patients regardless of baseline hematology values, is Azacitidine for injection75 mg/m 2 daily for 7 days to be administered by subcutaneous injection or intravenous infusion. See full prescribing information for schedule for subsequent cycles. Premedicate for nausea and vomiting ( 2.2 ). Continue treatment as long as the patient continues to benefit( 2.3 ). Monitor all patients for hematologic response and for renal toxicity; delay or reduce dosage as appropriate ( 2.3 , 2.6 , 2.7 ). 2.1 Important Administration Information Do not substitute azacitidine for injection for oral azacitidine. The indications and dosing regimen for azacitidine for injection differ from that of oral azacitidine [see Warnings and Precautions ( 5.1 )] 2.2 First Treatment Cycle for Adults The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg/m 2 subcutaneously or intravenously, daily for 7 days. Premedicate patients for nausea and vomiting. Obtain complete blood counts, liver chemistries and serum creatinine prior to the first dose. 2.3 Subsequent Treatment Cycles for Adults Repeat cycles every 4 weeks. The dose may be increased to 100 mg/m 2 if no beneficial effect is seen after 2 treatment cycles and if no toxicity other than nausea and vomiting has occurred. It is recommended that patients be treated for a minimum of 4 to 6 cycles. However, complete or partial response may require additional treatment cycles. Treatment may be continued as long as the patient continues to benefit. Monitor patients for hematologic response and renal toxicities [see Warnings and Precautions ( 5.4 )] , and delay or reduce dosage if necessary [see Dosage and Administration ( 2.6 )]. 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. 2.5 Dosage Adjustment Based on Hematology Laboratory Values For adult patients with baseline (start of treatment) WBC greater than or equal to 3 x10 9 /L, ANC greater than or equal to 1.5 x10 9 /L, and platelets greater than or equal to 75 x10 9 /L, adjust the dose as follows, based on nadir counts for any given cycle: Nadir Counts % Dose in the Next Course ANC (x10 9 /L) Less than 0.5 0.5 –1.5 Greater than 1.5 Platelets (x10 9 /L) Less than 25 25-50 Greater than 50 50% 67% 100% For adult patients whose baseline counts are WBC less than 3 x10 9 /L, ANC less than 1.5 x10 9 /L, or platelets less than 75 x10 9 /L, base dose adjustments on nadir counts and bone marrow biopsy cellularity at the time of the nadir as noted below, unless there is clear improvement in differentiation (percentage of mature granulocytes is higher and ANC is higher than at onset of that course) at the time of the next cycle, in which case continue the current dose. WBC or Platelet Nadir% decrease in countsfrom baseline Bone MarrowBiopsy Cellularity at Timeof Nadir (%) 30-60 15-30 Less than 15 50-75 Greater than 75 % Dose in theNext Course 100 50 33 75 50 33 If a nadir as defined in the table above has occurred, give the next course 28 days after the start of the preceding course, provided that both the WBC and the platelet counts are greater than 25% above the nadir and rising. If a greater than 25% increase above the nadir is not seen by day 28, reassess counts every 7 days. If a 25% increase is not seen by day 42, reduce the scheduled dose by 50%. 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. 2.6 Dosage Adjustment Based on Serum Electrolytes and Renal Toxicity If unexplained reductions in serum bicarbonate levels to less than 20 mEq/L occur, reduce the dosage by 50% for the next course. Similarly, if unexplained elevations of BUN or serumcreatinine occur, delay the next cycle until values return to normal or baseline and reduce the dose by 50% for the next course [see Warnings and Precautions ( 5.4 )] . 2.7 Use in Geriatric Patients 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, select the dose carefully and monitor renal function [see Warnings and Precautions (5.4) and Use in Specific Populations ( 8.5 )]. 2.8 Preparation of Azacitidine For Injection Azacitidine for injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1 The azacitidine for injection vial is single-dose and does not contain any preservatives. Discard unused portions of each vial properly [see How Supplied/Storage and Handling ( 16 )] . Do not save any unused portions for later administration. 2.9 Instructions for Subcutaneous Administration Reconstitute azacitidine for injection aseptically with 4 mL Sterile Water for Injection, USP to obtain a concentration of 25 mg/mL. Inject the diluent slowly into the vial. Vigorously shake or roll the vial until a uniform suspension is achieved. The suspension will be cloudy. Do not filter the suspension after reconstitution. Doing so could remove the active substance. Preparation for Immediate Subcutaneous Administration: For doses requiring more than 1 vial, divide the dose equally between the syringes (e.g., dose 150 mg = 6 mL, 2 syringes with 3 mL in each syringe) and inject into two separate sites. Due to retention in the vial and needle, it may not be feasible to withdraw all of the suspension from the vial. The product may be held at room temperature for up to 1 hour, but must be administered within 1 hour after reconstitution. Preparation for Delayed Subcutaneous Administration: The reconstituted product may be kept in the vial or drawn into a syringe. For doses requiring more than 1 vial, divide the dose equally between the syringes (e.g., dose 150 mg = 6 mL, 2 syringes with 3 mL in each syringe) and inject into two separate sites. Due to retention in the vial and needle, it may not be feasible to withdraw all of the suspension from the vial. The product must be refrigerated immediately. See Table 2 for suspension stability storage timelines based on the temperature of the diluent for delayed subcutaneous administration. After removal from refrigerated conditions, the suspension may be allowed to equilibrate to room temperature for up to 30 minutes prior to administration. Subcutaneous Administration To provide a homogeneous suspension, the contents of the syringe must be re-suspended by inverting the syringe 2-3 times and vigorously rolling the syringe between the palms for 30 seconds immediately prior to administration. Azacitidine for injection suspension is administered subcutaneously. Rotate sites for each injection (thigh, abdomen, or upper arm). New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, red, or hard. Table 2 Suspension Stability : Storage timelines based on the temperature of the diluent for suspension stability storage: Suspension Stability Storagetimelines Diluent Storage Temperature/Duration Room temperature (25°C / 77°F) Sterile Water for Injection, USP Store at room temperature at 25°C (77°F) for up to 1 hour or refrigerated at 2°C to 8°C (36°F to 46°F) for up to 8 hours. Cold (2°C to 8°C / 36°F to 46°F) Sterile Water for Injection, USP Store refrigerated at 2°C to 8°C(36°F to 46°F)for up to 22 hours. 2.10 Instructions for Intra

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 ). 5.1 Risks 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. 5.4 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 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 )] .

CONTRAINDICATIONS Advanced Malignant Hepatic Tumors ( 4.1 ) . Hypersensitivity to Azacitidine or Mannitol (4 .2 ) . 4.1 Advanced Malignant Hepatic Tumors Azacitidine for injection is contraindicated in patients with advanced malignant hepatic tumors [see Warnings and Precautions ( 5.3 )]. 4.2 Hypersensitivity to Azacitidine or Mannitol Azacitidine for injection is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol.

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Azacitidine is a pyrimidine nucleoside analog of cytidine. Azacitidine is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine. 12.2 Pharmacodynamics 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. 12.3 Pharmacokinetics The area under the curve (AUC) and peak concentration (C max ) of subcutaneous administration of azacitidine in patients with cancer were approximately dose proportional within the dose range of 25 mg/m 2 (0.33 times the lowest approved recommended dosage) to 100 mg/m 2 (the maximum approved recommended dosage). The mean and standard deviation (SD) of C max was 750 ± 403 ng/mL after a single subcutaneous administration of 75 mg/m 2 azacitidine. Multiple dosing at the recommended dose-regimen does not result in drug accumulation. Absorption Azacitidine is rapidly absorbed after subcutaneous administration with a median time to C max (T max ) of 0.5 hour. The bioavailability of subcutaneous azacitidine relative to intravenous azacitidine is approximately 89%, based on AUC. Distribution Mean volume of distribution following intravenous dosing is 76 ± 26 L. Elimination Mean apparent subcutaneous clearance is 167 ± 49 L/hour and mean half-life after subcutaneous administration is 41 ± 8 minutes. Excretion Published studies indicate that urinary excretion is the primary route of elimination of azacitidine and its metabolites. Following intravenous administration of radioactive azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for less than 1% of administered radioactivity over 3 days. Mean excretion of radioactivity in urine following subcutaneous administration of 14 C-azacitidine was 50%. The mean elimination half-lives of total radioactivity (azacitidine and its metabolites) were similar after intravenous and subcutaneous administrations, about 4 hours. Specific Populations The effects of hepatic impairment, gender, or race/ethnicity on the pharmacokinetics of intravenous and subcutaneous azacitidine have not been studied. Pediatric Patients 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. Patients with Renal Impairment In adult patients with cancer, the pharmacokinetics of azacitidine in 6 patients with normal renal function (CLcr >80 mL/min) and 6 patients with severe renal impairment (CLcr <30 mL/min) were compared following daily subcutaneous dosing (Days 1 through 5) at 75 mg/m 2 /day. Severe renal impairment increased azacitidine exposure by approximately 70% after single and 41% after multiple subcutaneous administrations.). This increase in exposure was not correlated with an increase in adverse events. The exposure was similar to exposure in patients with normal renal function receiving 100 mg/m 2 . Drug Interaction Studies No formal clinical drug interaction studies with azacitidine have been conducted. In vitro Studies Cytochrome P450 (CYP) Enzymes: An in vitro study at azacitidine concentrations up to 100 μM (IV C max = 10.6 μM) in human liver microsomes indicated that azacitidine does not cause any inhibition of CYP isoforms CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP2E1 at clinically achievable concentrations. In vitro studies with human cultured hepatocytes indicate that azacitidine at concentrations of 1.0 μM to 100 μM does not induce CYP 1A2, 2C19, or 3A4/5. Transporter Systems: An in vitro study with LLC-PK1 cells expressing P-glycoprotein (P-gp) indicated that azacitidine is not a substrate or inhibitor of P-gp. Azacitidine does not inhibit, breast cancer resistance protein (BCRP), organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptides (OATP) OATP1B1 and OATP1B3, or organic cation transporter (OCT) OCT2 at clinically relevant concentrations.