Decitabine

12.1 Mechanism of Action Decitabine is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated into DNA. Non-proliferating cells are relatively insensitive to decitabine.

1 INDICATIONS AND USAGE Decitabine for Injection is indicated for treatment of adult patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. Decitabine for Injection is a nucleoside metabolic inhibitor indicated for treatment of adult patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. ( 1 )

2 DOSAGE AND ADMINISTRATION Three Day Regimen : Administer Decitabine for Injection at a dose of 15 mg/m 2 by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days. Repeat cycle every 6 weeks. ( 2.1 ) Five Day Regimen : Administer Decitabine for Injection at a dose of 20 mg/m 2 by continuous intravenous infusion over 1 hour repeated daily for 5 days. Repeat cycle every 4 weeks. ( 2.1 ) 2.1 Recommended Dosage Pre-Medications and Baseline Testing Consider pre-medicating for nausea with antiemetics. Conduct baseline laboratory testing: complete blood count (CBC) with platelets, serum hepatic panel, and serum creatinine. Decitabine for Injection Regimen Options Three Day Regimen Administer Decitabine for Injection at a dose of 15 mg/m 2 by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days. Repeat cycles every 6 weeks upon hematologic recovery (ANC at least 1,000/mcL and platelets at least 50,000/mcL) for a minimum of 4 cycles. A complete or partial response may take longer than 4 cycles. Delay and reduce dose for hematologic toxicity [see Dosage and Administration ( 2.2 )] . Five Day Regimen Administer Decitabine for Injection at a dose of 20 mg/m 2 by continuous intravenous infusion over 1 hour daily for 5 days. Delay and reduce dose for hematologic toxicity [see Dosage and Administration ( 2.2 )] . Repeat cycles every 4 weeks upon hematologic recovery (ANC at least 1,000/mcL and platelets at least 50,000/mcL) for a minimum of 4 cycles. A complete or partial response may take longer than 4 cycles. Patients with Renal or Severe Hepatic Impairment Treatment with Decitabine for Injection has not been studied in patients with pre-existing renal or hepatic impairment. For patients with pre-existing renal or hepatic impairment, consider the potential risks and benefits before initiating treatment with Decitabine for Injection. 2.2 Dosage Modifications for Adverse Reactions Hematologic Toxicity If hematologic recovery from a previous Decitabine for Injection treatment cycle requires more than 6 weeks, delay the next cycle of Decitabine for Injection therapy and reduce Decitabine for Injection dose temporarily by following this algorithm: Recovery requiring more than 6, but less than 8 weeks: delay Decitabine for Injection dosing for up to 2 weeks and reduce the dose temporarily to 11 mg/m 2 every 8 hours (33 mg/m 2 /day, 99 mg/m 2 /cycle) upon restarting therapy. Recovery requiring more than 8, but less than 10 weeks: Perform bone marrow aspirate to assess for disease progression. In the absence of progression, delay Decitabine for Injection dosing for up to 2 more weeks and reduce the dose to 11 mg/m 2 every 8 hours (33 mg/m 2 /day, 99 mg/m 2 /cycle) upon restarting therapy, then maintain or increase dose in subsequent cycles as clinically indicated. Non-hematologic Toxicity Delay subsequent Decitabine for Injection treatment for any the following nonhematologic toxicities and do not restart until toxicities resolve: Serum creatinine greater than or equal to 2 mg/dL Alanine transaminase (ALT), total bilirubin greater than or equal to 2 times upper limit of normal (ULN) Active or uncontrolled infection 2.3 Preparation and Administration Decitabine for Injection is a cytotoxic drug. Follow special handling and disposal procedures. 1 Aseptically reconstitute Decitabine for Injection with room temperature (20° to 25°C) 10 mL of Sterile Water for Injection, USP. Upon reconstitution, the final concentration of the reconstituted Decitabine for Injection solution is 5 mg per mL. You must dilute the reconstituted solution with 0.9% Sodium Chloride Injection or 5% Dextrose Injection prior to administration. Temperature of the diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) depends on time of administration after preparation. For Administration Within 15 Minutes of Preparation If Decitabine for Injection is intended to be administered within 15 minutes from the time of preparation, dilute the reconstituted solution with room temperature (20° to 25°C) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 0.1 mg per mL to 1 mg per mL. Discard unused portion. For Delayed Administration If Decitabine for Injection is intended to be administered after 15 minutes of preparation, dilute the reconstituted solution with cold (2° to 8°C) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 0.1 mg per mL to 1 mg per mL. Store at 2° to 8°C for up to 4 hours. Diluted stored solution must be used within 4 hours from the time of preparation. Discard unused portion. Use the diluted, refrigerated solution within 4 hours from the time of preparation or discard. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if there is evidence of particulate matter or discoloration.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions ( 5.1 )] Most common adverse reactions (> 50%) are neutropenia, thrombocytopenia, anemia, and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical 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 safety of Decitabine for Injection was studied in 3 single-arm studies (N = 66, N = 98, N = 99) and 1 controlled supportive care study (N = 83 Decitabine for Injection, N = 81 supportive care). The data described below reflect exposure to Decitabine for Injection in 83 patients in the MDS trial. In the trial, patients received 15 mg/m 2 intravenously every 8 hours for 3 days every 6 weeks. The median number of Decitabine for Injection cycles was 3 (range 0 to 9). Most Common Adverse Reactions: neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia. Adverse Reactions Most Frequently (≥ 1%) Resulting in Clinical Intervention and or Dose Modification in the Controlled Supportive Care Study in the Decitabine for Injection Arm: Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardio-respiratory arrest, increased blood bilirubin, intracranial hemorrhage, abnormal liver function tests. Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile neutropenia. Dose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia, depression, pharyngitis. Table 1 presents all adverse reactions occurring in at least 5% of patients in the Decitabine for Injection group and at a rate greater than supportive care. Table 1: Adverse Reactions Reported in ≥ 5% of Patients in the Decitabine for Injection Group and at a Rate Greater than Supportive Care in the Controlled Trial in MDS Decitabine for Injection N = 83 (%) Supportive Care N = 81 (%) Blood and lymphatic system disorders Neutropenia 75 (90) 58 (72) Thrombocytopenia 74 (89) 64 (79) Anemia NOS 68 (82) 60 (74) Febrile neutropenia 24 (29) 5 (6) Leukopenia NOS 23 (28) 11 (14) Lymphadenopathy 10 (12) 6 (7) Thrombocythemia 4 (5) 1 (1) Cardiac disorders Pulmonary edema NOS 5 (6) 0 (0) Eye disorders Vision blurred 5 (6) 0 (0) Gastrointestinal disorders Nausea 35 (42) 13 (16) Constipation 29 (35) 11 (14) Diarrhea NOS 28 (34) 13 (16) Vomiting NOS 21 (25) 7 (9) Abdominal pain NOS 12 (14) 5 (6) Oral mucosal petechiae 11 (13) 4 (5) Stomatitis 10 (12) 5 (6) Dyspepsia 10 (12) 1 (1) Ascites 8 (10) 2 (2) Gingival bleeding 7 (8) 5 (6) Hemorrhoids 7 (8) 3 (4) Loose stools 6 (7) 3 (4) Tongue ulceration 6 (7) 2 (2) Dysphagia 5 (6) 2 (2) Oral soft tissue disorder NOS 5 (6) 1 (1) Lip ulceration 4 (5) 3 (4) Abdominal distension 4 (5) 1 (1) Abdominal pain upper 4 (5) 1 (1) Gastro-esophageal reflux disease 4 (5) 0 (0) Glossodynia 4 (5) 0 (0) General disorders and administrative site disorders Pyrexia 44 (53) 23 (28) Edema peripheral 21 (25) 13 (16) Rigors 18 (22) 14 (17) Edema NOS 15 (18) 5 (6) Pain NOS 11 (13) 5 (6) Lethargy 10 (12) 3 (4) Tenderness NOS 9 (11) 0 (0) Fall 7 (8) 3 (4) Chest discomfort 6 (7) 3 (4) Intermittent pyrexia 5 (6) 3 (4) Malaise 4 (5) 1 (1) Crepitations NOS 4 (5) 1 (1) Catheter site erythema 4 (5) 1 (1) Catheter site pain 4 (5) 0 (0) Injection site swelling 4 (5) 0 (0) Hepatobiliary disorders Hyperbilirubinemia 12 (14) 4 (5) Infections and infestations Pneumonia NOS 18 (22) 11 (14) Cellulitis 10 (12) 6 (7) Candidal infection NOS 8 (10) 1 (1) Catheter related infection 7 (8) 0 (0) Urinary tract infection NOS 6 (7) 1 (1) Staphylococcal infection 6 (7) 0 (0) Oral candidiasis 5 (6) 2 (2) Sinusitis NOS 4 (5) 2 (2) Bacteremia 4 (5) 0 (0) Injury, poisoning and procedural complications Transfusion reaction 6 (7) 3 (4) Abrasion NOS 4 (5) 1 (1) Investigations Cardiac murmur NOS 13 (16) 9 (11) Blood alkaline phosphatase NOS increased 9 (11) 7 (9) Aspartate aminotransferase increased 8 (10) 7 (9) Blood urea increased 8 (10) 1 (1) Blood lactate dehydrogenase increased 7 (8) 5 (6) Blood albumin decreased 6 (7) 0 (0) Blood bicarbonate increased 5 (6) 1 (1) Blood chloride decreased 5 (6) 1 (1) Protein total decreased 4 (5) 3 (4) Blood bicarbonate decreased 4 (5) 1 (1) Blood bilirubin decreased 4 (5) 1 (1) Metabolism and nutrition disorders Hyperglycemia NOS 27 (33) 16 (20) Hypoalbuminemia 20 (24) 14 (17) Hypomagnesemia 20 (24) 6 (7) Hypokalemia 18 (22) 10 (12) Hyponatremia 16 (19) 13 (16) Appetite decreased NOS 13 (16) 12 (15) Anorexia 13 (16) 8 (10) Hyperkalemia 11 (13) 3 (4) Dehydration 5 (6) 4 (5) Musculoskeletal and co

7 DRUG INTERACTIONS Drug interaction studies with decitabine have not been conducted. In vitro studies in human liver microsomes suggest that decitabine is unlikely to inhibit or induce cytochrome P450 enzymes. In vitro metabolism studies have suggested that decitabine is not a substrate for human liver cytochrome P450 enzymes. As plasma protein binding of decitabine is negligible (<1%), interactions due to displacement of more highly protein bound drugs from plasma proteins are not expected.