Decitabine

6 ADVERSE REACTIONS Most common adverse reactions (> 50%) are neutropenia, thrombocytopenia, anemia, and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies 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 Commonly Occurring 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 Phase 3 Trials in the Decitabine for Injection Arm: Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardiorespiratory 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 Phase 3 MDS Trial 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) Decitabine for Injection N = 83 (%) Supportive Care N = 81 (%) Abdominal distension 4 (5) 1 (1) Abdominal pain upper 4 (5) 1 (1) Gastro-esophageal relux 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 connective tissue disorders Arthralgia 17 (20) 8 (10) Pain in limb 16 (19) 8 (10) Back pain 14 (17) 5 (6) Chest wall pain 6 (7) 1 (1) Musculoskeletal discomfort 5 (6) 0 (0) Myalgia 4 (5) 1 (1) Nervous system disorders Headache 23 (28) 11 (14) Dizziness 15 (18) 10 (12) Hypoesthesia 9 (11) 1 (1) Psychiatric disorders Insomnia 23 (28) 11 (14) Confusional state 10 (12) 3 (4) Anxiety 9 (11) 8 (10) Renal and urinary disorders Dysuria 5 (6) 3 (4) Urinary frequency 4 (5) 1 (1) Respiratory, thoracic and Mediastinal disorders Cough 33 (40) 25 (31) Pharyngitis 13 (16) 6 (7) Crackles lung 12 (14) 1 (1) Breath sounds decreased 8 (10) 7 (9) Hypoxia 8 (10) 4 (5) Rales 7 (8) 2 (2) Postnasal drip 4 (5) 2 (2) Skin and subcutaneous tissue disorders Ecchymosis 18 (22) 12 (15) Rash NOS 16 (19) 7 (9) Erythema 12 (14) 5 (6) Skin lesion NOS 9 (11) 3 (4) Pruritus 9 (11) 2 (2) Decitabine for Injection N = 83 (%) Supportive Care N = 81 (%) Alopecia 7 (8) 1 (1) Urticaria NOS 5 (6) 1 (1) Swelling face 5 (6) 0 (0) Vascular disorders Petechiae 32 (39) 13 (16) Pallor 19 (23) 10 (12) Hypotension NOS 5 (6) 4 (5) Hematoma NOS 4 (5) 3 (4) In a single-arm MDS study (N=99) decitabine for injection was dosed at 20 mg/m 2 intravenous, infused over one hour daily for 5 consecutive days of a 4 week cycle. Table 2 presents all adverse reactions occurring in at least 5% of patients. Table 2 Adverse Reactions Reported in ≥ 5% of Patients in a Single-arm Study* * In this single arm study, investigators reported adverse events based on clinical signs and symptoms rather than predefined laboratory abnormalities. Thus, not all laboratory abnormalities were recorded as adverse events. Decitabine for Injection N = 99 (%) Blood and lymphatic system disorders Anemia 31 (31%) Febrile neutropenia 20 (20%) Leukopenia 6 (6%) Neutropenia 38 (38%) Pancytopenia 5 (5%) Thrombocythemia 5 (5%) Thrombocytopenia 27 (27%) Cardiac disorders Cardiac failure congestive 5 (5%) Tachycardia 8 (8%) Ear and labyrinth disorders Ear pain 6 (6%) Gastrointestinal disorders Abdominal pain 14 (14%) Abdominal pain upper 6 (6%) Constipation 30 (30%) Diarrhea 28 (28%) Dyspepsia 10 (10%) Dysphagia 5 (5%) Gastro-esophageal relux disease 5 (5%) Nausea 40 (40%) Oral pain 5 (5%) Stomatitis 11 (11%) Toothache 6 (6%) Vomiting 16 (16%) General disorders and administration site conditions Asthenia 15 (15%) Chest pain 6 (6%) Chills 16 (16%) Fatigue 46 (46%) Mucosal Inflammation 9 (9%) Edema 5 (5%) Edema peripheral 27 (27%) Pain 5 (5%) Pyrexia 36 (36%) Infections and infestations Cellulitis 9 (9%) Oral candidiasis 6 (6%) Pneumonia 20 (20%) Sinusitis 6 (6%) Staphylococcal bacteremia 8 (8%) Tooth abscess 5 (5%) Upper respiratory tract infection 10 (10%) Urinary tract infection 7 (7%) Injury, poisoning and procedural complications Contusion 9 (9%) Investigations Blood bilirubin increased 6 (6%) Breath sounds abnormal 5 (5%) Weight decreased 9 (9%) Metabolism and nutrition disorders Anorexia 23 (23%) Decreased appetite 8 (8%) Dehydration 8 (8%) Hyperglycemia 6 (6%) Hypokalemia 12 (12%) Hypomagnesemia 5 (5%) Musculoskeletal and connective tissue disorders Arthralgia 17 (17%) Back pain 18 (18%) Bone pain 6 (6%) Muscle spasms 7 (7%) Muscular weakness 5 (5%) Decitabine for Injection N = 99 (%) Musculoskeletal pain 5 (5%) Myalgia 9 (9%) Pain in extremity 18 (18%) Nervous system disorders Dizziness 21 (21%) Headache 23 (23%) Psychiatric disorders Anxiety 9 (9%) Confusional state 8 (8%) Depression 9 (9%) Insomnia 14 (14%) Respiratory, thoracic and mediastinal disorders Cough 27 (27%) Dyspnea 29 (29%) Epistaxis 13 (13%) Pharyngolaryngeal pain 8 (8%) Pleural effusion 5 (5%) Sinus congestion 5 (5%) Skin and subcutaneous tissue disorders Dry skin 8 (8%) Ecchymosis 9 (9%) Erythema 5 (5%) Night sweats 5 (5%) Petechiae 12 (12%) Pruritus 9 (9%) Rash 11 (11%) Skin lesion 5 (5%) Vascular disorders Hypertension 6 (6%) Hypotension 11 (11%) No overall difference in safety was detected between patients > 65 years of age and younger patients in these myelodysplasia trials. No significant gender differences in safety or efficacy were detected. Patients with renal or hepatic dysfunction were not studied. Insufficient numbers of non-white patients were available to draw conclusions in these clinical trials. Serious adverse reactions that occurred in patients receiving decitabine for injection regardless of causality, not previously reported in Tables 1 and 2 include: Blood and Lymphatic System Disorders: myelosuppression, splenomegaly. Cardiac Disorders: myocardial infarction, cardio-respiratory arrest, cardiomyopathy, atrial fibrillation, supraventricular tachycardia. Gastrointestinal Disorders: gingival pain, upper gastrointestinal hemorrhage. General Disorders and Administrative Site Conditions: chest pain, catheter site hemorrhage. Hepatobiliary Disorders: cholecystitis. Infections and Infestations: fungal infection, sepsis, bronchopulmonary aspergillosis, peridiverticular abscess, respiratory tract infection, pseudomonal lung infection, Mycobacterium avium complex infection. Injury, Poisoning and Procedural Complications: post procedural pain, post procedural hemorrhage. Nervous System Disorders: intracranial hemorrhage. Psychiatric Disorders: mental status changes. Renal and Urinary Disorders: renal failure, urethral hemorrhage. Respiratory, Thoracic and Mediastinal Disorders: hemoptysis, lung infiltration, pulmonary embolism, respiratory arrest, pulmonary mass. Allergic Reaction: Hypersensitivity (anaphylactic reaction) to decitabine for injection has been reported in a Phase 2 trial. 6.2 Post-marketing Experience The following adverse reactions have been identified during post - approval use of decitabine for injection. 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. Cases of Sweet's Syndrome (acute febrile neutrophilic dermatosis) have been reported.

4 CONTRAINDICATIONS None None

11 DESCRIPTION Decitabine for Injection contains decitabine (5-aza-2'-deoxycitidine), an analogue of the natural nucleoside 2'-deoxycytidine. Decitabine is white to off-white solid with the molecular formula of C 8 H 12 N 4 O 4 and a molecular weight of 228.21. Its chemical name is 4-amino-1-(2-deoxy- β -D- erythro -pentofuranosyl)-s-triazin-2(1 H )-one and it has the following structural formula: Decitabine is slightly soluble in ethanol/water (50/50), methanol/water (50/50) and methanol; sparingly soluble in water and soluble in dimethylsulfoxide (DMSO). Decitabine for Injection is a white to almost white sterile lyophilized solid friable lumps or powder supplied in a clear glass vial. Each 20 mL, single dose, glass vial contains 50 mg decitabine, 68 mg monobasic potassium phosphate (potassium dihydrogen phosphate) and 11.6 mg sodium hydroxide. Figure

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. ( 2.2 ) 2.1 Recommended Starting Dosage Pre-Medications and Baseline Testing Consider pre-medicating for nausea with antiemetics. Conduct baseline laboratory testing: 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/microliter and platelets at least 50,000/microliter) 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 Dose Modifications for Toxicity ) . 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 Dose Modifications for Toxicity ) . Repeat cycles every 4 weeks upon hematologic recovery (ANC at least 1,000/microliter and platelets at least 50,000/microliter) for a minimum of 4 cycles. A complete or partial response may take longer than 4 cycles. 2.2 Dose Modifications for Toxicity 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 the decitabine for injection dose 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 non-hematologic toxicities and do not restart until toxicities resolve: Serum creatinine greater than or equal to 2 mg/dL SGPT, total bilirubin greater than or equal to 2 times ULN Active or uncontrolled infection 2.3 Instructions for Intravenous Administration Decitabine is a cytotoxic drug and caution should be exercised when handling and preparing decitabine for injection 1 . Aseptically reconstitute decitabine for injection with room temperature (20°C 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/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˚C to 25˚C) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 0.1 mg/mL to 1 mg/mL. For Delayed Administration If decitabine for injection is intended to be administered after 15 minutes of preparation, dilute the reconstituted solution with cold (2˚C to 8˚C) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 0.1 mg/mL to 1 mg/mL. Store at 2˚C to 8˚C for up to 4 hours. Diluted stored solution must be used within 4 hours from the time of preparation. 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.

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 )

10 OVERDOSAGE There is no known antidote for overdosage with decitabine for injection. Higher doses are associated with increased myelosuppression including prolonged neutropenia and thrombocytopenia. Standard supportive measures should be taken in the event of an overdose.

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.

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics Decitabine has been shown to induce hypomethylation both in vitro and in vivo . However, there have been no studies of decitabine-induced hypomethylation and pharmacokinetic parameters. 12.3 Pharmacokinetics Pharmacokinetic parameters were evaluated in patients. Eleven patients received 20 mg/m 2 infused over 1 hour intravenously (treatment Option 2). Fourteen patients received 15 mg/m 2 infused over 3 hours (treatment Option 1). PK parameters are shown in Table 3 . Plasma concentration-time profiles after discontinuation of infusion showed a biexponential decline. The CL of decitabine was higher following treatment Option 2. Upon repeat doses there was no systemic accumulation of decitabine or any changes in PK parameters. Population PK analysis (N=35) showed that the cumulative AUC per cycle for treatment Option 2 was 2.3-fold lower than the cumulative AUC per cycle following treatment Option 1. Table 3: Mean (CV% or 95% CI) Pharmacokinetic Parameters of Decitabine *N=14, **N=11, ***N=35 Cumulative AUC per cycle Dose C max (ng/mL) AUC 0 to ∞ (ng•h/mL) T 1/2 (h) CL (L/h/m 2 ) AUC cumulative *** (ng•h/mL) 15 mg/m 2 3-hr infusion every 8 hours for 3 days (Option 1)* 73.8 (66) 163 (62) 0.62 (49) 125 (53) 1332 (1010 to 1730) 20 mg/m 2 1-hr infusion daily for 5 days (Option 2)** 147 (49) 115 (43) 0.54 (43) 210 (47) 570 (470 to 700) The exact route of elimination and metabolic fate of decitabine is not known in humans. One of the pathways of elimination of decitabine appears to be deamination by cytidine deaminase found principally in the liver but also in granulocytes, intestinal epithelium and whole blood. Specific Populations Patients with Renal Impairment There are no data on the use of decitabine for injection in patients with renal impairment; therefore, if decitabine for injection is administered to these patients, monitor them frequently for excessive toxicity. Patients with Hepatic Impairment There are no data on the use of decitabine for injection in patients with hepatic impairment; therefore, if decitabine for injection is administered to these patients, monitor them frequently for excessive toxicity.

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.

12.2 Pharmacodynamics Decitabine has been shown to induce hypomethylation both in vitro and in vivo . However, there have been no studies of decitabine-induced hypomethylation and pharmacokinetic parameters.

12.3 Pharmacokinetics Pharmacokinetic parameters were evaluated in patients. Eleven patients received 20 mg/m 2 infused over 1 hour intravenously (treatment Option 2). Fourteen patients received 15 mg/m 2 infused over 3 hours (treatment Option 1). PK parameters are shown in Table 3 . Plasma concentration-time profiles after discontinuation of infusion showed a biexponential decline. The CL of decitabine was higher following treatment Option 2. Upon repeat doses there was no systemic accumulation of decitabine or any changes in PK parameters. Population PK analysis (N=35) showed that the cumulative AUC per cycle for treatment Option 2 was 2.3-fold lower than the cumulative AUC per cycle following treatment Option 1. Table 3: Mean (CV% or 95% CI) Pharmacokinetic Parameters of Decitabine *N=14, **N=11, ***N=35 Cumulative AUC per cycle Dose C max (ng/mL) AUC 0 to ∞ (ng•h/mL) T 1/2 (h) CL (L/h/m 2 ) AUC cumulative *** (ng•h/mL) 15 mg/m 2 3-hr infusion every 8 hours for 3 days (Option 1)* 73.8 (66) 163 (62) 0.62 (49) 125 (53) 1332 (1010 to 1730) 20 mg/m 2 1-hr infusion daily for 5 days (Option 2)** 147 (49) 115 (43) 0.54 (43) 210 (47) 570 (470 to 700) The exact route of elimination and metabolic fate of decitabine is not known in humans. One of the pathways of elimination of decitabine appears to be deamination by cytidine deaminase found principally in the liver but also in granulocytes, intestinal epithelium and whole blood. Specific Populations Patients with Renal Impairment There are no data on the use of decitabine for injection in patients with renal impairment; therefore, if decitabine for injection is administered to these patients, monitor them frequently for excessive toxicity. Patients with Hepatic Impairment There are no data on the use of decitabine for injection in patients with hepatic impairment; therefore, if decitabine for injection is administered to these patients, monitor them frequently for excessive toxicity.

20191023

2

3 DOSAGE FORMS AND STRENGTHS For Injection: Decitabine for injection is supplied as a sterile, lyophilized white to almost white powder, in a single-dose vial, packaged in cartons of 1 vial. Each vial contains 50 mg of decitabine. For Injection: 50 mg of decitabine as a lyophilized powder in a single-dose vial for reconstitution. ( 3 )

Decitabine Decitabine SODIUM HYDROXIDE DECITABINE DECITABINE POTASSIUM PHOSPHATE, MONOBASIC

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility Carcinogenicity studies with decitabine have not been conducted. The mutagenic potential of decitabine was tested in several in vitro and in vivo systems. Decitabine increased mutation frequency in L5178Y mouse lymphoma cells, and mutations were produced in an Escherichia coli lac-I transgene in colonic DNA of decitabine-treated mice. Decitabine caused chromosomal rearrangements in larvae of fruit flies. In male mice given IP injections of 0.15, 0.3 or 0.45 mg/m 2 decitabine (approximately 0.3% to 1% the recommended clinical dose) 3 times a week for 7 weeks, decitabine did not affect survival, body weight gain or hematological measures (hemoglobin and WBC counts). Testes weights were reduced, abnormal histology was observed and significant decreases in sperm number were found at doses ≥ 0.3 mg/m 2 . In females mated to males dosed with≥ 0.3 mg/m 2 decitabine, pregnancy rate was reduced and preimplantation loss was significantly increased.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility Carcinogenicity studies with decitabine have not been conducted. The mutagenic potential of decitabine was tested in several in vitro and in vivo systems. Decitabine increased mutation frequency in L5178Y mouse lymphoma cells, and mutations were produced in an Escherichia coli lac-I transgene in colonic DNA of decitabine-treated mice. Decitabine caused chromosomal rearrangements in larvae of fruit flies. In male mice given IP injections of 0.15, 0.3 or 0.45 mg/m 2 decitabine (approximately 0.3% to 1% the recommended clinical dose) 3 times a week for 7 weeks, decitabine did not affect survival, body weight gain or hematological measures (hemoglobin and WBC counts). Testes weights were reduced, abnormal histology was observed and significant decreases in sperm number were found at doses ≥ 0.3 mg/m 2 . In females mated to males dosed with≥ 0.3 mg/m 2 decitabine, pregnancy rate was reduced and preimplantation loss was significantly increased.

ANDA210756

Decitabine

Decitabine

63323-825

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

Principal Display Panel – Vial Label NDC 63323-825-20 Decitabine for Injection 50 mg/vial FOR INTRAVENOUS INFUSION ONLY WARNING: Cytotoxic Agent Single-Dose Vial Discard unused portion Rx only STERILE Principal Display Panel – Vial Label

17 PATIENT COUNSELING INFORMATION Advise women of childbearing potential to avoid pregnancy and to use effective contraception while receiving decitabine for injection and for 6 months after last dose [see Warnings and Precautions ( 5.2 ) ] . Advise men not to father a child while receiving treatment with decitabine for injection, and for 3 months after the last dose. Advise men with female partners of childbearing potential to use effective contraception [see Warnings and Precautions ( 5.2 ) and Nonclinical Toxicology ( 13.1 )] . Advise patients to avoid breastfeeding while receiving decitabine for injection and for at 1 week after the last dose [see Use in Specific Populations ( 8.2 )] . Advise patients of the risk of myelosuppression and to report any symptoms of infection, anemia, or bleeding to their healthcare provider as soon as possible. Advise patients for the need for laboratory monitoring [see Warnings and Precautions ( 5.1 )] . Manufactured for: Lake Zurich, IL 60047 www.fresenius-kabi.com/us Made in India 451632 Issued: June 2019 4500142 Figure

14 CLINICAL STUDIES 14.1 Controlled Trial in Myelodysplastic Syndrome A randomized open-label, multicenter, controlled trial evaluated 170 adult patients with myelodysplastic syndromes (MDS) meeting French-American-British (FAB) classification criteria and International Prognostic Scoring System (IPSS) High-Risk, Intermediate-2 and Intermediate-1 prognostic scores. Eighty-nine patients were randomized to decitabine for injection therapy plus supportive care (only 83 received decitabine for injection), and 81 to Supportive Care (SC) alone. Patients with Acute Myeloid Leukemia (AML) were not intended to be included. Of the 170 patients included in the study, independent review (adjudicated diagnosis) found that 12 patients (9 in the decitabine for injection arm and 3 in the SC arm) had the diagnosis of AML at baseline. Baseline demographics and other patient characteristics in the Intent-to-Treat (ITT) population were similar between the 2 groups, as shown in Table 4 . Table 4 Baseline Demographics and Other Patient Characteristics (ITT) Demographic or Other Patient Characteristic Decitabine for Injection N=89 Supportive Care N=81 Age (years) Mean(±SD) Median (IQR) (Range: min-max) 69±10 70 (65 to 76) (31 to 85) 67±10 70 (62 to 74) (30 to 82) Gender n (%) Male Female 59 (66) 30 (34) 57 (70) 24 (30) Race n (%) White Black Other 83 (93) 4 (4) 2 (2) 76 (94) 2(2) (4) Weeks Since MDS Diagnosis Mean (±SD) Median (IQR) (Range: min-max) 86±131 29 (10 to 87) (2 to 667) 77±119 35 (7 to 98) (2 to 865) Previous MDS Therapy n (%) Yes No 27 (30) 62 (70) 19 (23) 62 (77) RBC Transfusion Status n (%) Independent Dependent 23 (26) 66 (74) 27 (33) 54 (67) Platelet Transfusion Status n (%) Independent Dependent 69 (78) 20 (22) 62 (77) 19 (23) IPSS Classification n (%) Intermediate-1 Intermediate-2 High Risk 28 (31) 38 (43) 23 (26) 24 (30) 36 (44) 21 (26) FAB Classification n (%) RA RARS RAEB RAEB-t CMML 12 (13) 7 (8) 47 (53) 17 (19) 6 (7) 12 (15) 4 (5) 43 (53) 14 (17) 8 (10) Patients randomized to the decitabine for injection arm received decitabine for injection intravenously infused at a dose of 15 mg/m 2 over a 3-hour period, every 8 hours, for 3 consecutive days. This cycle was repeated every 6 weeks, depending on the patient's clinical response and toxicity. Supportive care consisted of blood and blood product transfusions, prophylactic antibiotics, and hematopoietic growth factors. The study endpoints were overall response rate (complete response + partial response) and time to AML or death. Responses were classified using the MDS International Working Group (IWG) criteria; patients were required to be RBC and platelet transfusion independent during the time of response. Response criteria are given in Table 5 : Table 5 Response Criteria for Phase 3 MDS Trial* *Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS. Blood. 2000; 96:3671-3674. Complete Response (CR) ≥ 8 weeks Bone Marrow On repeat aspirates: < 5% myeloblasts No dysplastic changes Peripheral Blood In all samples during response: Hgb > 11 g /dL (no transfusions or erythropoietin ANC ≥1500/microliter(no growth factor) Platelets ≥100,000/microliter (no thrombopoietic agent) No blasts and no dysplasia Partial Response (PR) ≥ 8 weeks Bone Marrow On repeat aspirates: ≥50% decrease in blasts over pretreatment values OR Improvement to a less advanced MDS FAB classification Peripheral Blood Same as for CR The overall response rate (CR+PR) in the ITT population was 17% in decitabine for injection - treated patients and 0% in the SC group (p<0.001). (See Table 6 ) The overall response rate was 21% (12/56) in decitabine for injection treated patients considered evaluable for response (i.e., those patients with pathologically confirmed MDS at baseline who received at least 2 cycles of treatment). The median duration of response (range) for patients who responded to decitabine for injection was 288 days (116 to 388) and median time to response (range) was 93 days (55 to 272). All but one of the decitabine for injection-treated patients who responded did so by the fourth cycle. Benefit was seen in an additional 13% of decitabine for injection-treated patients who had hematologic improvement, defined as a response less than PR lasting at least 8 weeks, compared to 7% of SC patients. Decitabine for injection treatment did not significantly delay the median time to AML or death versus supportive care. Table 6 Analysis of Response (ITT) ** p-value <0.001 from two-sided Fisher's Exact Test comparing Decitabine for Injection vs. Supportive Care. t In the statistical analysis plan, a p-value of ≤ 0.024 was required to achieve statistical significance. Parameter Decitabine for injection N=89 Supportive Care N=81 Overall Response Rate (CR+PR) t Complete Response (CR) Partial Response (PR) 15 (17%)** 8 (9%) 7 (8%) 0 (0%) 0 (0%) 0 (0%) Duration of Response Median time to (CR+PR) response - Days (range) Median Duration of (CR+PR) response - Days (range) 93 (55 to 272) 288 (116 to 388) NA NA All patients with a CR or PR were RBC and platelet transfusion independent in the absence of growth factors. Responses occurred in patients with an adjudicated baseline diagnosis of AML. 14.2 Single-arm Studies in Myelodysplastic Syndrome Three open-label, single-arm, multicenter studies were conducted to evaluate the safety and efficacy of decitabine for injection in MDS patients with any of the FAB subtypes. In one study conducted in North America, 99 patients with IPSS Intermediate-1, Intermediate-2, or high risk prognostic scores received decitabine for injection by intravenous infusion at a dose of 20 mg/m 2 IV over 1-hour daily, on days 1 to 5 of week 1 every 4 weeks (1 cycle). The results were consistent with the results of the controlled trial and summarized in Table 8 . Table 7 Baseline Demographics and Other Patient Characteristics (ITT) Demographic or Other Patient Characteristic Decitabine for Injection N = 99 Age (years) Mean (±SD) 71±9 Median (Range: min-max) 72 (34 to 87) Gender n (%) Male 71 (72) Female 28 (28) Race n (%) White 86 (87) Black 6 (6) Asian 4 (4) Other 3 (3) Days From MDS Diagnosis to First Dose Mean (±SD) 444±626 Median (Range: min-max) 154 (7 to 3079) Previous MDS Therapy n (%) Yes 27 (27) No 72 (73) RBC Transfusion Status n (%) Independent 33 (33) Dependent 66 (67) Platelet Transfusion Status n (%) Independent 84 (85) Dependent 15 (15) IPSS Classification n (%) Low Risk 1 (1) Intermediate–1 52 (53) Intermediate–2 23 (23) High Risk 23 (23) FAB Classification n (%) RA 20 (20) RARS 17 (17) RAEB 45 (45) RAEB-t 6 (6) CMML 11 (11) Table 8 Analysis of Response (ITT)* + indicates censored observation * Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS. Blood. 2000; 96:3671-3674. Parameter Decitabine for Injection N=99 Overall Response Rate (CR+PR) 16 (16%) Complete Response (CR) 15 (15%) Partial Response (PR) 1 (1%) Duration of Response Median time to (CR+PR) response-Days (range) 162 (50 to 267) Median Duration of (CR+PR) response-Days (range) 443 (72 to 722+)

15 REFERENCES OSHA Hazardous Drugs. OSHA. https://www.osha.gov/SLTC/hazardousdrugs/index.html

8.5 Geriatric Use Of the total number of patients exposed to decitabine for injection in the controlled clinical trial, 61 of 83 patients were age 65 and over, while 21 of 83 patients were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.4 Pediatric Use The safety and effectiveness of decitabine for injection in pediatric patients have not been established.

8.1 Pregnancy Risk Summary Based on findings from human data, animal studies, and the mechanism of action, decitabine for injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . Limited published data on decitabine for injection use throughout the first trimester during pregnancy describe adverse developmental outcomes including major birth defects (structural abnormalities). In animal reproduction studies, administration of decitabine to pregnant mice and rats during organogenesis caused adverse developmental outcomes and was teratogenic, fetotoxic, and embryotoxic starting at doses approximately 7% of the recommended human dose on a mg/m 2 basis (see Data ) . Advise pregnant women of the potential risk to a fetus.The estimated background risk 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. The estimated background risk of major birth defects and miscarriage in the U.S. general population is 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively. Data Human Data A single published case report of decitabine pregnancy exposure in a 39-year old woman with a hematologic malignancy described multiple structural abnormalities after 6 cycles of therapy in the 18 th week of gestation. These abnormalities included holoprosencephaly, absence of nasal bone, mid-facial deformity, cleft lip and palate, polydactyly and rocker-bottom feet. The pregnancy was terminated. Animal Data In utero exposure to decitabine causes temporal related defects in the rat and/or mouse, which include growth suppression, exencephaly, defective skull bones, rib/sternebrae defects, phocomelia, digit defects, micrognathia, gastroschisis, micromelia. Decitabine inhibits proliferation and increases apoptosis of neural progenitor cells of the fetal CNS and induces palatal clefting in the developing murine fetus. Studies in mice have also shown that decitabine administration during osteoblastogenesis (day 10 of gestation) induces bone loss in offspring. In mice exposed to single IP (intraperitoneal) injections (0, 0.9 and 3.0 mg/m 2 , approximately 2% and 7% of the recommended daily clinical dose, respectively) over gestation days 8, 9, 10 or 11, no maternal toxicity was observed but reduced fetal survival was observed after treatment at 3 mg/m 2 and decreased fetal weight was observed at both dose levels. The 3 mg/m 2 dose elicited characteristic fetal defects for each treatment day, including supernumerary ribs (both dose levels), fused vertebrae and ribs, cleft palate, vertebral defects, hind-limb defects and digital defects of fore- and hind-limbs. In rats given a single IP injection of 2.4, 3.6 or 6 mg/m 2 (approximately 5, 8, or 13% the daily recommended clinical dose, respectively) on gestation days 9 to 12, no maternal toxicity was observed. No live fetuses were seen at any dose when decitabine was injected on gestation day 9. A significant decrease in fetal survival and reduced fetal weight at doses greater than 3.6 mg/m 2 was seen when decitabine was given on gestation day 10. Increased incidences of vertebral and rib anomalies were seen at all dose levels, and induction of exophthalmia, exencephaly, and cleft palate were observed at 6.0 mg/m 2 . Increased incidence of foredigit defects was seen in fetuses at doses greater than 3.6 mg/m 2 . Reduced size and ossification of long bones of the fore-limb and hind-limb were noted at 6.0 mg/m 2 . The effect of decitabine on postnatal development and reproductive capacity was evaluated in mice administered a single 3 mg/m 2 IP injection (approximately 7% the recommended daily clinical dose) on day 10 of gestation. Body weights of males and females exposed in utero to decitabine were significantly reduced relative to controls at all postnatal time points. No consistent effect on fertility was seen when female mice exposed in utero were mated to untreated males. Untreated females mated to males exposed in utero showed decreased fertility at 3 and 5 months of age (36% and 0% pregnancy rate, respectively). Follow up studies indicated that treatment of pregnant mice with decitabine on gestation day 10 was associated with a reduced pregnancy rate resulting from effects on sperm production in the F1-generation.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings from human data, animal studies, and the mechanism of action, decitabine for injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . Limited published data on decitabine for injection use throughout the first trimester during pregnancy describe adverse developmental outcomes including major birth defects (structural abnormalities). In animal reproduction studies, administration of decitabine to pregnant mice and rats during organogenesis caused adverse developmental outcomes and was teratogenic, fetotoxic, and embryotoxic starting at doses approximately 7% of the recommended human dose on a mg/m 2 basis (see Data ) . Advise pregnant women of the potential risk to a fetus.The estimated background risk 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. The estimated background risk of major birth defects and miscarriage in the U.S. general population is 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively. Data Human Data A single published case report of decitabine pregnancy exposure in a 39-year old woman with a hematologic malignancy described multiple structural abnormalities after 6 cycles of therapy in the 18 th week of gestation. These abnormalities included holoprosencephaly, absence of nasal bone, mid-facial deformity, cleft lip and palate, polydactyly and rocker-bottom feet. The pregnancy was terminated. Animal Data In utero exposure to decitabine causes temporal related defects in the rat and/or mouse, which include growth suppression, exencephaly, defective skull bones, rib/sternebrae defects, phocomelia, digit defects, micrognathia, gastroschisis, micromelia. Decitabine inhibits proliferation and increases apoptosis of neural progenitor cells of the fetal CNS and induces palatal clefting in the developing murine fetus. Studies in mice have also shown that decitabine administration during osteoblastogenesis (day 10 of gestation) induces bone loss in offspring. In mice exposed to single IP (intraperitoneal) injections (0, 0.9 and 3.0 mg/m 2 , approximately 2% and 7% of the recommended daily clinical dose, respectively) over gestation days 8, 9, 10 or 11, no maternal toxicity was observed but reduced fetal survival was observed after treatment at 3 mg/m 2 and decreased fetal weight was observed at both dose levels. The 3 mg/m 2 dose elicited characteristic fetal defects for each treatment day, including supernumerary ribs (both dose levels), fused vertebrae and ribs, cleft palate, vertebral defects, hind-limb defects and digital defects of fore- and hind-limbs. In rats given a single IP injection of 2.4, 3.6 or 6 mg/m 2 (approximately 5, 8, or 13% the daily recommended clinical dose, respectively) on gestation days 9 to 12, no maternal toxicity was observed. No live fetuses were seen at any dose when decitabine was injected on gestation day 9. A significant decrease in fetal survival and reduced fetal weight at doses greater than 3.6 mg/m 2 was seen when decitabine was given on gestation day 10. Increased incidences of vertebral and rib anomalies were seen at all dose levels, and induction of exophthalmia, exencephaly, and cleft palate were observed at 6.0 mg/m 2 . Increased incidence of foredigit defects was seen in fetuses at doses greater than 3.6 mg/m 2 . Reduced size and ossification of long bones of the fore-limb and hind-limb were noted at 6.0 mg/m 2 . The effect of decitabine on postnatal development and reproductive capacity was evaluated in mice administered a single 3 mg/m 2 IP injection (approximately 7% the recommended daily clinical dose) on day 10 of gestation. Body weights of males and females exposed in utero to decitabine were significantly reduced relative to controls at all postnatal time points. No consistent effect on fertility was seen when female mice exposed in utero were mated to untreated males. Untreated females mated to males exposed in utero showed decreased fertility at 3 and 5 months of age (36% and 0% pregnancy rate, respectively). Follow up studies indicated that treatment of pregnant mice with decitabine on gestation day 10 was associated with a reduced pregnancy rate resulting from effects on sperm production in the F1-generation. 8.2 Lactation Risk Summary There are no data on the presence of decitabine or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from decitabine for injection in a nursing child, advise lactating women to avoid breastfeeding during treatment with decitabine for injection and for at least 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Conduct pregnancy testing of females of reproductive potential prior to initiating decitabine for injection. Contraception Females Advise females of reproductive potential to avoid pregnancy and use effective contraception while receiving decitabine for injection and for 6 months following the last dose. Males Advise males with female partners of reproductive potential to use effective contraception while receiving treatment with decitabine for injection and for 3 months following the last dose. [see Nonclinical Toxicology ( 13.1 )] . Infertility Based on findings of decitabine in animals, male fertility may be compromised by treatment with decitabine for injection [see Nonclinical Toxicology ( 13.1 )]. 8.4 Pediatric Use The safety and effectiveness of decitabine for injection in pediatric patients have not been established. 8.5 Geriatric Use Of the total number of patients exposed to decitabine for injection in the controlled clinical trial, 61 of 83 patients were age 65 and over, while 21 of 83 patients were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

16 HOW SUPPLIED/STORAGE AND HANDLING Decitabine for injection is a white to almost white solid friable lumps or powder forming clear colorless solution free from visible particulate matter on reconstitution as directed. It is supplied as 50 mg single-dose vial individually packaged in a carton as follows: Product Code Unit of Sale Strength 825020 NDC 63323-825-20 Individually Packaged 50 mg per vial Storage Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Storage Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].