ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:oMyelosuppression [see Warnings and Precautions (5.1)]. oMyelosuppression [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 Amneal Pharmaceuticals at 1-877-835-5472, 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 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 single-arm studies (N 66, = 98, = 99) and controlled supportive care study (N 83 Decitabine for Injection, = 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/m2 intravenously every hours for days every weeks. The median number of Decitabine for Injection cycles was (range 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: oDiscontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardio-respiratory arrest, increased blood bilirubin, intracranial hemorrhage, abnormal liver function tests.oDose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile neutropenia.oDose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia, depression, pharyngitis.Table presents all adverse reactions occurring in at least 5% of patients in the Decitabine for Injection group and at rate greater than supportive care. Table Adverse Reactions Reported in >= 5% of Patients in the Decitabine for Injection Group and at Rate Greater than Supportive Care in the Controlled Trial in MDSDecitabine for InjectionN 83 (%)Supportive CareN 81 (%)Blood and lymphatic system disordersNeutropenia75(90)58 (72)Thrombocytopenia74 (89)64 (79)Anemia NOS68 (82)60 (74)Febrile neutropenia24 (29)5 (6)Leukopenia NOS23 (28)11 (14)Lymphadenopathy10 (12)6 (7)Thrombocythemia4 (5)1 (1)Cardiac disordersPulmonary edema NOS5 (6)0 (0)Eye disordersVision blurred5 (6)0 (0)Gastrointestinal disordersNausea35 (42)13 (16)Constipation29 (35)11 (14)Diarrhea NOS28 (34)13 (16)Vomiting NOS21 (25)7 (9)Abdominal pain NOS12 (14)5 (6)Oral mucosal petechiae11 (13)4 (5)Stomatitis10 (12)5 (6)Dyspepsia10 (12)1 (1)Ascites8 (10)2 (2)Gingival bleeding7 (8)5 (6)Hemorrhoids7 (8)3 (4)Loose stools6 (7)3 (4)Tongue ulceration6 (7)2 (2)Dysphagia5 (6)2 (2)Oral soft tissue disorder NOS5 (6)1 (1)Lip ulceration4 (5)3 (4)Abdominal distension4 (5)1 (1)Abdominal pain upper4 (5)1 (1)Gastro-esophageal reflux disease4 (5)0 (0)Glossodynia4 (5)0 (0)General disorders and administrative site disordersPyrexia44 (53)23 (28)Edema peripheral21 (25)13 (16)Rigors18 (22)14 (17)Edema NOS15 (18)5 (6)Pain NOS11 (13)5 (6)Lethargy10 (12)3 (4)Tenderness NOS9 (11)0 (0)Fall7 (8)3 (4)Chest discomfort6 (7)3 (4)Intermittent pyrexia5 (6)3 (4)Malaise4 (5)1 (1)Crepitations NOS4 (5)1 (1)Catheter site erythema4 (5)1 (1)Catheter site pain4 (5)0 (0)Injection site swelling4 (5)0 (0)Hepatobiliary DisordersHyperbilirubinemia12 (14)4 (5)Infections and InfestationsPneumonia NOS18 (22)11 (14)Cellulitis10 (12)6 (7)Candidal infection NOS8 (10)1 (1)Catheter related infection7 (8)0 (0)Urinary tract infection NOS6 (7)1 (1)Staphylococcal infection6 (7)0 (0)Oral candidiasis5 (6)2 (2)Sinusitis NOS4 (5)2 (2)Bacteremia4 (5)0 (0)Injury, poisoning and procedural complicationsTransfusion reaction6 (7)3 (4)Abrasion NOS4 (5)1 (1)InvestigationsCardiac murmur NOS13 (16)9 (11)Blood alkaline phosphatase NOS increased9 (11)7 (9)Aspartate aminotransferase increased8 (10)7 (9)Blood urea increased8 (10)1 (1)Blood lactate dehydrogenase increased7 (8)5 (6)Blood albumin decreased6 (7)0 (0)Blood bicarbonate increased5 (6)1 (1)Blood chloride decreased5 (6)1 (1)Protein total decreased4 (5)3 (4)Blood bicarbonate decreased4 (5)1 (1)Blood bilirubin decreased4 (5)1 (1)Metabolism and nutrition disordersHyperglycemia NOS27 (33)16 (20)Hypoalbuminemia20 (24)14 (17)Hypomagnesemia20 (24)6 (7)Hypokalemia18 (22)10 (12)Hyponatremia16 (19)13 (16)Appetite decreased NOS13 (16)12 (15)Anorexia13 (16)8 (10)Hyperkalemia11 (13)3 (4)Dehydration5 (6)4 (5)Musculoskeletal and connective tissue disordersArthralgia17 (20)8 (10)Pain in limb16 (19)8 (10)Back pain14 (17)5 (6)Chest wall pain6 (7)1 (1)Musculoskeletal discomfort5 (6)0 (0)Myalgia4 (5)1 (1)Nervous system disordersHeadache23 (28)11 (14)Dizziness15 (18)10 (12)Hypoesthesia9 (11)1 (1)Psychiatric disordersInsomnia23 (28)11 (14)Confusional state10 (12)3 (4)Anxiety9 (11)8 (10)Renal and urinary disordersDysuria5 (6)3 (4)Urinary frequency4 (5)1 (1)Respiratory, thoracic and Mediastinal disordersCough33 (40)25 (31)Pharyngitis13 (16)6 (7)Crackles lung12 (14)1 (1)Breath sounds decreased8 (10)7 (9)Hypoxia8 (10)4 (5)Rales7 (8)2 (2)Postnasal drip4 (5)2 (2)Skin and subcutaneous tissue disordersEcchymosis18 (22)12 (15)Rash NOS16 (19)7 (9)Erythema12 (14)5 (6)Skin lesion NOS9 (11)3 (4)Pruritis9 (11)2 (2)Alopecia7 (8)1 (1)Urticaria NOS5 (6)1 (1)Swelling face5 (6)0 (0)Vascular disordersPetechiae32 (39)13 (16)Pallor19 (23)10 (12)Hypotension NOS5 (6)4 (5)Hematoma NOS4 (5)3 (4)In single-arm MDS study (N=99) Decitabine for Injection was dosed at 20 mg/m2 intravenously, infused over one hour daily for consecutive days of 4-week cycle. Table presents all adverse reactions occurring in at least 5% of patients. Table Adverse Reactions Reported in >= 5% of Patients in Single-arm Study Decitabine for Injection = 99 (%)Blood and lymphatic system disorders Anemia 31 (31) Febrile neutropenia 20 (20) Leukopenia (6) Neutropenia 38 (38) Pancytopenia (5) Thrombocythemia (5) Thrombocytopenia 27 (27) Cardiac disorders Cardiac failure congestive (5) Tachycardia (8) Ear and labyrinth disorders Ear pain (6) Gastrointestinal disorders Abdominal pain 14 (14) Abdominal pain upper (6) Constipation 30 (30) Diarrhea 28 (28) Dyspepsia 10 (10) Dysphagia (5) Gastro-esophageal reflux disease (5) Nausea 40 (40) Oral pain (5) Stomatitis 11 (11) Toothache (6) Vomiting 16 (16) General disorders and administration site conditions Asthenia 15 (15) Chest pain (6) Chills 16 (16) Fatigue 46 (46) Mucosal inflammation (9) Edema (5) Edema peripheral 27 (27) Pain (5) Pyrexia 36 (36) Infections and infestations Cellulitis (9) Oral candidiasis (6) Pneumonia 20 (20) Sinusitis (6) Staphylococcal bacteremia (8) Tooth abscess (5) Upper respiratory tract infection 10 (10) Urinary tract infection (7) Injury, poisoning and procedural complications Contusion (9) Investigations Blood bilirubin increased (6) Breath sounds abnormal (5) Weight decreased (9) Metabolism and nutrition disorders Anorexia 23 (23) Decreased appetite (8) Dehydration (8) Hyperglycemia (6) Hypokalemia 12 (12) Hypomagnesemia (5) Musculoskeletal and connective tissue disorders Arthralgia 17 (17) Back pain 18 (18) Bone pain (6) Muscle spasms (7) Muscular weakness (5) Musculoskeletal pain (5) Myalgia (9) Pain in extremity 18 (18) Nervous system disorders Dizziness 21 (21) Headache 23 (23) Psychiatric disorders Anxiety (9) Confusional state (8) Depression (9) Insomnia 14 (14) Respiratory, thoracic and mediastinal disorders Cough 27 (27) Dyspnea 29 (29) Epistaxis 13 (13) Pharyngolaryngeal pain (8) Pleural effusion (5) Sinus congestion (5) Skin and subcutaneous tissue disorders Dry skin (8) Ecchymosis (9) Erythema (5) Night sweats (5) Petechiae 12 (12) Pruritus (9) Rash 11 (11) Skin lesion (5) Vascular disorders Hypertension (6) Hypotension 1111) No overall difference in safety was detected between patients 65 years of age and younger patients in these MDS trials. No significant differences in safety were detected between males and females. 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, not previously reported in Tables and include: oAllergic Reaction hypersensitivity (anaphylactic reaction).oBlood and Lymphatic System Disorders: myelosuppression, splenomegaly.oCardiac Disorders: myocardial infarction, cardio-respiratory arrest, cardiomyopathy, atrial fibrillation, supraventricular tachycardia.oGastrointestinal Disorders: gingival pain, upper gastrointestinal hemorrhage.oGeneral Disorders and Administrative Site Conditions: chest pain, catheter site hemorrhage.oHepatobiliary Disorders: cholecystitis.oInfections and Infestations: fungal infection, sepsis, bronchopulmonary aspergillosis, peridiverticular abscess, respiratory tract infection, pseudomonal lung infection, Mycobacterium avium complex infection.oInjury, Poisoning and Procedural Complications: post procedural pain, post procedural hemorrhage.oNervous System Disorders: intracranial hemorrhage.oPsychiatric Disorders: mental status changes.oRenal and Urinary Disorders: renal failure, urethral hemorrhage.oRespiratory, Thoracic and Mediastinal Disorders: hemoptysis, lung infiltration, pulmonary embolism, respiratory arrest, pulmonary mass.. oDiscontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardio-respiratory arrest, increased blood bilirubin, intracranial hemorrhage, abnormal liver function tests.. oDose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile neutropenia.. oDose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia, depression, pharyngitis.. 1111) oAllergic Reaction hypersensitivity (anaphylactic reaction).. oBlood and Lymphatic System Disorders: myelosuppression, splenomegaly.. oCardiac Disorders: myocardial infarction, cardio-respiratory arrest, cardiomyopathy, atrial fibrillation, supraventricular tachycardia.. oGastrointestinal Disorders: gingival pain, upper gastrointestinal hemorrhage.. oGeneral Disorders and Administrative Site Conditions: chest pain, catheter site hemorrhage.. oHepatobiliary Disorders: cholecystitis.. oInfections and Infestations: fungal infection, sepsis, bronchopulmonary aspergillosis, peridiverticular abscess, respiratory tract infection, pseudomonal lung infection, Mycobacterium avium complex infection.. oInjury, Poisoning and Procedural Complications: post procedural pain, post procedural hemorrhage.. oNervous System Disorders: intracranial hemorrhage.. oPsychiatric Disorders: mental status changes.. oRenal and Urinary Disorders: renal failure, urethral hemorrhage.. oRespiratory, Thoracic and Mediastinal Disorders: hemoptysis, lung infiltration, pulmonary embolism, respiratory arrest, pulmonary mass.. 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. oSweets Syndrome (acute febrile neutrophilic dermatosis) oDifferentiation SyndromeoInterstitial lung disease. oSweets Syndrome (acute febrile neutrophilic dermatosis) oDifferentiation Syndrome. oInterstitial lung disease.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, 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 DNULL 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/m2 decitabine (approximately 0.3% to 1% the recommended clinical dose) times week for weeks, decitabine did not affect survival, body weight gain or hematological measures (hemoglobin and white blood cell counts). Testes weights were reduced, abnormal histology was observed and significant decreases in sperm number were found at doses >= 0.3 mg/m2. In females mated to males dosed with >= 0.3 mg/m2 decitabine, pregnancy rate was reduced and preimplantation loss was significantly increased.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action Decitabine is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNULL and inhibition of DNULL methyltransferase, causing hypomethylation of DNULL and cellular differentiation or apoptosis. Decitabine inhibits DNULL methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNULL 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 DNULL methyltransferase and decitabine incorporated into DNULL. 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 (PK) parameters were evaluated in patients. Eleven patients received 20 mg/m2 infused over hour intravenously (treatment Option 2), Fourteen patients received 15 mg/m2 infused over hours intravenously (treatment Option 1). PK parameters are shown in Table 3. Plasma concentration-time profiles after discontinuation of infusion showed biexponential decline. The clearance (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 was 2.3-fold lower than the cumulative AUC per cycle following treatment Option 1.Table Mean (CV% or 95% CI) Pharmacokinetic Parameters of DecitabineDoseCmax (ng/mL)AUC0-INF (ngoh/mL)T1/2 (h)CL (L/h/m2)AUCCumulative (ngoh/mL)15 mg/m2 3-hr infusion every hours for days (Option 1)73.8 (66)163 (62)0.62 (49)125 (53)1332 (1010 to1730)20 mg/m2 1-hr infusion daily for days (Option 2)+ 147 (49)115 (43)0.54 (43)210 (47)570 (470 to 700) N=14, +N=11, N=35 Cumulative AUC per cycle. 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 PopulationsPatients with Renal ImpairmentThere are no data on the use of Decitabine for Injection in patients with renal impairment.Patients with Hepatic ImpairmentThere are no data on the use of Decitabine for Injection in patients with hepatic impairment.

CLINICAL STUDIES SECTION.


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 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 groups, as shown in Table 4.Table Baseline Demographics and Other Patient Characteristics (ITT)Demographic or OtherPatient CharacteristicDecitabine for Injection = 89Supportive CareN= 81Age (years) Mean (+-SD) Median (IQR) (Range: min to max) 69+-10 70 (65 to 76) (31 to 85) 67+-10 70 (62 to 74) (30 to 82) Gender (%)Male Female 59 (66) 30 (34) 57 (70) 24 (30) Race (%)White Black Other 83 (93) (4) (2) 76 (94) (2) (4) Weeks Since MDS DiagnosisMean (+-SD) Median (IQR) (Range: min to max) 86+-131 29 (10 to 87) (2 to 667) 77+-119 35 (7 to 98) (2 to 865) Previous MDS Therapy (%)Yes No 27 (30) 62 (70) 19 (23) 62 (77) RBC Transfusion Status (%)Independent Dependent 23 (26) 66 (74) 27 (33) 54 (67) Platelet Transfusion Status (%)IndependentDependent 69 (78) 20 (22) 62 (77) 19 (23) IPSS Classification (%)Intermediate-1 Intermediate-2 High Risk 28 (31) 38 (43) 23 (26) 24 (30) 36 (44) 21 (26) FAB Classification (%)RA RARS RAEB RAEB-t CMML 12 (13) (8) 47 (53) 17 (19) (7) 12 (15) (5) 43 (53) 14 (17) (10) Patients randomized to the Decitabine for Injection arm received Decitabine for Injection intravenously infused at dose of 15 mg/m2 over 3-hour period, every hours, for consecutive days. This cycle was repeated every weeks, depending on the patients 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 Response Criteria for the Controlled Trial in MDS Complete Response (CR) >=8 weeksBone MarrowOn repeat aspirates: < 5% myeloblasts No dysplastic changes Peripheral Blood In all samples during response: Hgb 11 g/dL (no transfusions or erythropoietin ANC >=1500/ uL (no growth factor) Platelets >= 100,000/ uL (no thrombopoietic agent) No blasts and no dysplasia Partial Response (PR) >=8 weeksBone MarrowOn repeat aspirates: >= 50% decrease in blasts over pretreatment values OR Improvement to less advanced MDS FAB classification Peripheral BloodSame as for CRThe 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 ) 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 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 response less than PR lasting at least 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 Analysis of Response (ITT)ParameterDecitabine for InjectionN=89Supportive CareN=81Overall Response Rate (CR+PR)+ Complete Response (CR) Partial Response (PR) 15 (17%)8 (9%) (8%) (0%) (0%) (0%) Duration of ResponseMedian time to (CR+PR) response Days (range) Median Duration of (CR+PR) response Days (range) 93 (55 to 272) 288 (116 to 388) NULLNULL p-value <0.001 from two-sided Fishers Exact Test comparing Decitabine For Injection vs. Supportive Care.+In the statistical analysis plan, p-value of <= 0.024 was required to achieve statistical significance. All patients with 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 20 mg/m2 as an intravenous infusion over 1-hour daily, on days 1to of week 1, every weeks (1 cycle). The results were consistent with the results of the controlled trial and are summarized in Table 8. Table Baseline Demographics and Other Patient Characteristics (ITT)Demographic or Other Patient CharacteristicDecitabine for Injection = 99Age (years)Mean (+-SD) Median (Range: min to max)71+-9 72 (34 to 87)Gender (%)Male Female71 (72)28 (28)Race (%)White Black Asian Other86 (87) (6) (4) (3)Days from MDS Diagnosis to First DoseMean (+-SD) Median (Range: min-max)444+-626 154 (7 to 3079)Previous MDS Therapy (%)Yes No27 (27) 72 (73)RBC Transfusion Status (%)Independent Dependent33 (33) 66 (67)Platelet Transfusion Status (%)Independent Dependent84 (85) 15 (15)IPSS Classification (%)Low Risk Intermediate-1 Intermediate-2 High Risk1 (1) 52 (53) 23 (23) 23 (23)FAB Classification (%)RA RARS RAEB RAEB-t CMML20 (20) 17 (17) 45 (45) (6)11 (11) Table Analysis of Response (ITT) ParameterDecitabine for Injection N=99Overall Response Rate (CR+PR)Complete Response (CR) Partial Response (PR)16 (16%)15 (15%) (1%)Duration of ResponseMedian time to (CR+PR) response Days (range) Median Duration of (CR+PR) response Days (range)162 (50 to 267) 443 (72 to 722 +) Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS. Blood. 2000; 96:3671-3674.+ indicates censored observation.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. None. None.

DESCRIPTION SECTION.


11 DESCRIPTION. Decitabine is nucleoside metabolic inhibitor. Decitabine is fine, white to almost white powder with the molecular formula of C8H12N4O4 and molecular weight of 228.21. Its chemical name is 4-amino-1-(2-deoxy--D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-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, for intravenous use, is sterile, white to almost white lyophilized powder supplied in clear colorless glass single-dose vial. Each 20 mL vial contains 50 mg decitabine, 68 mg monobasic potassium phosphate (potassium dihydrogen phosphate) and 11.6 mg sodium hydroxide. Sodium hydroxide and/or hydrochloric acid are used for pH adjustment. structure.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Three Day Regimen Administer Decitabine for injection at dose of 15 mg/m2 by continuous intravenous infusion over hours repeated every hours for days. Repeat cycle every weeks. (2.1) Five Day Regimen Administer Decitabine for injection at dose of 20 mg/m2 by continuous intravenous infusion over hour repeated daily for days. Repeat cycle every weeks. (2.1) 2.1 Recommended Dosage Pre-Medications and Baseline TestingoConsider pre-medicating for nausea with antiemeticsoConduct baseline laboratory testing: complete blood count (CBC) with platelets, serum hepatic panel, and serum creatinine.Decitabine for Injection Regimen OptionsThree Day RegimenAdminister Decitabine for Injection at dose of 15 mg/m2 by continuous intravenous infusion over hours repeated every hours for days. Repeat cycles every weeks upon hematologic recovery (ANC at least 1,000/uL and platelets at least 50,000/uL) for minimum of cycles. complete or partial response may take longer than cycles. Delay and reduce dose for hematologic toxicity [see Dosage and Administration (2.2)].Five Day RegimenAdminister Decitabine for Injection at dose of 20 mg/m2 by continuous intravenous infusion over hour daily for days. Delay and reduce dose for hematologic toxicity [see Dosage and Administration (2.2)]. Repeat cycles every weeks upon hematologic recovery (ANC at least 1,000/uL and platelets at least 50,000/uL) for minimum of cycles. complete or partial response may take longer than cycles.Patients with Renal or Severe Hepatic ImpairmentTreatment 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. For patients with pre-existing renal or hepatic impairment, consider the potential risks and benefits before initiating treatment with Decitabine for Injection. oConsider pre-medicating for nausea with antiemetics. oConduct baseline laboratory testing: complete blood count (CBC) with platelets, serum hepatic panel, and serum creatinine.. 2.2 Dosage Modifications for Adverse Reactions Hematologic ToxicityIf hematologic recovery from previous Decitabine for Injection treatment cycle requires more than weeks, delay the next cycle of Decitabine for Injection therapy and reduce Decitabine for Injection dose temporarily by following this algorithm:oRecovery requiring more than 6, but less than weeks delay Decitabine for Injection dosing for up to weeks and reduce the dose temporarily to 11 mg/m2 every hours (33 mg/m2/day, 99 mg/m2/cycle)) upon restarting therapy. oRecovery 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 up to more weeks and reduce the dose to 11 mg/m2 every hours (33mg/m2/day, 99mg/m2/cycle) upon restarting therapy, then maintain or increase dose in subsequent cycles as clinically indicated.Non-Hematologic ToxicityDelay subsequent Decitabine for Injection treatment for any the following non-hematologic toxicities and do not restart until toxicities resolve:oSerum creatinine greater than or equal to mg/dLoAlanine transaminase (ALT), total bilirubin greater than or equal to times upper limit of normal (ULN)oActive or uncontrolled infection. oRecovery requiring more than 6, but less than weeks delay Decitabine for Injection dosing for up to weeks and reduce the dose temporarily to 11 mg/m2 every hours (33 mg/m2/day, 99 mg/m2/cycle)) upon restarting therapy. oRecovery 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 up to more weeks and reduce the dose to 11 mg/m2 every hours (33mg/m2/day, 99mg/m2/cycle) upon restarting therapy, then maintain or increase dose in subsequent cycles as clinically indicated.. oSerum creatinine greater than or equal to mg/dL. oAlanine transaminase (ALT), total bilirubin greater than or equal to times upper limit of normal (ULN). oActive or uncontrolled infection. 2.3 Preparation and Administration Decitabine for Injection is cytotoxic drug. Follow special handling and disposal procedures1. Aseptically reconstitute Decitabine for Injection with room temperature (20oC to 25 oC) 10 mL of Sterile Water for Injection, USP. Upon reconstitution, the final concentration of the reconstituted Decitabine for Injection solution is 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 PreparationIf Decitabine for Injection is intended to be administered within 15 minutes from the time of preparation, dilute the reconstituted solution with room temperature (20oC 25 oC) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to final concentration of 0.1 mg/mL to mg/mL. Discard unused portion.For Delayed AdministrationIf Decitabine for Injection is intended to be administered after 15 minutes of preparation, dilute the reconstituted solution with cold (2oC to 8oC) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to final concentration of 0.1mg/mL to mg/mL. Store at 2oC to oC for up to hours. Diluted stored solution must be used within hours from the time of preparation. Discard unused portion.Use the diluted, refrigerated solution within hours from the time of preparation or discard.Parental 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.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. For Injection: 50mg of decitabine as sterile, white to almost white lyophilized powder, in single-dose vial for reconstitution.. For Injection: 50 mg of decitabine as lyophilized powder in single-dose vial for reconstitution. (3).

DRUG INTERACTIONS SECTION.


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 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.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.


8.3 Females and Males of Reproductive Potential Pregnancy TestingConduct pregnancy testing of females of reproductive potential prior to initiating Decitabine for Injection.ContraceptionFemalesDecitabine for Injection can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception while receiving Decitabine for Injection and for months following the last dose.MalesAdvise males with female partners of reproductive potential to use effective contraception while receiving treatment with Decitabine for Injection and for months following the last dose [see Nonclinical Toxicology (13.1)] InfertilityBased on findings of decitabine in animals, male fertility may be compromised by treatment with Decitabine for Injection. The reversibility of the effect on fertility is unknown [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.


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 years and over, while 21 of 83 patients were age 75 years 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.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. Decitabine for Injection is sterile, white to almost white lyophilized powder for intravenous use supplied as:NDC 68001-422-37, 50 mg single-dose vial individually packaged in carton. Store vials at 20C to 25C (68F to 77F); excursions permitted between 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.


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 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).

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. MyelosuppressionAdvise 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)]. Embryo-Fetal ToxicityAdvise pregnant women of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [See Warnings and Precautions (5.2) and Use in Specific Populations (8.1)].Advise females of reproductive potential to use effective contraception while receiving Decitabine for Injection and for months after last dose [See Use in Specific Populations (8.3)].Advise males with female partners of reproductive potential to use effective contraception while receiving treatment with Decitabine for Injection and for months after the last dose [See Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)]. LactationAdvise women to avoid breastfeeding while receiving Decitabine for Injection and for at least weeks after the last dose [see Use in Specific Populations (8.2)]. Manufactured by:Chemi Pharma LtdHHF014 Halfar Industrial Estate,Halfar, Birzebbugia, BBG3000Malta, Manufactured for:BluePoint LaboratoriesRev.07-2020-02.

LACTATION SECTION.


8.2 Lactation Risk SummaryThere 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 of the potential for serious adverse reactions from Decitabine for Injection in breastfed child, advise women not to breastfeed while receiving Decitabine for Injection and for at least weeks after the last dose.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action Decitabine is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNULL and inhibition of DNULL methyltransferase, causing hypomethylation of DNULL and cellular differentiation or apoptosis. Decitabine inhibits DNULL methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNULL 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 DNULL methyltransferase and decitabine incorporated into DNULL. Non-proliferating cells are relatively insensitive to decitabine.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, 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 DNULL 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/m2 decitabine (approximately 0.3% to 1% the recommended clinical dose) times week for weeks, decitabine did not affect survival, body weight gain or hematological measures (hemoglobin and white blood cell counts). Testes weights were reduced, abnormal histology was observed and significant decreases in sperm number were found at doses >= 0.3 mg/m2. In females mated to males dosed with >= 0.3 mg/m2 decitabine, pregnancy rate was reduced and preimplantation loss was significantly increased.

OVERDOSAGE SECTION.


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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL. NDC 68001-422-37 Rx ONLYDECITABINE for Injection 50 mg per vial FOR INTRAVENOUS USE ONLYWARNING: Cytotoxic AgentSingle use sterile vialEach vial contains 50 mg decitabine, 68 mg monobasic potassium phosphate and 11.6 mg sodium hydroxide. See package insert and/or carton for detailed indications, reconstitution information, dosage information, and precautions. Store at 25C (77F) (see insert)Manufactured by: Chemi Pharma Ltd, HHF014 Halfar Industrial Estate, Halfar, Birzebbugia, BBG3000,MaltaManufactured for:BluePoint LaboratoriesRev 04-2020-01NDC 68001-422-37DECITABINE for Injection50 mg per vialFOR INTRAVENOUS USE ONLY WARNING: Cytotoxic Agent Single use sterile vialRx ONLYBluePoint LaboratoriesSee bottom flap for batch number and expiration date.KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.Storage: Store vials at 25C (77F) excursions permitted to 15C to 30C (59F to 86F) [See USP Controlled Room Temperature] Manufactured by: Chemi Pharma Ltd, HHF014 Halfar Industrial Estate, Halfar, Birzebbugia, BBG3000,MaltaManufactured for:BluePoint LaboratoriesRev 04-2020-01Each vial contains 50 mg decitabine, 68 mg monobasic potassium phosphate and 11.6 mg sodium hydroxide.Reconstitution: Aseptically reconstitute with 10 mL of Sterile Water for Injection USP: each mL will contain mg of decitabine.Final Concentration: The resultant solution will have 5 mg per mL (5 mg/mL) concentration and pH of 6.7 to 7.3.Stability: Unless used within 15 minutes of reconstitution, the diluted solution must be prepared using cold (2C to 8C) infusion fluids and stored at 2C to 8C (36F to 46F) for up to maximum of hours until administration. See package insert for detailed indications, reconstitution information, dosage information, and precautions. batch no.: exp. date: Decitabine for Injection 50mg/Vial Vial Label Rev 04/2020. Decitabine for Injection 50mg/vial Carton Rev 04/2020.

PEDIATRIC USE SECTION.


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

PHARMACODYNULLMICS SECTION.


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.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. Pharmacokinetic (PK) parameters were evaluated in patients. Eleven patients received 20 mg/m2 infused over hour intravenously (treatment Option 2), Fourteen patients received 15 mg/m2 infused over hours intravenously (treatment Option 1). PK parameters are shown in Table 3. Plasma concentration-time profiles after discontinuation of infusion showed biexponential decline. The clearance (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 was 2.3-fold lower than the cumulative AUC per cycle following treatment Option 1.Table Mean (CV% or 95% CI) Pharmacokinetic Parameters of DecitabineDoseCmax (ng/mL)AUC0-INF (ngoh/mL)T1/2 (h)CL (L/h/m2)AUCCumulative (ngoh/mL)15 mg/m2 3-hr infusion every hours for days (Option 1)73.8 (66)163 (62)0.62 (49)125 (53)1332 (1010 to1730)20 mg/m2 1-hr infusion daily for days (Option 2)+ 147 (49)115 (43)0.54 (43)210 (47)570 (470 to 700) N=14, +N=11, N=35 Cumulative AUC per cycle. 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 PopulationsPatients with Renal ImpairmentThere are no data on the use of Decitabine for Injection in patients with renal impairment.Patients with Hepatic ImpairmentThere are no data on the use of Decitabine for Injection in patients with hepatic impairment.

PREGNULLNCY SECTION.


8.1 Pregnancy Risk SummaryBased on findings from human data, animal studies, and the mechanism of action, Decitabine for Injection can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)] 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 including malformations and embryo-fetal lethality starting at doses approximately 7% of the recommended human dose on mg/m2 basis (see Data). Advise pregnant women of the potential risk to fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 populations is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively.DataHuman DataA single published case report of decitabine pregnancy exposure in 39-year old woman with hematologic malignancy described multiple structural abnormalities after cycles of therapy in the 18th 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 DataIn utero exposure to decitabine causes temporal related defects in the rat and/or mouse, which include growth suppression, exencephaly, defective skull bones, rib/sternabrae 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 (0.09 and 3.0 mg/m2, 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 mg/m2 and decreased fetal weight was observed at both dose levels. The mg/m2 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 single IP injection of 2.4, 3.6 or mg/m2 (approximately 5%, 8%, or 13% the daily recommended clinical dose, respectively) on gestation days to 12, no maternal toxicity was observed. No live fetuses were seen at any dose when decitabine was injected on gestation day 9. significant decrease in fetal survival and reduced fetal weight at doses greater than 3.6 mg/m2 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/m2. Increased incidence of foredigit defects was seen in fetuses at doses greater than 3.6 mg/m2. Reduced size and ossification of long bones of the fore-limb and hind-limb were noted at 6.0 mg/m2. The effect of Decitabine on postnatal development and reproductive capacity was evaluated in mice administered single mg/m2 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 and 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 reduced pregnancy rate resulting from effects on sperm production in the F1-generation.

REFERENCES SECTION.


15 REFERENCES. 1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html 1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

SPL UNCLASSIFIED SECTION.


2.1 Recommended Dosage Pre-Medications and Baseline TestingoConsider pre-medicating for nausea with antiemeticsoConduct baseline laboratory testing: complete blood count (CBC) with platelets, serum hepatic panel, and serum creatinine.Decitabine for Injection Regimen OptionsThree Day RegimenAdminister Decitabine for Injection at dose of 15 mg/m2 by continuous intravenous infusion over hours repeated every hours for days. Repeat cycles every weeks upon hematologic recovery (ANC at least 1,000/uL and platelets at least 50,000/uL) for minimum of cycles. complete or partial response may take longer than cycles. Delay and reduce dose for hematologic toxicity [see Dosage and Administration (2.2)].Five Day RegimenAdminister Decitabine for Injection at dose of 20 mg/m2 by continuous intravenous infusion over hour daily for days. Delay and reduce dose for hematologic toxicity [see Dosage and Administration (2.2)]. Repeat cycles every weeks upon hematologic recovery (ANC at least 1,000/uL and platelets at least 50,000/uL) for minimum of cycles. complete or partial response may take longer than cycles.Patients with Renal or Severe Hepatic ImpairmentTreatment 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. For patients with pre-existing renal or hepatic impairment, consider the potential risks and benefits before initiating treatment with Decitabine for Injection. oConsider pre-medicating for nausea with antiemetics. oConduct baseline laboratory testing: complete blood count (CBC) with platelets, serum hepatic panel, and serum creatinine.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy Risk SummaryBased on findings from human data, animal studies, and the mechanism of action, Decitabine for Injection can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)] 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 including malformations and embryo-fetal lethality starting at doses approximately 7% of the recommended human dose on mg/m2 basis (see Data). Advise pregnant women of the potential risk to fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 populations is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively.DataHuman DataA single published case report of decitabine pregnancy exposure in 39-year old woman with hematologic malignancy described multiple structural abnormalities after cycles of therapy in the 18th 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 DataIn utero exposure to decitabine causes temporal related defects in the rat and/or mouse, which include growth suppression, exencephaly, defective skull bones, rib/sternabrae 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 (0.09 and 3.0 mg/m2, 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 mg/m2 and decreased fetal weight was observed at both dose levels. The mg/m2 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 single IP injection of 2.4, 3.6 or mg/m2 (approximately 5%, 8%, or 13% the daily recommended clinical dose, respectively) on gestation days to 12, no maternal toxicity was observed. No live fetuses were seen at any dose when decitabine was injected on gestation day 9. significant decrease in fetal survival and reduced fetal weight at doses greater than 3.6 mg/m2 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/m2. Increased incidence of foredigit defects was seen in fetuses at doses greater than 3.6 mg/m2. Reduced size and ossification of long bones of the fore-limb and hind-limb were noted at 6.0 mg/m2. The effect of Decitabine on postnatal development and reproductive capacity was evaluated in mice administered single mg/m2 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 and 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 reduced pregnancy rate resulting from effects on sperm production in the F1-generation.. 8.2 Lactation Risk SummaryThere 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 of the potential for serious adverse reactions from Decitabine for Injection in breastfed child, advise women not to breastfeed while receiving Decitabine for Injection and for at least weeks after the last dose.. 8.3 Females and Males of Reproductive Potential Pregnancy TestingConduct pregnancy testing of females of reproductive potential prior to initiating Decitabine for Injection.ContraceptionFemalesDecitabine for Injection can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception while receiving Decitabine for Injection and for months following the last dose.MalesAdvise males with female partners of reproductive potential to use effective contraception while receiving treatment with Decitabine for Injection and for months following the last dose [see Nonclinical Toxicology (13.1)] InfertilityBased on findings of decitabine in animals, male fertility may be compromised by treatment with Decitabine for Injection. The reversibility of the effect on fertility is unknown [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 years and over, while 21 of 83 patients were age 75 years 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.

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. oNeutropenia and thrombocytopenia: Perform complete blood counts and platelet counts. (5.1)oEmbryo-fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to fetus and to use effective contraception. (5.2, 8.1, 8.3) oNeutropenia and thrombocytopenia: Perform complete blood counts and platelet counts. (5.1). oEmbryo-fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to fetus and to use effective contraception. (5.2, 8.1, 8.3).