ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Myelosuppression [see Warnings and Precautions (5.1)] Myelosuppression [see Warnings and Precautions (5.1)] Most common adverse reactions (> 50%) are neutropenia, thrombocytopenia, anemia, and pyrexia. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals, Inc. at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 was studied in single-arm studies (N 66, = 98, = 99) and controlled supportive care study (N 83 decitabine, = 81 supportive care). The data described below reflect exposure to decitabine 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 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 Arm:Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardio-respiratory arrest, increased blood bilirubin, intracranial hemorrhage, abnormal liver function tests.Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile neutropenia.Dose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia, depression, pharyngitis.Table presents all adverse reactions occurring in at least 5% of patients in the decitabine group and at rate greater than supportive care.Table Adverse Reactions Reported in >= 5% of Patients in the Decitabine Group and at Rate Greater than Supportive Care in the Controlled Trial in MDSDecitabineN 83 (%)Supportive CareN 81 (%)Blood and lymphatic system disorders Neutropenia75 (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 disorders Pulmonary edema NOS5 (6)0 (0)Eye disorders Vision blurred5 (6)0 (0)Gastrointestinal disorders Nausea35 (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 disorders Pyrexia44 (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 disorders Hyperbilirubinemia12 (14)4 (5)Infections and infestations Pneumonia 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 complications Transfusion reaction6 (7)3 (4) Abrasion NOS4 (5)1 (1)Investigations Cardiac 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 disorders Hyperglycemia 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 disorders Arthralgia17 (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 disorders Headache23 (28)11 (14) Dizziness15 (18)10 (12) Hypoesthesia9 (11)1 (1)Psychiatric disorders Insomnia23 (28)11 (14) Confusional state10 (12)3 (4) Anxiety9 (11)8 (10)Renal and urinary disorders Dysuria5 (6)3 (4) Urinary frequency4 (5)1 (1)Respiratory, thoracic and mediastinal disorders Cough33 (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 disorders Ecchymosis18 (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 disorders Petechiae32 (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 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 In this single arm study, investigators reported adverse reactions based on clinical signs and symptoms rather than predefined laboratory abnormalities. Thus, not all laboratory abnormalities were recorded as adverse reactions.DecitabineN 99 (%)Blood and lymphatic system disorders Anemia31 (31) Febrile neutropenia20 (20) Leukopenia6 (6) Neutropenia38 (38) Pancytopenia5 (5) Thrombocythemia5 (5) Thrombocytopenia27 (27)Cardiac disorders Cardiac failure congestive5 (5) Tachycardia8 (8)Ear and labyrinth disorders Ear pain6 (6)Gastrointestinal disorders Abdominal pain14 (14) Abdominal pain upper6 (6) Constipation30 (30) Diarrhea28 (28) Dyspepsia10 (10) Dysphagia5 (5) Gastro-esophageal reflux disease5 (5) Nausea40 (40) Oral pain5 (5) Stomatitis11 (11) Toothache6 (6) Vomiting16 (16)General disorders and administration site conditions Asthenia15 (15) Chest pain6 (6) Chills16 (16) Fatigue46 (46) Mucosal inflammation9 (9) Edema5 (5) Edema peripheral27 (27) Pain5 (5) Pyrexia36 (36)Infections and infestations Cellulitis9 (9) Oral candidiasis6 (6) Pneumonia20 (20) Sinusitis6 (6) Staphylococcal bacteremia8 (8) Tooth abscess5 (5) Upper respiratory tract infection10 (10) Urinary tract infection7 (7)Injury, poisoning and procedural complications Contusion9 (9)Investigations Blood bilirubin increased6 (6) Breath sounds abnormal5 (5) Weight decreased9 (9)Metabolism and nutrition disorders Anorexia23 (23) Decreased appetite8 (8) Dehydration8 (8) Hyperglycemia6 (6) Hypokalemia12 (12) Hypomagnesemia5 (5)Musculoskeletal and connective tissue disorders Arthralgia17 (17) Back pain18 (18) Bone pain6 (6) Muscle spasms7 (7) Muscular weakness5 (5) Musculoskeletal pain5 (5) Myalgia9 (9) Pain in extremity18 (18)Nervous system disorders Dizziness21 (21) Headache23 (23)Psychiatric disorders Anxiety9 (9) Confusional state8 (8) Depression9 (9) Insomnia14 (14)Respiratory, thoracic and mediastinal disorders Cough27 (27) Dyspnea29 (29) Epistaxis13 (13) Pharyngolaryngeal pain8 (8) Pleural effusion5 (5) Sinus congestion5 (5)Skin and subcutaneous tissue disorders Dry skin8 (8) Ecchymosis9 (9) Erythema5 (5) Night sweats5 (5) Petechiae12 (12) Pruritus9 (9) Rash11 (11) Skin lesion5 (5)Vascular disorders Hypertension6 (6) Hypotension11 (11)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 not previously reported in Tables and include:Allergic Reaction: hypersensitivity (anaphylactic reaction)Blood and Lymphatic System Disorders: myelosuppression, splenomegalyCardiac Disorders: myocardial infarction, cardio-respiratory arrest, cardiomyopathy, atrial fibrillation, supraventricular tachycardiaGastrointestinal Disorders: gingival pain, upper gastrointestinal hemorrhageGeneral Disorders and Administrative Site Conditions: chest pain, catheter site hemorrhageHepatobiliary Disorders: cholecystitisInfections and Infestations: fungal infection, sepsis, bronchopulmonary aspergillosis, peridiverticular abscess, respiratory tract infection, pseudomonal lung infection, Mycobacterium avium complex infectionInjury, Poisoning and Procedural Complications: post procedural pain, post procedural hemorrhageNervous System Disorders: intracranial hemorrhagePsychiatric Disorders: mental status changesRenal and Urinary Disorders: renal failure, urethral hemorrhageRespiratory, Thoracic and Mediastinal Disorders: hemoptysis, lung infiltration, pulmonary embolism, respiratory arrest, pulmonary mass. Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardio-respiratory arrest, increased blood bilirubin, intracranial hemorrhage, abnormal liver function tests.. Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile neutropenia.. Dose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia, depression, pharyngitis.. Allergic Reaction: hypersensitivity (anaphylactic reaction). 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. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of decitabine. 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.Sweets syndrome (acute febrile neutrophilic dermatosis)Differentiation syndromeInterstitial lung disease. Sweets syndrome (acute febrile neutrophilic dermatosis). Differentiation syndrome. Interstitial lung disease.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


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 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 DecitabineN=14, +N=11, N=35 Cumulative AUC per cycleDoseCmax(ng/mL)AUC0-INF(ngh/mL)T 1/2 (h)CL (L/h/m2)AUCCumulative(ngh/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 to 1730)20 mg/m2 1-hr infusion daily for 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 ImpairmentThere are no data on the use of decitabine in patients with renal impairment.. Patients with Hepatic ImpairmentThere are no data on the use of decitabine in patients with hepatic impairment.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. 14.1 Controlled Trial in Myelodysplastic Syndrome. 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 therapy plus supportive care (only 83 received decitabine), 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 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 Other Patient CharacteristicDecitabineN 89Supportive CareN= 81Age (years)Mean (+-SD)69+-1067+-10Median (IQR)70 (65 to 76)70 (62 to 74)(Range: min-max)(31 to 85)(30 to 82)Sex (%)Male59 (66)57 (70)Female30 (34)24 (30)Race (%)White83 (93)76 (94)Black4 (4)2 (2)Other2 (2)3 (4)Weeks Since MDS DiagnosisMean (+-SD)86+-13177+-119Median (IQR)29 (10 to 87)35 (7 to 98)(Range: min-max)(2 to 667)(2 to 865)Previous MDS Therapy (%)Yes27 (30)19 (23)No62 (70)62 (77)RBC Transfusion Status (%)Independent23 (26)27 (33)Dependent66 (74)54 (67)Platelet Transfusion Status (%)IndependentDependent69 (78)20 (22)62 (77)19 (23)IPSS Classification (%)Intermediate-128 (31)24 (30)Intermediate-238 (43)36 (44)High Risk23 (26)21 (26)FAB Classification (%)RA12 (13)12 (15)RARS7 (8)4 (5)RAEB47 (53)43 (53)RAEB-t17 (19)14 (17)CMML6 (7)8 (10)Patients randomized to the decitabine arm received decitabine 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 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)>= weeksBone MarrowOn repeat aspirates:< 5% myeloblastsNo dysplastic changesPeripheral BloodIn all samples during response:Hgb 11 g/dL (no transfusions or erythropoietinANC >= 1500/uL (no growth factor)Platelets >= 100,000/uL (no thrombopoietic agent)No blasts and no dysplasiaPartial Response (PR)>= weeksBone MarrowOn repeat aspirates:>= 50% decrease in blasts over pretreatment valuesORImprovement to less advanced MDS FAB classificationPeripheral BloodSame as for CRThe overall response rate (CR+PR) in the ITT population was 17% in decitabine-treated patients and 0% in the SC group (p<0.001) (see Table 6). The overall response rate was 21% (12/56) in decitabine-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 was 288 days (116 to 388) and median time to response (range) was 93 days (55 to 272). All but one of the decitabine-treated patients who responded did so by the fourth cycle. Benefit was seen in an additional 13% of decitabine-treated patients who had hematologic improvement, defined as response less than PR lasting at least weeks, compared to 7% of SC patients. Decitabine treatment did not significantly delay the median time to AML or death versus supportive care.Table Analysis of Response (ITT)p-value <0.001 from two-sided Fishers Exact Test comparing Decitabine vs. Supportive Care.+In the statistical analysis plan, p-value of <= 0.024 was required to achieve statistical significance.ParameterDecitabineN=89Supportive CareN=81Overall Response Rate (CR+PR)+ Complete Response (CR) Partial Response (PR)15 (17%)8 (9%)7 (8%)0 (0%)0 (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)NULLNULLAll 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.. 5% myeloblasts. No dysplastic changes. 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. >= 50% decrease in blasts over pretreatment valuesOR. Improvement to less advanced MDS FAB classification. 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 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 20 mg/m2 as an intravenous infusion over 1-hour daily, on days to 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 CharacteristicDecitabineN 99Age (years)Mean (+-SD)71+-9Median (Range: min-max)72 (34 to 87)Sex (%)Male71 (72)Female28 (28)Race (%)White86 (87)Black6 (6)Asian4 (4)Other3 (3)Days From MDS Diagnosis to First DoseMean (+-SD)Median (Range: min-max)444+-626154 (7 to 3079)Previous MDS Therapy (%)Yes27 (27)No72 (73)RBC Transfusion Status (%)Independent33 (33)Dependent66 (67)Platelet Transfusion Status (%)Independent84 (85)Dependent15 (15)IPSS Classification (%)Low Risk1 (1)Intermediate-152 (53)Intermediate-2High Risk23 (23)23 (23)FAB Classification (%)RARARSRAEBRAEB-tCMML20 (20)17 (17)45 (45)6 (6)11 (11)Table Analysis of Response (ITT) 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 observationParameterDecitabineN=99Overall Response Rate (CR+PR) Complete Response (CR) Partial Response (PR)16 (16%)15 (15%)1 (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+).

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 infusion, 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 is used for pH adjustment.. Structural Formula.

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). 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 TestingConsider pre-medicating for nausea with antiemetics.Conduct baseline laboratory testing: complete blood count (CBC) with platelets, serum hepatic panel, and serum creatinine.. Consider pre-medicating for nausea with antiemetics.. Conduct baseline laboratory testing: complete blood count (CBC) with platelets, serum hepatic panel, and serum creatinine.. Decitabine for Injection Regimen Options. Three Day 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/mcL and platelets at least 50,000/mcL) 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/mcL and platelets at least 50,000/mcL) 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, consider the potential risks and benefits before initiating with decitabine for injection.. 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:Recovery 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.Recovery requiring more than 8, but less than 10 weeks: Perform bone marrow aspirate to assess for disease progression. In the absence of progression, delay decitabine for injection dosing for up to more weeks and reduce the dose to 11 mg/m2 every hours (33 mg/m2/day, 99 mg/m2/cycle) upon restarting therapy, then maintain or increase dose in subsequent cycles as clinically indicated.. Recovery 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.. Recovery requiring more than 8, but less than 10 weeks: Perform bone marrow aspirate to assess for disease progression. In the absence of progression, delay decitabine for injection dosing for up to more weeks and reduce the dose to 11 mg/m2 every hours (33 mg/m2/day, 99 mg/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:Serum creatinine greater than or equal to mg/dLAlanine transaminase (ALT), total bilirubin greater than or equal to times upper limit of normal (ULN)Active or uncontrolled infection. Serum creatinine greater than or equal to mg/dL. Alanine transaminase (ALT), total bilirubin greater than or equal to times upper limit of normal (ULN). Active 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 (20C to 25C) 10 mL of Sterile Water for Injection, USP. Upon reconstitution, the final concentration of the reconstituted decitabine for injection solution is mg per mL. You must dilute the reconstituted solution with 0.9% Sodium Chloride Injection or 5% Dextrose Injection prior to administration. Temperature of the diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) depends on time of administration after preparation.. For Administration Within 15 Minutes of PreparationIf decitabine for injection is intended to be administered within 15 minutes from the time of preparation, dilute the reconstituted solution with room temperature (20C to 25C) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to final concentration of 0.1 mg per mL to mg per 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 (2C to 8C) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to final concentration of 0.1 mg per mL to mg per mL. Store at 2C to 8C for up to hours. Diluted stored solution must be used within hours from the time of preparation.Use the diluted, refrigerated solution within 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.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. Decitabine for Injection: 50 mg 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.

GERIATRIC USE SECTION.


8.5 Geriatric Use. Of the total number of patients exposed to decitabine 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 supplied as follows:NDCDecitabine for InjectionPackage Factor25021-231-2050 mg Single-Dose Vial1 vial per cartonDecitabine for Injection is sterile, white to almost white lyophilized powder for intravenous use.. Storage ConditionsStore at 20 to 25C (68 to 77F); excursions permitted between 15 and 30C (59 and 86F). [See USP Controlled Room Temperature.]Discard unused portion.Keep this and all medications out of the reach of children.Sterile, Nonpyrogenic, Preservative-free.The container closure is not made with natural rubber latex.

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 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, 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 and for at least weeks after the last dose [see Use in Specific Populations (8.2)].SAGENT(R) Mfd. for SAGENT PharmaceuticalsSchaumburg, IL 60195 (USA)Made in China(C)2020 Sagent Pharmaceuticals, Inc.Revised: October 2020SAGENT Pharmaceuticals (R).

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 in breastfed child, advise women not to breastfeed while receiving decitabine 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 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 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. 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.


PACKAGE LABEL PRINCIPAL DISPLAY PANEL Vial LabelNDC 25021-231-20Rx onlyDecitabine for Injection50 mg per vialFOR INTRAVENOUS INFUSION ONLYSingle-Dose VialCaution: Cytotoxic Agent. PACKAGE LABEL PRINCIPAL DISPLAY PANEL Vial Label.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. The safety and effectiveness of decitabine 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 DecitabineN=14, +N=11, N=35 Cumulative AUC per cycleDoseCmax(ng/mL)AUC0-INF(ngh/mL)T 1/2 (h)CL (L/h/m2)AUCCumulative(ngh/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 to 1730)20 mg/m2 1-hr infusion daily for 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 ImpairmentThere are no data on the use of decitabine in patients with renal impairment.. Patients with Hepatic ImpairmentThere are no data on the use of decitabine 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 can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. Limited published data on decitabine 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 population is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively.. Data. Human 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, 0.9 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. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

SPL UNCLASSIFIED SECTION.


2.1 Recommended Dosage. Pre-Medications and Baseline TestingConsider pre-medicating for nausea with antiemetics.Conduct baseline laboratory testing: complete blood count (CBC) with platelets, serum hepatic panel, and serum creatinine.. Consider pre-medicating for nausea with antiemetics.. Conduct baseline laboratory testing: complete blood count (CBC) with platelets, serum hepatic panel, and serum creatinine.. Decitabine for Injection Regimen Options. Three Day 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/mcL and platelets at least 50,000/mcL) 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/mcL and platelets at least 50,000/mcL) 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, consider the potential risks and benefits before initiating with decitabine for injection.

STORAGE AND HANDLING SECTION.


Storage ConditionsStore at 20 to 25C (68 to 77F); excursions permitted between 15 and 30C (59 and 86F). [See USP Controlled Room Temperature.]Discard unused portion.Keep this and all medications out of the reach of children.Sterile, Nonpyrogenic, Preservative-free.The container closure is not made with natural rubber latex.

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 can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. Limited published data on decitabine 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 population is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively.. Data. Human 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, 0.9 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 in breastfed child, advise women not to breastfeed while receiving decitabine 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.. Contraception. FemalesDecitabine 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 and for months following the last dose.. MalesAdvise males with female partners of reproductive potential to use effective contraception while receiving treatment with decitabine 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. The reversibility of the effect on fertility is unknown [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. The safety and effectiveness of decitabine in pediatric patients have not been established.. 8.5 Geriatric Use. Of the total number of patients exposed to decitabine 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. Neutropenia and Thrombocytopenia: Perform complete blood counts and platelet counts. (5.1)Embryo-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). Neutropenia and Thrombocytopenia: Perform complete blood counts and platelet counts. (5.1). Embryo-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). 5.1 Myelosuppression. Fatal and serious myelosuppression occurs in decitabine-treated patients. Myelosuppression (anemia, neutropenia, and thrombocytopenia) is the most frequent cause of decitabine dose reduction, delay, and discontinuation. Neutropenia of any grade occurred in 90% of decitabine-treated patients with grade or occurring in 87% of patients. Grade or febrile neutropenia occurred in 23% of patients. Thrombocytopenia of any grade occurred in 89% of patients with grade or occurring in 85% of patients. Anemia of any grade occurred in 82% of patients. Perform complete blood count with platelets at baseline, prior to each cycle, and as needed to monitor response and toxicity. Manage toxicity using dose-delay, dose-reduction, growth factors, and anti-infective therapies as needed [see Dosage and Administration (2.2)]. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate progression of underlying MDS.. 5.2 Embryo-Fetal Toxicity. Based on findings from human data, animal studies and its mechanism of action, decitabine can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. In preclinical studies in mice and rats, decitabine caused adverse developmental outcomes including embryo-fetal lethality and malformations. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception while receiving decitabine and for months following the last dose. Advise males with female partners of reproductive potential to use effective contraception while receiving treatment with decitabine, and for months following the last dose [see Use in Specific Populations (8.1, 8.3)].