NDC 16714-928 Decitabine

Decitabine

NDC Product Code 16714-928

NDC Product Information

Decitabine with NDC 16714-928 is a a human prescription drug product labeled by Northstar Rx Llc. The generic name of Decitabine is decitabine. The product's dosage form is injection, powder, lyophilized, for solution and is administered via intravenous form.

Labeler Name: Northstar Rx Llc

Dosage Form: Injection, Powder, Lyophilized, For Solution - A dosage form intended for the solution prepared by lyophilization ("freeze drying"), a process which involves the removal of water from products in the frozen state at extremely low pressures; this is intended for subsequent addition of liquid to create a solution that conforms in all respects to the requirements for Injections.

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Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.


Decitabine Active Ingredient(s)

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This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • DECITABINE 50 mg/10mL

Inactive Ingredient(s)

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  • POTASSIUM PHOSPHATE, MONOBASIC (UNII: 4J9FJ0HL51)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)

Administration Route(s)

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  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

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  • Nucleic Acid Synthesis Inhibitors - [MoA] (Mechanism of Action)
  • Nucleoside Metabolic Inhibitor - [EPC] (Established Pharmacologic Class)

Product Labeler Information

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Labeler Name: Northstar Rx Llc
Labeler Code: 16714
FDA Application Number: ANDA203131 Additional informationCallout TooltipWhat is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. Additional informationCallout TooltipWhat is the Marketing Category?
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Start Marketing Date: 02-18-2019 Additional informationCallout TooltipWhat is the Start Marketing Date?
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Listing Expiration Date: 12-31-2020 Additional informationCallout TooltipWhat is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N Additional informationCallout TooltipWhat is the NDC Exclude Flag?
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Decitabine Product Label Images

Decitabine Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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.

  • Pre-Medications and Baseline Testing Consider pre-medicating for nausea with antiemetics.Conduct baseline laboratory testing: CBC with platelets, serum hepatic panel, and serum creatinine.Decitabine for injection Regimen OptionsThree Day RegimenAdminister decitabine for injection at a dose of 15 mg/m2 by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days. Repeat cycles every 6 weeks upon hematologic recovery (ANC at least 1,000/microliter and platelets at least 50,000/microliter) for a minimum of 4 cycles. A complete or partial response may take longer than 4 cycles. Delay and reduce dose for hematologic toxicity (see Dose Modifications for Toxicity).Five Day RegimenAdminister decitabine for injection at a dose of 20 mg/m2 by continuous intravenous infusion over 1 hour daily for 5 days. Delay and reduce dose for hematologic toxicity (see Dose Modifications for Toxicity). Repeat cycles every 6 weeks upon hematologic recovery (ANC at least 1,000/microliter and platelets at least 50,000/microliter) for a minimum of 4 cycles. A complete or partial response may take longer than 4 cycles.

2.2 Dose Modifications For Toxicity

  • Hematologic ToxicityIf hematologic recovery from a previous decitabine for injection treatment cycle requires more than 6 weeks, delay the next cycle of decitabine for injection therapy and reduce decitabine for injection dose temporarily by following this algorithm: Recovery requiring more than 6, but less than 8 weeks – delay decitabine for injection dosing for up to 2 weeks and reduce the dose temporarily to 11 mg/m2 every 8 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 the decitabine for injection dose up to 2 more weeks and reduce the dose to 11 mg/m2 every 8 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 2 mg/dL SGPT, total bilirubin greater than or equal to 2 times ULNActive or uncontrolled infection

2.3 Instructions For Intravenous Administration

Decitabine for injection is a cytotoxic drug and caution should be exercised when handling and preparing decitabine for injection1.Aseptically reconstitute decitabine for injection with room temperature (20°C to 25°C) 10 mL of Sterile Water for Injection, USP. Upon reconstitution, the final concentration of the reconstituted decitabine for injection solution is 5 mg/mL. You must dilute the reconstituted solution with 0.9% Sodium Chloride Injection or 5% Dextrose Injection prior to administration. Temperature of the diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) depends on time of administration after preparation.For Administration Within 15 Minutes of PreparationIf decitabine for injection is intended to be administered within 15 minutes from the time of preparation, dilute the reconstituted solution with room temperature (20°C to 25°C) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 0.1 mg/mL- 1 mg/mL.For Delayed AdministrationIf decitabine for injection is intended to be administered after 15 minutes of preparation, dilute the reconstituted solution with cold (2°C to 8°C) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 0.1 mg/mL to 1 mg/mL. Store at 2°C to 8°C for up to 4 hours. Diluted stored solution must be used within 4 hours from the time of preparation.Use the diluted, refrigerated solution within 4 hours from the time of preparation or discard.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if there is evidence of particulate matter or discoloration.

3 Dosage Forms And Strengths

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

4 Contraindications

None

5.1 Myelosuppression

Fatal and serious myelosuppression occurs in decitabine for injection-treated patients. Myelosuppression (anemia, neutropenia, and thrombocytopenia) is the most frequent cause of decitabine for injection dose reduction, delay, and discontinuation. Neutropenia of any grade occurred in 90% of decitabine for injection treated patients with grade 3 or 4 occurring in 87% of patients. Thrombocytopenia of any grade occurred in 89% of patients with grade 3 or 4 occurring in 85% of patients. Grade 3 or 4 febrile neutropenia occurred in 23% 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 [seeDosage 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

Decitabine for injection can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, decitabine for injection alters DNA synthesis and is expected to result in adverse reproductive effects [seeClinical Pharmacology (12.1)]. In preclinical studies in mice and rats, decitabine was teratogenic, fetotoxic, and embryotoxic. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Advise women of childbearing potential to avoid becoming pregnant while taking decitabine for injection and for 6 months following the last dose. Advise men with female partners of childbearing potential to avoid fathering a child while receiving treatment with decitabine for injection, and for 3 months following the last dose, Counsel patients of childbearing potential to use effective contraception during this time [seeUse in Specific Populations (8.1, 8.3)].

6.1 Clinical Studies Experience

  • Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.  The safety of decitabine for injection was studied in 3 single-arm studies (N=66, N=98, N=99) and 1 controlled supportive care study (N=83 decitabine for injection, N=81 supportive care). The data described below reflect exposure to decitabine for injection in 83 patients in the MDS trial. In the trial, patients received 15 mg/m2 intravenously every 8 hours for 3 days every 6 weeks. The median number of decitabine for injection cycles was 3 (range 0 to 9). Most Commonly Occurring Adverse Reactions: neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia.Adverse Reactions Most Frequently (≥ 1%) Resulting in Clinical Intervention and or Dose Modification in the Phase 3 Trials in the decitabine for injection Arm: Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardio-respiratory arrest, increased blood bilirubin, intracranial hemorrhage, abnormal liver function tests. Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile neutropenia. Dose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia, depression, pharyngitis. Table 1 presents all adverse reactions occurring in at least 5% of patients in the decitabine for injection group and at a rate greater than supportive care.Table 1 Adverse Reactions Reported in ≥ 5% of Patients in the Decitabine For Injection Group and at a Rate Greater than Supportive Care in Phase 3 MDS Trial  Decitabine For InjectionN = 83 (%)Supportive CareN = 81 (%) Blood and lymphatic system disorders    Neutropenia 75 (90)58 (72)Thrombocytopenia 74 (89)64 (79)Anemia NOS 68 (82)60 (74)Febrile neutropenia 24 (29)5 (6)Leukopenia NOS 23 (28)11 (14)Lymphadenopathy 10 (12)6 (7)Thrombocythemia 4 (5)1 (1)Cardiac disorders  Pulmonary edema NOS 5 (6)0 (0)Eye disorders  Vision blurred 5 (6)0 (0)Gastrointestinal disorders  Nausea 35 (42)13 (16)Constipation 29 (35)11 (14)Diarrhea NOS 28 (34)13 (16)Vomiting NOS 21 (25)7 (9)Abdominal pain NOS 12 (14)5 (6)Oral mucosal petechiae 11 (13)4 (5)Stomatitis 10 (12)5 (6)Dyspepsia 10 (12)1 (1)Ascites 8 (10)2 (2)Gingival bleeding 7 (8)5 (6)Hemorrhoids 7 (8)3 (4)Loose stools 6 (7)3 (4)Tongue ulceration 6 (7)2 (2)Dysphagia 5 (6)2 (2)Oral soft tissue disorder NOS 5 (6)1 (1)Lip ulceration 4 (5)3 (4)Abdominal distension 4 (5)1 (1)Abdominal pain upper 4 (5)1 (1)Gastro-esophageal reflux disease 4 (5)0 (0)Glossodynia 4 (5)0 (0) General disorders and administrative site disorders  Pyrexia 44 (53)23 (28) Edema peripheral 21 (25)13 (16) Rigors 18 (22)14 (17) Edema NOS 15 (18)5 (6) Pain NOS 11 (13)5 (6) Lethargy 10 (12)3 (4) Tenderness NOS 9 (11)0 (0) Fall 7 (8)3 (4) Chest discomfort 6 (7)3 (4) Intermittent pyrexia 5 (6)3 (4) Malaise 4 (5)1 (1) Crepitations NOS 4 (5)1 (1) Catheter site erythema 4 (5)1 (1) Catheter site pain 4 (5)0 (0) Injection site swelling 4 (5)0 (0) Hepatobiliary disorders  Hyperbilirubinemia 12 (14)4 (5) Infections and infestations  Pneumonia NOS 18 (22)11 (14) Cellulitis 10 (12)6 (7) Candidal infection NOS 8 (10)1 (1) Catheter related infection 7 (8)0 (0) Urinary tract infection NOS 6 (7)1 (1) Staphylococcal infection 6 (7)0 (0) Oral candidiasis 5 (6)2 (2) Sinusitis NOS 4 (5)2 (2) Bacteremia 4 (5)0 (0) Injury, poisoning and procedural complications  Transfusion reaction 6 (7)3 (4) Abrasion NOS 4 (5)1 (1) Investigations  Cardiac murmur NOS 13 (16)9 (11) Blood alkaline phosphatase NOS increased 9 (11)7 (9) Aspartate aminotransferase increased 8 (10)7 (9) Blood urea increased 8 (10)1 (1) Blood lactate dehydrogenase increased 7 (8)5 (6)0 (0) Blood albumin decreased 6 (7) Blood bicarbonate increased 5 (6)1 (1) Blood chloride decreased 5 (6)1 (1) Protein total decreased 4 (5)3 (4) Blood bicarbonate decreased 4 (5)1 (1) Blood bilirubin decreased 4 (5)1 (1) Metabolism and nutrition disorders  Hyperglycemia NOS 27 (33)16 (20) Hypoalbuminemia 20 (24)14 (17) Hypomagnesemia 20 (24)6 (7) Hypokalemia 18 (22)10 (12) Hyponatremia 16 (19)13 (16) Appetite decreased NOS 13 (16)12 (15) Anorexia 13 (16)8 (10) Hyperkalemia 11 (13)3 (4) Dehydration 5 (6)4 (5) Musculoskeletal and connective tissue disorders  Arthralgia 17 (20)8 (10) Pain in limb 16 (19)8 (10) Back pain 14 (17)5 (6) Chest wall pain 6 (7)1 (1) Musculoskeletal discomfort 5 (6)0 (0) Myalgia 4 (5)1 (1) Nervous system disorders  Headache 23 (28)11 (14) Dizziness 15 (18)10 (12) Hypoesthesia 9 (11)1 (1) Psychiatric disorders  Insomnia 23 (28)11 (14) Confusional state 10 (12)3 (4) Anxiety 9 (11)8 (10) Renal and urinary disorders  Dysuria 5 (6)3 (4)  Urinary frequency 4 (5)1 (1) Respiratory, thoracic and Mediastinal disorders  Cough 33 (40)25 (31) Pharyngitis 13 (16)6 (7) Crackles lung 12 (14)1 (1) Breath sounds decreased 8 (10)7 (9) Hypoxia 8 (10)4 (5) Rales 7 (8)2 (2) Postnasal drip 4 (5)2 (2) Skin and subcutaneous tissue disorders  Ecchymosis 18 (22)12 (15) Rash NOS 16 (19)7 (9) Erythema 12 (14)5 (6) Skin lesion NOS 9 (11)3 (4) Pruritis 9 (11)2 (2) Alopecia 7 (8)1 (1) Urticaria NOS 5 (6)1 (1) Swelling face 5 (6)0 (0) Vascular disorders  Petechiae 32 (39)13 (16) Pallor 19 (23)10 (12) Hypotension NOS 5 (6)4 (5) Hematoma NOS 4 (5)3 (4) In a single-arm MDS study (N=99) decitabine for injection was dosed at 20 mg/m2 intravenous, infused over one hour daily for 5 consecutive days of a 4 week cycle. Table 2 presents all adverse reactions occurring in at least 5% of patients. Table 2 Adverse Reactions Reported in ≥ 5% of Patients in a Single-arm Study* Decitabine For InjectionN = 99 (%)Blood and lymphatic system disorders Anemia 31 (31% )Febrile neutropenia 20 (20% )Leukopenia 6(6%)Neutropenia 38 (38% )Pancytopenia 5(5%)Thrombocythemia5(5%)Thrombocytopenia 27 (27% )Cardiac disorders Cardiac failure congestive 5 (5% )Tachycardia 8(8%)Ear and labyrinth disorders Ear pain 6 (6% )Gastrointestinal disorders Abdominal pain 14 (14% )Abdominal pain upper 6 (6% )Constipation 30 (30% )Diarrhea 28 (28% )Dyspepsia 10 (10% )Dysphagia 5(5%)Gastro-esophageal reflux disease 5 (5% )Nausea 40 (40% )Oral pain 5 (5% )Stomatitis 11 (11% )Toothache 6(6%)Vomiting 16 (16% )General disorders and administration site conditions Asthenia 15 (15% )Chest pain 6 (6% )Chills 16 (16% )Fatigue 46 (46% )Mucosal inflammation 9 (9% )Edema 5(5%)Edema peripheral 27 (27% )Pain5(5%)Pyrexia 36 (36% )Infections and infestations Cellulitis9(9%)Oral candidiasis 6 (6% )Pneumonia 20 (20% )Sinusitis 6(6%)Staphylococcal bacteremia 8 (8% )Tooth abscess 5 (5% )Upper respiratory tract infection 10 (10% )Urinary tract infection 7 (7% )Injury, poisoning and procedural complications Contusion 9(9%)Investigations Blood bilirubin increased 6 (6% )Breath sounds abnormal 5 (5% )Weight decreased 9 (9% )Metabolism and nutrition disorders  Anorexia 23 (23% )Decreased appetite 8 (8% )Dehydration 8(8%)Hyperglycemia 6(6%)Hypokalemia 12 (12% )Hypomagnesemia 5(5%)Musculoskeletal and connective tissue disorders  Arthralgia 17 (17% )Back pain 18 (18% )Bone pain 6 (6% )Muscle spasms 7 (7% )Muscular weakness 5 (5% )Musculoskeletal pain 5 (5% )Myalgia 9(9%)Pain in extremity 18 (18% )Nervous system disorders  Dizziness 21 (21% )Headache 23 (23% )Psychiatric disorders  Anxiety9(9%)Confusional state 8 (8% )Depression 9(9%)Insomnia 14 (14% )Respiratory, thoracic and mediastinal disorders  Cough 27 (27% )Dyspnea 29 (29% )Epistaxis 13 (13% )Pharyngolaryngeal pain 8 (8% )Pleural effusion 5 (5% )Sinus congestion 5 (5% )Skin and subcutaneous tissue disorders  Dry skin 8 (8% )Ecchymosis 9(9%)Erythema 5(5%)Night sweats 5 (5% )Petechiae 12 (12% )Pruritus 9(9%)Rash 11 (11% )Skin lesion 5 (5% )Vascular disorders  Hypertension 6(6%)Hypotension 11 (11% )* In this single arm study, investigators reported adverse events based on clinical signs and symptoms rather than predefined laboratory abnormalities. Thus not all laboratory abnormalities were recorded as adverse events. No overall difference in safety was detected between patients > 65 years of age and younger patients in these myelodysplasia trials. No significant gender differences in safety or efficacy were detected. Patients with renal or hepatic dysfunction were not studied. Insufficient numbers of non-white patients were available to draw conclusions in these clinical trials. Serious adverse reactions that occurred in patients receiving decitabine for injection regardless of causality, not previously reported in Tables 1 and 2 include: Blood and Lymphatic System Disorders: myelosuppression, splenomegaly. Cardiac Disorders: myocardial infarction, cardio-respiratory arrest, cardiomyopathy, atrial fibrillation, supraventricular tachycardia. Gastrointestinal Disorders: gingival pain, upper gastrointestinal hemorrhage. General Disorders and Administrative Site Conditions: chest pain, catheter site hemorrhage. Hepatobiliary Disorders: cholecystitis. Infections and Infestations: fungal infection, sepsis, bronchopulmonary aspergillosis, peridiverticular abscess, respiratory tract infection, pseudomonal lung infection, Mycobacterium avium complex infection. Injury, Poisoning and Procedural Complications: post procedural pain, post procedural hemorrhage. Nervous System Disorders: intracranial hemorrhage. Psychiatric Disorders: mental status changes. Renal and Urinary Disorders: renal failure, urethral hemorrhage. Respiratory, Thoracic and Mediastinal Disorders: hemoptysis, lung infiltration, pulmonary embolism, respiratory arrest, pulmonary mass. Allergic Reaction: Hypersensitivity (anaphylactic reaction) to decitabine for injection has been reported in a Phase 2 trial.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of decitabine for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cases of Sweet’s Syndrome (acute febrile neutrophilic dermatosis) have been reported.

7 Drug Interactions

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

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 a pregnant woman [seeClinical Pharmacology (12.1)].Limited published data on decitabine for injection use throughout the first trimester during pregnancy describe adverse developmental outcomes including major birth defects (structural abnormalities). In animal reproduction studies, administration of decitabine to pregnant mice and rats during organogenesis caused adverse developmental outcomes and was teratogenic, fetotoxic, and embryotoxic starting at doses approximately 7% of the recommended human dose on a mg/m2 basis (see Data). Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage in the U.S. general population is 2-4% and 15-20% of clinically recognized pregnancies, respectively.DataHuman DataA single published case report of decitabine pregnancy exposure in a 39-year old woman with a hematologic malignancy described multiple structural abnormalities after 6 cycles of therapy in the 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 3 mg/m2 and decreased fetal weight was observed at both dose levels. The 3 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 a single IP injection of 2.4, 3.6 or 6 mg/m2 (approximately 5, 8, or 13% the daily recommended clinical dose, respectively) on gestation days 9-12, no maternal toxicity was observed. No live fetuses were seen at any dose when decitabine was injected on gestation day 9. A significant decrease in fetal survival and reduced fetal weight at doses greater than 3.6 mg/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 a single 3 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 3 and 5 months of age (36% and 0% pregnancy rate, respectively). Follow up studies indicated that treatment of pregnant mice with decitabine on gestation day 10 was associated with a reduced pregnancy rate resulting from effects on sperm production in the F1-generation.

8.2 Lactation

Risk 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 many drugs are excreted in human milk, and because of the potential for serious adverse reactions from decitabine for injection in a nursing child, advise lactating women to avoid breastfeeding during treatment with decitabine for injection and for at least 1 week after the last dose.

8.3 Females And Males Of Reproductive Potential

Pregnancy TestingConduct pregnancy testing of females of reproductive potential prior to initiating decitabine for injection.ContraceptionFemales Advise females of reproductive potential to avoid pregnancy and use effective contraception while receiving decitabine for injection and for 6 months following the last dose. MalesAdvise males with female partners of reproductive potential to use effective contraception while receiving treatment with decitabine for injection and for 3 months following the last dose. [seeNonclinical Toxicology (13.1)].InfertilityBased on findings of decitabine in animals, male fertility may be compromised by treatment with decitabine for injection [seeNonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of decitabine for injection in pediatric patients have not been established

8.5 Geriatric Use

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

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.

11 Description

Decitabine for injection contains decitabine (5-aza-2’deoxycitidine), an analogue of the natural nucleoside 2’-deoxycytidine. Decitabine is a white to off white coloured powder with the molecular formula of C8H12N4O4 and a molecular weight of 228.21. Its chemical name is 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one and it has the following structural formula:Decitabine is soluble in dimethyl sulphoxide and sparingly soluble in water. Decitabine for injection is a white to almost white sterile lyophilized powder supplied in a clear colorless glass vial. Each 20 mL, single dose, glass vial contains 50 mg decitabine, 68 mg monobasic potassium phosphate (potassium dihydrogen phosphate) and 11.6 mg sodium hydroxide.

12.1 Mechanism Of Action

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

12.2 Pharmacodynamics

Decitabine has been shown to induce hypomethylation both in vitro and in vivo. However, there have been no studies of decitabineinduced hypomethylation and pharmacokinetic parameters.

12.3 Pharmacokinetics

Pharmacokinetic parameters were evaluated in patients. Eleven patients received 20 mg/m2 infused over 1 hour intravenously (treatment Option 2). Fourteen patients received 15 mg/m2 infused over 3 hours (treatment Option 1). PK parameters are shown in Table 3. Plasma concentration-time profiles after discontinuation of infusion showed a biexponential decline. The CL of decitabine was higher following treatment Option 2. Upon repeat doses there was no systemic accumulation of decitabine or any changes in PK parameters. Population PK analysis (N=35) showed that the cumulative AUC per cycle for treatment Option 2 was 2.3-fold lower than the cumulative AUC per cycle following treatment Option 1. Table 3 Mean (CV% or 95% CI) Pharmacokinetic Parameters of DecitabineDose Cmax(ng/ mL)AUC0-∞(ng·h/m L)T½ (h)CL (L/h/m2)AUCCumulative ***(ng·h/mL) 15 mg/m2 3-hr infusion every 8 hours for 3 days (Option 1)* 73.8(66)163(62)0.62 (49)125(53)1332(1010 - 1730)20 mg/m2 1-hr infusion daily for 5 days (Option 2)** 147(49)115(43)0.54 (43)210(47)570(470 -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 Impairment There are no data on the use of decitabine for injection in patients with renal impairment; therefore, if decitabine for injection is administered to these patients, monitor them frequently for excessive toxicity.Patients with Hepatic ImpairmentThere are no data on the use of decitabine for injection in patients with hepatic impairment; therefore, if decitabine for injection is administered to these patients, monitor them frequently for excessive toxicity.

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-l transgene in colonic DNA of decitabine-treated mice. Decitabine caused chromosomal rearrangements in larvae of fruit flies.   In male mice given IP injections of 0.15, 0.3 or 0.45 mg/m2 decitabine (approximately 0.3% to 1% the recommended clinical dose) 3 times a week for 7 weeks, decitabine did not affect survival, body weight gain or hematological measures (hemoglobin and WBC counts). Testes weights were reduced, abnormal histology was observed and significant decreases in sperm number were found at doses ≥ 0.3 mg/m2. In females mated to males dosed with ≥ 0.3 mg/m2 decitabine, pregnancy rate was reduced and preimplantation loss was significantly increased.

14.1 Controlled Trial In Myelodysplastic Syndrome

A randomized open-label, multicenter, controlled trial evaluated 170 adult patients with myelodysplastic syndromes (MDS) meeting French-American-British (FAB) classification criteria and International Prognostic Scoring System (IPSS) High-Risk, Intermediate-2 and Intermediate-1 prognostic scores. Eighty-nine patients were randomized to decitabine for injection therapy plus supportive care (only 83 received decitabine for injection), and 81 to Supportive Care (SC) alone. Patients with Acute Myeloid Leukemia (AML) were not intended to be included. Of the 170 patients included in the study, independent review (adjudicated diagnosis) found that 12 patients (9 in the decitabine for injection arm and 3 in the SC arm) had the diagnosis of AML at baseline. Baseline demographics and other patient characteristics in the Intent-to-Treat (ITT) population were similar between the 2 groups, as shown in Table 4. Table 4 Baseline Demographics and Other Patient Characteristics (ITT)Demographic or Other Patient Decitabine For InjectionSupportive CareCharacteristic N = 89N= 81Age (years)  Mean (±SD) 69±1067±10 Median (IQR) 70 (65-76)70 (62-74) (Range: min-max) (31-85)(30-82) Gender n (%)  Male 59 (66)57 (70) Female 30 (34)24 (30) Race n (%)  White 83 (93)76 (94) Black 4 (4)2 (2) Other 2 (2)3 (4) Weeks Since MDS Diagnosis  Mean (±SD) 86±13177±119SupportiveMedian (IQR) 29 (10-87)35 (7-98)(Range: min-max) (2-667)(2-865)Previous MDS Therapy n (%)  Yes 27 (30)19 (23)No 62 (70)62 (77)RBC Transfusion Status n (%)  Independent 23 (26)27 (33)Dependent 66 (74)54 (67)Platelet Transfusion Status n (%) Independent69 (78)62 (77)Dependent20 (22)19 (23)IPSS Classification n (%)  Intermediate–1 28 (31)24 (30)Intermediate–2 38 (43)36 (44)High Risk 23 (26)21 (26)FAB Classification n (%)  RA 12 (13)12 (15)RARS 7 (8)4 (5)RAEB 47 (53)43 (53)RAEB-t 17 (19)14 (17)CMML 6 (7)8 (10)Patients randomized to the decitabine for injection arm received decitabine for injection intravenously infused at a dose of 15 mg/m2 over a 3-hour period, every 8 hours, for 3 consecutive days. This cycle was repeated every 6 weeks, depending on the patient’s clinical response and toxicity. Supportive care consisted of blood and blood product transfusions, prophylactic antibiotics, and hematopoietic growth factors. The study endpoints were overall response rate (complete response + partial response) and time to AML or death. Responses were classified using the MDS International Working Group (IWG) criteria; patients were required to be RBC and platelet transfusion independent during the time of response. Response criteria are given in Table 5:  Table 5 Response Criteria for Phase 3 MDS Trial*Complete Response (CR) ≥ 8 weeks Bone Marrow On repeat aspirates:• < 5% myeloblasts• No dysplastic changes Peripheral Blood In all samples during response: • Hgb > 11 g/dL (no transfusions or erythropoietin • ANC ≥ 1500/μL (no growth factor)• Platelets ≥ 100,000/ μL (no thrombopoietic agent) • No blasts and no dysplasia Partial Response (PR) ≥ 8 weeks Bone Marrow On repeat aspirates: • ≥ 50% decrease in blasts over pretreatment values OR • Improvement to a less advanced MDS FAB classification Peripheral Blood Same as for CR * Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS. Blood. 2000; 96:3671-3674. The overall response rate (CR+PR) in the ITT population was 17% in decitabine for injection-treated patients and 0% in the SC group (p<0.001). (See Table 6) The overall response rate was 21% (12/56) in decitabine for injection-treated patients considered evaluable for response (i.e., those patients with pathologically confirmed MDS at baseline who received at least 2 cycles of treatment). The median duration of response (range) for patients who responded to decitabine for injection was 288 days (116 to 388) and median time to response (range) was 93 days (55 to 272). All but one of the decitabine for injection-treated patients who responded did so by the fourth cycle. Benefit was seen in an additional 13% of decitabine for injection-treated patients who had hematologic improvement, defined as a response less than PR lasting at least 8 weeks, compared to 7% of SC patients. decitabine for injection treatment did not significantly delay the median time to AML or death versus supportive care.Table 6 Analysis of Response (ITT)Parameter Decitabine For InjectionN=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 Response Median time to (CR+PR) response - Days (range) Median Duration of (CR+PR) response - Days (range)  93 (55-272)288 (116-388) NA NA**p-value <0.001 from two-sided Fisher’s Exact Test comparing Decitabine For Injection vs. Supportive Care.†In the statistical analysis plan, a p-value of ≤ 0.024 was required to achieve statistical significance. All patients with a CR or PR were RBC and platelet transfusion independent in the absence of growth factors. Responses occurred in patients with an adjudicated baseline diagnosis of AML.

14.2 Single-Arm Studies In Myelodysplastic Syndrome

Three open-label, single-arm, multicenter studies were conducted to evaluate the safety and efficacy of decitabine for injection in MDS patients with any of the FAB subtypes. In one study conducted in North America, 99 patients with IPSS Intermediate-1, Intermediate-2, or high risk prognostic scores received decitabine for injection by intravenous infusion at a dose of 20 mg/m2 IV over 1-hour daily, on days 1 to 5 of week 1 every 4 weeks (1 cycle). The results were consistent with the results of the controlled trial and summarized in Table 8.  Table 7 Baseline Demographics and Other Patient Demographic or Other Patient Characteristic Decitabine For InjectionN = 99Age (years)  Mean (±SD) 71±9Median (Range: min-max) 72 (34-87)Gender n (%)  Male 71 (72)Female 28 (28)Race n (%)  White 86 (87)Black 6 (6)Asian 4 (4)Other 3 (3)Days From MDS Diagnosis to First Dose Mean (±SD)444±626 Median (Range: min-max) 154 (7-3079)Previous MDS Therapy n (%)  Yes 27 (27)No 72 (73)RBC Transfusion Status n (%) Independent 33 (33)Dependent 66 (67)Platelet Transfusion Status n (%)  Independent 84 (85)Dependent 15 (15)IPSS Classification n (%)  Low Risk 1 (1)Intermediate–1 52 (53)Intermediate–223 (23)High Risk23 (23)FAB Classification n (%)  RA20 (20)RARS17 (17)RAEB45 (45)RAEB-t6 (6)CMML11 (11)Table 8 Analysis of Response (ITT)*Parameter Decitabine For Injection N=99Overall Response Rate (CR+PR) Complete Response (CR) Partial Response (PR) 16 (16%) 15 (15%) 1 (1%) Duration of Response Median time to (CR+PR) response - Days (range) Median Duration of (CR+PR) response - Days (range) 162 (50-267) 443 (72-722+)+ indicates censored observation* Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS. Blood. 2000; 96:3671-3674.

15 References

  • OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 How Supplied/Storage And Handling

Decitabine for injection is a white to almost white sterile lyophilized powder supplied as 50 mg single-dose vial individually packaged in a carton. NDC 16714-928-01Storage Store vials at 20° to 25°C (68° to 77°F); [See USP Controlled Room Temperature].

* Please review the disclaimer below.

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