NDC 69539-115 Decitabine

Decitabine

NDC Product Code 69539-115

NDC 69539-115-01

Package Description: 1 VIAL, SINGLE-USE in 1 CARTON > 20 mL in 1 VIAL, SINGLE-USE

NDC Product Information

Decitabine with NDC 69539-115 is a a human prescription drug product labeled by Msn Laboratories Private Limited. 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: Msn Laboratories Private Limited

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.

Product Type: Human Prescription Drug What kind of product is this?
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)

What is the Active Ingredient(s) List?
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)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • POTASSIUM PHOSPHATE, MONOBASIC (UNII: 4J9FJ0HL51)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)
  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

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

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

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

Product Labeler Information

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Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Msn Laboratories Private Limited
Labeler Code: 69539
FDA Application Number: ANDA212265 What 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. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 08-28-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What 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 What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

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/μL and platelets at least 50,000/μL) for a minimum of 4 cycles. . A complete or partial response may take longer than 4 cycles. Delay and reduce dose for hematologic toxicity (see Dose Modifications for Toxicity). Five Day Regimen Administer decitabine for injection at a dose of 20 mg/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 4 weeks upon hematologic recovery (ANC at least 1,000/μL and platelets at least 50,000/μL) for a minimum of 4 cycles. A complete or partial response may take longer than 4 cycles.

2.2 Dose Modifications For Toxicity

Hematologic Toxicity If hematologic recovery from a previous decitabine for injection treatment cycle requires more than 6 weeks, delay the next cycle of decitabine for injection therapy and reduce decitabine for injection dose temporarily by following this algorithm: • Recovery requiring more than 6, but less than 8 weeks – delay decitabine for injection dosing for up to 2 weeks and reduce the dose temporarily to 11 mg/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 Toxicity Delay subsequent decitabine for injection treatment for any the following non-hematologic toxicities and do not restart until toxicities resolve: • Serum creatinine greater than or equal to 2 mg/dL • SGPT, total bilirubin greater than or equal to 2 times ULN • Active or uncontrolled infection

2.3 Instructions For Intravenous Administration

Decitabine 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 Preparation If decitabine for injection is intended to be administered within 15 minutes from the time of preparation, dilute the reconstituted solution with room temperature (20°C - 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 Administration If decitabine for injection is intended to be administered after 15 minutes of preparation, dilute the reconstituted solution with cold (2°C - 8°C) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 0.1 mg/mL- 1 mg/mL. Store at 2°C - 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, white to almost white lyophilized cake or 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-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 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 [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

Decitabine can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, decitabine alters DNA synthesis and is expected to result in adverse reproductive effects [see Clinical 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 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, and for 3 months following the last dose, Counsel patients of childbearing potential to use effective contraception during this time [see Use 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 was studied in 3 single-arm studies (N = 66, N = 98, N = 99) and 1 controlled supportive care study (N = 83 decitabine, N = 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 8 hours for 3 days every 6 weeks. The median number of decitabine 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 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 group and at a rate greater than supportive care.

Other

Table 1 Adverse Reactions Reported in ≥ 5% of Patients in the Decitabine Group and at a Rate Greater than Supportive Care in Phase 3 MDS Trial DecitabineN = 83 (%)Supportive CareN = 81 (%)Blood and lymphatic system disordersNeutropenia75 (90)58 (72)Thrombocytopenia74 (89)64 (79)Anemia NOS68 (82)60 (74)Febrile neutropenia24 (29)5 (6)Leukopenia NOS23 (28)11 (14)Lymphadenopathy10 (12)6 (7)Thrombocythemia4 (5)1 (1)Cardiac disordersPulmonary edema NOS5 (6)0 (0)Eye disordersVision blurred5 (6)0 (0)Gastrointestinal disordersNausea35 (42)13 (16)Constipation29 (35)11 (14)Diarrhea NOS28 (34)13 (16)Vomiting NOS21 (25)7 (9)Abdominal pain NOS12 (14)5 (6)Oral mucosal petechiae11 (13)4 (5)Stomatitis10 (12)5 (6)Dyspepsia10 (12)1 (1)Ascites8 (10)2 (2)Gingival bleeding7 (8)5 (6)Hemorrhoids7 (8)3 (4)Loose stools6 (7)3 (4)Tongue ulceration6 (7)2 (2)Dysphagia5 (6)2 (2)Oral soft tissue disorder NOS5 (6)1 (1)Lip ulceration4 (5)3 (4)Abdominal distension4 (5)1 (1)Abdominal pain upper4 (5)1 (1)Gastro-esophageal reflux disease4 (5)0 (0)Glossodynia4 (5)0 (0)General disorders and administrative site disordersPyrexia44 (53)23 (28)Edema peripheral21 (25)13 (16)Rigors18 (22)14 (17)Edema NOS15 (18)5 (6)Pain NOS11 (13)5 (6)Lethargy10 (12)3 (4)Tenderness NOS9 (11)0 (0)Fall7 (8)3 (4)Chest discomfort6 (7)3 (4)Intermittent pyrexia5 (6)3 (4)Malaise4 (5)1 (1)Crepitations NOS4 (5)1 (1)Catheter site erythema4 (5)1 (1)Catheter site pain4 (5)0 (0)Injection site swelling4 (5)0 (0)Hepatobiliary disordersHyperbilirubinemia12 (14)4 (5)Infections and infestationsPneumonia NOS18 (22)11 (14)Cellulitis10 (12)6 (7)Candidal infection NOS8 (10)1 (1)Catheter related infection7 (8)0 (0)Urinary tract infection NOS6 (7)1 (1)Staphylococcal infection6 (7)0 (0)Oral candidiasis5 (6)2 (2)Sinusitis NOS4 (5)2 (2)Bacteremia4 (5)0 (0)Injury, poisoning and procedural complicationsTransfusion reaction6 (7)3 (4)Abrasion NOS4 (5)1 (1)InvestigationsCardiac murmur NOS13 (16)9 (11)Blood alkaline phosphatase NOS  increased9 (11)7 (9)Aspartate aminotransferase increased8 (10)7 (9)Blood urea increased8 (10)1 (1)Blood lactate dehydrogenase increased7 (8)5 (6)Blood albumin decreased6 (7)0 (0)Blood bicarbonate increased5 (6)1 (1)Blood chloride decreased5 (6)1 (1)Protein total decreased4 (5)3 (4)Blood bicarbonate decreased4 (5)1 (1)Blood bilirubin decreased4 (5)1 (1)Metabolism and nutrition disordersHyperglycemia NOS27 (33)16 (20)Hypoalbuminemia20 (24)14 (17)Hypomagnesemia20 (24)6 (7)Hypokalemia18 (22)10 (12)Hyponatremia16 (19)13 (16)Appetite decreased NOS13 (16)12 (15)Anorexia13 (16)8 (10)Hyperkalemia11 (13)3 (4)Dehydration5 (6)4 (5)Musculoskeletal and connective tissue disordersArthralgia17 (20)8 (10)Pain in limb16 (19)8 (10)Back pain14 (17)5 (6)Chest wall pain6 (7)1 (1)Musculoskeletal discomfort5 (6)0 (0)Myalgia4 (5)1 (1)Nervous system disordersHeadache23 (28)11 (14)Dizziness15 (18)10 (12)Hypoesthesia9 (11)1 (1)Psychiatric disordersInsomnia23 (28)11 (14)Confusional state10 (12)3 (4)Anxiety9 (11)8 (10)Renal and urinary disordersDysuria5 (6)3 (4)Urinary frequency4 (5)1 (1)Respiratory, thoracic and Mediastinal disordersCough33 (40)25 (31)Pharyngitis13 (16)6 (7)Crackles lung12 (14)1 (1)Breath sounds decreased8 (10)7 (9)Hypoxia8 (10)4 (5)Rales7 (8)2 (2)Postnasal drip4 (5)2 (2)Skin and subcutaneous tissue disordersEcchymosis18 (22)12 (15)Rash NOS16 (19)7 (9)Erythema12 (14)5 (6)Skin lesion NOS9 (11)3 (4)Pruritis9 (11)2 (2)Alopecia7 (8)1 (1)Urticaria NOS5 (6)1 (1)Swelling face5 (6)0 (0)Vascular disordersPetechiae32 (39)13 (16)Pallor19 (23)10 (12)Hypotension NOS5 (6)4 (5)Hematoma NOS4 (5)3 (4)

In a single-arm MDS study (N=99) decitabine 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 events regardless of causality occurring in at least 5% of patients.

Table 2 Adverse Reactions Reported in ≥ 5% of Patients in a Single-arm Study1 DecitabineN = 99 (%)Blood and lymphatic system disordersAnemia31 (31%)Febrile neutropenia20 (20%)Leukopenia6 (6% )Neutropenia38 (38% )Pancytopenia5 (5% )Thrombocythemia5 (5% )Thrombocytopenia27 (27%)Cardiac disordersCardiac failure congestive5 (5% )Tachycardia8 (8% )Ear and labyrinth disordersEar pain6 (6% )Gastrointestinal disordersAbdominal 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 conditionsAsthenia15 (15%)Chest pain6 (6% )Chills16 (16%)Fatigue46 (46%)Mucosal inflammation9 (9% )Edema5 (5% )Edema peripheral27 (27%)Pain5 (5% )Pyrexia36 (36%)Infections and infestationsCellulitis9 (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 complicationsContusion9 (9% )InvestigationsBlood bilirubin increased6 (6% )Breath sounds abnormal5 (5% )Weight decreased9 (9% )Metabolism and nutrition disordersAnorexia23 (23%)Decreased appetite8 (8% )Dehydration8 (8% )Hyperglycemia6 (6% )Hypokalemia12 (12%)Hypomagnesemia5 (5% )Musculoskeletal and connective tissue disordersArthralgia17 (17%)Back pain18 (18%)Bone pain6 (6% )Muscle spasms7 (7% )Muscular weakness5 (5% )Musculoskeletal pain5 (5% )Myalgia9 (9% )Pain in extremity18 (18%)Nervous system disordersDizziness21 (21%)Headache23 (23%)Psychiatric disordersAnxiety9 (9% )Confusional state8 (8% )Depression9 (9% )Insomnia14 (14%)Respiratory, thoracic and mediastinal disordersCough27 (27%)Dyspnea29 (29%)Epistaxis13 (13%)Pharyngolaryngeal pain8 (8% )Pleural effusion5 (5% )Sinus congestion5 (5% )Skin and subcutaneous tissue disordersDry skin8 (8% )Ecchymosis9 (9% )Erythema5 (5% )Night sweats5 (5% )Petechiae12 (12%)Pruritus9 (9% )Rash11 (11%)Skin lesion5 (5% )Vascular disordersHypertension6 (6% )Hypotension11 (11%)1. 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 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 has been reported in a Phase 2 trial.

Decitabine is soluble in dimethyl sulfoxide; sparingly soluble in water; slightly soluble in ethanol and water (50:50), in methanol and water (50:50), and in methanol. Decitabine for Injection is a sterile white to almost white lyophilized cake or 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.

Table 3 Mean (CV% or 95% CI) Pharmacokinetic Parameters of DecitabineDoseCmax(ng/mL)AUC0-∞(ng·h/mL)T1/2(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 in patients with renal impairment; therefore, if decitabine is administered to these patients, monitor them frequently for excessive toxicity.Patients with Hepatic Impairment There are no data on the use of decitabine in patients with hepatic impairment; therefore, if decitabine is administered to these patients, monitor them frequently for excessive toxicity.

  • Table 5 Response Criteria for Phase 3 MDS Trial*Complete Response (CR) ≥ 8 weeksBone MarrowOn repeat aspirates:<5% myeloblastsNo dysplastic changesPeripheral BloodIn all samples during response:Hgb >11 g/dL (no transfusions or erythropoietinANC ≥1500/μL (no growth factor)Platelets ≥100,000/μL (no thrombopoietic agent)No blasts and no dysplasiaPartial Response (PR) ≥ 8 weeksBone MarrowOn repeat aspirates:≥ 50% decrease in blasts over pretreatment values             ORImprovement to a less advanced MDS FAB classificationPeripheral BloodSame 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-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 2 cycles of treatment). The median duration of response (range) for patients who responded to decitabine was 288 days (116-388) and median time to response (range) was 93 days (55-272). 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 a response less than PR lasting at least 8 weeks, compared to 7% of SC patients. Decitabine treatment did not significantly delay the median time to AML or death versus supportive care.Table 6 Analysis of Response (ITT)ParameterDecitabine N=89Supportive Care         N=81Overall Response Rate (CR+PR)†15 (17%)**0 (0%)Complete Response (CR)8 (9%)0 (0%)Partial Response (PR)7 (8%)0 (0%)Duration of Response  Median time to (CR+PR) response - Days (range)93 (55-272)NAMedian Duration of (CR+PR) response - Days (range)288 (116-388)NA

**p-value <0.001 from two-sided Fisher's Exact Test comparing Decitabine 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.

Advise women of childbearing potential to avoid pregnancy and to use effective contraception while receiving decitabine and for 6 months after last dose [See Warnings and Precautions (5.2)]. Advise men  not to father a child while receiving treatment with decitabine, and for 3 months after the last dose.  Advise men with female partners of childbearing potential to use effective contraception [see Warnings and Precautions (5.2) and Nonclinical Toxicology (13.1)]. Advise patients to avoid breastfeeding while receiving decitabine and for at 1 week after the last dose [see Use in Specific Populations (8.2)]. Advise patients of the risk of myelosuppression and to report any symptoms of infection, anemia, or bleeding to their healthcare provider as soon as possible. Advise patients for the need for laboratory monitoring [see Warnings and Precautions (5.1)].Manufactured by:MSN Laboratories Private Limited Telangana – 509 216, INDIADistributed by:MSN Pharmaceuticals Inc. Piscataway, NJ 08854 -3714 Issued on: 07/2019

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of decitabine. 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 Summary Based on findings from human data, animal studies, and the mechanism of action, decitabine can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. 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 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 Data A single published case report of decitabine pregnancy exposure in a 39-year old woman with a hematologic malignancy described multiple structural abnormalities after 6 cycles of therapy in the 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 Data In utero exposure to decitabine causes temporal related defects in the rat and/or mouse, which include growth suppression, exencephaly, defective skull bones, rib/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 Summary There are no data on the presence of decitabine or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from decitabine in a nursing child, advise lactating women to avoid breastfeeding during treatment with decitabine and for at least 1 week after the last dose.

8.3 Females And Males Of Reproductive Potential

Pregnancy Testing Conduct pregnancy testing of females of reproductive potential prior to initiating decitabine.ContraceptionFemales Advise females of reproductive potential to avoid pregnancy and use effective contraception while receiving decitabine and for 6 months following the last dose. Males Advise males with female partners of reproductive potential to use effective contraception while receiving treatment with decitabine and for 3 months following the last dose. [see Nonclinical Toxicology (13.1)].Infertility Based on findings of decitabine in animals, male fertility may be compromised by treatment with decitabine [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 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. 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 fine, white to almost white 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:

12.1 Mechanism Of Action

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

Pharmacokinetic parameters were evaluated in patients. Eleven patients received 20 mg/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.

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 invivo systems. Decitabine increased mutation frequency in L5178Y mouse lymphoma cells, and mutations were produced in an Escherichia coli lac-I transgene in colonic DNA of decitabine-treated mice. Decitabine caused chromosomal rearrangements in larvae of fruit flies. In male mice given IP injections of 0.15, 0.3 or 0.45 mg/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. 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 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 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)Demographics and Other Patient CharacteristicDecitabineN = 89Supportive CareN = 81Age (years)  Mean (±SD)69±1067±10 Median (IQR)70 (65-76)70 (62-74) (Range: min-max)(31-85)(30-82)Gender n (%)  Male59 (66)57 (70) Female30 (34)24 (30)Race n (%)  White83 (93)76 (94) Black4 (4)2 (2) Other2 (2)3 (4)Weeks Since MDS Diagnosis  Mean (±SD)86±13177±119 Median (IQR)29 (10-87)35 (7-98) (Range: min-max)(2-667)(2-865)Previous MDS Therapy n (%)  Yes27 (30)19 (23) No62 (70)62 (77)RBC Transfusion Status n (%)  Independent23 (26)27 (33) Dependent66 (74)54 (67)Platelet Transfusion Status n (%)  Independent69 (78)62 (77) Dependent20 (22)19 (23)IPSS Classification n (%)  Intermediate-128 (31)24 (30) Intermediate-238 (43)36 (44) High Risk23 (26)21 (26)FAB Classification n (%)  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 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:

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 by intravenous infusion at a dose of 20 mg/m2 IV over 1-hour daily, on days 1-5 of week 1 every 4 weeks (1 cycle). The results were consistent with the results of the controlled trial and summarized in Table 8Table 7 Baseline Demographics and Other Patient Characteristics (ITT)Demographic or Other Patient CharacteristicDecitabine N = 99Age (years) Mean (±SD)71±9Median (Range:  min-max)72 (34-87)Gender n (%) Male71 (72)Female28 (28)Race n (%) White86 (87)Black6  (6)Asian4  (4)Other3  (3)Days From MDS Diagnosis to First Dose Mean (±SD)444±626Median (Range:  min-max)154 (7-3079)Previous MDS Therapy n (%) Yes27 (27)No72 (73)RBC Transfusion Status n (%) Independent33 (33)Dependent66 (67)Platelet Transfusion Status n (%) Independent84 (85)Dependent15 (15)IPSS Classification n (%) Low Risk1  (1)Intermediate–152 (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)*ParameterDecitabine N=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 (50-267)                 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 50 mg is White to almost white Lyophilized cake or powder in 20 mL Type-I clear glass vial with 20 mm igloo grey rubber stopper and sealed with 20 mm aluminum seal having blue color polypropylene disc. NDC 69539-115-01, 50 mg single-dose vial individually packaged in a carton. Storage Store vials at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F). [See USP Controlled Room Temperature.]

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