MGI PHARMA, Inc.
`NDA: 21-790 Dacogen™ (decitabine) for Injection
`
`Approved Labeling
`5/2/2006
`
`DACOGEN™ (DECITABINE) FOR INJECTION
`
`DESCRIPTION
`Dacogen™ (decitabine) for Injection contains decitabine (5-aza-2’-deoxycytydine), 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:
`
`O
`
`23
`
`N
`
`NH2
`
`4
`
`V }->-
`
`N
`
`5 6
`
`O
`
`1
`N
`
`H
`
`2'
`
`1'
`
`HO
`
`5'
`
`4'
`
`H
`
`H
`
`3'
`OH
`
`H
`
`H
`
`Decitabine is slightly soluble in ethanol/water (50/50), methanol/water (50/50) and methanol; sparingly
`soluble in water and soluble in dimethylsulfoxide (DMSO).
`
`Dacogen™ (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.
`
`CLINICAL PHARMACOLOGY
`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.
`Pharmacokinetics
`No information is available on the pharmacokinetics of decitabine at the indicated dosage of 15 mg/m2.
`Patients with advanced solid tumors received a 72-hour infusion of decitabine at 20 to 30 mg/m2/day.
`1
`CELGENE 2138
`APOTEX v. CELGENE
`IPR2023-00512
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`

`

`Approved Labeling
`MGI PHARMA, Inc.
`5/2/2006
`NDA: 21-790 Dacogen™ (decitabine) for Injection
`
`Decitabine pharmacokinetics were characterized by a biphasic disposition. The total body clearance
`(mean ± SD) was 124 ± 19 L/hr/m2, and the terminal phase elimination half-life was 0.51 ± 0.31 hr.
`Plasma protein binding of decitabine is negligible (<1%).
`
`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.
`
`Special Populations
`The effects of renal or hepatic impairment, gender, age or race on the pharmacokinetics of decitabine
`have not been studied.
`
`Drug-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 the 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.
`
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`

`

`Approved Labeling
`5/2/2006
`
`
`MGI PHARMA, Inc.
`NDA: 21-790 Dacogen™ (decitabine) for Injection
`
`CLINICAL STUDIES
`Phase 3 Trial
`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 Dacogen therapy plus supportive care (only 83 received
`Dacogen), 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 Dacogen 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 1.
`
`Table 1
`
`Baseline Demographics and Other Patient Characteristics (ITT)
`
`41
`42
`43
`44
`45
`46
`47
`48
`49
`50
`51
`
`52
`
`Demographic or Other Patient Characteristic
`
`Age (years)
`Mean (±SD)
`Median (IQR)
`(Range: min-max)
`Gender n (%)
`Male
`Female
`Race n (%)
`White
`Black
`Other
`Weeks Since MDS Diagnosis
`Mean (±SD)
`Median (IQR)
`(Range: min-max)
`Previous MDS Therapy n (%)
`Yes
`No
`RBC Transfusion Status n (%)
`Independent
`Dependent
`Platelet Transfusion Status n (%)
`Independent
`Dependent
`IPSS Classification n (%)
`Intermediate–1
`Intermediate–2
`High Risk
`
`
`
`3
`
`Dacogen
`N=89
`
`69±10
`70 (65-76)
`(31-85)
`
`59 (66)
`30 (34)
`
`83 (93)
`4 (4)
`2 (2)
`
`86±131
`29 (10-87)
`(2-667)
`
`27 (30)
`62 (70)
`
`23 (26)
`66 (74)
`
`69 (78)
`20 (22)
`
`28 (31)
`38 (43)
`23 (26)
`
`Supportive Care
`N=81
`
`67±10
`70 (62-74)
`(30-82)
`
`57 (70)
`24 (30)
`
`76 (94)
`2 (2)
`3 (4)
`
`77±119
`35 (7-98)
`(2-865)
`
`19 (23)
`62 (77)
`
`27 (33)
`54 (67)
`
`62 (77)
`19 (23)
`
`24 (30)
`36 (44)
`21 (26)
`
`

`

`53
`54
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`60
`61
`62
`63
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`64
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`65
`66
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`Baseline Demographics and Other Patient Characteristics (Cont'd)
`
`Approved Labeling
`5/2/2006
`
`
`MGI PHARMA, Inc.
`NDA: 21-790 Dacogen™ (decitabine) for Injection
`
`
`Table 1
`
`Demographic or Other Patient Characteristic
`
`Dacogen
`N=89
`
`12 (13)
`7 (8)
`47 (53)
`17 (19)
`6 (7)
`
`Supportive Care
`N=81
`
`12 (15)
`4 (5)
`43 (53)
`14 (17)
`8 (10)
`
`FAB Classification n (%)
`RA
`RARS
`RAEB
`RAEB-t
`CMML
`
`
`Patients randomized to the Dacogen arm received Dacogen 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. Co-primary endpoints
`of the study 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 2:
`
`Table 2
`
`Response Criteria for Phase 3 Trial*
`
`Complete
`Response (CR)
`≥ 8 weeks
`
`Bone
`Marrow
`
`Peripheral
`Blood
`
`Partial
`Response (PR)
`≥ 8 weeks
`
`Bone
`Marrow
`
`On repeat aspirates:
`• < 5% myeloblasts
`• No dysplastic changes
`In all samples during response:
`• Hgb > 11g/dL (no transfusions or erythropoietin)
`• ANC ≥ 1500/μL (no growth factor)
`• Platelets ≥ 100,000/μL (no thrombopoietic agent)
`• No blasts and no dysplasia
`On repeat aspirates:
`• ≥ 50% decrease in blasts over pretreatment values
`OR
`• Improvement to a less advanced MDS FAB classification
`Same as for CR
`
`Peripheral
`Blood
`* Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS.
`Blood. 2000; 96:3671-3674.
`
`
`
`4
`
`

`

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`86
`87
`
`Approved Labeling
`
`MGI PHARMA, Inc.
`5/2/2006
`NDA: 21-790 Dacogen™ (decitabine) for Injection
`
`The overall response rate (CR+PR) in the ITT population was 17% in Dacogen-treated patients and 0%
`in the SC group (p<0.001). (See Table 3) The overall response rate was 21% (12/56) in Dacogen-
`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 Dacogen was 288 days (116-388) and median time to response (range)
`was 93 days (55-272). All but one of the Dacogen-treated patients who responded did so by the fourth
`cycle. Benefit was seen in an additional 13% of Dacogen-treated patients who had hematologic
`improvement, defined as a response less than PR lasting at least 8 weeks, compared to 7% of SC
`patients. Dacogen treatment did not significantly delay the median time to AML or death versus
`supportive care.
`
`Table 3
`
`Analysis of Response (ITT)
`
`Dacogen
`N=89
`15 (17%)**
`8 (9%)
`7 (8%)
`
`93 (55-272)
`
`
`
`Supportive Care
`N=81
`0 (0%)
`0 (0%)
`0 (0%)
`
`NA
`
`
`Parameter
`Overall Response Rate (CR+PR) †
`Complete Response (CR)
`Partial Response (PR)
`Duration of Response
`Median time to (CR+PR) response
`Days (range)
`Median Duration of (CR+PR) response
`Days (range)
` ** p-value <0.001 from two-sided Fisher’s Exact Test comparing Dacogen vs. Supportive Care.
`†In the co-primary endpoint model, a p-value of ≤ 0.024 was required to achieve statistical significance.
`
`288 (116-388)
`
`NA
`
`
`All patients with a CR or PR were RBC and platelet transfusion independent in the absence of growth
`factors.
`
`Responses occurred in patients with an adjudicated baseline diagnosis of AML.
`
`Phase 2 Studies
`Two additional open-label, single-arm, multicenter studies in Europe were conducted to evaluate the
`safety and efficacy of Dacogen in MDS patients with any of the FAB subtypes. Dacogen was
`intravenously infused at a dose of 15 mg/m2 over a 4-hour period, every 8 hours, on days 1, 2 and 3 of
`week 1 every 6 weeks (1 cycle). The results of the Phase 2 studies were consistent with the results of
`the Phase 3 trial with overall response rates of 26% (N=66) and 24% (N=98).
`
`
`
`5
`
`

`

`
`MGI PHARMA, Inc.
`NDA: 21-790 Dacogen™ (decitabine) for Injection
`
`INDICATIONS AND USAGE
`Dacogen is indicated for treatment of 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.
`
`Approved Labeling
`5/2/2006
`
`CONTRAINDICATIONS
`Dacogen is contraindicated in patients with a known hypersensitivity to decitabine.
`
`WARNINGS
`Pregnancy – Teratogenic effects: Pregnancy Category D
`Dacogen may cause fetal harm when administered to a pregnant woman. The developmental toxicity of
`decitabine was examined 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.
`
`There are no adequate and well-controlled studies in pregnant women using Dacogen. Women of
`childbearing potential should be advised to avoid becoming pregnant while receiving treatment with
`Dacogen. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this
`drug, the patient should be apprised of the potential hazard to the fetus.
`
`Use in Males
`Men should be advised not to father a child while receiving treatment with Dacogen. and for 2 months
`afterwards. (See PRECAUTIONS: Carcinogenesis, Mutagenesis, and Impairment of Fertility for
`discussion of pre-mating effects of decitabine exposure on male fertility and embryonic viability.)
`
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`Approved Labeling
`5/2/2006
`
`
`MGI PHARMA, Inc.
`NDA: 21-790 Dacogen™ (decitabine) for Injection
`
`PRECAUTIONS
`General
`Treatment with Dacogen is associated with neutropenia and thrombocytopenia. Complete blood and
`platelet counts should be performed as needed to monitor response and toxicity, but at a minimum, prior
`to each dosing cycle. After administration of the recommended dosage for the first cycle, dosage for
`subsequent cycles should be adjusted as described in DOSAGE AND ADMINISTRATION. Clinicians
`should consider the need for early institution of growth factors and/or antimicrobial agents for the
`prevention or treatment of infections in patients with MDS. Myelosuppression and worsening
`neutropenia may occur more frequently in the first or second treatment cycles, and may not necessarily
`indicate progression of underlying MDS.
`
`There are no data on the use of Dacogen in patients with renal or hepatic dysfunction; therefore,
`Dacogen should be used with caution in these patients. While metabolism is extensive, the cytochrome
`P450 system does not appear to be involved. In clinical trials, Dacogen was not administered to patients
`with serum creatinine > 2.0 mg/dL, transaminase greater than 2 times normal, or serum bilirubin > 1.5
`mg/dL.
`
`Information for Patients
`
`Patients should inform their physician about any underlying liver or kidney disease.
`
`Women of childbearing potential should be advised to avoid becoming pregnant while receiving
`treatment with Dacogen.
`
`Men should be advised not to father a child while receiving treatment with Dacogen, and for 2 months
`afterwards.
`
`
`Laboratory Tests
`
`
`Complete blood counts and platelet counts should be performed as needed to monitor response and
`toxicity, but at a minimum, prior to each cycle. Liver chemistries and serum creatinine should be
`obtained prior to initiation of treatment.
`
`Drug-Drug Interactions
`
`
`No formal assessments of drug-drug interactions between decitabine and other agents have been
`conducted. (See CLINICAL PHARMACOLOGY.)
`
`Carcinogenesis, Mutagenesis, and Impairment of Fertility
`
`
`No formal carcinogenicity evaluation of decitabine has been performed.
`
`
`
`7
`
`

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`
`
`MGI PHARMA, Inc.
`NDA: 21-790 Dacogen™ (decitabine) for Injection
`
`
`
`Approved Labeling
`5/2/2006
`
`The mutagenic potential of decitabine was tested in several in vitro and in vivo systems. Decitabine
`increased mutation frequency in L5178Y mouse lymphoma cells, and mutations were produced in an
`Escherichia coli lac-I transgene in colonic DNA of decitabine-treated mice. Decitabine caused
`chromosomal rearrangements in larvae of fruit flies.
`
`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). 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.
`
`
`Pregnancy
`
`Teratogenic Effects: Category D. See WARNINGS section
`
`Nursing Mothers:
`It is not known whether decitabine or its metabolites are excreted in human milk. Because many drugs
`are excreted in human milk, and because of the potential for serious adverse reactions from Dacogen in
`nursing infants, a decision should be made whether to discontinue the drug, taking into account the
`importance of the drug to the mother.
`
`
`
`Pediatric Use:
`
`The safety and effectiveness in pediatric patients have not been established.
`
`
`Geriatric Use:
`Of the total number of patients exposed to Dacogen in the phase 3 study, 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
`
`
`
`8
`
`

`

`193
`194
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`
`Approved Labeling
`
`MGI PHARMA, Inc.
`5/2/2006
`NDA: 21-790 Dacogen™ (decitabine) for Injection
`
`not identified differences in responses between the elderly and younger patients, but greater sensitivity
`of some older individuals cannot be ruled out.
`
`
`
`ADVERSE REACTIONS
`
`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 in the Phase 3 Trial
`in the Dacogen 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.
`
`
`
`Discussion of Adverse Reactions Information
`Dacogen was studied in 2 single-arm Phase 2 studies (N = 66, N = 98) and 1 controlled Phase 3
`(Supportive Care) study (N = 83 exposed to Dacogen). The data described below reflect exposure to
`Dacogen in 83 patients in the Phase 3 MDS trial. In the Phase 3 trial, patients received 15 mg/m2
`intravenously every 8 hours for 3 days every 6 weeks. The median number of Dacogen cycles was 3
`(range 0 to 9).
`
`
`Table 4 presents all adverse events regardless of causality occurring in at least 5% of patients in the
`Dacogen group and at a rate greater than supportive care.
`
`
`
`
`
`
`
`
`9
`
`

`

`Approved Labeling
`
`MGI PHARMA, Inc.
`5/2/2006
`NDA: 21-790 Dacogen™ (decitabine) for Injection
` Table 4 Adverse Events Reported in ≥5% of Patients in the Dacogen Group and at a Rate
`
`Greater than Supportive Care in Phase 3 MDS Trial
`
`223
`224
`
`
`
`Blood and lymphatic system disorders
` Neutropenia
` Thrombocytopenia
` Anemia NOS
` Febrile neutropenia
` Leukopenia NOS
` Lymphadenopathy
` Thrombocythemia
`Cardiac disorders
` Pulmonary edema NOS
`Eye disorders
` Vision blurred
`Gastrointestinal disorders
` Nausea
` Constipation
` Diarrhea NOS
` Vomiting NOS
` Abdominal pain NOS
` Oral mucosal petechiae
` Stomatitis
` Dyspepsia
` Ascites
` Gingival bleeding
` Hemorrhoids
` Loose stools
` Tongue ulceration
` Dysphagia
` Oral soft tissue disorder NOS
` Lip ulceration
` Abdominal distension
` Abdominal pain upper
` Gastro-esophageal reflux disease
` Glossodynia
`General disorders and administrative site
`disorders
`
`Dacogen
`N = 83 (%)
`
`75 (90)
`74 (89)
`68 (82)
`24 (29)
`23 (28)
`10 (12)
`4 (5)
`
`5 (6)
`
`5 (6)
`
`Supportive Care
`N = 81 (%)
`
`58 (72)
`64 (79)
`60 (74)
`5 (6)
`11 (14)
`6 (7)
`1 (1)
`
`0 (0)
`
`0 (0)
`
`
`
`
`
`35 (42)
`29 (35)
`28 (34)
`21 (25)
`12 (14)
`11 (13)
`10 (12)
`10 (12)
`8 (10)
`7 (8)
`7 (8)
`6 (7)
`6 (7)
`5 (6)
`5 (6)
`4 (5)
`4 (5)
`4 (5)
`4 (5)
`4 (5)
`
`
`13 (16)
`11 (14)
`13 (16)
`7 (9)
`5 (6)
`4 (5)
`5 (6)
`1 (1)
`2 (2)
`5 (6)
`3 (4)
`3 (4)
`2 (2)
`2 (2)
`1 (1)
`3 (4)
`1 (1)
`1 (1)
`0 (0)
`0 (0)
`
`
`
`
`10
`
`

`

`
`MGI PHARMA, Inc.
`NDA: 21-790 Dacogen™ (decitabine) for Injection
`
`
`Approved Labeling
`5/2/2006
`
`
`
` Pyrexia
` Edema peripheral
` Rigors
` Edema NOS
` Pain NOS
` Lethargy
` Tenderness NOS
` Fall
` Chest discomfort
` Intermittent pyrexia
` Malaise
` Crepitations NOS
` Catheter site erythema
` Catheter site pain
` Injection site swelling
`Hepatobiliary Disorders
` Hyperbilirubinemia
`Infections and Infestations
` Pneumonia NOS
` Cellulitis
` Candidal infection NOS
` Catheter related infection
` Urinary tract infection NOS
` Staphylococcal infection
` Oral candidiasis
` Sinusitis NOS
` Bacteremia
`Injury, poisoning and procedural complications
` Transfusion reaction
` Abrasion NOS
`Investigations
` Cardiac murmur NOS
` Blood alkaline phosphatase NOS increased
` Aspartate aminotransferase increased
` Blood urea increased
` Blood lactate dehydrogenase increased
` Blood albumin decreased
` Blood bicarbonate increased
` Blood chloride decreased
` Protein total decreased
` Blood bicarbonate decreased
` Blood bilirubin decreased
`Metabolism and nutrition disorders
` Hyperglycemia NOS
` Hypoalbuminemia
`
`
`
`Dacogen
`N = 83 (%)
`44 (53)
`21 (25)
`18 (22)
`15 (18)
`11 (13)
`10 (12)
`9 (11)
`7 (8)
`6 (7)
`5 (6)
`4 (5)
`4 (5)
`4 (5)
`4 (5)
`4 (5)
`
`12 (14)
`
`18 (22)
`10 (12)
`8 (10)
`7 (8)
`6 (7)
`6 (7)
`5 (6)
`4 (5)
`4 (5)
`
`6 (7)
`4 (5)
`
`13 (16)
`9 (11)
`8 (10)
`8 (10)
`7 (8)
`6 (7)
`5 (6)
`5 (6)
`4 (5)
`4 (5)
`4 (5)
`
`27 (33)
`20 (24)
`11
`
`Supportive Care
`N = 81 (%)
`23 (28)
`13 (16)
`14 (17)
`5 (6)
`5 (6)
`3 (4)
`0 (0)
`3 (4)
`3 (4)
`3 (4)
`1 (1)
`1 (1)
`1 (1)
`0 (0)
`0 (0)
`
`4 (5)
`
`11 (14)
`6 (7)
`1 (1)
`0 (0)
`1 (1)
`0 (0)
`2 (2)
`2 (2)
`0 (0)
`
`3 (4)
`1 (1)
`
`9 (11)
`7 (9)
`7 (9)
`1 (1)
`5 (6)
`0 (0)
`1 (1)
`1 (1)
`3 (4)
`1 (1)
`1 (1)
`
`16 (20)
`14 (17)
`
`

`

`
`MGI PHARMA, Inc.
`NDA: 21-790 Dacogen™ (decitabine) for Injection
`
`
`Approved Labeling
`5/2/2006
`
`
`
` Hypomagnesemia
` Hypokalemia
` Hyponatremia
` Appetite decreased NOS
` Anorexia
` Hyperkalemia
` Dehydration
`Musculoskeletal and connective tissue disorders
` Arthralgia
` Pain in limb
` Back pain
` Chest wall pain
` Musculoskeletal discomfort
` Myalgia
`Nervous system disorders
` Headache
` Dizziness
` Hypoesthesia
`Psychiatric disorders
` Insomnia
` Confusional state
` Anxiety
`Renal and urinary disorders
` Dysuria
` Urinary frequency
`Respiratory, thoracic and mediastinal disorders
` Cough
` Pharyngitis
` Crackles lung
` Breath sounds decreased
` Hypoxia
` Rales
` Postnasal drip
`Skin and subcutaneous tissue disorders
` Ecchymosis
` Rash NOS
`
`
`
`Dacogen
`N = 83 (%)
`20 (24)
`18 (22)
`16 (19)
`13 (16)
`13 (16)
`11 (13)
`5 (6)
`
`17 (20)
`16 (19)
`14 (17)
`6 (7)
`5 (6)
`4 (5)
`
`23 (28)
`15 (18)
`9 (11)
`
`23 (28)
`10 (12)
`9 (11)
`
`5 (6)
`4 (5)
`
`33 (40)
`13 (16)
`12 (14)
`8 (10)
`8 (10)
`7 (8)
`4 (5)
`
`18 (22)
`16 (19)
`12
`
`Supportive Care
`N = 81 (%)
`6 (7)
`10 (12)
`13 (16)
`12 (15)
`8 (10)
`3 (4)
`4 (5)
`
`8 (10)
`8 (10)
`5 (6)
`1 (1)
`0 (0)
`1 (1)
`
`11 (14)
`10 (12)
`1 (1)
`
`11 (14)
`3 (4)
`8 (10)
`
`3 (4)
`1 (1)
`
`25 (31)
`6 (7)
`1 (1)
`7 (9)
`4 (5)
`2 (2)
`2 (2)
`
`12 (15)
`7 (9)
`
`

`

`Approved Labeling
`5/2/2006
`Supportive Care
`N = 81 (%)
`5 (6)
`3 (4)
`2 (2)
`1 (1)
`1 (1)
`0 (0)
`
`13 (16)
`10 (12)
`4 (5)
`3 (4)
`
`
`MGI PHARMA, Inc.
`NDA: 21-790 Dacogen™ (decitabine) for Injection
`
`
`Dacogen
`N = 83 (%)
`12 (14)
`9 (11)
`9 (11)
`7 (8)
`5 (6)
`5 (6)
`
`32 (39)
`19 (23)
`5 (6)
`4 (5)
`
` Erythema
` Skin lesion NOS
` Pruritis
` Alopecia
` Urticaria NOS
` Swelling face
`Vascular disorders
` Petechiae
` Pallor
` Hypotension NOS
` Hematoma NOS
`
`
`Discussion of Clinically Important Adverse Reactions:
` In the Phase 3 trial, the highest incidence of Grade 3 or Grade 4 adverse events in the Dacogen arm
`were neutropenia (87%), thrombocytopenia (85%), febrile neutropenia (23%) and leukopenia (22%).
`Bone marrow suppression was the most frequent cause of dose reduction, delay and discontinuation.
`Six patients had fatal events associated with their underlying disease and myelosuppression (anemia,
`neutropenia, and thrombocytopenia) that were considered at least possibly related to drug treatment.
`(See PRECAUTIONS). Of the 83 Dacogen-treated patients, 8 permanently discontinued therapy for
`adverse events; compared to 1 of 81 patients in the supportive care arm.
`
`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 Events that occurred in patients receiving Dacogen regardless of causality, not
`previously reported in Table 4 include:
`
`Blood and Lymphatic System Disorders: myelosuppression, splenomegaly.
`
`Cardiac Disorders: myocardial infarction, congestive cardiac failure, cardio-respiratory arrest,
`cardiomyopathy, atrial fibrillation, supraventricular tachycardia.
`
`Gastrointestinal Disorders: gingival pain, upper gastrointestinal hemorrhage.
`
`General Disorders and Administrative Site Conditions: chest pain, asthenia, mucosal inflammation,
`catheter site hemorrhage.
`
`Hepatobiliary Disorders: cholecystitis.
`
`
`
`13
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`226
`227
`228
`229
`230
`231
`232
`233
`234
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`236
`237
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`239
`240
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`241
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`242
`243
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`244
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`245
`246
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`247
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`250
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`253
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`254
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`255
`256
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`257
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`259
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`260
`261
`262
`263
`264
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`265
`266
`267
`268
`269
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`270
`271
`272
`273
`
`274
`275
`276
`277
`
`278
`279
`280
`
`Approved Labeling
`
`MGI PHARMA, Inc.
`5/2/2006
`NDA: 21-790 Dacogen™ (decitabine) for Injection
`
`Infections and Infestations: fungal infection, sepsis, upper respiratory tract infection, 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: dyspnea, hemoptysis, lung infiltration, pulmonary
`embolism, respiratory arrest, pulmonary mass.
`
`Allergic Reaction: Hypersensitivity (anaphylactic reaction) to Dacogen has been reported in a Phase 2
`trial.
`
`
`
`
`OVERDOSAGE
`There is no known antidote for overdosage with Dacogen. Higher doses are associated with increased
`myelosuppression including prolonged neutropenia and thrombocytopenia. Standard supportive
`measures should be taken in the event of an overdose.
`
`DOSAGE AND ADMINISTRATION
`First Treatment Cycle
`The recommended Dacogen dose is 15 mg/m2 administered by continuous intravenous infusion over 3
`hours repeated every 8 hours for 3 days. Patients may be premedicated with standard anti-emetic
`therapy.
`
`Subsequent Treatment Cycles
`The above cycle should be repeated every 6 weeks. It is recommended that patients be treated for a
`minimum of 4 cycles; however, a complete or partial response may take longer than 4 cycles. Treatment
`may be continued as long as the patient continues to benefit.
`
`Dose Adjustment or Delay Based on Hematology Laboratory Values
`If hematologic recovery (ANC ≥ 1,000/μL and platelets ≥ 50,000/μL) from a previous Dacogen
`treatment cycle requires more than 6 weeks, then the next cycle of Dacogen therapy should be delayed
`and dosing temporarily reduced by following this algorithm:
`
`• Recovery requiring more than 6, but less than 8 weeks - Dacogen dosing to be delayed for up to
`2 weeks and the dose temporarily reduced to 11 mg/m2 every 8 hours (33 mg/m2/day, 99
`mg/m2/cycle) upon restarting therapy.
`
`
`
`14
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`
`MGI PHARMA, Inc.
`NDA: 21-790 Dacogen™ (decitabine) for Injection
`
`
`Approved Labeling
`5/2/2006
`
`• Recovery requiring more than 8, but less than 10 weeks - Patient should be assessed for disease
`progression (by bone marrow aspirates); in the absence of progression, the Dacogen dose should
`be delayed up to 2 more weeks and the dose reduced to 11 mg/m2 every 8 hours (33 mg/m2/day,
`99 mg/m2/cycle) upon restarting therapy, then maintained or increased in subsequent cycles as
`clinically indicated.
`
`
`If any of the following non-hematologic toxicities are present, Dacogen treatment should not be
`restarted until the toxicity is resolved: 1) serum creatinine ≥ 2 mg/dL; 2) SGPT, total bilirubin ≥ 2 times
`ULN; and 3) active or uncontrolled infection.
`
`Use in Geriatric Patients
`Geriatric patients were generally dosed at the same level as younger adult patients. Dose adjustments
`for toxicity should be conducted as specified for the general population.
`
`Preparation of Dacogen
`Dacogen is a cytotoxic drug and, as with other potentially toxic compounds, caution should be exercised
`when handling and preparing Dacogen. Please refer to Handling and Disposal section.
`
`Dacogen should be aseptically reconstituted with 10 mL of Sterile Water for Injection (USP); upon
`reconstitution, each mL contains approximately 5.0 mg of decitabine at pH 6.7-7.3. Immediately after
`reconstitution, the solution should be further diluted with 0.9% Sodium Chloride Injection, 5% Dextrose
`Injection, or Lactated Ringer’s Injection to a final drug concentration of 0.1 - 1.0 mg/mL. Unless used
`within 15 minutes of reconstitution, the diluted solution must be prepared using cold (2˚C - 8˚C)
`infusion fluids and stored at 2˚C - 8˚C (36˚F 46˚F) for up to a maximum of 7 hours until administration.
`
`HOW SUPPLIED
`Dacogen™ (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. (NDC 58063-
`600-50).
`
`Storage
`Store vials at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
`
`Stability
`
`
`Unless used within 15 minutes of reconstitution, the diluted solution must be prepared using cold (2°C -
`8°C) infusion fluids and stored at 2°C - 8°C (36°F - 46°F) for up to a maximum of 7 hours until
`administration.
`
`Handling and Disposal
`Procedures for proper handling and disposal of antineoplastic drugs should be applied. Several
`guidances on this subject have been published.1-8 There is no general agreement that all of the
`procedures recommended in the guidelines are necessary or appropriate.
`
`15