DACOGEN(tm) (DECITABINE) FOR INJECTION
Dacogen(tm) (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-b-D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one and it has the following structural formula:
NH2
N N
N O
2' H 1'
H
OH 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(tm) (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.
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.
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.
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.
The effects of renal or hepatic impairment, gender, age or race on the pharmacokinetics of decitabine have not been studied.
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.
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.
| Age (years) | N=89 | N=81 |
| Mean (+-SD) | 69+-10 | 67+-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+-131 | 77+-119 |
| Median (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 (%) | ||
| Independent | 69 (78) | 62 (77) |
| Dependent | 20 (22) | 19 (23) |
| IPSS Classification n (%) | ||
| Intermediate-1 | 28 (31) | 24 (30) |
| Intermediate-2 | 38 (43) | 36 (44) |
| High Risk | 23 (26) | 21 (26) |
54 Table 1 Baseline Demographics and Other Patient Characteristics (Cont'd)
| FAB Classification n (%) | N=89 | N=81 |
| 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 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:
| Response (CR) >= 8 weeks Partial | Marrow Peripheral | < 5% myeloblasts No dysplastic changes In all samples during response: |
| Blood Bone | Hgb > 11g/dL (no transfusions or erythropoietin) ANC >= 1500/mL (no growth factor) Platelets >= 100,000/mL (no thrombopoietic agent) No blasts and no dysplasia On repeat aspirates: | |
| Response (PR) >= 8 weeks * Cheson BD, Bennett JM | Marrow Peripheral | >= 50% decrease in blasts over pretreatment values OR Improvement to a less advanced MDS FAB classification Same as for CR |
| Blood , et al. Report of | an International Working Group to Standardize Response Criteria for M |
Complete
Bone
On repeat aspirates:
Blood
. 2000; 96:3671-3674.
DS.
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.
| Parameter Overall Response Rate (CR+PR) + | N=89 15 (17%) * * | N=81 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 | 93 (55-272) | NA | |
| Days (range) | |||
| Median Duration of (CR+PR) response | 288 (116-388) | NA | |
| Days (range) | |||
| * * p-value <0.001 from two-sided Fisher's Exact Test compari | ng Dacogen vs. Supportive | Care. | |
+
In the co-primary endpoint model, 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.
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).
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.
Dacogen is contraindicated in patients with a known hypersensitivity to decitabine.
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.
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.)
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.
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.
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.
No formal assessments of drug-drug interactions between decitabine and other agents have been conducted. (See CLINICAL PHARMACOLOGY.)
No formal carcinogenicity evaluation of decitabine has been performed.
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.
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.
The safety and effectiveness in pediatric patients have not been established.
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
not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
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.
MGI PHARMA, Inc. Approved Labeling
NDA: 21-790 Dacogen(tm) (decitabine) for Injection 5/2/2006
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
Supportive Care
| Blood and lymphatic system disorders | N = 83 (%) | N = 81 (%) |
| 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 |
MGI PHARMA, Inc. Approved Labeling
NDA: 21-790 Dacogen(tm) (decitabine) for Injection 5/2/2006
| Dacogen N = 83 (%) | Supportive Care N = 81 (%) | |
| 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) |
| Blood albumin decreased | 6 (7) | 0 (0) |
| 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) |
MGI PHARMA, Inc. Approved Labeling
NDA: 21-790 Dacogen(tm) (decitabine) for Injection 5/2/2006
| Dacogen N = 83 (%) | Supportive Care N = 81 (%) | |
| 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) |
MGI PHARMA, Inc. Approved Labeling
NDA: 21-790 Dacogen(tm) (decitabine) for Injection 5/2/2006
| Erythema | N = 83 (%) 12 (14) | N = 81 (%) 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) |
Supportive Care
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.
MGI PHARMA, Inc. Approved Labeling
NDA: 21-790 Dacogen(tm) (decitabine) for Injection 5/2/2006
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.
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.
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.
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.
If hematologic recovery (ANC >= 1,000/mL and platelets >= 50,000/mL) 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.
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.
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.
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.
Dacogen(tm) (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).
Store vials at 25degC (77degF); excursions permitted to 15-30degC (59-86degF).
Unless used within 15 minutes of reconstitution, the diluted solution must be prepared using cold (2degC - 8degC) infusion fluids and stored at 2degC - 8degC (36degF - 46degF) for up to a maximum of 7 hours until administration.
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.
| MGI PHARMA, Inc. | Approved Labeling | |
| 317 | NDA: 21-790 Dacogen(tm) (decitabine) for Injection REFERENCES | 5/2/2006 |
ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41.
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