Decitabine

Decitabine for Injection is indicated for treatment of adult patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. Decitabine for Injection is a nucleoside metabolic inhibitor indicated for treatment of adult patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate­-2, and high-risk International Prognostic Scoring System groups. (1)

For Injection: 50 mg of decitabine as a sterile, lyophilized white to off white powder in a single-dose vial for reconstitution with the supplied diluent. For Injection: 50 mg of decitabine as a lyophilized powder in a single-dose vial for reconstitution with the supplied diluent. (3)

None None

Neutropenia and Thrombocytopenia: Perform complete blood counts and platelet counts. (5.1) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception (5.2, 8.1, 8.3)

5.1 Myelosuppression Fatal and serious myelosuppression occurs in Decitabine for Injection-treated patients. Myelosuppression (anemia, neutropenia, and thrombocytopenia) is the most frequent cause of 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. Grade 3 or 4 febrile neutropenia occurred in 23% of patients. Thrombocytopenia of any grade occurred in 89% of patients with grade 3 or 4 occurring in 85% of patients. Anemia of any grade occurred in 82% of patients. Perform complete blood count with platelets at baseline, prior to each cycle, and as needed to monitor response and toxicity. Manage toxicity using dose-delay, dose-reduction, growth factors, and anti-infective therapies as needed [see Dosage and Administration (2.2)] . Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate progression of underlying MDS.

5.2 Embryo-Fetal Toxicity Based on findings from human data, animal studies and its mechanism of action, Decitabine for Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)] . In preclinical studies in mice and rats, decitabine caused adverse developmental outcomes including embryo-fetal lethality and malformations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception while receiving Decitabine for Injection and for 6 months following the last dose. Advise males with female partners of reproductive potential to use effective contraception while receiving treatment with Decitabine for Injection and for 3 months following the last dose [see Use in Specific Populations (8.1, 8.3)].

The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions (5.1)] Most common adverse reactions (> 50%) are neutropenia, thrombocytopenia, anemia, and pyrexia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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/m 2 intravenously every 8 hours for 3 days every 6 weeks. The median number of cycles was 3 (range 0 to 9). Most Common Adverse Reactions: neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia. Adverse Reactions Most Frequently (≥ 1%) Resulting in Clinical Intervention and or Dose Modification in the Controlled Supportive Care Study in the Decitabine Arm: Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardio-respiratory arrest, increased blood bilirubin, intracranial hemorrhage, abnormal liver function tests. Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile neutropenia. Dose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia, depression, pharyngitis. Table 1 presents all adverse reactions occurring in at least 5% of patients in the decitabine group and at a rate greater than supportive care. Table 1 Adverse Reactions Reported in ≥ 5% of Patients in the Decitabine Group and at a Rate Greater than Supportive Care in the Controlled Trial in MDS Decitabine N = 83 (%) Supportive Care N = 81 (%) Blood and lymphatic system disorders Neutropenia 75 (90) 58 (72) Thrombocytopenia 74 (89) 64 (79) Anemia NOS 68 (82) 60 (74) Febrile neutropenia 24 (29) 5 (6) Leukopenia NOS 23 (28) 11 (14) Lymphadenopathy 10 (12) 6 (7) Thrombocythemia 4 (5) 1 (1) Cardiac disorders Pulmonary edema NOS 5 (6) 0 (0) Eye disorders Vision blurred 5 (6) 0 (0) Gastrointestinal disorders Nausea 35 (42) 13 (16) Constipation 29 (35) 11 (14) Diarrhea NOS 28 (34) 13 (16) Vomiting NOS 21 (25) 7 (9) Abdominal pain NOS 12 (14) 5 (6) Oral mucosal petechiae 11 (13) 4 (5) Stomatitis 10 (12) 5 (6) Dyspepsia 10 (12) 1 (1) Ascites 8 (10) 2 (2) Gingival bleeding 7 (8) 5 (6) Hemorrhoids 7 (8) 3 (4) Loose stools 6 (7) 3 (4) Tongue ulceration 6 (7) 2 (2) Dysphagia 5 (6) 2 (2) Oral soft tissue disorder NOS 5 (6) 1 (1) Lip ulceration 4 (5) 3 (4) Abdominal distension 4 (5) 1 (1) Abdominal pain upper 4 (5) 1 (1) Gastro-esophageal reflux disease 4 (5) 0 (0) Glossodynia 4 (5) 0 (0) General disorders and administrative site disorders Pyrexia 44 (53) 23 (28) Edema peripheral 21 (25) 13 (16) Rigors 18 (22) 14 (17) Edema NOS 15 (18) 5 (6) Pain NOS 11 (13) 5 (6) Lethargy 10 (12) 3 (4) Tenderness NOS 9 (11) 0 (0) Fall 7 (8) 3 (4) Chest discomfort 6 (7) 3 (4) Intermittent pyrexia 5 (6) 3 (4) Malaise 4 (5) 1 (1) Crepitations NOS 4 (5) 1 (1) Catheter site erythema 4 (5) 1 (1) Catheter site pain 4 (5) 0 (0) Injection site swelling 4 (5) 0 (0) Hepatobiliary disorders Hyperbilirubinemia 12 (14) 4 (5) Infections and infestations Pneumonia NOS 18 (22) 11 (14) Cellulitis 10 (12) 6 (7) Candidal infection NOS 8 (10) 1 (1) Catheter related infection 7 (8) 0 (0) Urinary tract infection NOS 6 (7) 1 (1) Staphylococcal infection 6 (7) 0 (0) Oral candidiasis 5 (6) 2 (2) Sinusitis NOS 4 (5) 2 (2) Bacteremia 4 (5) 0 (0) Injury, poisoning and procedural complications Transfusion reaction 6 (7) 3 (4) Abrasion NOS 4 (5) 1 (1) Investigations Cardiac murmur NOS 13 (16) 9 (11) Blood alkaline phosphatase NOS increased 9 (11) 7 (9) Aspartate aminotransferase increased 8 (10) 7 (9) Blood urea increased 8 (10) 1 (1) Blood lactate dehydrogenase increased 7 (8) 5 (6) 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) Hypomagnesemia 20 (24) 6 (7) Hypokalemia 18 (22) 10 (12) Hyponatremia 16 (19) 13 (16) Appetite decreased NOS 13 (16) 12 (15) Anorexia 13 (16) 8 (10) Hyperkalemia 11 (13) 3 (4) Dehydration 5 (6) 4 (5) Musculoskeletal and connective tissue disorders Arthralgia 17 (20) 8 (10) Pain in limb 16 (19) 8 (10) Back pain 14 (17) 5 (6) Chest wall pain 6 (7) 1 (1) Musculoskeletal discomfort 5 (6) 0 (0) Myalgia 4 (5) 1 (1) Nervous system disorders Headache 23 (28) 11 (14) Dizziness 15 (18) 10 (12) Hypoesthesia 9 (11) 1 (1) Psychiatric disorders Insomnia 23 (28) 11 (14) Confusional state 10 (12) 3 (4) Anxiety 9 (11) 8 (10) Renal and urinary disorders Dysuria 5 (6) 3 (4) Urinary frequency 4 (5) 1 (1) Respiratory, thoracic and Mediastinal disorders Cough 33 (40) 25 (31) Pharyngitis 13 (16) 6 (7) Crackles lung 12 (14) 1 (1) Breath sounds decreased 8 (10) 7 (9) Hypoxia 8 (10) 4 (5) Rales 7 (8) 2 (2) Postnasal drip 4 (5) 2 (2) Skin and subcutaneous tissue disorders Ecchymosis 18 (22) 12 (15) Rash NOS 16 (19) 7 (9) Erythema 12 (14) 5 (6) Skin lesion NOS 9 (11) 3 (4) Pruritis 9 (11) 2 (2) Alopecia 7 (8) 1 (1) Urticaria NOS 5 (6) 1 (1) Swelling face 5 (6) 0 (0) Vascular disorders Petechiae 32 (39) 13 (16) Pallor 19 (23) 10 (12) Hypotension NOS 5 (6) 4 (5) Hematoma NOS 4 (5) 3 (4) In a single-arm MDS study (N=99) decitabine was dosed at 20 mg/m 2 intravenously, infused over one hour daily, for 5 consecutive days of a 4-week cycle. Table 2 presents all adverse reactions occurring in at least 5% of patients. […]

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.

Lactation: Advise not to breastfeed. (8.2)

8.1 Pregnancy Risk Summary Based on findings from human data, animal studies, and the mechanism of action, Decitabine for Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)] . Limited published data on decitabine use throughout the first trimester during pregnancy describe adverse developmental outcomes including major birth defects (structural abnormalities). In animal reproduction studies, administration of decitabine to pregnant mice and rats during organogenesis caused adverse developmental outcomes including malformations and embryo-fetal lethality starting at doses approximately 7% of the recommended human dose on a mg/m 2 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% to 4% and 15% to 20% of clinically recognized pregnancies, respectively. Data Human 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/m 2 , 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/m 2 and decreased fetal weight was observed at both dose levels. The 3 mg/m 2 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/m 2 (approximately 5%, 8%, or 13% the daily recommended clinical dose, respectively) on gestation days 9 to 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/m 2 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/m 2 . Increased incidence of foredigit defects was seen in fetuses at doses greater than 3.6 mg/m 2 . Reduced size and ossification of long bones of the fore-limb and hind-limb were noted at 6.0 mg/m 2 . The effect of decitabine on postnatal development and reproductive capacity was evaluated in mice administered a single 3 mg/m 2 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 of the potential for serious adverse reactions from decitabine in a breastfed child, advise women not to breastfeed while receiving Decitabine for Injection and for at least 2 weeks 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 for njection. ContraceptionI Females Decitabine for Injection can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception while receiving Decitabine for Injection 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 for Injection 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. The reversibility of the effect on fertility is unknown [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use The safety and effectiveness of Decitabine for Injection in pediatric patients have not been established.

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

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.