Decitabine

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. 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 )

2 DOSAGE AND ADMINISTRATION Three Day Regimen: Administer decitabine for injection at a dose of 15 mg/m 2 by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days. Repeat cycle every 6 weeks. ( 2.1 ) Five Day Regimen: Administer decitabine for injection at a dose of 20 mg/m 2 by continuous intravenous infusion over 1 hour repeated daily for 5 days. Repeat cycle every 4 weeks. (2.1 ) 2.1 Recommended Dosage Pre-Medications and Baseline Testing • Consider pre-medicating for nausea with antiemetics. • Conduct baseline laboratory testing: complete blood count (CBC) with platelets, serum hepatic panel, and serum creatinine. Decitabine for Injection Regimen Options Three Day Regimen Administer decitabine for injection at a dose of 15 mg/m 2 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 Dosage and Administration (2.2)]. Five Day Regimen Administer decitabine for injection at a dose of 20 mg/m 2 by continuous intravenous infusion over 1 hour daily for 5 days. Delay and reduce dose for hematologic toxicity [ see Dosage and Administration (2.2)]. 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. Patients with Renal or Severe Hepatic Impairment Treatment with decitabine for injection has not been studied in patients with pre-existing renal or hepatic impairment. For patients with pre-existing renal or hepatic impairment, consider the potential risks and benefits before initiating treatment with decitabine for injection. 2.2 Dosage Modifications for Adverse Reactions 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/m 2 every 8 hours (33 mg/m 2 /day, 99 mg/m 2 /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 decitabine for injection dosing for up to 2 more weeks and reduce the dose to 11 mg/m 2 every 8 hours (33 mg/m 2 /day, 99 mg/m 2 /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 nonhematologic toxicities and do not restart until toxicities resolve: • Serum creatinine greater than or equal to 2 mg/dL • Alanine transaminase (ALT), total bilirubin greater than or equal to 2 times upper limit of normal (ULN) • Active or uncontrolled infection 2.3 Preparation and Administration Decitabine for injection is a cytotoxic drug. Follow special handling and disposal procedures. 1 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 prep…

5 WARNINGS AND PRECAUTIONS 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-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. 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 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 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 and for 3 months following the last dose [ see Use in Specific Populations (8.1, 8.3 )].

4 CONTRAINDICATIONS None. None.

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) 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 9-12, 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 expose…

8.3 Females and Males of Reproductive Potential Pregnancy Testing Conduct pregnancy testing of females of reproductive potential prior to initiating decitabine. Contraception Females Decitabine 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 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. The reversibility of the effect on fertility is unknown [ see Nonclinical Toxicology (13.1) ].

6 ADVERSE REACTIONS 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 Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trails 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 decitabine 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) Inj…