OVERDOSAGE SECTION.

10 OVERDOSAGE. One case of overdose with VIDAZA was reported during clinical trials. patient experienced diarrhea, nausea, and vomiting after receiving single intravenous dose of approximately 290 mg/m2, almost times the recommended starting dose. The events resolved without sequelae, and the correct dose was resumed the following day. In the event of overdosage, the patient should be monitored with appropriate blood counts and should receive supportive treatment, as necessary. There is no known specific antidote for VIDAZA overdosage.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package Label Principal Display Panel 100 mg Vial Label. Principal Display Panel 100 mg Vial Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. VIDAZA (azacitidine for injection) is supplied as lyophilized powder in 100 mg single-dose vials.. Lyophilized powder in 100 mg single-dose vials (3).. Lyophilized powder in 100 mg single-dose vials (3).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are described in other labeling sections:Anemia, Neutropenia and Thrombocytopenia [see Warnings and Precautions (5.1)] Hepatotoxicity in Patients with Severe Pre-existing Hepatic Impairment [see Warnings and Precautions (5.2)] Renal Toxicity [see Warnings and Precautions (5.3)] Tumor Lysis Syndrome [see Warnings and Precautions (5.4)] Embryo-Fetal Risk [see Warnings and Precautions (5.5)] Anemia, Neutropenia and Thrombocytopenia [see Warnings and Precautions (5.1)] Hepatotoxicity in Patients with Severe Pre-existing Hepatic Impairment [see Warnings and Precautions (5.2)] Renal Toxicity [see Warnings and Precautions (5.3)] Tumor Lysis Syndrome [see Warnings and Precautions (5.4)] Embryo-Fetal Risk [see Warnings and Precautions (5.5)] Most common adverse reactions (>30%) by subcutaneous route are: nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia and ecchymosis. Most common adverse reactions by intravenous route also included petechiae, rigors, weakness and hypokalemia (6.1).To report SUSPECTED ADVERSE REACTIONS, contact Celgene Corporation at 1-888-423-5436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Most Commonly Occurring Adverse Reactions (Subcutaneous or Intravenous Route): nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by intravenous route also included petechiae, rigors, weakness and hypokalemia.. Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (Subcutaneous or Intravenous Route):Discontinuation: leukopenia, thrombocytopenia, neutropenia.Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia.Dose Reduced: leukopenia, neutropenia, thrombocytopenia.. 6.1 Adverse Reactions in Clinical Trials. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data described below reflect exposure to VIDAZA in 443 MDS patients from clinical studies. Study was supportive-care controlled trial (subcutaneous administration), Studies and were single arm studies (one with subcutaneous administration and one with intravenous administration), and Study was an international randomized trial (subcutaneous administration) [see Clinical Studies (14)]. In Studies 1, and 3, total of 268 patients were exposed to VIDAZA, including 116 exposed for cycles (approximately months) or more and 60 exposed for greater than 12 cycles (approximately one year). VIDAZA was studied primarily in supportive-care controlled and uncontrolled trials (n=150 and n=118, respectively). The population in the subcutaneous studies (n=220) was 23 to 92 years old (mean 66.4 years), 68% male, and 94% white, and had MDS or AML. The population in the intravenous study (n=48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white. Most patients received average daily doses between 50 and 100 mg/m2.In Study 4, total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed to VIDAZA. Of these patients, 119 were exposed for or more cycles, and 63 for at least 12 cycles. The mean age of this population was 68.1 years (ranging from 42 to 83 years), 74% were male, and 99% were white. Most patients received daily VIDAZA doses of 75 mg/m2.Table presents adverse reactions occurring in at least 5% of patients treated with VIDAZA (subcutaneous) in Studies and 2. It is important to note that duration of exposure was longer for the VIDAZA-treated group than for the observation group: patients received VIDAZA for mean of 11.4 months while mean time in the observation arm was 6.1 months.Table 1: Most Frequently Observed Adverse Reactions (>= 5.0% in All Subcutaneous VIDAZA Treated Patients; Studies and 2)Number (%) of PatientsSystem Organ Class Preferred TermaAll VIDAZAb(N=220)Observationc(N=92)a Multiple terms of the same preferred terms for patient are only counted once within each treatment group.b Includes adverse reactions from all patients exposed to VIDAZA, including patients after crossing over from observations.c Includes adverse reactions from observation period only; excludes any adverse events after crossover to VIDAZA.Blood and lymphatic system disorders Anemia153 (70)59 (64) Anemia aggravated12 (6)5 (5) Febrile neutropenia36 (16)4 (4) Leukopenia106 (48)27 (29) Neutropenia71 (32)10 (11) Thrombocytopenia144 (66)42 (46)Gastrointestinal disorders Abdominal tenderness26 (12)1 (1) Constipation74 (34)6 (7) Diarrhea80 (36)13 (14) Gingival bleeding21 (10)4 (4) Loose stools12 (6)0 Mouth hemorrhage11 (5)1 (1) Nausea155 (71)16 (17) Stomatitis17 (8)0 Vomiting119 (54)5 (5)General disorders and administration site conditions Chest pain36 (16)5 (5) Injection site bruising31 (14)0 Injection site erythema77 (35)0 Injection site granuloma11 (5)0 Injection site pain50 (23)0 Injection site pigmentation changes11 (5)0 Injection site pruritus15 (7)0 Injection site reaction30 (14)0 Injection site swelling11 (5)0 Lethargy17 (8)2 (2) Malaise24 (11)1 (1) Pyrexia114 (52)28 (30)Infections and infestations Nasopharyngitis32 (15)3 (3) Pneumonia24 (11)5 (5) Upper respiratory tract infection28 (13)4 (4)Injury, poisoning, and procedural complications Post procedural hemorrhage13 (6)1 (1)Metabolism and nutrition disorders Anorexia45 (21)6 (7)Musculoskeletal and connective tissue disorders Arthralgia49 (22)3 (3) Chest wall pain11 (5)0 Myalgia35 (16)2 (2)Nervous system disorders Dizziness41 (19)5 (5) Headache48 (22)10 (11)Psychiatric disorders Anxiety29 (13)3 (3) Insomnia24 (11)4 (4)Respiratory, thoracic and mediastinal disorders Dyspnea64 (29)11 (12)Skin and subcutaneous tissue disorders Dry skin11 (5)1 (1) Ecchymosis67 (31)14 (15) Erythema37 (17)4 (4) Rash31 (14)9 (10) Skin nodule11 (5)1 (1) Urticaria13 (6)1 (1)Vascular disorders Hematoma19 (9)0 Hypotension15 (7)2 (2) Petechiae52 (24)8 (9)Table presents adverse reactions occurring in at least 5% of patients treated with VIDAZA in Study 4. Similar to Studies and described above, duration of exposure to treatment with VIDAZA was longer (mean 12.2 months) compared with best supportive care (mean 7.5 months).Table 2: Most Frequently Observed Adverse Reactions (>= 5.0% in the VIDAZA Treated Patients and the Percentage with NCI CTC Grade 3/4 Reactions; Study 4)Number (%) of PatientsAny GradeGrade 3/4System Organ Class Preferred TermaVIDAZA(N=175)Best Supportive Care Only (N=102)VIDAZA(N=175)Best Supportive Care Only (N=102)a Multiple reports of the same preferred term from patient were only counted once within each treatment.Blood and lymphatic system disorders Anemia90 (51)45 (44)24 (14)9 (9) Febrile neutropenia24 (14)10 (10)22 (13)7 (7) Leukopenia32 (18)2 (2)26 (15)1 (1) Neutropenia115 (66)29 (28)107 (61)22 (22) Thrombocytopenia122 (70)35 (34)102 (58)29 (28)Gastrointestinal disorders Abdominal pain22 (13)7 (7)7 (4)0 Constipation88 (50)8 (8)2 (1)0 Dyspepsia10 (6)2 (2)00 Nausea84 (48)12 (12)3 (2)0 Vomiting47 (27)7 (7)00General disorders and administration site conditions Fatigue42 (24)12 (12)6 (3)2 (2) Injection site bruising9 (5)000 Injection site erythema75 (43)000 Injection site hematoma11 (6)000 Injection site induration9 (5)000 Injection site pain33 (19)000 Injection site rash10 (6)000 Injection site reaction51 (29)01 (1)0 Pyrexia53 (30)18 (18)8 (5)1 (1)Infections and infestations Rhinitis10 (6)1 (1)00 Upper respiratory tract infection16 (9)4 (4)3 (2)0 Urinary tract infection15 (9)3 (3)3 (2)0Investigations Weight decreased14 (8)01 (1)0Metabolism and nutrition disorders Hypokalemia11 (6)3 (3)3 (2)3 (3)Nervous system disorders Lethargy13 (7)2 (2)01 (1)Psychiatric disorders Anxiety9 (5)1 (1)00 Insomnia15 (9)3 (3)00Renal and urinary disorders Hematuria11 (6)2 (2)4 (2)1 (1)Respiratory, thoracic and mediastinal disorders Dyspnea26 (15)5 (5)6 (3)2 (2) Dyspnea exertional9 (5)1 (1)00 Pharyngolaryngeal pain11 (6)3 (3)00Skin and subcutaneous tissue disorders Erythema13 (7)3 (3)00 Petechiae20 (11)4 (4)2 (1)0 Pruritus21 (12)2 (2)00 Rash18 (10)1 (1)00Vascular disorders Hypertension15 (9)4 (4)2 (1)2 (2)In Studies 1, and with subcutaneous administration of VIDAZA, adverse reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site erythema/reaction tended to increase in incidence with higher doses of VIDAZA. Adverse reactions that tended to be more pronounced during the first to cycles of subcutaneous treatment compared with later cycles included thrombocytopenia, neutropenia, anemia, nausea, vomiting, injection site erythema/pain/bruising/reaction, constipation, petechiae, dizziness, anxiety, hypokalemia, and insomnia. There did not appear to be any adverse reactions that increased in frequency over the course of treatment.Overall, adverse reactions were qualitatively similar between the intravenous and subcutaneous studies. Adverse reactions that appeared to be specifically associated with the intravenous route of administration included infusion site reactions (e.g. erythema or pain) and catheter site reactions (e.g. infection, erythema, or hemorrhage).In clinical studies of either subcutaneous or intravenous VIDAZA, the following serious adverse reactions occurring at rate of <5% (and not described in Tables or 2) were reported:Blood and lymphatic system disorders: agranulocytosis, bone marrow failure, pancytopenia splenomegaly.Cardiac disorders: atrial fibrillation, cardiac failure, cardiac failure congestive, cardio-respiratory arrest, congestive cardiomyopathy.Eye disorders: eye hemorrhageGastrointestinal disorders: diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess.General disorders and administration site conditions: catheter site hemorrhage, general physical health deterioration, systemic inflammatory response syndrome.Hepatobiliary disorders: cholecystitis.Immune system disorders: anaphylactic shock, hypersensitivity.Infections and infestations: abscess limb, bacterial infection, cellulitis, blastomycosis, injection site infection, Klebsiella sepsis, neutropenic sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, septic shock, Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis.Metabolism and nutrition disorders: dehydration.Musculoskeletal and connective tissue disorders: bone pain aggravated, muscle weakness, neck pain.Neoplasms benign, malignant and unspecified: leukemia cutis.Nervous system disorders: cerebral hemorrhage, convulsions, intracranial hemorrhage.Renal and urinary disorders: loin pain, renal failure.Respiratory, thoracic and mediastinal disorders: hemoptysis, lung infiltration, pneumonitis, respiratory distress.Skin and subcutaneous tissue disorders: pyoderma gangrenosum, rash pruritic, skin induration.Surgical and medical procedures: cholecystectomy.Vascular disorders: orthostatic hypotension.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postmarketing use of VIDAZA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.- Interstitial lung disease- Tumor lysis syndrome- Injection site necrosis- Sweets syndrome (acute febrile neutrophilic dermatosis)- Necrotizing fasciitis (including fatal cases)- Differentiation syndrome. Interstitial lung disease. Tumor lysis syndrome. Injection site necrosis. Sweets syndrome (acute febrile neutrophilic dermatosis). Necrotizing fasciitis (including fatal cases). Differentiation syndrome.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. VIDAZA is pyrimidine nucleoside analog of cytidine. VIDAZA is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine.. 12.3 Pharmacokinetics. The pharmacokinetics of azacitidine were studied in MDS patients following single 75 mg/m2 subcutaneous dose and single 75 mg/m2 intravenous dose. AbsorptionAzacitidine is rapidly absorbed after subcutaneous administration; the peak plasma azacitidine concentration of 750 +- 403 ng/ml occurred in 0.5 hour. DistributionThe bioavailability of subcutaneous azacitidine relative to intravenous azacitidine is approximately 89%, based on area under the curve. Mean volume of distribution following intravenous dosing is 76 +- 26 L. Mean apparent subcutaneous clearance is 167 +- 49 L/hour and mean half-life after subcutaneous administration is 41 +- minutes. The AUC and Cmax of subcutaneous administration of azacitidine in 21 patients with cancer were approximately dose proportional within the 25 to 100 mg/m2 dose range. Multiple dosing at the recommended dose-regimen does not result in drug accumulation. EliminationPublished studies indicate that urinary excretion is the primary route of elimination of azacitidine and its metabolites. Following intravenous administration of radioactive azacitidine to cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for <1% of administered radioactivity over days. Mean excretion of radioactivity in urine following subcutaneous administration of 14C-azacitidine was 50%. The mean elimination half-lives of total radioactivity (azacitidine and its metabolites) were similar after intravenous and subcutaneous administrations, about hours.. Specific PopulationsIn patients with cancer the pharmacokinetics of azacitidine in patients with normal renal function (CLcr >80 mL/min) and patients with severe renal impairment (CLcr <30 mL/min) were compared following daily subcutaneous dosing (Days through 5) at 75 mg/m2/day. Severe renal impairment increased azacitidine exposure by approximately 70% after single and 41% after multiple subcutaneous administrations. This increase in exposure was not correlated with an increase in adverse events. The exposure was similar to exposure in patients with normal renal function receiving 100 mg/m2. Therefore, Cycle dose modification is not recommended. The effects of hepatic impairment, gender, age, or race on the pharmacokinetics of azacitidine have not been studied.. Drug-Drug InteractionsNo formal clinical drug interaction studies with azacitidine have been conducted.An in vitro study of azacitidine incubation in human liver fractions indicated that azacitidine may be metabolized by the liver. Whether azacitidine metabolism may be affected by known microsomal enzyme inhibitors or inducers has not been studied.An in vitro study with cultured human hepatocytes indicated that azacitidine at concentrations up to 100 uM (IV Cmax 10.6 uM) does not cause any inhibition of CYP2B6 and CYP2C8.The potential of azacitidine to inhibit other cytochrome P450 (CYP) enzymes is not known.In vitro studies with human cultured hepatocytes indicate that azacitidine at concentrations of 1.0 uM to 100 uM does not induce CYP 1A2, 2C19, or 3A4/5.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Myelodysplastic Syndromes (MDS)Study was randomized, open-label, controlled trial carried out in 53 U.S. sites compared the safety and efficacy of subcutaneous VIDAZA plus supportive care with supportive care alone (observation) in patients with any of the five FAB subtypes of myelodysplastic syndromes (MDS): refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL). RA and RARS patients were included if they met one or more of the following criteria: required packed RBC transfusions; had platelet counts <=50.0 109/L; required platelet transfusions; or were neutropenic (ANC <1.0 109/L) with infections requiring treatment with antibiotics. Patients with acute myelogenous leukemia (AML) were not intended to be included. Supportive care allowed in this study included blood transfusion products, antibiotics, antiemetics, analgesics and antipyretics. The use of hematopoietic growth factors was prohibited. Baseline patient and disease characteristics are summarized in Table 3; the groups were similar.VIDAZA was administered at subcutaneous dose of 75 mg/m2 daily for days every weeks. The dose was increased to 100 mg/m2 if no beneficial effect was seen after treatment cycles. The dose was decreased and/or delayed based on hematologic response or evidence of renal toxicity. Patients in the observation arm were allowed by protocol to cross over to VIDAZA if they had increases in bone marrow blasts, decreases in hemoglobin, increases in red cell transfusion requirements, or decreases in platelets, or if they required platelet transfusion or developed clinical infection requiring treatment with antibiotics. For purposes of assessing efficacy, the primary endpoint was response rate (as defined in Table 4).Of the 191 patients included in the study, independent review (adjudicated diagnosis) found that 19 had the diagnosis of AML at baseline. These patients were excluded from the primary analysis of response rate, although they were included in an intent-to-treat (ITT) analysis of all patients randomized. Approximately 55% of the patients randomized to observation crossed over to receive VIDAZA treatment.Table 3. Baseline Demographics and Disease Characteristics VIDAZA(N=99)Observation(N=92)Gender (n%) Male 72 (72.7) 60 (65.2) Female 27 (27.3) 32 (34.8)Race (n%) White 93 (93.9) 85 (92.4) Black (1.0) (1.1) Hispanic (3.0) (5.4) Asian/Oriental (2.0) (1.1)Age (years) N9991 Mean +- SD67.3 +- 10.3968.0 +- 10.23 Range31 9235 88Adjudicated MDS diagnosis atstudy entry (n%) RA21 (21.2)18 (19.6) RARS6 (6.1)5 (5.4) RAEB38 (38.4)39 (42.4) RAEB-T16 (16.2)14 (15.2) CMMoL8 (8.1)7 (7.6) AML10 (10.1)9 (9.8)Transfusion product used in 3months before study entry (n%) Any transfusion product70 (70.7)59 (64.1) Blood cells, packed human66 (66.7)55 (59.8) Platelets, human blood15 (15.2)12 (13.0) Hetastarch0(0.0)1(1.1) Plasma protein fraction1(1.0)0(0.0) Other2(2.0)2(2.2)Table 4. Response CriteriaRARARSRAEBRAEB-TCMMoLComplete Response (CR),duration >=4 weeksMarrow<5% blastsPeripheralBloodNormal CBC if abnormal at baselineAbsence of blasts in the peripheral circulationPartialResponse(PR),duration >=4 weeksMarrowNo marrow requirements >=50% decrease in blastsImprovement of marrow dyspoiesisPeripheralBlood>=50% restoration in the deficit from normal levels of baseline white cells, hemoglobin and platelets if abnormal at baseline No blasts in the peripheral circulation For CMMoL, if WBC is elevated at baseline, >=75% reduction in the excess count over the upper limit of normal The overall response rate (CR PR) of 15.7% in VIDAZA-treated patients without AML (16.2% for all VIDAZA randomized patients including AML) was statistically significantly higher than the response rate of 0% in the observation group (p<0.0001) (Table 5). The majority of patients who achieved either CR or PR had either or cell line abnormalities at baseline (79%; 11/14) and had elevated bone marrow blasts or were transfusion dependent at baseline. Patients responding to VIDAZA had decrease in bone marrow blasts percentage, or an increase in platelets, hemoglobin or WBC. Greater than 90% of the responders initially demonstrated these changes by the 5th treatment cycle. All patients who had been transfusion dependent became transfusion independent during PR or CR. The mean and median duration of clinical response of PR or better was estimated as 512 and 330 days, respectively; 75% of the responding patients were still in PR or better at completion of treatment. Response occurred in all MDS subtypes as well as in patients with adjudicated baseline diagnosis of AML.Table 5. Response Rates VIDAZA(N=89)Observation Before Crossover(N=83) Responsen (%)n (%)P value Overall (CR+PR)14 (15.7)0 0.0)(<0.0001) Complete (CR)5 5.6)0 0.0)(0.06) Partial (PR)9 (10.1)0 0.0)--Patients in the observation group who crossed over to receive VIDAZA treatment (47 patients) had response rate of 12.8%.Study 2, multi-center, open-label, single-arm study of 72 patients with RAEB, RAEB-T, CMMoL, or AML was also carried out. Treatment with subcutaneous VIDAZA resulted in response rate (CR PR) of 13.9%, using criteria similar to those described above. The mean and median duration of clinical response of PR or better was estimated as 810 and 430 days, respectively; 80% of the responding patients were still in PR or better at the time of completion of study involvement. In Study 3, another open-label, single-arm study of 48 patients with RAEB, RAEB-T, or AML, treatment with intravenous VIDAZA resulted in response rate of 18.8%, again using criteria similar to those described above. The mean and median duration of clinical response of PR or better was estimated as 389 and 281 days, respectively; 67% of the responding patients were still in PR or better at the time of completion of treatment. Response occurred in all MDS subtypes as well as in patients with adjudicated baseline diagnosis of AML in both of these studies. VIDAZA dosage regimens in these studies were similar to the regimen used in the controlled study. Benefit was seen in patients who did not meet the criteria for PR or better, but were considered improved. About 24% of VIDAZA-treated patients were considered improved, and about 2/3 of those lost transfusion dependence. In the observation group, only 5/83 patients met criteria for improvement; none lost transfusion dependence. In all studies, about 19% of patients met criteria for improvement with median duration of 195 days.Study was an international, multicenter, open-label, randomized trial in MDS patients with RAEB, RAEB-T or modified CMMoL according to FAB classification and Intermediate-2 and High risk according to IPSS classification. Of the 358 patients enrolled in the study, 179 were randomized to receive azacitidine plus best supportive care (BSC) and 179 were randomized to receive conventional care regimens (CCR) plus BSC (105 to BSC alone, 49 to low dose cytarabine and 25 to chemotherapy with cytarabine and anthracycline). The primary efficacy endpoint was overall survival.The azacitidine and CCR groups were comparable for baseline parameters. The median age of patients was 69 years (range was 38-88 years), 98% were Caucasian, and 70% were male. At baseline, 95% of the patients were higher risk by FAB classification: RAEB (58%), RAEB-T (34%), and CMMoL (3%). By IPSS classification, 87% were higher risk: Int-2 (41%), High (47%). At baseline, 32% of patients met WHO criteria for AML.Azacitidine was administered subcutaneously at dose of 75 mg/m2 daily for consecutive days every 28 days (which constituted one cycle of therapy). Patients continued treatment until disease progression, relapse after response, or unacceptable toxicity. Azacitidine patients were treated for median of cycles (range to 39), BSC only patients for median of cycles (range to 26), low dose cytarabine patients for median of 4.5 cycles (range to 15), and chemotherapy with cytarabine and anthracycline patients for median of cycle (range to 3, i.e. induction plus or consolidation cycles). In the Intent-to-Treat analysis, patients treated with azacitidine demonstrated statistically significant difference in overall survival as compared to patients treated with CCR (median survival of 24.5 months vs. 15.0 months; stratified log-rank p=0.0001). The hazard ratio describing this treatment effect was 0.58 (95% CI: 0.43, 0.77). Kaplan-Meier Curve of Time to Death from Any Cause: (Intent-to-Treat Population)Key: AZA azacitidine; CCR conventional care regimens; CI confidence interval; HR Hazard RatioAzacitidine treatment led to reduced need for red blood cell transfusions (see Table 6). In patients treated with azacitidine who were RBC transfusion dependent at baseline and became transfusion independent, the median duration of RBC transfusion independence was 13.0 months.Table 6. Effect of Azacitidine on RBC Transfusions in MDS Patients1A patient was considered RBC transfusion independent during the treatment period if the patient had no RBC transfusions during any 56 consecutive days or more during the treatment period. Otherwise, the patient was considered transfusion dependent.Efficacy ParameterAzacitidine plus BSC(n= 179)Conventional CareRegimens(n= 179)Number and percent of patients who were transfusion dependent at baseline who became transfusion independent on treatment1 50/111 (45.0%)13/114 (11.4%)(95% CI: 35.6%, 54.8%) (95% CI: 6.2%, 18.7%) Number and percent of patients who were transfusion-independent at baseline who became transfusion-dependent on treatment 10/68 (14.7%) 28/65 (43.1%) (95% CI: 7.3%, 25.4%) (95% CI: 30.9%, 56.0%) Kaplan-Meier Curve of Time to Death from Any Cause: (Intent-to-Treat Population).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Advanced Malignant Hepatic Tumors (4.1).Hypersensitivity to Azacitidine or Mannitol (4.2).. Advanced Malignant Hepatic Tumors (4.1).. Hypersensitivity to Azacitidine or Mannitol (4.2).. 4.1 Advanced Malignant Hepatic Tumors. VIDAZA is contraindicated in patients with advanced malignant hepatic tumors [see Warnings and Precautions (5.2)].. 4.2 Hypersensitivity to Azacitidine or Mannitol. VIDAZA is contraindicated in patients with known hypersensitivity to azacitidine or mannitol.

DESCRIPTION SECTION.

11 DESCRIPTION. VIDAZA (azacitidine for injection) contains azacitidine, which is pyrimidine nucleoside analog of cytidine. Azacitidine is 4-amino-1--D-ribofuranosyl-s-triazin-2(1H)-one. The structural formula is as follows:The empirical formula is C8H12N4O5. The molecular weight is 244. Azacitidine is white to off-white solid. Azacitidine was found to be insoluble in acetone, ethanol, and methyl ethyl ketone; slightly soluble in ethanol/water (50/50), propylene glycol, and polyethylene glycol; sparingly soluble in water, water saturated octanol, 5% dextrose in water, N-methyl-2-pyrrolidone, normal saline and 5% Tween 80 in water; and soluble in dimethylsulfoxide (DMSO).The finished product is supplied in sterile form for reconstitution as suspension for subcutaneous injection or reconstitution as solution with further dilution for intravenous infusion. Vials of VIDAZA contain 100 mg of azacitidine and 100 mg mannitol as sterile lyophilized powder.. Azacitidine Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology values, is VIDAZA 75 mg/m2 daily for days to be administered by subcutaneous injection or intravenous infusion. Premedicate for nausea and vomiting. (2.1)Repeat cycles every weeks (2.2). After cycles, may increase dose to 100 mg/m2 if no beneficial effect is seen and no toxicity other than nausea and vomiting has occurred (2.2). Patients should be treated for minimum of to cycles. Complete or partial response may require additional treatment cycles (2.2).Continue treatment as long as the patient continues to benefit (2.2).Monitor patients for hematologic response and for renal toxicity; delay or reduce dosage as appropriate (2.3, 2.4, 2.5).. The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology values, is VIDAZA 75 mg/m2 daily for days to be administered by subcutaneous injection or intravenous infusion. Premedicate for nausea and vomiting. (2.1). Repeat cycles every weeks (2.2). After cycles, may increase dose to 100 mg/m2 if no beneficial effect is seen and no toxicity other than nausea and vomiting has occurred (2.2). Patients should be treated for minimum of to cycles. Complete or partial response may require additional treatment cycles (2.2).. Continue treatment as long as the patient continues to benefit (2.2).. Monitor patients for hematologic response and for renal toxicity; delay or reduce dosage as appropriate (2.3, 2.4, 2.5).. 2.1 First Treatment Cycle. The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg/m2 subcutaneously or intravenously, daily for days. Premedicate patients for nausea and vomiting.Obtain complete blood counts, liver chemistries and serum creatinine prior to the first dose.. 2.2 Subsequent Treatment Cycles. Repeat cycles every weeks. The dose may be increased to 100 mg/m2 if no beneficial effect is seen after treatment cycles and if no toxicity other than nausea and vomiting has occurred. It is recommended that patients be treated for minimum of to cycles. However, complete or partial response may require additional treatment cycles. Treatment may be continued as long as the patient continues to benefit.Monitor patients for hematologic response and renal toxicities [see Warnings and Precautions (5.3)], and delay or reduce dosage if necessary as described below.. 2.3 Dosage Adjustment Based on Hematology Laboratory Values. For patients with baseline (start of treatment) WBC greater than or equal to 3.0 x109/L, ANC greater than or equal to 1.5 x109/L, and platelets greater than or equal to 75.0 x109/L, adjust the dose as follows, based on nadir counts for any given cycle:Nadir Counts% Dose in the NextCourseANC (x109/L)Less than 0.50.5 -1.5Greater than 1.5Platelets (x109/L)Less than 2525-50Greater than 5050%67%100%For patients whose baseline counts are WBC less than 3.0 x109/L, ANC less than 1.5 x109/L, or platelets less than 75.0 x109/L, base dose adjustments on nadir counts and bone marrow biopsy cellularity at the time of the nadir as noted below, unless there is clear improvement in differentiation (percentage of mature granulocytes is higher and ANC is higher than at onset of that course) at the time of the next cycle, in which case continue the current dose.WBC or PlateletNadir% decrease incountsfrom baselineBone MarrowBiopsy Cellularity at Time of Nadir(%)30-6015-30Less than 15% Dose in the Next Course50 751005033Greater than 75755033If nadir as defined in the table above has occurred, give the next course 28 days after the start of the preceding course, provided that both the WBC and the platelet counts are greater than 25% above the nadir and rising. If greater than 25% increase above the nadir is not seen by day 28, reassess counts every days. If 25% increase is not seen by day 42, reduce the scheduled dose by 50%.. For patients with baseline (start of treatment) WBC greater than or equal to 3.0 x109/L, ANC greater than or equal to 1.5 x109/L, and platelets greater than or equal to 75.0 x109/L, adjust the dose as follows, based on nadir counts for any given cycle:. For patients whose baseline counts are WBC less than 3.0 x109/L, ANC less than 1.5 x109/L, or platelets less than 75.0 x109/L, base dose adjustments on nadir counts and bone marrow biopsy cellularity at the time of the nadir as noted below, unless there is clear improvement in differentiation (percentage of mature granulocytes is higher and ANC is higher than at onset of that course) at the time of the next cycle, in which case continue the current dose.. 2.4 Dosage Adjustment Based on Serum Electrolytes and Renal Toxicity. If unexplained reductions in serum bicarbonate levels to less than 20 mEq/L occur, reduce the dosage by 50% for the next course. Similarly, if unexplained elevations of BUN or serum creatinine occur, delay the next cycle until values return to normal or baseline and reduce the dose by 50% for the next course [see Warnings and Precautions (5.3)]. 2.5 Use in Geriatric Patients. Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, select the dose carefully and monitor renal function [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5)]. 2.6 Preparation of VIDAZA. VIDAZA is cytotoxic drug. Follow applicable special handling and disposal procedures. The VIDAZA vial is single-dose and does not contain any preservatives. Discard unused portions of each vial properly [see How Supplied/Storage and Handling (16)]. Do not save any unused portions for later administration.. 2.7 Instructions for Subcutaneous Administration. Reconstitute VIDAZA aseptically with mL sterile water for injection. Inject the diluent slowly into the vial. Vigorously shake or roll the vial until uniform suspension is achieved. The suspension will be cloudy. The resulting suspension will contain azacitidine 25 mg/mL. Do not filter the suspension after reconstitution. Doing so could remove the active substance.. Preparation for Immediate Subcutaneous Administration: For doses requiring more than vial, divide the dose equally between the syringes (e.g., dose 150 mg 6 mL, syringes with mL in each syringe) and inject into two separate sites. Due to retention in the vial and needle, it may not be feasible to withdraw all of the suspension from the vial. The product may be held at room temperature for up to hour, but must be administered within hour after reconstitution.. Preparation for Delayed Subcutaneous Administration: The reconstituted product may be kept in the vial or drawn into syringe. For doses requiring more than vial, divide the dose equally between the syringes (e.g., dose 150 mg 6 mL, syringes with mL in each syringe) and inject into two separate sites. Due to retention in the vial and needle, it may not be feasible to withdraw all of the suspension from the vial. The product must be refrigerated immediately. When VIDAZA is reconstituted using water for injection that has not been refrigerated, the reconstituted product may be held under refrigerated conditions (2oC 8oC, 36oF 46oF) for up to hours. When VIDAZA is reconstituted using refrigerated (2oC 8oC, 36oF 46oF) water for injection, the reconstituted product may be stored under refrigerated conditions (2oC 8oC, 36oF 46oF) for up to 22 hours. After removal from refrigerated conditions, the suspension may be allowed to equilibrate to room temperature for up to 30 minutes prior to administration.. Subcutaneous AdministrationTo provide homogeneous suspension, the contents of the dosing syringe must be re-suspended immediately prior to administration. To re-suspend, vigorously roll the syringe between the palms until uniform, cloudy suspension is achieved.VIDAZA suspension is administered subcutaneously. Rotate sites for each injection (thigh, abdomen, or upper arm). New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, red, or hard. Suspension Stability: VIDAZA reconstituted with non-refrigerated water for injection for subcutaneous administration may be stored for up to hour at 25C (77F) or for up to hours between 2C and 8C (36F and 46F); when reconstituted with refrigerated (2oC 8oC, 36oF 46oF) water for injection, it may be stored for 22 hours between 2C and 8C (36F and 46F).. 2.8 Instructions for Intravenous Administration. Reconstitute the appropriate number of VIDAZA vials to achieve the desired dose. Reconstitute each vial with 10 mL sterile water for injection. Vigorously shake or roll the vial until all solids are dissolved. The resulting solution will contain azacitidine 10 mg/mL. The solution should be clear. Parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.Withdraw the required amount of VIDAZA solution to deliver the desired dose and inject into 50 -100 mL infusion bag of either 0.9% Sodium Chloride Injection or Lactated Ringers Injection.. Intravenous Solution IncompatibilityVIDAZA is incompatible with 5% Dextrose solutions, Hespan, or solutions that contain bicarbonate. These solutions have the potential to increase the rate of degradation of VIDAZA and should therefore be avoided.. Intravenous AdministrationVIDAZA solution is administered intravenously. Administer the total dose over period of 10 40 minutes. The administration must be completed within hour of reconstitution of the VIDAZA vial.. Solution Stability: VIDAZA reconstituted for intravenous administration may be stored at 25C (77F), but administration must be completed within hour of reconstitution.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Based on its mechanism of action and findings in animals, VIDAZA can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating VIDAZA.ContraceptionFemalesAdvise females of reproductive potential to avoid pregnancy during treatment with VIDAZA.MalesMales with female sexual partners of reproductive potential should not father child and should use effective contraception during treatment with VIDAZA.InfertilityBased on animal data, azacitidine could have an effect on male or female fertility [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the total number of patients in Studies 1, and 3, 62% were 65 years and older and 21% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In addition there were no relevant differences in the frequency of adverse reactions observed in patients 65 years and older compared to younger patients.Of the 179 patients randomized to azacitidine in Study 4, 68% were 65 years and older and 21% were 75 years and older. Survival data for patients 65 years and older were consistent with overall survival results. The majority of adverse reactions occurred at similar frequencies in patients <65 years of age and patients 65 years of age and older. Elderly patients are more likely to have decreased renal function. Monitor renal function in these patients [see Dosage and Administration (2.5) and Warnings and Precautions (5.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedVIDAZA (azacitidine for injection) is supplied as lyophilized powder in 100 mg single-dose vials packaged in cartons of vial (NDC 59572-102-01).. StorageStore unreconstituted vials at 25o (77o F); excursions permitted to 15o-30o (59o-86o F) (See USP Controlled Room Temperature).. Handling and DisposalVIDAZA is cytotoxic drug. Follow applicable special handling and disposal procedures.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. VIDAZA is nucleoside metabolic inhibitor indicated for the treatment of patients with the following FAB myelodysplastic syndrome (MDS) subtypes: Refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL). (1). 1.1 Myelodysplastic Syndromes (MDS). VIDAZA(R) is indicated for treatment of patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Hepatotoxicity in Patients with Severe Pre-Existing Hepatic ImpairmentInstruct patients to inform their physician about any underlying liver disease [see Warnings and Precautions (5.2)].Renal ToxicityInstruct patients to inform their physician about any underlying renal disease [see Warnings and Precautions (5.3)].Embryo-Fetal RiskAdvise pregnant women of the potential risk to fetus [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1)].Advise females of reproductive potential to avoid pregnancy during treatment with VIDAZA. Advise males with female sexual partners of reproductive potential to not father child and to use effective contraception during treatment with VIDAZA. Advise patients to report pregnancy to their physicians immediately [see Warnings and Precautions (5.5) and Use in Specific Populations (8.3)]. LactationAdvise patients to avoid breastfeeding while receiving VIDAZA [see Use in Specific Populations (8.2)].Manufactured for:Celgene CorporationSummit, NJ 07901 Manufactured by:Baxter Oncology GmbH33790 Halle/Westfalen Germany OrBSP Pharmaceuticals S.p.A.04013 Latina Scalo (Lt) ItalyVIDAZA(R) is registered trademark of Celgene Corporation. (C) 2004-2020 Celgene Corporation, All Rights Reserved. VIDPI.14.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no information regarding the presence of azacitidine in human milk, the effects of VIDAZA on the breastfed infant, or the effects of VIDAZA on milk production. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for azacitidine in animal studies [see Nonclinical Toxicology (13.1)] and the potential for serious adverse reactions in nursing infants from VIDAZA, advise patients not to breastfeed during treatment with VIDAZA.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. VIDAZA is pyrimidine nucleoside analog of cytidine. VIDAZA is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m2, approximately 8% the recommended human daily dose on mg/m2 basis) administered IP three times per week for 52 weeks. An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine IP at 2.0 mg/kg (6.0 mg/m2, approximately 8% the recommended human daily dose on mg/m2 basis) once week for 50 weeks. tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m2 (approximately 20%-80% the recommended human daily dose on mg/m2 basis) revealed an increased incidence of testicular tumors compared with controls.The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems Salmonella typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Pro, WP3103P, WP3104P, and CC103; in in vitro forward gene mutation assay in mouse lymphoma cells and human lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells.Administration of azacitidine to male mice at 9.9 mg/m2 (approximately 9% the recommended human daily dose on mg/m2 basis) daily for days prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats times per week for 11 or 16 weeks at doses of 15-30 mg/m2 (approximately 20%-40%, the recommended human daily dose on mg/m2 basis) resulted in decreased weight of the testes and epididymides, and decreased sperm counts accompanied by decreased pregnancy rates and increased loss of embryos in mated females. In related study, male rats treated for 16 weeks at 24 mg/m2 resulted in an increase in abnormal embryos in mated females when examined on day of gestation.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of azacitidine were studied in MDS patients following single 75 mg/m2 subcutaneous dose and single 75 mg/m2 intravenous dose. AbsorptionAzacitidine is rapidly absorbed after subcutaneous administration; the peak plasma azacitidine concentration of 750 +- 403 ng/ml occurred in 0.5 hour. DistributionThe bioavailability of subcutaneous azacitidine relative to intravenous azacitidine is approximately 89%, based on area under the curve. Mean volume of distribution following intravenous dosing is 76 +- 26 L. Mean apparent subcutaneous clearance is 167 +- 49 L/hour and mean half-life after subcutaneous administration is 41 +- minutes. The AUC and Cmax of subcutaneous administration of azacitidine in 21 patients with cancer were approximately dose proportional within the 25 to 100 mg/m2 dose range. Multiple dosing at the recommended dose-regimen does not result in drug accumulation. EliminationPublished studies indicate that urinary excretion is the primary route of elimination of azacitidine and its metabolites. Following intravenous administration of radioactive azacitidine to cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for <1% of administered radioactivity over days. Mean excretion of radioactivity in urine following subcutaneous administration of 14C-azacitidine was 50%. The mean elimination half-lives of total radioactivity (azacitidine and its metabolites) were similar after intravenous and subcutaneous administrations, about hours.. Specific PopulationsIn patients with cancer the pharmacokinetics of azacitidine in patients with normal renal function (CLcr >80 mL/min) and patients with severe renal impairment (CLcr <30 mL/min) were compared following daily subcutaneous dosing (Days through 5) at 75 mg/m2/day. Severe renal impairment increased azacitidine exposure by approximately 70% after single and 41% after multiple subcutaneous administrations. This increase in exposure was not correlated with an increase in adverse events. The exposure was similar to exposure in patients with normal renal function receiving 100 mg/m2. Therefore, Cycle dose modification is not recommended. The effects of hepatic impairment, gender, age, or race on the pharmacokinetics of azacitidine have not been studied.. Drug-Drug InteractionsNo formal clinical drug interaction studies with azacitidine have been conducted.An in vitro study of azacitidine incubation in human liver fractions indicated that azacitidine may be metabolized by the liver. Whether azacitidine metabolism may be affected by known microsomal enzyme inhibitors or inducers has not been studied.An in vitro study with cultured human hepatocytes indicated that azacitidine at concentrations up to 100 uM (IV Cmax 10.6 uM) does not cause any inhibition of CYP2B6 and CYP2C8.The potential of azacitidine to inhibit other cytochrome P450 (CYP) enzymes is not known.In vitro studies with human cultured hepatocytes indicate that azacitidine at concentrations of 1.0 uM to 100 uM does not induce CYP 1A2, 2C19, or 3A4/5.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on its mechanism of action and findings in animals, VIDAZA can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no data on the use of azacitidine in pregnant women. Azacitidine was teratogenic and caused embryo-fetal lethality in animals at doses lower than the recommended human daily dose (see Data). Advise pregnant women of the potential risk to the fetus.The background rate of major birth defects and miscarriage is unknown for the indicated population. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.DataAnimal DataEarly embryotoxicity studies in mice revealed 44% frequency of intrauterine embryonal death (increased resorption) after single IP (intraperitoneal) injection of mg/m2 (approximately 8% of the recommended human daily dose on mg/m2 basis) azacitidine on gestation day 10. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3-12 mg/m2 (approximately 4%-16% the recommended human daily dose on mg/m2 basis).In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4-8 (postimplantation) at dose of mg/m2 (approximately 8% of the recommended human daily dose on mg/m2 basis), although treatment in the preimplantation period (on gestation days 1-3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after single IP dose of to 12 mg/m2 (approximately 8% the recommended human daily dose on mg/m2 basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused fetal death when administered at 3-12 mg/m2 on gestation days and 10; average live animals per litter was reduced to 9% of control at the highest dose on gestation day 9. Fetal anomalies included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, edema, and rib abnormalities).

REFERENCES SECTION.

15 REFERENCES. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

SPL UNCLASSIFIED SECTION.

1.1 Myelodysplastic Syndromes (MDS). VIDAZA(R) is indicated for treatment of patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).

STORAGE AND HANDLING SECTION.

StorageStore unreconstituted vials at 25o (77o F); excursions permitted to 15o-30o (59o-86o F) (See USP Controlled Room Temperature).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Discontinue nursing taking into consideration the importance of drug to mother (8.2).. Lactation: Discontinue nursing taking into consideration the importance of drug to mother (8.2).. 8.1 Pregnancy. Risk SummaryBased on its mechanism of action and findings in animals, VIDAZA can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no data on the use of azacitidine in pregnant women. Azacitidine was teratogenic and caused embryo-fetal lethality in animals at doses lower than the recommended human daily dose (see Data). Advise pregnant women of the potential risk to the fetus.The background rate of major birth defects and miscarriage is unknown for the indicated population. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.DataAnimal DataEarly embryotoxicity studies in mice revealed 44% frequency of intrauterine embryonal death (increased resorption) after single IP (intraperitoneal) injection of mg/m2 (approximately 8% of the recommended human daily dose on mg/m2 basis) azacitidine on gestation day 10. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3-12 mg/m2 (approximately 4%-16% the recommended human daily dose on mg/m2 basis).In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4-8 (postimplantation) at dose of mg/m2 (approximately 8% of the recommended human daily dose on mg/m2 basis), although treatment in the preimplantation period (on gestation days 1-3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after single IP dose of to 12 mg/m2 (approximately 8% the recommended human daily dose on mg/m2 basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused fetal death when administered at 3-12 mg/m2 on gestation days and 10; average live animals per litter was reduced to 9% of control at the highest dose on gestation day 9. Fetal anomalies included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, edema, and rib abnormalities).. 8.2 Lactation. Risk SummaryThere is no information regarding the presence of azacitidine in human milk, the effects of VIDAZA on the breastfed infant, or the effects of VIDAZA on milk production. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for azacitidine in animal studies [see Nonclinical Toxicology (13.1)] and the potential for serious adverse reactions in nursing infants from VIDAZA, advise patients not to breastfeed during treatment with VIDAZA. 8.3 Females and Males of Reproductive Potential. Based on its mechanism of action and findings in animals, VIDAZA can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating VIDAZA.ContraceptionFemalesAdvise females of reproductive potential to avoid pregnancy during treatment with VIDAZA.MalesMales with female sexual partners of reproductive potential should not father child and should use effective contraception during treatment with VIDAZA.InfertilityBased on animal data, azacitidine could have an effect on male or female fertility [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.. 8.5 Geriatric Use. Of the total number of patients in Studies 1, and 3, 62% were 65 years and older and 21% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In addition there were no relevant differences in the frequency of adverse reactions observed in patients 65 years and older compared to younger patients.Of the 179 patients randomized to azacitidine in Study 4, 68% were 65 years and older and 21% were 75 years and older. Survival data for patients 65 years and older were consistent with overall survival results. The majority of adverse reactions occurred at similar frequencies in patients <65 years of age and patients 65 years of age and older. Elderly patients are more likely to have decreased renal function. Monitor renal function in these patients [see Dosage and Administration (2.5) and Warnings and Precautions (5.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Anemia, Neutropenia and Thrombocytopenia: Monitor complete blood counts (CBC) frequently (5.1).Hepatotoxicity: Patients with severe preexisting hepatic impairment are at higher risk for toxicity (5.2).Renal Toxicity: Monitor patients with renal impairment for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys (5.3).Tumor Lysis Syndrome: VIDAZA may cause fatal or serious tumor lysis syndrome, including in patients with MDS. Assess baseline risk and monitor and treat as appropriate (5.4).Embryo-Fetal Risk: VIDAZA can cause fetal harm. Advise females with reproductive potential of the potential risk to fetus and to avoid pregnancy (5.5).. Anemia, Neutropenia and Thrombocytopenia: Monitor complete blood counts (CBC) frequently (5.1).. Hepatotoxicity: Patients with severe preexisting hepatic impairment are at higher risk for toxicity (5.2).. Renal Toxicity: Monitor patients with renal impairment for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys (5.3).. Tumor Lysis Syndrome: VIDAZA may cause fatal or serious tumor lysis syndrome, including in patients with MDS. Assess baseline risk and monitor and treat as appropriate (5.4).. Embryo-Fetal Risk: VIDAZA can cause fetal harm. Advise females with reproductive potential of the potential risk to fetus and to avoid pregnancy (5.5).. 5.1 Anemia, Neutropenia and Thrombocytopenia. VIDAZA causes anemia, neutropenia and thrombocytopenia. Monitor complete blood counts frequently for response and/or toxicity, at minimum, prior to each dosing cycle. After administration of the recommended dosage for the first cycle, adjust dosage for subsequent cycles based on nadir counts and hematologic response [see Dosage and Administration (2.3)].. 5.2 Hepatotoxicity in Patients with Severe Pre-existing Hepatic Impairment. Because azacitidine is potentially hepatotoxic in patients with severe pre-existing hepatic impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have been reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline albumin <30 g/L. Azacitidine is contraindicated in patients with advanced malignant hepatic tumors [see Contraindications (4.1)]. Monitor liver chemistries prior to initiation of therapy and with each cycle.Safety and effectiveness of VIDAZA in patients with MDS and hepatic impairment have not been studied as these patients were excluded from the clinical trials.. 5.3 Renal Toxicity. Renal toxicity ranging from elevated serum creatinine to renal failure and death have been reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for nonMDS conditions. In addition, renal tubular acidosis, defined as fall in serum bicarbonate to <20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium <3 mEq/L) developed in patients with CML treated with azacitidine and etoposide. Monitor serum creatinine and electrolytes prior to initiation of therapy and with each cycle. If unexplained reductions in serum bicarbonate <20 mEq/L or elevations of BUN or serum creatinine occur, reduce or hold the dose [see Dosage and Administration (2.4)].Patients with renal impairment may be at increased risk for renal toxicity. Also, azacitidine and its metabolites are primarily excreted by the kidney. Therefore, monitor these patients closely for toxicity [see Dosage and Administration (2.4, 2.5)]. Patients with MDS and renal impairment were excluded from the clinical studies.. 5.4 Tumor Lysis Syndrome. VIDAZA may cause fatal or serious tumor lysis syndrome, including in patients with MDS. Tumor lysis syndrome may occur despite concomitant use of allopurinol. Assess baseline risk and monitor and treat as appropriate.. 5.5 Embryo-Fetal Risk. Based on the mechanism of action and findings in animals, VIDAZA can cause fetal harm when administered to pregnant woman. Azacitidine administered to pregnant rats via single intraperitoneal (IP) dose approximating 8% of the recommended human daily dose caused fetal death and anomalies [see Use in Specific Populations (8.1)]. Advise females with reproductive potential to avoid pregnancy during treatment with VIDAZA [see Use in Specific Populations (8.3)]. Men should be advised to not father child while receiving treatment with VIDAZA.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics In pediatric patients with JMML post azacitidine treatment (75 mg/m2 or 2.5 mg/kg), reductions in genome-wide DNA methylation (global DNA methylation scores) were attained in bone marrow granulocytes during the first treatment cycle, confirming the DNA-hypomethylating activity of azacitidine.

RECENT MAJOR CHANGES SECTION.

Indications and Usage, JMML (1.2) 5/2022Dosage and Administration (2.1, 2.4, 2.5, 2.10) 5/2022Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.6) 5/2022.