FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

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

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)] HepatotoxicityinPatientswithSeverePre-existingHepaticImpairment[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 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.DoseHeld:leukopenia,neutropenia,thrombocytopenia, pyrexia, pneumonia, febrile neutropenia.Dose Reduced: leukopenia, neutropenia, thrombocytopenia.. Anemia, Neutropenia and Thrombocytopenia [see Warnings and Precautions (5.1)] HepatotoxicityinPatientswithSeverePre-existingHepaticImpairment[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 Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 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 toratesintheclinicaltrialsofanotherdrug and may not reflectthe rates observed in practice.Thedata describedbelowreflectexposuretoazacitidine 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 azacitidine, including 116 exposed for cycles (approximately months) or more and 60 exposed for greater than 12 cycles (approximately one year). Azacitidine 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 azacitidine. 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 azacitidine doses of 75 mg/m2.Table presents adverse reactions occurring in at least 5% of patients treated with azacitidine (subcutaneous) in Studies and 2. It is important to note that duration of exposure was longer for the azacitidine-treated group than for the observation group: patients received azacitidine for injection 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 Azacitidine Treated Patients; Studies and 2)Number (%) of PatientsSystem Organ ClassPreferred TermMultiple terms of the same preferred terms for patient are only counted once within each treatment group. All Azacitidine for InjectionIncludes adverse reactions from all patients exposed to azacitidine, including patients after crossing over from observations. (N=220)ObservationIncludes adverse reactions from observation period only; excludes any adverse events after crossover to azacitidine. (N=92)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 azacitidine in Study 4. Similar to Studies and described above, duration of exposure to treatment with azacitidine 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 Azacitidine Treated Patients and the Percentage with NCI CTC Grade 3/4 Reactions; Study 4)Number (%) of PatientsAny GradeGrade 3/4System Organ ClassPreferred TermMultiple reports of the same preferred term from patient were only counted once within each treatment. Azacitidine for Injection(N=175)Best Supportive Care Only(N=102)Azacitidine for Injection(N=175)Best Supportive Care Only(N=102)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 disordersAbdominal pain22 (13)7 (7)7 (4)0Constipation88 (50)8 (8)2 (1)0Dyspepsia10 (6)2 (2)00Nausea84 (48)12 (12)3 (2)0Vomiting47 (27)7 (7)00General disorders and administration site conditionsFatigue42 (24)12 (12)6 (3)2 (2)Injection site bruising9 (5)000Injection site erythema75 (43)000Injection site hematoma11 (6)000Injection site induration9 (5)000Injection site pain33 (19)000Injection site rash10 (6)000Injection site reaction51 (29)01 (1)0Pyrexia53 (30)18 (18)8 (5)1 (1)Infections and infestationsRhinitis10 (6)1 (1)00 Upper respiratory tract infection16 (9)4 (4)3 (2)0 Urinary tract infection15 (9)3 (3)3 (2)0 Investigations 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)00 Vascular disorders Hypertension15 (9)4 (4)2 (1)2 (2)In Studies 1, and with subcutaneous administration of azacitidine, adverse reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site erythema/reaction tended to increase in incidence with higher doses of azacitidine for injection.Adverse reactions that tended to bemore pronounced during thefirst1to2 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 andsubcutaneousstudies.Adversereactionsthatappearedtobespecificallyassociated 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 azacitidine, 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:atrialfibrillation,cardiacfailure, 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 healthdeterioration, systemicinflammatory 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. Thefollowingadversereactions have been identified duringpostmarketinguse of azacitidine. 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 oftrpE8,EscherichiacolistrainsWP14Pro,WP3103P,WP3104P,andCC103;inin vitro forward gene mutation assay in mouse lymphoma cells andhumanlymphoblastcells; and inanin 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Azacitidine for injection is pyrimidine nucleoside analog of cytidine. Azacitidine for injection 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 ofDNAsynthesis.Hypomethylation may restore normal functiontogenesthat 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 absorbedafter 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 1dose 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 thatazacitidine may bemetabolizedby 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=10.6uM) 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 atconcentrations of 1.0 uM to 100 uM does not induceCYP 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 safetyandefficacyofsubcutaneousazacitidine forinjection plus supportive care with supportive care alone (observation) in patientswith any of the fiveFAB subtypesofmyelodysplasticsyndromes(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;hadplatelet counts <=50.0 109/L;required platelettransfusions; 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 anddiseasecharacteristics aresummarizedinTable 3;the2groupsweresimilar. Azacitidine for injection was administered at subcutaneous dose of 75 mg/m2 daily for days every weeks. The dose was increased to 100 mg/m2 ifnobeneficialeffectwasseen after treatment cycles.Thedose 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 azacitidine for injection 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 azacitidine for injection treatment.Table 3. Baseline Demographics and Disease CharacteristicsAzacitidine for Injection(N=99)Observation(N=92)Gender (n%)Male72 (72.7)60 (65.2)Female27 (27.3)32 (34.8)Race (n%) White93 (93.9)85 (92.4)Black1 (1.0)1 (1.1)Hispanic3 (3.0)5 (5.4)Asian/Oriental2 (2.0)1 (1.1)Age (years)N9991Mean +- SD67.3 +- 10.3968.0 +- 10.23Range31 9235 88Adjudicated MDS diagnosis at study 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 months before study entry (n%)Any transfusion product70 (70.7)59 (64.1)Blood cells, packed human 66 (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% blastsPeripheral BloodNormal CBC if abnormal at baselineAbsence of blasts in the peripheral circulationPartial Response (PR), duration >=4 weeksMarrow No marrow requirements>=50% decrease in blastsImprovement of marrow dyspoiesisPeripheral Blood>=50% restoration in the deficit from normal levels of baseline white cells, hemoglobin and platelets if abnormal at baselineNo blasts in the peripheral circulationFor CMMoL, if WBC is elevated at baseline, >=75% reduction in the excess count over the upper limit of normalThe overall response rate (CR PR) of 15.7% in azacitidine for injection-treated patients without AML (16.2% for all azacitidine for injection randomizedpatientsincludingAML)wasstatisticallysignificantlyhigher 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 lineabnormalities at baseline (79%;11/14)andhadelevated bonemarrowblasts or were transfusion dependent at baseline. Patients responding to azacitidine for injection had decrease in bone marrow blasts percentage, or an increaseinplatelets, hemoglobin or WBC. Greater than 90%of theresponders 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 theresponding 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 RatesAzacitidine for Injection(N=89)Observation Before Crossover(N=83)Responsen (%)n (%)P valueOverall (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 azacitidine for injection 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 azacitidine for injection 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 and430 days,respectively; 80% of therespondingpatientswere still in PRor 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 azacitidine for injection 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 as389and281days, respectively; 67% of the responding patients werestillin 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. Azacitidine for injection 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,butwere considered improved. About 24% of azacitidine for injection-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; nonelosttransfusiondependence. In all3 studies,about19% of patients met criteria for improvement with median duration of 195 days. Study was an international, multicenter, open-label, randomized trial in MDSpatientswith RAEB, RAEB-T or modifiedCMMoLaccordingtoFABclassificationandIntermediate-2andHighriskaccordingtoIPSSclassification. 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 primaryefficacyendpoint was overallsurvival.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 FABclassification:RAEB(58%), RAEB-T (34%), and CMMoL (3%).By IPSSclassification,87% werehigher risk: Int-2(41%), High (47%).Atbaseline, 32% of patientsmetWHO 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 astatistically significant difference in overall survival as compared to patients treated with CCR(mediansurvivalof 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 PatientsEfficacy ParameterAzacitidine plus BSC(n= 179)Conventional Care Regimens(n= 179)Number and percent of patients who were transfusion dependent at baseline who became transfusion independent on treatmentA 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. 50/111 (45.0%)(95% CI: 35.6%, 54.8%)13/114 (11.4%)(95% CI: 6.2%, 18.7%)Number and percent of patients who were transfusion-independent at baseline who became transfusion-dependent on treatment10/68 (14.7%)(95% CI: 7.3%, 25.4%)28/65 (43.1%)(95% CI: 30.9%, 56.0%). Image.

CLINICAL TRIALS EXPERIENCE SECTION.

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 toratesintheclinicaltrialsofanotherdrug and may not reflectthe rates observed in practice.Thedata describedbelowreflectexposuretoazacitidine 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 azacitidine, including 116 exposed for cycles (approximately months) or more and 60 exposed for greater than 12 cycles (approximately one year). Azacitidine 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 azacitidine. 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 azacitidine doses of 75 mg/m2.Table presents adverse reactions occurring in at least 5% of patients treated with azacitidine (subcutaneous) in Studies and 2. It is important to note that duration of exposure was longer for the azacitidine-treated group than for the observation group: patients received azacitidine for injection 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 Azacitidine Treated Patients; Studies and 2)Number (%) of PatientsSystem Organ ClassPreferred TermMultiple terms of the same preferred terms for patient are only counted once within each treatment group. All Azacitidine for InjectionIncludes adverse reactions from all patients exposed to azacitidine, including patients after crossing over from observations. (N=220)ObservationIncludes adverse reactions from observation period only; excludes any adverse events after crossover to azacitidine. (N=92)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 azacitidine in Study 4. Similar to Studies and described above, duration of exposure to treatment with azacitidine 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 Azacitidine Treated Patients and the Percentage with NCI CTC Grade 3/4 Reactions; Study 4)Number (%) of PatientsAny GradeGrade 3/4System Organ ClassPreferred TermMultiple reports of the same preferred term from patient were only counted once within each treatment. Azacitidine for Injection(N=175)Best Supportive Care Only(N=102)Azacitidine for Injection(N=175)Best Supportive Care Only(N=102)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 disordersAbdominal pain22 (13)7 (7)7 (4)0Constipation88 (50)8 (8)2 (1)0Dyspepsia10 (6)2 (2)00Nausea84 (48)12 (12)3 (2)0Vomiting47 (27)7 (7)00General disorders and administration site conditionsFatigue42 (24)12 (12)6 (3)2 (2)Injection site bruising9 (5)000Injection site erythema75 (43)000Injection site hematoma11 (6)000Injection site induration9 (5)000Injection site pain33 (19)000Injection site rash10 (6)000Injection site reaction51 (29)01 (1)0Pyrexia53 (30)18 (18)8 (5)1 (1)Infections and infestationsRhinitis10 (6)1 (1)00 Upper respiratory tract infection16 (9)4 (4)3 (2)0 Urinary tract infection15 (9)3 (3)3 (2)0 Investigations 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)00 Vascular disorders Hypertension15 (9)4 (4)2 (1)2 (2)In Studies 1, and with subcutaneous administration of azacitidine, adverse reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site erythema/reaction tended to increase in incidence with higher doses of azacitidine for injection.Adverse reactions that tended to bemore pronounced during thefirst1to2 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 andsubcutaneousstudies.Adversereactionsthatappearedtobespecificallyassociated 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 azacitidine, 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:atrialfibrillation,cardiacfailure, 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 healthdeterioration, systemicinflammatory 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.

CONTRAINDICATIONS SECTION.

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

DESCRIPTION SECTION.

11 DESCRIPTION. Azacitidine for injection contains azacitidine, which is pyrimidine nucleosideanalog of cytidine. Azacitidine is 4-amino-1--D-ribofuranosyl-s-triazin-2(1H)-one. The structural formulaisas 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,andmethyl ethylketone;slightlysolubleinethanol/water (50/50), propylene glycol, and polyethylene glycol; sparingly soluble inwater,water saturated octanol, 5% dextrose in water, N-methyl-2-pyrrolidone, normal saline and 5% Tween 80 in water; andsoluble indimethylsulfoxide (DMSO).Thefinishedproductissupplied in sterile form for reconstitution as asuspension for subcutaneous injection or reconstitution as solution with furtherdilution for intravenous infusion. Vials of azacitidine for injection contain 100 mg of azacitidine and 100 mg mannitol as sterile lyophilized powder.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Therecommendedstartingdose for the firsttreatmentcycle,for all patientsregardless of baseline hematology values, is azacitidine for injection 75 mg/m2 daily for days to be administered by subcutaneous injection or intravenous infusion. Premedicate for nausea and vomiting. (2.1)Repeatcycles every4weeks (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 tobenefit (2.2).Monitorpatientsfor hematologic response and for renal toxicity; delay or reduce dosage as appropriate (2.3, 2.4, 2.5).. Therecommendedstartingdose for the firsttreatmentcycle,for all patientsregardless of baseline hematology values, is azacitidine for injection 75 mg/m2 daily for days to be administered by subcutaneous injection or intravenous infusion. Premedicate for nausea and vomiting. (2.1). Repeatcycles every4weeks (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 tobenefit (2.2).. Monitorpatientsfor hematologic response and for renal toxicity; delay or reduce dosage as appropriate (2.3, 2.4, 2.5).. 2.1 First Treatment Cycle Therecommendedstartingdoseforthefirsttreatment 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 isseen after2treatmentcyclesandifnotoxicityotherthannausea and vomiting has occurred. It is recommended that patients be treated for minimumof 4to6 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. Forpatientswith baseline (start of treatment) WBCgreater thanor equalto3.0 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 Next CourseANC (x109/L)Platelets (x109/L)Less than 0.5Less than 2550%0.5 -1.525-5067%Greater than 1.5Greater than 50100%Forpatientswhose baseline counts are WBC lessthan 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 Platelet Nadir% decrease in counts from baselineBone MarrowBiopsy Cellularity at Time of Nadir(%)30-6015-30Less than 15% Dose in the Next Course50 751005033greater than 75755033Ifa nadir as defined in the table above has occurred, give the next course 28 daysafter thestart of the preceding course, provided thatboth theWBC and the plateletcounts 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%.. Forpatientswith baseline (start of treatment) WBCgreater thanor equalto3.0 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:. Forpatientswhose baseline counts are WBC lessthan 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 Azacitidine for Injection. Azacitidine for injection is cytotoxic drug. Follow applicable special handling and disposal procedures.1 The azacitidine for injection 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 azacitidine for injection aseptically with mL sterile water for injection. Inject thediluentslowlyintothevial. Vigorouslyshakeorrollthevialuntilauniformsuspension is achieved. The suspension will be cloudy. The resulting suspension willcontainazacitidine 25 mg/mL. Donotfilter thesuspensionafter 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 suspensionfrom thevial.Theproductmust berefrigerated immediately.WhenAzacitidine for injection is reconstituted using water for injection that has not been refrigerated, the reconstituted product may be held under refrigerated conditions (2C 8C, 36F 46F) for up to8 hours. When Azacitidine for injection is reconstitutedusingrefrigerated (2C 8C, 36F 46F) water for injection, the reconstituted product may be stored under refrigerated conditions (2C 8C, 36F 46F) 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.Azacitidine for injection 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: Azacitidine for injection reconstituted with non-refrigerated water for injection for subcutaneous administration may be stored for up to hour at25C (77F) or for up to8 hoursbetween 2C and 8C (36F and46F);whenreconstituted with refrigerated (2C 8C, 36F 46F) 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 azacitidine for injection vials to achieve the desired dose. Reconstitute each vial with 10 mL sterile water for injection. Vigorouslyshakeor rollthe vial until all solidsaredissolved.Theresulting 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 ofazacitidine for injectionsolutiontodeliver the desired dose and inject into 50 -100 mL infusion bag of either 0.9% Sodium Chloride Injection or Lactated Ringers Injection.. Intravenous Solution IncompatibilityAzacitidine forinjection is incompatible with5% Dextrose solutions, Hespan, or solutions that contain bicarbonate. These solutions have the potential to increase the rate of degradation of azacitidine for injection and should therefore be avoided.. Intravenous Administration Azacitidine for injection 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 azacitidine for injection vial.. Solution Stability: Azacitidine for injection reconstituted for intravenous administration may be stored at 25C (77F), but administration must be completed within hour of reconstitution.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Azacitidine for injection is supplied as lyophilized powder in 100 mg single-dose vials.. Lyophilizedpowderin100mgsingle-dose vials (3).. Lyophilizedpowderin100mgsingle-dose vials (3).

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 SuppliedAzacitidine for injection is supplied as lyophilized powder in 100 mg single-dose vials packaged in cartons of vial (NDC 51991-797-98).. StorageStore unreconstituted vials at 25 (77 F); excursions permittedto15-30 (59-86 F) (See USP Controlled Room Temperature).. Handling and DisposalAzacitidine for injection is cytotoxic drug. Follow applicable special handling and disposal procedures.1.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Azacitidine for injection 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) Azacitidine for injection 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. HepatotoxicityinPatientswith 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 azacitidine for injection. Advise males with female sexual partners of reproductive potential to not father child and to use effective contraception during treatment with azacitidine for injection. 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 azacitidine for injection [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no information regarding the presence of azacitidine in human milk, the effects of azacitidine on the breastfed infant, or the effects of azacitidine 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 azacitidine advise patients not to breastfeed during treatment with azacitidine.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Azacitidine for injection is pyrimidine nucleoside analog of cytidine. Azacitidine for injection 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 ofDNAsynthesis.Hypomethylation may restore normal functiontogenesthat 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 oftrpE8,EscherichiacolistrainsWP14Pro,WP3103P,WP3104P,andCC103;inin vitro forward gene mutation assay in mouse lymphoma cells andhumanlymphoblastcells; and inanin 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.

OVERDOSAGE SECTION.

10 OVERDOSAGE. One case of overdose with azacitidine 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 azacitidine overdosage.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 100 mg Vial Carton. NDC 51991-797-98Azacitidinefor Injection100 mg/vialFor Subcutaneous AndIntravenous Use OnlySingle-Dose VialbreckenridgeA TowaCompanyRx Only. PRINCIPAL DISPLAY PANEL 100 mg Vial Carton.

PEDIATRIC USE SECTION.

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

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 absorbedafter 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 1dose 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 thatazacitidine may bemetabolizedby 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=10.6uM) 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 atconcentrations of 1.0 uM to 100 uM does not induceCYP 1A2, 2C19, or 3A4/5.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. Thefollowingadversereactions have been identified duringpostmarketinguse of azacitidine. 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary Based on its mechanismof action and findings in animals,azacitidine 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. Data. Animal 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 gestationdays and10; averageliveanimalsperlitterwasreducedto9%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) Azacitidine for injection 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 25 (77 F); excursions permittedto15-30 (59-86 F) (See USP Controlled Room Temperature).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation:Discontinuenursingtakingintoconsideration the importance of drug to mother (8.2).. Lactation:Discontinuenursingtakingintoconsideration the importance of drug to mother (8.2).. 8.1 Pregnancy. Risk Summary Based on its mechanismof action and findings in animals,azacitidine 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. Data. Animal 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 gestationdays and10; averageliveanimalsperlitterwasreducedto9%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 azacitidine on the breastfed infant, or the effects of azacitidine 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 azacitidine advise patients not to breastfeed during treatment with azacitidine. 8.3 Females and Males of Reproductive Potential. Based on its mechanism of action and findings in animals,azacitidine for injection can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingVerifythe pregnancy status of females of reproductive potential prior to initiating azacitidine for injection.. Contraception. FemalesAdvise females of reproductive potential to avoid pregnancy during treatment with azacitidine for injection.. MalesMales with female sexual partners of reproductive potential should not father child and should use effective contraception during treatment with azacitidine for injection.. 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,NeutropeniaandThrombocytopenia: Monitor complete blood counts (CBC) frequently (5.1).Hepatotoxicity: Patients with severe preexistinghepaticimpairment are at higher risk for toxicity (5.2).RenalToxicity: Monitorpatientswith renalimpairment for toxicitysince azacitidine and its metabolites are primarily excreted by the kidneys (5.3). Tumor LysisSyndrome: Azacitidinefor injection maycausefatal or serious tumor lysis syndrome, including in patients with MDS. Assess baseline risk and monitor and treat as appropriate (5.4). Embryo-FetalRisk: Azacitidine for injection can cause fetal harm. Advisefemales with reproductive potential of the potential risk to fetus and to avoid pregnancy (5.5).. Anemia,NeutropeniaandThrombocytopenia: Monitor complete blood counts (CBC) frequently (5.1).. Hepatotoxicity: Patients with severe preexistinghepaticimpairment are at higher risk for toxicity (5.2).. RenalToxicity: Monitorpatientswith renalimpairment for toxicitysince azacitidine and its metabolites are primarily excreted by the kidneys (5.3). Tumor LysisSyndrome: Azacitidinefor injection maycausefatal or serious tumor lysis syndrome, including in patients with MDS. Assess baseline risk and monitor and treat as appropriate (5.4). Embryo-FetalRisk: Azacitidine for injection can cause fetal harm. Advisefemales with reproductive potential of the potential risk to fetus and to avoid pregnancy (5.5).. 5.1 Anemia, Neutropenia and Thrombocytopenia. Azacitidine causes anemia, neutropenia and thrombocytopenia. Monitor complete blood counts frequently for response and/or toxicity, at minimum, prior to each dosingcycle.Afteradministrationoftherecommendeddosageforthefirstcycle,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 azacitidine 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, definedas afall inserum bicarbonateto <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. Azacitidine for injection 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 findingsinanimals,azacitidine for injection 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 azacitidine for injection [see Use in Specific Populations (8.3)]. Men should be advised to not father child while receiving treatment with azacitidine for injection.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Pediatric use information is approved for Celgene Corporations Vidaza (azacitidine for injection). However, due to Celgene Corporations marketing exclusivity rights, this drug product is not labeled with that information.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.1)5/2022Warnings and Precautions (5.1, 5.6) 5/2022.