Azacitidine

Azacitidine for injection is a nucleoside metabolic inhibitor indicated for the treatment of: Adult 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).

1.1Myelodysplastic Syndromes

(MDS) Azacitidine for injection is indicated for treatment of adult 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). Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection). However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

Do not substitute azacitidine for injection for oral azacitidine. The indications and dosing regimen for azacitidine for injection differ from that of oral azacitidine ( 2.1 , 5.1 ). MDS: The recommended starting dosage for the first treatment cycle, for all patients regardless of baseline hematology values, is Azacitidine for injection75 mg/m 2 daily for 7 days to be administered by subcutaneous injection or intravenous infusion. See full prescribing information for schedule for subsequent cycles. Premedicate for nausea and vomiting. Continue treatment as long as the patient continues to benefit. Monitor all patients for hematologic response and for renal toxicity; delay or reduce dosage as appropriate ( 2.3 , 2.6 , 2.7 ).

2.1Important Administration Information Do

not substitute azacitidine for injection for oral azacitidine. The indications and dosing regimen for azacitidine for injection differ from that of oral azacitidine

2.2First Treatment Cycle for Adults The

recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg/m 2 subcutaneously or intravenously, daily for 7 days. Premedicate patients for nausea and vomiting. Obtain complete blood counts, liver chemistries and serum creatinine prior to the first dose.

2.3Subsequent Treatment Cycles for Adults Repeat

cycles every 4 weeks. The dose may be increased to 100 mg/m 2 if no beneficial effect is seen after 2 treatment cycles and if no toxicity other than nausea and vomiting has occurred. It is recommended that patients be treated for a minimum of 4 to 6 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 , and delay or reduce dosage if necessary . Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection). However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

2.5Dosage Adjustment Based on Hematology Laboratory

Values For adult patients with baseline (start of treatment) WBC greater than or equal to 3 x10 9 /L, ANC greater than or equal to 1.5 x10 9 /L, and platelets greater than or equal to 75 x10 9 /L, adjust the dose as follows, based on nadir counts for any given cycle: Nadir Counts % Dose in the Next Course ANC (x10 9 /L) Less than 0.5 0.5 –1.5 Greater than

1.5Platelets

(x10 9 /L) Less than 25 25-50 Greater than 50 50% 67% 100% For adult patients whose baseline counts are WBC less than 3 x10 9 /L, ANC less than 1.5 x10 9 /L, or platelets less than 75 x10 9 /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 baseline Bone Marrow Biopsy Cellularity at Time of Nadir (%) 30-60 15-30 Less than 15 50-75 Greater than 75 % Dose in the Next Course 100 50 33 75 50 33 If a 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 a greater than 25% increase above the nadir is not seen by day 28, reassess counts every 7 days.

If a 25% increase is not seen by day 42, reduce the scheduled dose by 50%. Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection). However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

2.6Dosage 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 serumcreatinine occur, delay the next cycle until values return to normal or baseline and reduce the dose by 50% for the next course .

2.7Use 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 .

2.8Preparation of Azacitidine For Injection Azacitidine for

injection is a hazardous 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. Do not save any unused portions for later administration.

2.9Instructions for Subcutaneous Administration Reconstitute

azacitidine for injection aseptically with 4 mL Sterile Water for Injection, USP to obtain a concentration of 25 mg/mL. Inject the diluent slowly into the vial. Vigorously shake or roll the vial until a uniform suspension is achieved. The suspension will be cloudy. Do not filter the suspension after reconstitution.

Doing so could remove the active substance. Preparation for Immediate Subcutaneous Administration: For doses requiring more than 1 vial, divide the dose equally between the syringes (e.g., dose 150 mg = 6 mL, 2 syringes with 3 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 1 hour, but must be administered within 1 hour after reconstitution. Preparation for Delayed Subcutaneous Administration: The reconstituted product may be kept in the vial or drawn into a syringe. For doses requiring more than 1 vial, divide the dose equally between the syringes (e.g., dose 150 mg = 6 mL, 2 syringes with 3 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. See Table 2 for suspension stability storage timelines based on the temperature of the diluent for delayed subcutaneous administration.

After removal from refrigerated conditions, the suspension may be allowed to equilibrate to room temperature for up to 30 minutes prior to administration. Subcutaneous Administration To provide a homogeneous suspension, the contents of the syringe must be re-suspended by inverting the syringe 2-3 times and vigorously rolling the syringe between the palms for 30 seconds immediately prior to administration. 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. Table 2 Suspension Stability : Storage timelines based on the temperature of the diluent for suspension stability storage: Suspension Stability Storage timelines Diluent Storage Temperature/Duration Room temperature (25°C / 77°F) Sterile Water for Injection, USP Store at room temperature at 25°C (77°F) for up to 1 hour or refrigerated at 2°C to 8°C (36°F to 46°F) for up to 8 hours.

Cold (2°C to 8°C / 36°F to 46°F) Sterile Water for Injection, USP Store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 22 hours.

2.10Instructions for Intravenous Administration Parenteral

drug product should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use the product if there is evidence of particulate matter or discoloration. Adult Patients with MDS Reconstitute the appropriate number of azacitidine for injection vials to achieve the desired dose.

Reconstitute each vial with 10 mL Sterile Water for Injection, USP. 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. Withdraw the required amount of azacitidine for injection solution to deliver the desired dose and inject into a 50 -100 mL infusion bag of either 0.9% Sodium Chloride Injection, USP or Lactated Ringer’s Injection, USP. Intravenous Solution Incompatibility Azacitidine for injection is incompatible with 5% Dextrose Injection, USP 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 a period of 10 - 40 minutes.

The administration must be completed within 1 hour of reconstitution of the azacitidine for injection vial. Solution Stability : Azacitidine for injection reconstituted and diluted for intravenous administration may be stored at 25°C (77°F), but administration must be completed within 1 hour of reconstitution. Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection).

However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

Risks of Substitution with Other Azacitidine Products: Do not substitute azacitidine for injection for oral azacitidine ( 2.1 , 5.1 ). Anemia, Neutropenia and Thrombocytopenia: Monitor complete blood counts (CBC) frequently. Hepatotoxicity: Patients with severe preexisting hepatic impairment are at higher risk for toxicity. Renal Toxicity: Monitor patients with renal impairment for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys. Tumor Lysis Syndrome: Azacitidine for injection may cause fatal or serious tumor lysis syndrome, including in patients with MDS. Assess baseline risk and monitor and treat as appropriate. Embryo-Fetal Toxicity: Azacitidine for injection can cause fetal harm. Advise female patients and male patients with female partners of reproductive potential of the potential risk to a fetus and to use effective contraception.

5.1Risks of Substitution with Other Azacitidine Products

Due to substantial differences in the pharmacokinetic parameters , the recommended dose and schedule for azacitidine for injection are different from those of oral azacitidine products. Treatment of patients using azacitidine for injection at the recommended dosage of oral azacitidine may result in a fatal adverse reaction. Treatment of patients using oral azacitidine at the doses recommended for azacitidine for injection may not be effective.

Do not substitute azacitidine for injection for oral azacitidine .

5.2Anemia, Neutropenia and Thrombocytopenia Azacitidine for

injection causes anemia, neutropenia and thrombocytopenia in adult patients with MDS. Monitor complete blood counts frequently for response and/or toxicity, at a minimum, prior to each dosing cycle. In adult patients with MDS, after administration of the recommended dosage for the first cycle, adjust dosage for subsequent cycles based on nadir counts and hematologic response . Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection). However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

5.3Hepatotoxicity 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 . Monitor liver chemistries prior to initiation of therapy and with each cycle. Safety and effectiveness of azacitidine for injection in patients with MDS and hepatic impairment have not been studied as these patients were excluded from the clinical trials.

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

5.4Renal 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 non-MDS conditions. In addition, renal tubular acidosis, defined as a fall in serum bicarbonate to <20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium <3 mEq/L) developed in 5 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 . 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 closelyfor toxicity . Patients with MDS and renal impairment were excluded from the clinical studies.

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

5.5Tumor 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.

5.6Embryo-Fetal Toxicity Based on the

mechanism of action and findings in animals, azacitidine for injection can cause fetal harm when administered to a pregnant woman. Azacitidine administered to pregnant rats via a single intraperitoneal (IP) dose approximating 8% of the recommended human daily dose caused fetal death and anomalies. Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment with azacitidine for injection and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with azacitidine for injection and for 3 months after the last dose .

Advanced Malignant Hepatic Tumors . Hypersensitivity to Azacitidine or Mannitol (4 .2 ) .

4.1Advanced Malignant Hepatic Tumors Azacitidine

for injection is contraindicated in patients with advanced malignant hepatic tumors .

4.2Hypersensitivity to Azacitidine or Mannitol Azacitidine for

injection is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol.

8.1Pregnancy Risk Summary Based on

its mechanism of action and findings in animals, azacitidine for injection can cause fetal harm when administered to a pregnant woman . 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 . 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 a 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 Data Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single IP (intraperitoneal) injection of 6 mg/m 2 (approximately 8% of the recommended human daily dose on a mg/m 2 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/m 2 (approximately 4%-16% the recommended human daily dose on a mg/m 2 basis). In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4-8 (postimplantation) at a dose of 6 mg/m 2 (approximately 8% of the recommended human daily dose on a mg/m 2 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 a single IP dose of 3 to 12 mg/m 2 (approximately 8% the recommended human daily dose on a mg/m 2 basis) given on gestation day 9, 10, 11 or 12.

In this study azacitidine caused fetal death when administered at 3-12 mg/m 2 on gestation days 9 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).

8.3Females 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 a pregnant woman . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating azacitidine for injection. Contraception Females Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with azacitidine for injection and for 6 months after the last dose.

Males Advise males with female partners of reproductive potential to use effective contraception during treatment with azacitidine for injection and for 3 months after the last dose. Infertility Based on animal data, azacitidine could have an effect on male or female fertility.

The following adverse reactions are described in other labelingsections: Anemia, Neutropenia and Thrombocytopenia Hepatotoxicity in Patients with Severe Pre-existing Hepatic Impairment Renal Toxicity Tumor Lysis Syndrome Most common adverse reactions (>30%) in adult patients with MDS 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. To report SUSPECTED ADVERSE REACTIONS, contact Dr. REDDY’S LABORATORIES Inc., at 1-888-375-3784or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1Clinical Trials Experience Because

clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. MDS The data described below reflect exposure to azacitidine for injection in 443 patients with MDS from 4 clinical studies. Study 1 was a supportive-care controlled trial (subcutaneous administration), Studies 2 and 3 were single arm studies (one with subcutaneous administration and one with intravenous administration), and Study 4 was an international randomized trial (subcutaneous administration) . In Studies 1, 2 and 3, a total of 268 patients were exposed to azacitidine for injection, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one year).

Azacitidine for injection 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/m 2 . In Study 4, a total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed to azacitidine for injection.

Of these patients, 119 were exposed for 6 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 for injection doses of 75 mg/m 2 . Most Commonly Occurring Adverse Reactions (Subcutaneous or Intravenous Route) in Adult Patients with MDS: 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) in Adult Patients with MDS: Discontinuation: leukopenia, thrombocytopenia, neutropenia. Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia.

Dose Reduced: leukopenia, neutropenia, thrombocytopenia. Table 3 presents adverse reactions occurring in at least 5% of patients treated with azacitidine for injection (subcutaneous) in Studies 1 and 2. It is important to note that duration of exposure was longer for the azacitidine for injection-treated group than for the observation group: patients received azacitidine for injection for a mean of 11.4 months while mean time in the observation arm was 6.1 months.

Table 3: Most Frequently Observed Adverse Reactions ( ≥ 5% in All Subcutaneous Azacitidine for Injection Treated Patients; Studies 1 and 2) Number (%) of Patients System Organ Class Preferred Term a All Azacitidine For Injection b (N=220) Observation c (N=92) Blood and lymphatic system disorders Anemia 153 59 Anemia aggravated 12 5 Febrile neutropenia 36 4 Leukopenia 106 27 Neutropenia 71 10 Thrombocytopenia 144 42 Gastrointestinal disorders Abdominal tenderness 26 1 Constipation 74 6 Diarrhea 80 13 Gingival bleeding 21 4 Loose stools 12 0 Mouth hemorrhage 11 1 Nausea 155 16 Stomatitis 17 0 Vomiting 119 5 General disorders and administration site conditions Chest pain 36 5 Injection site bruising 31 0 Injection site erythema 77 0 Injection site granuloma 11 0 Injection site pain 50 0 Injection site pigmentation changes 11 0 Injection site pruritus 15 0 Injection site reaction 30 0 Injection site swelling 11 0 Lethargy 17 2 Malaise 24 1 Pyrexia 114 28 Infections and infestations Nasopharyngitis 32 3 Pneumonia 24 5 Upper respiratory tract infection 28 4 Injury, poisoning, and procedural complications Post procedural hemorrhage 13 1 Metabolism and nutrition disorders Anorexia 45 6 Musculoskeletal and connective tissue disorders Arthralgia 49 3 Chest wall pain 11 0 Myalgia 35 2 Nervous system disorders Dizziness 41 5 Headache 48 10 Psychiatric disorders Anxiety 29 3 Insomnia 24 4 Respiratory, thoracic and mediastinal disorders Dyspnea 64 11 Skin and subcutaneous tissue disorders Dry skin 11 1 Ecchymosis 67 14 Erythema 37 4 Rash 31 9 Skin nodule 11 1 Urticaria 13 1 Vascular disorders Hematoma 19 0 Hypotension 15 2 Petechiae 52 8 a Multiple terms of the same preferred terms for a patient are only counted once within each treatment group. b Includes adverse reactions from all patients exposed to azacitidine for injection, including patients after crossing over from observations. c Includes adverse reactions from observation period only; excludes any adverse events after crossover to azacitidine for injection. Table 4 presents adverse reactions occurring in at least 5% of patients treated with azacitidine for injection in Study 4. Similar to Studies 1 and 2 described above, duration of exposure to treatment with azacitidine for injection was longer (mean 12.2 months) compared with best supportive care (mean 7.5 months).

Table 4: Most Frequently Observed Adverse Reactions ( ≥ 5% in the Azacitidine For Injection Treated Patients and the Percentage with NCI CTC Grade 3/4 Reactions; Study 4) Number (%) of Patients Any Grade Grade 3/4 System Organ Class Preferred Term a 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 Anemia 90 45 24 9 Febrile neutropenia 24 10 22 7 Leukopenia 32 2 26 1 Neutropenia 115 29 107 22 Thrombocytopenia 122 35 102 29 Gastrointestinal disorders Abdominal pain 22 7 7 0 Constipation 88 8 2 0 Dyspepsia 10 2 0 0 Nausea 84 12 3 0 Vomiting 47 7 0 0 General disorders and administration site conditions Fatigue 42 12 6 2 Injection site bruising 9 0 0 0 Injection site erythema 75 0 0 0 Injection site hematoma 11 0 0 0 Injection site induration 9 0 0 0 Injection site pain 33 0 0 0 Injection site rash 10 0 0 0 Injection site reaction 51 0 1 0 Pyrexia 53 18 8 1 Infections and infestations Rhinitis 10 1 0 0 Upper respiratory tract infection 16 4 3 0 Urinary tract infection 15 3 3 0 Investigations Weight decreased 14 0 1 0 Metabolism and nutrition disorders Hypokalemia 11 3 3 3 Nervous system disorders Lethargy 13 2 0 1 Psychiatric disorders Anxiety 9 1 0 0 Insomnia 15 3 0 0 Renal and urinary disorders Hematuria 11 2 4 1 Respiratory, thoracic and mediastinal disorders Dyspnea 26 5 6 2 Dyspnea exertional 9 1 0 0 Pharyngolaryngeal pain 11 3 0 0 Skin and subcutaneous tissue disorders Erythema 13 3 0 0 Petechiae 20 4 2 0 Pruritus 21 2 0 0 Rash 18 1 0 0 Vascular disorders Hypertension 15 4 2 2 a Multiple reports of the same preferred term from a patient were only counted once within each treatment. In Studies 1, 2 and 4 with subcutaneous administration of azacitidine for injection, 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 be more pronounced during the first 1 to 2 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 azacitidine for injection, the following serious adverse reactions occurring at a rate of <5% (and not described in Tables 2 or 3) 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 hemorrhage Gastrointestinal 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. Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection). However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

6.2Postmarketing Experience The

following adverse reactions have been identified during postmarketing use of azacitidine for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Interstitial lung disease -Tumor lysis syndrome - Injection site necrosis - Sweet’s syndrome (acute febrile neutrophilic dermatosis) - Necrotizing fasciitis (including fatal cases) - Differentiation syndrome - Pericardial effusion - Pericarditis - Cutaneous vasculitis