AZACITIDINE AZACITIDINE

Azacitidine for injection contains Azacitidine, which is a pyrimidine nucleoside analog of cytidine. Azacitidine is 4-amino-1-β-D-ribofuranosyl-1-s-triazin-2(1 H )-one. The structural formula is as follows: The empirical formula is C 8 H 12 N 4 O 5 . The molecular weight is 244. Azacitidine is a white to off white crystalline powder. Azacitidine was found to be insoluble in acetone, ethanol, and methyl ethyl ketone; slightly soluble in ethanol/water (50/50), propylene glycol, and polyethylene glycol; sparingly soluble in water, water saturated octanol, 5% dextrose in water, N-methyl-2-pyrrolidone, normal saline and 5% Tween 80 in water; and soluble in dimethylsulfoxide (DMSO). The finished product is supplied in a sterile form for reconstitution as a suspension for subcutaneous injection or reconstitution as a solution with further dilution for intravenous infusion. Vials of Azacitidine for injection contain 100 mg of Azacitidine and 100 mg mannitol as a sterile lyophilized powder. structure

Azacitidine for injection is a 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).

The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology values, is Azacitidine for injection 75 mg/m 2 daily for 7 days to be administered by subcutaneous (SC) injection or intravenous (IV) infusion. Premedicate for nausea and vomiting. ( 2.1 ) Repeat cycles every 4 weeks (2.2) . After 2 cycles, may increase dose to 100 mg/m 2 if no beneficial effect is seen and no toxicity other than nausea and vomiting has occurred ( 2.2 ). Patients should be treated for a minimum of 4 to 6 cycles. Complete or partial response may require additional treatment cycles ( 2.2 ). Continue treatment as long as the patient continues to benefit ( 2.2 ). Monitor patients for hematologic response and for renal toxicity; delay or reduce dosage as appropriate ( 2.3 , 2.4 , 2.5 ). 2.1 First Treatment Cycle The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg/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. 2.2 Subsequent Treatment Cycles 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 [ see Warnings and Precautions (5.3) ], and delay or reduce dosage if necessary as described below. 2.3 Dosage Adjustment Based on Hematology Laboratory Values For patients with baseline (start of treatment) WBC ≥3.0 x10 9 /L, ANC ≥1.5 x 10 9 /L, and platelets ≥75.0 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 ) Platelets ( x10 9 / L ) <0.5 <25.0 50% 0.5 –1.5 25.0-50.0 67% >1.5 >50.0 100% For patients whose baseline counts are WBC <3.0 x10 9 /L, ANC<1.5 x10 9 /L, or platelets <75.0 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. Bone Marrow Biopsy Cellularity at Time of Nadir (%) WBC or Platelet Nadir % decrease in counts from baseline 30-60 15-30 <15 % Dose in the Next Course 50-75 100 50 33 >75 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 >25% above the nadir and rising. If a >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%. 2.4 Dosage Adjustment Based on Serum Electrolytes and Renal Toxicity If unexplained reductions in serum bicarbonate levels to <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 a 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 4 mL sterile water for injection. Inject the diluent slowly into the vial. Vigorously shake or roll the vial until a uniform suspension is achieved. The suspension will be cloudy. The resulting suspension will contain Azacitidine 25 mg/mL. Do not filter the suspension after reconstitution. Doing so could remove the active substance. Preparation for Immediate Subcutaneous Administration : Doses greater than 4 mL should be divided equally into 2 syringes. 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. Doses greater than 4 mL should be divided equally into 2 syringes. The product must be refrigerated immediately. When Azacitidine for injection is reconstituted using water for injection that has not been refrigerated, the reconstituted product may be held under refrigerated conditions (2ºC-8ºC, 36ºF-46ºF) for up to 8 hours. When azacitidine for injection is reconstituted using refrigerated (2ºC-8ºC, 36ºF-46ºF) water for injection, the reconstituted product may be stored under refrigerated conditions (2ºC-8ºC, 36ºF-46ºF) for up to 22 hours. After removal from refrigerated conditions, the suspension may be allowed to equilibrate to room temperature for up to 30 minutes prior to administration. Subcutaneous Administration To provide a 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 a uniform, cloudy suspension is achieved. Azacitidine for injection suspension is administered subcutaneously. Doses greater than 4 mL should be divided equally into 2 syringes and injected into 2 separate sites. 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 1 hour at 25°C (77°F) or for up to 8 hours between 2°C and 8°C (36°F and 46°F); when reconstituted with refrigerated (2ºC - 8ºC, 36ºF - 46ºF) water for injection, it may be stored for 22 hours between 2°C and 8°C (36°F and 46°F). 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. Vigorously shake or roll the vial until all solids are dissolved. The resulting solution will contain Azacitidine 10 mg/mL. The solution should be clear. Parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Withdraw the required amount of 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 or Lactated Ringer's Injection. Intravenous Solution Incompatibility Azacitidine for injection is incompatible with 5% 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 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 for intravenous administration may be stored at 25°C (77°F), but administration must be completed within 1 hour of reconstitution.

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

The following adverse reactions are described in other labeling sections: Anemia, Neutropenia and Thrombocytopenia [see Warnings and Precautions (5.1) ] Hepatotoxicity in Patients with Severe Pre-existing Hepatic Impairment [see Warnings and Precautions (5.2) ] Renal Toxicity [see Warnings and Precautions (5.3) ] Tumor Lysis Syndrome [see Warnings and Precautions (5.4) ] Embryo-Fetal Risk [see Warnings and Precautions (5.5) ] Most Commonly Occurring Adverse Reactions (SC or IV Route) : nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by IV route also included petechiae, rigors, weakness and hypokalemia. Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (SC or IV Route): Discontinuation: leukopenia, thrombocytopenia, neutropenia. Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia. Dose Reduced: leukopenia, neutropenia, thrombocytopenia. Most common adverse reactions (>30%) by SC route are: nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia and ecchymosis. Most common adverse reactions by IV route also included petechiae, rigors, weakness and hypokalemia (6.1) . To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy's Laboratories Inc., at 1-888-375-3784 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 a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to azacitidine in 443 MDS patients from 4 clinical studies. Study 1 was a supportive-care controlled trial (SC administration), Studies 2 and 3 were single arm studies (one with SC administration and one with IV administration), and Study 4 was an international randomized trial (SC administration) [ see Clinical Studies (14) ]. In Studies 1, 2 and 3, a total of 268 patients were exposed to Azacitidine, including 116 exposed for 6 cycles (approximately 6 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 IV 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. 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 doses of 75 mg/m 2 . Table 1 presents adverse reactions occurring in at least 5% of patients treated with Azacitidine (SC) in Studies 1 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 a 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 SC Azacitidine Treated Patients; Studies 1 and 2) Number (%) of Patients System Organ Class Preferred Term* All Azacitidine for Injection † ( N = 220 ) Observation ‡ ( N = 92 ) Blood and lymphatic system disorders Anemia 153 (69.5) 59 (64.1) Anemia aggravated 12 (5.5) 5 (5.4) Febrile neutropenia 36 (16.4) 4 (4.3) Leukopenia 106 (48.2) 27 (29.3) Neutropenia 71 (32.3) 10 (10.9) Thrombocytopenia 144 (65.5) 42 (45.7) Gastrointestinal disorders Abdominal tenderness 26 (11.8) 1 (1.1) Constipation 74 (33.6) 6 (6.5) Diarrhea 80 (36.4) 13 (14.1) Gingival bleeding 21 (9.5) 4 (4.3) Loose stools 12 (5.5) 0 Mouth hemorrhage 11 (5.0) 1 (1.1) Nausea 155 (70.5) 16 (17.4) Stomatitis 17 (7.7) 0 Vomiting 119 (54.1) 5 (5.4) General disorders and administration site conditions Chest pain 36 (16.4) 5 (5.4) Injection site bruising 31 (14.1) 0 Injection site erythema 77 (35.0) 0 Injection site granuloma 11 (5.0) 0 Injection site pain 50 (22.7) 0 Injection site pigmentation changes 11 (5.0) 0 Injection site pruritus 15 (6.8) 0 Injection site reaction 30 (13.6) 0 Injection site swelling 11 (5.0) 0 Lethargy 17 (7.7) 2 (2.2) Malaise 24 (10.9) 1 (1.1) Pyrexia 114 (51.8) 28 (30.4) Infections and infestations Nasopharyngitis 32 (14.5) 3 (3.3) Pneumonia 24 (10.9) 5 (5.4) Upper respiratory tract infection 28 (12.7) 4 (4.3) Injury , poisoning , and procedural complications Post procedural hemorrhage 13 (5.9) 1 (1.1) Metabolism and nutrition disorders Anorexia 45 (20.5) 6 (6.5) Musculoskeletal and connective tissue disorders Arthralgia 49 (22.3) 3 (3.3) Chest wall pain 11 (5.0) 0 Myalgia 35 (15.9) 2 (2.2) Nervous system disorders Dizziness 41 (18.6) 5 (5.4) Headache 48 (21.8) 10 (10.9) Psychiatric disorders Anxiety 29 (13.2) 3 (3.3) Insomnia 24 (10.9) 4 (4.3) Respiratory , thoracic and mediastinal disorders Dyspnea 64 (29.1) 11 (12.0) Skin and subcutaneous tissue disorders Dry skin 11 (5.0) 1 (1.1) Ecchymosis 67 (30.5) 14 (15.2) Erythema 37 (16.8) 4 (4.3) Rash 31 (14.1) 9 (9.8) Skin nodule 11 (5.0) 1 (1.1) Urticaria 13 (5.9) 1 (1.1) Vascular disorders Hematoma 19 (8.6) 0 Hypotension 15 (6.8) 2 (2.2) Petechiae 52 (23.6) 8 (8.7) * Multiple terms of the same preferred terms for a patient are only counted once within each treatment group. † Includes adverse reactions from all patients exposed to Azacitidine, including patients after crossing over from observations. ‡ Includes adverse reactions from observation period only; excludes any adverse events after crossover to Azacitidine . Table 2 presents adverse reactions occurring in at least 5% of patients treated with Azacitidine in Study 4. Similar to Studies 1 and 2 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 Patients Any Grade Grade 3 / 4 System Organ Class Preferred Term* Azacitidine ( N = 175 ) Best Supportive Care Only ( N = 102 ) Azacitidine ( N = 175 ) Best Supportive Care Only ( N = 102 ) Blood and lymphatic system disorders Anemia 90 (51.4) 45 (44.1) 24 (13.7) 9 (8.8) Febrile neutropenia 24 (13.7) 10 (9.8) 22 (12.6) 7 (6.9) Leukopenia 32 (18.3) 2 (2.0) 26 (14.9) 1 (1.0) Neutropenia 115 (65.7) 29 (28.4) 107 (61.1) 22 (21.6) Thrombocytopenia 122 (69.7) 35 (34.3) 102 (58.3) 29 (28.4) Gastrointestinal disorders Abdominal pain 22 (12.6) 7 (6.9) 7 (4.0) 0 Constipation 88 (50.3) 8 (7.8) 2 (1.1) 0 Dyspepsia 10 (5.7) 2 (2.0) 0 0 Nausea 84 (48) 12 (11.8) 3 (1.7) 0 Vomiting 47 (26.9) 7 (6.9) 0 0 General disorders and administration site conditions Fatigue 42 (24.0) 12 (11.8) 6 (3.4) 2 (2.0) Injection site bruising 9 (5.1) 0 0 0 Injection site erythema 75 (42.9) 0 0 0 Injection site hematoma 11 (6.3) 0 0 0 Injection site induration 9 (5.1) 0 0 0 Injection site pain 33 (18.9) 0 0 0 Injection site rash 10 (5.7) 0 0 0 Injection site reaction 51 (29.1) 0 1 (0.6) 0 Pyrexia 53 (30.3) 18 (17.6) 8 (4.6) 1(1.0) Infections and infestations Rhinitis 10 (5.7) 1 (1.0) 0 0 Upper respiratory tract infection 16 (9.1) 4 (3.9) 3 (1.7) 0 Urinary tract infection 15 (8.6) 3 (2.9) 3 (1.7) 0 Investigations Weight decreased 14 (8.0) 0 1 (0.6) 0 Metabolism and nutrition disorders Hypokalemia 11 (6.3) 3 (2.9) 3 (1.7) 3 (2.9) Nervous system disorders Lethargy 13 (7.4) 2 (2.0) 0 1 (1.0) Psychiatric disorders Anxiety 9 (5.1) 1 (1.0) 0 0 Insomnia 15 (8.6) 3 (2.9) 0 0 Renal and urinary disorders Hematuria 11 (6.3) 2 (2.0) 4 (2.3) 1 (1.0) Respiratory , thoracic and mediastinal disorders Dyspnea 26 (14.9) 5 (4.9) 6 (3.4) 2 (2.0) Dyspnea exertional 9 (5.1) 1 (1.0) 0 0 Pharyngolaryngeal pain 11 (6.3) 3 (2.9) 0 0 Skin and subcutaneous tissue disorders Erythema 13 (7.4) 3 (2.9) 0 0 Petechiae 20 (11.4) 4 (3.9) 2 (1.1) 0 Pruritus 21 (12.0) 2 (2.0) 0 0 Rash 18 (10.3) 1 (1.0) 0 0 Vascular disorders Hypertension 15 (8.6) 4 (3.9) 2 (1.1) 2 (2.0) *Multiple reports of the same preferred term from a patient were only counted once within each treatment. In Studies 1, 2 and 4 with SC 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. Adverse reactions that tended to be more pronounced during the first 1 to 2 cycles of SC 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 IV and SC studies. Adverse reactions that appeared to be specifically associated with the IV 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 SC or IV Azacitidine, the following serious adverse reactions occurring at a rate of < 5% (and not described in Tables 1 or 2) were reported: Blood and lymphatic system disorders : agranulocytosis, bone marrow failure, pancytopenia splenomegaly. Cardiac disorders : atrial fibrillation, cardiac failure, cardiac failure congestive, cardiorespiratory 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of Azacitidine. 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)