Azacitidine Drug Information

Myelodysplastic 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.

Clinical 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 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, 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 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. 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. 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 (subcutaneous) 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 3: Most Frequently Observed Adverse Reactions (≥ 5% in All Subcutaneous Azacitidine Treated Patients; Studies 1 and 2) Number (%) of Patients System Organ Class Preferred Term a All Azacitidine 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, including patients after crossing over from observations. c Includes adverse reactions from observation period only; excludes any adverse events after crossover to Azacitidine. Table 4 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 4: Most Frequently Observed Adverse Reactions (≥ 5% 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 a 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 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, 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 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, 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, 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. 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.

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) - Differentiation syndrome - Pericardial effusion - Pericarditis - Cutaneous vasculitis

Pregnancy Risk Summary Based on its mechanism of action and findings in animals, Azacitidine 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 ( 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 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).

Pediatric Use Safety and effectiveness of azacitidine in pediatric patients with MDS have not been established. 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.

Advanced Malignant Hepatic Tumors Azacitidine is contraindicated in patients with advanced malignant

hepatic tumors.

Hypersensitivity to Azacitidine or Mannitol Azacitidine is contraindicated in patients with a

known hypersensitivity to azacitidine or mannitol.

One case of overdose with Azacitidine was reported during clinical trials. A patient experienced diarrhea, nausea, and vomiting after receiving a single intravenous dose of approximately 290 mg/m 2, almost 4 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.