Vidaza Drug Information

Generic name: AZACITIDINE

Nucleoside Metabolic Inhibitor [EPC]

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Uses of Vidaza

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). ( 1.1 )
Pediatric patients aged 1 month and older with newly diagnosed Juvenile Myelomonocytic Leukemia (JMML). ( 1.2 ) 1.1 Myelodysplastic Syndromes (MDS) VIDAZA ® 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). 1.2 Juvenile Myelomonocytic Leukemia (JMML) VIDAZA is indicated for the treatment of pediatric patients aged one month and older with newly diagnosed JMML.

Dosage & Administration of Vidaza

Pediatric Patients with JMML	Recommended Dose
Age 1 month to less than 1 year ORweighing less than 10 kg	2.5 mg/kg
Age 1 year and older AND weighing 10 kgor greater	75 mg/m²

Side Effects of Vidaza

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 VIDAZA 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 VIDAZA, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one year). VIDAZA was studied primarily in supportive-care controlled and uncontrolled trials (n=150 and n=118, respectively). The population in the subcutaneous studies (n=220) was 23 to 92 years old (mean 66.4 years), 68% male, and 94% white, and had MDS or AML. The population in the intravenous study (n=48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white.

Most patients received average daily doses between 50 and 100 mg/m 2. In Study 4, a total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed to VIDAZA. Of these patients, 119 were exposed for 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 VIDAZA 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 VIDAZA (subcutaneous) in Studies 1 and 2. It is important to note that duration of exposure was longer for the VIDAZA-treated group than for the observation group: patients received VIDAZA for 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 VIDAZA Treated Patients; Studies 1 and 2) Number (%) of Patients System Organ Class Preferred Term a All VIDAZA b (N=220) Observation c (N=92) 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 VIDAZA, including patients after crossing over from observations. c Includes adverse reactions from observation period only; excludes any adverse events after crossover to VIDAZA. Blood and lymphatic system disorders 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 Table 4 presents adverse reactions occurring in at least 5% of patients treated with VIDAZA in Study 4. Similar to Studies 1 and 2 described above, duration of exposure to treatment with VIDAZA was longer (mean 12.2 months) compared with best supportive care (mean 7.5 months). Table 4: Most Frequently Observed Adverse Reactions (≥ 5% in the VIDAZA 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 VIDAZA (N=175) Best Supportive Care Only (N=102) VIDAZA (N=175) Best Supportive Care Only (N=102) a Multiple reports of the same preferred term from a patient were only counted once within each treatment.

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 In Studies 1, 2 and 4 with subcutaneous administration of VIDAZA, adverse reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site erythema/reaction tended to increase in incidence with higher doses of VIDAZA. Adverse reactions that tended to be more pronounced during the first 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 VIDAZA, 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. Juvenile Myelomonocytic Leukemia (JMML) The safety of VIDAZA was evaluated in pediatric patients with JMML (N=18; 0.2-6.9 years old) in Study AZA-JMML-001 . Patients received VIDAZA as intravenous infusion daily for 7 days in a 28-day cycle . Sixteen patients completed 3 cycles of therapy and 5 of the 16 patients completed 6 cycles. The median treatment duration was 12.3 weeks (range: 4.0 to 30.6 weeks) and the median total number of treatment cycles completed was 3 cycles (range: 1 to 6 cycles). Serious adverse reactions occurred in 67% of patients who received VIDAZA for JMML. Permanent discontinuation of VIDAZA due to an adverse reaction occurred in a single patient who had abdominal pain and acute respiratory distress syndrome.

The most common (≥30%) adverse reactions were pyrexia, rash, upper respiratory tract infection, and anemia. Table 5 summarizes the adverse reactions in pediatric JMML. Table 5: Most Frequently Observed Adverse Reactions (≥10%) in Pediatric Patients with JMML Receiving VIDAZA in Study AZA-JMML-001 Adverse Reaction All Grades N=18 % Grade 3 or 4 N=18 % General disorders and administration site conditions Pyrexia 61 0 Edema a 11 0 Skin and subcutaneous tissue disorders Rash b 44 0 Pruritus c 22 0 Dermatitis allergic 11 0 Petechiae 11 0 Infections and infestations Upper respiratory tract infection d 44 6 Febrile infection 11 6 Fungal infection e 11 6 Pneumonia f 11 0 Blood and lymphatic system disorders Anemia 39 33 Thrombocytopenia 28 22 Neutropenia 17 11 Febrile Neutropenia 11 6 Lymphadenopathy 11 6 Gastrointestinal disorders Vomiting 28 0 Abdominal pain g 22 11 Constipation 22 0 Diarrhea 22 6 Hemorrhage h 11 0 Nausea 11 0 Ascites 11 6 Respiratory, thoracic and mediastinal disorders Cough 22 0 Epistaxis 17 6 Metabolism and nutrition disorders Hyperuricemia 17 0 Fluid retention 11 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain i 11 0 a Grouped term includes: face edema, generalized edema, edema peripheral. b Grouped term includes: rash, rash macular, dermatitis bullous, rash maculo-papular, rash papular, rash pruritic. c Grouped term includes: pruritis, pruritis generalized. d Grouped term includes: influenza, nasopharyngitis, Parainfluenzae virus infection, respiratory tract infection, rhinitis, upper respiratory tract infection, and viral upper respiratory tract infection e Grouped term includes: anal candidiasis, Candida infection, oral candidiasis. f Grouped term includes: lung infection, pneumonia respiratory syncytial viral. g Grouped term includes: abdominal pain, abdominal pain upper. h Grouped term includes: mouth hemorrhage, rectal hemorrhage. i Grouped term includes: back pain, musculoskeletal pain, non-cardiac chest pain, pain in extremity.

Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of VIDAZA. 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

Warnings & Cautions for Vidaza

Risks of Substitution with Other Azacitidine Products: Do not substitute VIDAZA for oral azacitidine ( 2.1 , 5.1 ).
Anemia, Neutropenia and Thrombocytopenia: Monitor complete blood counts (CBC) frequently ( 5.2 ).
Hepatotoxicity: Patients with severe preexisting hepatic impairment are at higher risk for toxicity ( 5.3 ).
Renal Toxicity: Monitor patients with renal impairment for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys ( 5.4 ).
Tumor Lysis Syndrome: VIDAZA may cause fatal or serious tumor lysis syndrome, including in patients with MDS. Assess baseline risk and monitor and treat as appropriate ( 5.5 ).
Embryo-Fetal Toxicity: VIDAZA 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 ( 5.6 ). 5.1 Risks of Substitution with Other Azacitidine Products Due to substantial differences in the pharmacokinetic parameters [see Clinical Pharmacology ( 12.3 )] , the recommended dose and schedule for VIDAZA are different from those of oral azacitidine products. Treatment of patients using VIDAZA 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 VIDAZA may not be effective. Do not substitute VIDAZA for oral azacitidine [see Dosage and Administration ( 2.1 )] . 5.2 Anemia, Neutropenia and Thrombocytopenia VIDAZA causes anemia, neutropenia and thrombocytopenia in adult patients with MDS and in pediatric patients with JMML. 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 [see Dosage and Administration ( 2.5 )] . In pediatric patients with JMML, dose reductions due to hematological toxicity are not recommended within the first 3 cycles as hematological toxicity will be difficult to assess and to differentiate from the natural course of the underlying disorder [see Dosage and Administration ( 2.5 )] . 5.3 Hepatotoxicity in Patients with Severe Pre-existing Hepatic Impairment Because azacitidine is potentially hepatotoxic in patients with severe pre-existing hepatic impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have been reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline albumin <30 g/L. Azacitidine is contraindicated in patients with advanced malignant hepatic tumors [see Contraindications ( 4.1 )]. Monitor liver chemistries prior to initiation of therapy and with each cycle. Safety and effectiveness of VIDAZA in patients with MDS or in pediatric patients with JMML and hepatic impairment have not been studied as these patients were excluded from the clinical trials. 5.4 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 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 [see Dosage and Administration ( 2.6 )] . 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 ( 2.6 , 2.7 )] . Patients with MDS or pediatric patients with JMML and renal impairment were excluded from the clinical studies. 5.5 Tumor Lysis Syndrome VIDAZA may cause fatal or serious tumor lysis syndrome, including in patients with MDS. Tumor lysis syndrome may occur despite concomitant use of allopurinol. Assess baseline risk and monitor and treat as appropriate. 5.6 Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, VIDAZA 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 VIDAZA and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with VIDAZA and for 3 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

Pregnancy Safety for Vidaza

Pregnancy Risk Summary Based on its mechanism of action and findings in animals, VIDAZA 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 of Vidaza

Pediatric Use Safety and effectiveness of VIDAZA in pediatric patients with MDS have not been established. The safety and effectiveness of VIDAZA have been established in pediatric patients with newly diagnosed JMML aged 1 month and older and the information on this use is discussed throughout the labeling. The safety and effectiveness of VIDAZA have not been established in pediatric patients younger than 1 month old .

Contraindications for Vidaza

Advanced Malignant Hepatic Tumors ( 4.1 ).
Hypersensitivity to Azacitidine or Mannitol ( 4.2 ). 4.1 Advanced Malignant Hepatic Tumors VIDAZA is contraindicated in patients with advanced malignant hepatic tumors [see Warnings and Precautions ( 5.3 )] . 4.2 Hypersensitivity to Azacitidine or Mannitol VIDAZA is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol.

Overdosage Information for Vidaza

One case of overdose with VIDAZA 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 VIDAZA overdosage.

Clinical Studies of Vidaza

Myelodysplastic Syndromes (MDS) Study 1 was a randomized, open-label, controlled trial carried

out in 53 U.S. sites compared the safety and efficacy of subcutaneous VIDAZA plus supportive care with supportive care alone (“observation”) in adult patients with any of the five FAB subtypes of myelodysplastic syndromes (MDS): refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL). RA and RARS patients were included if they met one or more of the following criteria: required packed RBC transfusions; had platelet counts ≤50.0 x 10 9 /L; required platelet transfusions; or were neutropenic (ANC <1.0 x 10 9 /L) with infections requiring treatment with antibiotics. Patients with acute myelogenous leukemia (AML) were not intended to be included. Supportive care allowed in this study included blood transfusion products, antibiotics, antiemetics, analgesics and antipyretics.

The use of hematopoietic growth factors was prohibited. Baseline patient and disease characteristics are summarized in Table 6; the 2 groups were similar. VIDAZA was administered at a subcutaneous dose of 75 mg/m 2 daily for 7 days every 4 weeks.

The dose was increased to 100 mg/m 2 if no beneficial effect was seen after 2 treatment cycles. The dose was decreased and/or delayed based on hematologic response or evidence of renal toxicity. Patients in the observation arm were allowed by protocol to cross over to VIDAZA if they had increases in bone marrow blasts, decreases in hemoglobin, increases in red cell transfusion requirements, or decreases in platelets, or if they required a platelet transfusion or developed a clinical infection requiring treatment with antibiotics.

For purposes of assessing efficacy, the primary endpoint was response rate (as defined in Table 7). Of the 191 patients included in the study, independent review (adjudicated diagnosis) found that 19 had the diagnosis of AML at baseline. These patients were excluded from the primary analysis of response rate, although they were included in an intent-to-treat (ITT) analysis of all patients randomized. Approximately 55% of the patients randomized to observation crossed over to receive VIDAZA treatment.

Table 6. Baseline Demographics and Disease Characteristics VIDAZA (N=99) Observation (N=92) Gender (n%) Male 72 60 Female 27 32 Race (n%) White 93 85 Black 1 1 Hispanic 3 5 Asian/Oriental 2 1 Age (years) N 99 91 Mean ± SD 67.3 ± 10.39 68.0 ± 10.23 Range 31 - 92 35 - 88 Adjudicated MDS diagnosis at study entry (n%) RA 21 18 RARS 6 5 RAEB 38 39 RAEB-T 16 14 CMMoL 8 7 AML 10 9 Transfusion product used in 3 months before study entry (n%) Any transfusion product 70 59 Blood cells, packed human 66 55 Platelets, human blood 15 12 Hetastarch 0 1 Plasma protein fraction 1 0 Other 2 2 Table 7. Response Criteria RA RARS RAEB RAEB-T CMMoL Complete Response (CR), duration ≥4 weeks Marrow <5% blasts Peripheral Blood Normal CBC if abnormal at baseline Absence of blasts in the peripheral circulation Partial Response (PR), duration ≥4 weeks Marrow No marrow requirements ≥50% decrease in blasts Improvement of marrow dyspoiesis Peripheral Blood ≥50% restoration in the deficit from normal levels of baseline white cells, hemoglobin and platelets if abnormal at baseline No blasts in the peripheral circulation For CMMoL, if WBC is elevated at baseline, a ≥75% reduction in the excess count over the upper limit of normal The overall response rate (CR + PR) of 15.7% in VIDAZA-treated patients without AML (16.2% for all VIDAZA randomized patients including AML) was statistically significantly higher than the response rate of 0% in the observation group (p<0.0001) (Table 8). The majority of patients who achieved either CR or PR had either 2 or 3 cell line abnormalities at baseline (79%; 11/14) and had elevated bone marrow blasts or were transfusion dependent at baseline. Patients responding to VIDAZA had a decrease in bone marrow blasts percentage, or an increase in platelets, hemoglobin or WBC. Greater than 90% of the responders initially demonstrated these changes by the 5 th treatment cycle. All patients who had been transfusion dependent became transfusion independent during PR or CR. The mean and median duration of clinical response of PR or better was estimated as 512 and 330 days, respectively; 75% of the responding patients were still in PR or better at completion of treatment.

Response occurred in all MDS subtypes as well as in patients with adjudicated baseline diagnosis of AML. Table 8. Response Rates VIDAZA (N=89) Observation Before Crossover (N=83) Response n (%) n (%) P value Overall (CR+PR) 14 0 (<0.0001) Complete (CR) 5 0 Partial (PR) 9 0 -- Patients in the observation group who crossed over to receive VIDAZA treatment (47 patients) had a response rate of 12.8%. Study 2, a multi-center, open-label, single-arm study of 72 patients with RAEB, RAEB-T, CMMoL, or AML was also carried out. Treatment with subcutaneous VIDAZA resulted in a response rate (CR + PR) of 13.9%, using criteria similar to those described above. The mean and median duration of clinical response of PR or better was estimated as 810 and 430 days, respectively; 80% of the responding patients were still in PR or better at the time of completion of study involvement.

In Study 3, another open-label, single-arm study of 48 patients with RAEB, RAEB-T, or AML, treatment with intravenous VIDAZA resulted in a response rate of 18.8%, again using criteria similar to those described above. The mean and median duration of clinical response of PR or better was estimated as 389 and 281 days, respectively; 67% of the responding patients were still in PR or better at the time of completion of treatment. Response occurred in all MDS subtypes as well as in patients with adjudicated baseline diagnosis of AML in both of these studies.

VIDAZA dosage regimens in these 2 studies were similar to the regimen used in the controlled study. Benefit was seen in patients who did not meet the criteria for PR or better, but were considered “improved.” About 24% of VIDAZA-treated patients were considered improved, and about 2/3 of those lost transfusion dependence. In the observation group, only 5/83 patients met criteria for improvement; none lost transfusion dependence.

In all 3 studies, about 19% of patients met criteria for improvement with a median duration of 195 days. Study 4 was an international, multicenter, open-label, randomized trial in patients with MDS with RAEB, RAEB-T or modified CMMoL according to FAB classification and Intermediate-2 and High risk according to IPSS classification. Of the 358 patients enrolled in the study, 179 were randomized to receive azacitidine plus best supportive care (BSC) and 179 were randomized to receive conventional care regimens (CCR) plus BSC (105 to BSC alone, 49 to low dose cytarabine and 25 to chemotherapy with cytarabine and anthracycline). The primary efficacy endpoint was overall survival.

The azacitidine and CCR groups were comparable for baseline parameters. The median age of patients was 69 years (range was 38-88 years), 98% were Caucasian, and 70% were male. At baseline, 95% of the patients were higher risk by FAB classification: RAEB (58%), RAEB-T (34%), and CMMoL (3%). By IPSS classification, 87% were higher risk: Int-2 (41%), High (47%). At baseline, 32% of patients met WHO criteria for AML. Azacitidine was administered subcutaneously at a dose of 75 mg/m 2 daily for 7 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 a median of 9 cycles (range 1 to 39), BSC only patients for a median of 7 cycles (range 1 to 26), low dose cytarabine patients for a median of 4.5 cycles (range 1 to 15), and chemotherapy with cytarabine and anthracycline patients for a median of 1 cycle (range 1 to 3, i.e. induction plus 1 or 2 consolidation cycles). In the Intent-to-Treat analysis, patients treated with azacitidine demonstrated a statistically significant difference in overall survival as compared to patients treated with CCR (median survival of 24.5 months vs. 15.0 months; stratified log-rank p=0.0001). The hazard ratio describing this treatment effect was 0.58 (95% CI: 0.43, 0.77). Kaplan-Meier Curve of Time to Death from Any Cause: (Intent-to-Treat Population) Key: AZA = azacitidine; CCR = conventional care regimens; CI = confidence interval; HR = Hazard Ratio Azacitidine treatment led to a reduced need for red blood cell transfusions (see Table 8). 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 9. Effect of Azacitidine on RBC Transfusions in Patients with MDS Efficacy Parameter Azacitidine 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 treatment 1 50/111 (45.0%) 13/114 (11.4%) (95% CI: 35.6%, 54.8%) (95% CI: 6.2%, 18.7%) Number and percent of patients who were transfusion-independent at baseline who became transfusion-dependent on treatment 10/68 (14.7%) 28/65 (43.1%) (95% CI: 7.3%, 25.4%) (95% CI: 30.9%, 56.0%) 1 A 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.

Kaplan-Meier Curve of Time to Death from Any Cause: (Intent-to-Treat Population)

Juvenile Myelomonocytic Leukemia (JMML)

AZA-JMML-001 (NCT02447666) was an international, multicenter, open-label study to evaluate the pharmacokinetics, pharmacodynamics, safety, and activity of VIDAZA prior to hematopoietic stem cell transplantation (HSCT) in a total of 18 pediatric patients (median age of 2.1 years, range 0.2-6.9 years; 61% male; 89% white) with juvenile myelomonocytic leukemia (JMML). Patients with newly diagnosed JMML were included if they met the following criteria: diagnosis confirmed in peripheral blood and bone marrow, and had one of the following: somatic mutation in PTPN11, KRAS, or NRAS and HbF % > 5 x normal value for age, or clinical diagnosis of neurofibromatosis Type 1 (NF-1). Additionally, patients included had no CNS involvement, isolated extramedullary disease, or germline molecular aberrations in CBL, PTPN11, NRAS, or KRAS. Eighteen patients with JMML (13 PTPN11, 3 NRAS, 1 KRAS somatic mutations and 1 clinical diagnosis of neurofibromatosis type 1 ) were enrolled. Patients were treated with intravenous VIDAZA , daily on Days 1 to 7 of a 28-day cycle for a minimum of 3 cycles and a maximum of 6 cycles, provided the patients did not have disease progression or were ready for HSCT between Cycles 4 and 6. The efficacy of VIDAZA was established based on clinical complete remission (cCR) or clinical partial remission (cPR) according to the International JMML response criteria at 3 months (Cycle 3 Day 28). Responses must have been sustained for at least 4 weeks either in the 4-week period preceding or succeeding Cycle 3 Day 28 (i.e., sustained over the period Cycle 2 Day 28 to Cycle 3 Day 28, or Cycle 3 Day 28 to Cycle 4 Day 28). There were a total of 9 patients (50%, 95% CI 26-74) with a confirmed clinical response. Of these 9 patients, there were 3 cCR and 6 cPR. The median time to response was 1.2 months (range 1-1.9 months). The proportion of patients with JMML undergoing HSCT was 94% and the median time to HSCT was 4.6 months (range 2.8-19 months).

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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