1.1 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.

2.1 Important 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 [see Warnings and Precautions (5.1)]

2.2 First 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/m2 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.

2.3 Subsequent Treatment Cycles for Adults

Repeat cycles every 4 weeks. The dose may be increased to 100 mg/m2 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 (5.4)], and delay or reduce dosage if necessary [see Dosage and Administration (2.6)].

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.

2.4

2.5 Dosage Adjustment Based on Hematology Laboratory Values

• For adult patients with baseline (start of treatment) WBC greater than or equal to 3 x109/L, ANC greater than or equal to 1.5 x109/L, and platelets greater than or equal to 75 x109/L, adjust the dose as follows, based on nadir counts for any given cycle:

• For adult patients whose baseline counts are WBC less than 3 x109/L, ANC less than 1.5 x109/L, or platelets less than 75 x109/L, base dose adjustments on nadir counts and bone marrow biopsy cellularity at the time of the nadir as noted below, unless there is clear improvement in differentiation (percentage of mature granulocytes is higher and ANC is higher than at onset of that course) at the time of the next cycle, in which case continue the current dose.

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.

2.6 Dosage Adjustment Based on Serum Electrolytes and Renal Toxicity

If unexplained reductions in serum bicarbonate levels to less than 20 mEq/L occur, reduce the dosage by 50% for the next course. Similarly, if unexplained elevations of BUN or serum creatinine occur, delay the next cycle until values return to normal or baseline and reduce the dose by 50% for the next course [see Warnings and Precautions (5.4)].

2.7 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 (5.4) and Use in Specific Populations (8.5)].

2.8 Preparation 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 [see How Supplied/Storage and Handling (16)]. Do not save any unused portions for later administration.

2.9 Instructions for Subcutaneous Administration

Reconstitute azacitidine for injection aseptically with 4 mL Sterile Water for Injection, USP to obtain a concentration of 25 mg per 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.

2.10 Instructions 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 per 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.

4.1 Advanced Malignant Hepatic Tumors

Azacitidine is contraindicated in patients with advanced malignant hepatic tumors [see Warnings and Precautions (5.3)].

4.2 Hypersensitivity to Azacitidine or Mannitol

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

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 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 [see Dosage and Administration (2.1)].

5.2 Anemia, Neutropenia and Thrombocytopenia

Azacitidine 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 [see Dosage and Administration (2.5)].

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.

5.3 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 azacitidine 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.

5.4 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 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.

5.5 Tumor Lysis Syndrome

Azacitidine 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, azacitidine 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 and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with azacitidine and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

6.1 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) [see Clinical Studies (14.1)].

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/m2.

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/m2.

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 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).

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 3 or 4) 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.

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

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

Based on its mechanism of action and findings in animals, azacitidine can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

8.4 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.

8.5 Geriatric Use

Of the total number of patients in Studies 1, 2 and 3, 62% were 65 years and older and 21% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In addition, there were no relevant differences in the frequency of adverse reactions observed in patients 65 years and older compared to younger patients.

Of the 179 patients randomized to azacitidine in Study 4, 68% were 65 years and older and 21% were 75 years and older. Survival data for patients 65 years and older were consistent with overall survival results. The majority of adverse reactions occurred at similar frequencies in patients <65 years of age and patients 65 years of age and older.

Elderly patients are more likely to have decreased renal function. Monitor renal function in these patients [see Dosage and Administration (2.7) and Warnings and Precautions (5.4)].

12.1 Mechanism of Action

Azacitidine is a pyrimidine nucleoside analog of cytidine. Azacitidine is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

The pharmacokinetics of azacitidine were studied in 6 adult patients with MDS following a single 75 mg/m2 subcutaneous dose and a single 75 mg/m2 intravenous dose.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m2, approximately 8% the recommended human daily dose on a mg/m2 basis) administered IP three times per week for 52 weeks. An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine IP at 2.0 mg/kg (6.0 mg/m2, approximately 8% the recommended human daily dose on a mg/m2 basis) once a week for 50 weeks. A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m2 (approximately 20%-80% the recommended human daily dose on a mg/m2 basis) revealed an increased incidence of testicular tumors compared with controls.

The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems Salmonella typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Pro, WP3103P, WP3104P, and CC103; in in vitro forward gene mutation assay in mouse lymphoma cells and human lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells.

Administration of azacitidine to male mice at 9.9 mg/m2 (approximately 9% the recommended human daily dose on a mg/m2 basis) daily for 3 days prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats 3 times per week for 11 or 16 weeks at doses of 15-30 mg/m2 (approximately 20%-40%, the recommended human daily dose on a mg/m2 basis) resulted in decreased weight of the testes and epididymides, and decreased sperm counts accompanied by decreased pregnancy rates and increased loss of embryos in mated females. In a related study, male rats treated for 16 weeks at 24 mg/m2 resulted in an increase in abnormal embryos in mated females when examined on day 2 of gestation.

14.1 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 azacitidine 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 109/L; required platelet transfusions; or were neutropenic (ANC <1.0 x 109/L) with infections requiring treatment with antibiotics. Patients with acute myelogenous leukemia (AML) were not intended to be included. Supportive care allowed in this study included blood transfusion products, antibiotics, antiemetics, analgesics and antipyretics. The use of hematopoietic growth factors was prohibited. Baseline patient and disease characteristics are summarized in Table 6; the 2 groups were similar.

Azacitidine was administered at a subcutaneous dose of 75 mg/m2 daily for 7 days every 4 weeks. The dose was increased to 100 mg/m2 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 azacitidine 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 azacitidine treatment.

The overall response rate (CR + PR) of 15.7% in azacitidine-treated patients without AML (16.2% for all azacitidine 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 azacitidine 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 5th treatment cycle. All patients who had been transfusion dependent became transfusion independent during PR or CR. The mean and median duration of clinical response of PR or better was estimated as 512 and 330 days, respectively; 75% of 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.

Patients in the observation group who crossed over to receive azacitidine 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 azacitidine 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 azacitidine 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. Azacitidine 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 azacitidine-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/m2 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 9). 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.

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.

14.2

How Supplied

Azacitidine for Injection is a white to off-white lyophilized powder or lyophilized cake and is supplied as follows:

Storage

Store unreconstituted vials at 20º to 25ºC (68º to 77ºF); excursions permitted between 15º to 30ºC (59º to 86ºF). [See USP Controlled Room Temperature.]

Discard unused portion.

Sterile, Nonpyrogenic, Preservative-free.
The container closure is not made with natural rubber latex.

Hepatotoxicity in Patients with Severe Pre-Existing Hepatic Impairment

Instruct patients to inform their physician about any underlying liver disease [see Warnings and Precautions (5.3)].

Renal Toxicity

Instruct patients to inform their physician about any underlying renal disease [see Warnings and Precautions (5.4)].

Embryo-Fetal Toxicity

Advise pregnant women of the potential risk to a fetus [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with azacitidine and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with azacitidine and for 3 months after the last dose. Advise patients to report known or suspected pregnancy to their physicians immediately [see Warnings and Precautions (5.6) and Use in Specific Populations (8.3)].

Lactation

Advise patients to avoid breastfeeding while receiving azacitidine and for 1 week after the last dose [see Use in Specific Populations (8.2)].

Infertility
Advise males and females that azacitidine may impair fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].

meitheal®

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Chicago, IL 60631 (USA)

©2024 Meitheal Pharmaceuticals Inc.

Mfd. by Kindos Pharmaceuticals Co., Ltd.
Chengdu, China 611731

Revised: September 2024

LB-194-V4