Azacitidine Injection

First Treatment Cycle

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. Patients should be premedicated for nausea and vomiting.

Complete blood counts, liver chemistries and serum creatinine should be obtained prior to first dose.

Subsequent Treatment Cycles

Cycles should be repeated 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.  Treat patients 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.

Patients should be monitored for hematologic response and renal toxicities [see Warnings and Precautions (5.3)], and dosage delay or reduction as described below may be necessary. 

Dosage Adjustment Based on Hematology Laboratory Values

• For 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:

Nadir Counts		% Dose in the Next
		Course
ANC (x109/L)	Platelets (x109/L)
<0.5	<25	50%
0.5 to 1.5	25.0 to 50	67%
>1.5	>50	100%

• For 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, dose adjustments should be based 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 the dose of the current treatment should be continued.

WBC or Platelet	Bone Marrow
Nadir	Biopsy Cellularity at Time of Nadir
% decrease in	(%)
counts from baseline	30 to 60	15 to 30	<15
	% Dose in the Next Course
50 to 75	100	50	33
>75	75	50	33

If a nadir as defined in the table above has occurred, the next course of treatment should be given 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, counts should be reassessed every 7 days. If a 25% increase is not seen by day 42, then the patient should be treated with 50% of the scheduled dose.

Dosage Adjustment Based on Serum Electrolytes and Renal Toxicity

If unexplained reductions in serum bicarbonate levels to less than 20 mEq/L occur, the dosage should be reduced by 50% on the next course. Similarly, if unexplained elevations of BUN or serum creatinine occur, the next cycle should be delayed until values return to normal or baseline and the dose should be reduced by 50% on the next treatment course [see Warnings and Precautions (5.3)].

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, care should be taken in dose selection, and it may be useful to monitor renal function [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5)].

Preparation of Azacitidine for Injection

Azacitidine for Injection is a cytotoxic drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing Azacitidine for Injection suspensions [see How Supplied/Storage and Handling (16)].

If reconstituted Azacitidine for Injection comes into contact with the skin, immediately and thoroughly wash with soap and water. If it comes into contact with mucous membranes, flush thoroughly with water.

The Azacitidine for Injection vial is single-dose and does not contain any preservatives. Unused portions of each vial should be discarded properly [see How Supplied/Storage and Handling (16)]. Do not save any unused portions for later administration.

Instructions for Subcutaneous Administration

Azacitidine for Injection should be reconstituted aseptically with 4 mL sterile water for injection. The diluent should be injected 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 (2°C to 8°C, 36°F to 46°F) for up to 12 hours. When Azacitidine for Injection is reconstituted using refrigerated (2°C to 8°C, 36°F to 46°F) water for injection, the reconstituted product may be stored under refrigerated conditions (2°C to 8°C, 36°F to 46°F) for up to 30 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 2 hours at 25°C (77°F) or for up to 12 hours between 2°C and 8°C (36°F and 46°F); when reconstituted with refrigerated (2°C to 8°C, 36°F to 46°F) water for injection, it may be stored for 30 hours between 2°C and 8°C (36°F and 46°F).

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 to 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 to 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.

Azacitidine for Injection is supplied as lyophilized powder in 100 mg single-dose vials. 

Advanced Malignant Hepatic Tumors

Azacitidine for Injection is contraindicated in patients with advanced malignant hepatic tumors [see Warnings and Precautions (5.2)].

Hypersensitivity to Azacitidine

Azacitidine for Injection is contraindicated in patients with a known hypersensitivity to azacitidine.

Azacitidine for Injection contains azacitidine, which is a pyrimidine nucleoside analog of cytidine. Azacitidine is 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one. The structural formula is as follows:

The molecular formula is C8H12N4O5. The molecular weight is 244. Azacitidine is a white to almost white 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. Each vial of Azacitidine for Injection contains 100 mg of azacitidine, 170 mg sucrose, monosodium phosphate monohydrate and disodium hydrogen phosphate, dihydrate as a sterile lyophilized powder.

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 for Injection plus supportive care with supportive care alone (“observation”) in 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 less than or equal to 50 x 109/L; required platelet transfusions; or were neutropenic (ANC less than 1 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 3; the 2 groups were similar.

Azacitidine for Injection 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 for Injection 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 4).

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 for Injection treatment.

Table 3. Baseline Demographics and Disease Characteristics

	Azacitidine for
	Injection	Observation
	(N=99)	(N=92)
Gender (n%)
Male	72 (72.7)	60 (65.2)
Female	27 (27.3)	32 (34.8)
Race (n%)
White	93 (93.9)	85 (92.4)
Black	1 (1.0)	1 (1.1)
Hispanic	3 (3.0)	5 (5.4)
Asian/Oriental	2 (2.0)	1 (1.1)
Age (years)
N	99	91
Mean ± SD	67.3 ± 10.39	68.0 ± 10.23
Range	31 to 92	35 to 88
Adjudicated MDS diagnosis at study entry (n%)
RA	21 (21.2)	18 (19.6)
RARS	6 (6.1)	5 (5.4)
RAEB	38 (38.4)	39 (42.4)
RAEB-T	16 (16.2)	14 (15.2)
CMMoL	8 (8.1)	7 (7.6)
AML	10 (10.1)	9 (9.8)
Transfusion product used in 3 months before study entry (n%)
Any transfusion product	70 (70.7)	59 (64.1)
Blood cells, packed human	66 (66.7)	55 (59.8)
Platelets, human blood	15 (15.2)	12 (13.0)
Hetastarch	0(0.0)	1(1.1)
Plasma protein fraction	1(1.0)	0(0.0)
Other	2(2.0)	2(2.2)

Table 4. Response Criteria

		RA	RARS	RAEB	RAEB-T	CMMoL
Complete Response	Marrow	<5% blasts
Peripheral	Normal CBC if abnormal at baseline
(CR), duration	Blood	Absence of blasts in the peripheral circulation
≥4 weeks
Partial	Marrow	No marrow requirements		≥50% decrease in blasts
Response				Improvement of marrow dyspoiesis
(PR), duration	Peripheral	≥50% restoration in the deficit from normal levels of baseline white cells,
≥4 weeks	Blood	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 Azacitidine for Injection-treated patients without AML (16.2% for all Azacitidine for Injection randomized patients including AML) was statistically significantly higher than the response rate of 0% in the observation group (p<0.0001) (Table 5). 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 for Injection 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.

Table 5. Response Rates

	Azacitidine for	Observation Before
	Injection	Crossover
	(N=89)	(N=83)
Response	n (%)	n (%)	P value
Overall (CR+PR)	14 (15.7)	0 ( 0.0)	(<0.0001)
Complete (CR)	5 ( 5.6)	0 ( 0.0)	(0.06)
Partial (PR)	9 (10.1)	0 ( 0.0)	--

Patients in the observation group who crossed over to receive Azacitidine for Injection 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 for Injection 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 for Injection 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 for Injection 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 for Injection-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 MDS patients 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 to 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 6). 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 6. Effect of Azacitidine on RBC Transfusions in MDS Patients

Efficacy Parameter		Conventional Care
	Azacitidine plus BSC	Regimens
	(n= 179)	(n= 179)
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.
Number and percent of patients who were	50/111 (45.0%)	13/114 (11.4%)
transfusion dependent at baseline who became
transfusion independent on treatment1
	(95% CI: 35.6%, 54.8%)	(95% CI: 6.2%, 18.7%)
Number and percent of patients who were
transfusion-independent at baseline who	10/68 (14.7%)	28/65 (43.1%)
became transfusion-dependent on treatment
	(95% CI: 7.3%, 25.4%)	(95% CI: 30.9%, 56.0%)

Instruct patients to inform their physician about any underlying liver or renal disease.

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)] .

Advise females of reproductive potential to use effective contraception during treatment with Azacitidine for Injection and for one week after the final dose [see Use in Specific Populations (8.3)].

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Azacitidine for Injection and for 3 months after the final dose [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with Azacitidine for Injection and for 24 hours after the final dose [see Use in Specific Populations (8.2)].

Infertility

Advise males of the potential for reduced fertility from Azacitidine for Injection [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].

Manufactured by:
Sindan Pharma SRL
11 Ion Mihalache Blvd.
Bucharest 1, Romania 011171

For BluePoint Laboratories

Revised – September 2016

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.