FDA Label for Azacitidine

1.1 Myelodysplastic Syndromes (Mds)

Azacitidine for Injection is indicated for treatment of patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).

2.1 First Treatment Cycle

The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg/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.

2.2 Subsequent Treatment Cycles

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 (5.3)], and delay or reduce dosage if necessary as described below. 

2.3 Dosage Adjustment Based On Hematology Laboratory Values

• •For patients with baseline (start of treatment) WBC 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) <0.5 0.5 to 1.5 >1.5	Platelets (x109/L) <25 25 to 50 >50	50% 67% 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, 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.

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

If a nadir as defined in the table above has occurred, give the next course 28 days after the start of the preceding course, provided that both the WBC and the platelet counts are 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%.

2.4 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 (5.3)].

2.5 Use In Geriatric Patients

Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, select the dose carefully and monitor renal function [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5)].

2.6 Preparation Of Azacitidine For Injection

Azacitidine for Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.¹

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

2.7 Instructions For Subcutaneous Administration

Reconstitute Azacitidine for Injection aseptically with 4 mL sterile water for injection. Inject the diluent slowly into the vial. Vigorously shake or roll the vial until a uniform suspension is achieved. The suspension will be cloudy. The resulting suspension will contain azacitidine 25 mg/mL. Do not filter the suspension after reconstitution. Doing so could remove the active substance.

Preparation for Immediate Subcutaneous Administration: Doses greater than 4 mL should be divided equally into 2 syringes. The product may be held at room temperature for up to 1 hour, but must be administered within 1 hour after reconstitution.

Preparation for Delayed Subcutaneous Administration: The reconstituted product may be kept in the vial or drawn into a syringe. Doses greater than 4 mL should be divided equally into 2 syringes. The product must be refrigerated immediately. When Azacitidine for Injection is reconstituted using water for injection that has not been refrigerated, the reconstituted product may be held under refrigerated conditions (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).

2.8 Instructions For Intravenous Administration

Reconstitute the appropriate number of Azacitidine for Injection vials to achieve the desired dose. Reconstitute each vial with 10 mL sterile water for injection. Vigorously shake or roll the vial until all solids are dissolved. The resulting solution will contain azacitidine 10 mg/mL. The solution should be clear. Parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Withdraw the required amount of Azacitidine for Injection solution to deliver the desired dose and inject into a 50 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.

3  Dosage Forms And Strengths

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

4.1 Advanced Malignant Hepatic Tumors

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

4.2 Hypersensitivity To Azacitidine

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

5.1 Myelosuppression

Azacitidine for Injection causes anemia, neutropenia and thrombocytopenia. Monitor complete blood counts frequently for response and/or toxicity, at a minimum, prior to each dosing cycle. 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 (2.3)].

5.2 Hepatic Toxicity 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 less than 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 for Injection in patients with MDS and hepatic impairment have not been studied as these patients were excluded from the clinical trials.

5.3 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 nonMDS conditions. In addition, renal tubular acidosis, defined as a fall in serum bicarbonate to less than 20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium less than 3 mEq/L) developed in 5 patients with CML (an unapproved use)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 less than 20 mEq/L or elevations of BUN or serum creatinine occur, reduce or hold the dose [see Dosage and Administration (2.4)].

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 (2.4, 2.5)]. Patients with MDS and renal impairment were excluded from the clinical studies.

5.4 Tumor Lysis Syndrome

Azacitidine for Injection 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.

5.5 Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animals, Azacitidine for Injection can cause fetal harm when administered to a pregnant woman. In animal studies, azacitidine caused adverse developmental outcomes when administered to mice and rats at doses of 3 to 12 mg/m² and 6 mg/m² (approximately 4% to 16% and 8%) of the recommended human daily dose of 75 mg/m², respectively. Advise pregnant women of the potential risk to the fetus [see Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with Azacitidine for Injection and for 6 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Azacitidine for Injection and for 3 months following the final dose [see Use in Specific Populations (8.1and 8.3) and Clinical Pharmacology (12.3)]. Advise men to avoid fathering a child while receiving treatment with Azacitidine for Injection.

6  Adverse Reactions

The following adverse reactions are described in other labeling sections:

• •Myelosuppression [see Warnings and Precautions (5.1)]
• •Hepatic Toxicity in Patients with Severe Pre-existing Hepatic Impairment [see Warnings and Precautions (5.2)] 
• •Renal Toxicity [see Warnings and Precautions (5.3)]
• •Tumor Lysis Syndrome [see Warnings and Precautions (5.4)]
• •Embryo-Fetal Toxicity [see Warnings and Precautions (5.5)]

6.1 Adverse Reactions In Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Azacitidine for Injection in 443 MDS patients 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)].

In Studies 1, 2 and 3, a total of 268 patients were exposed to Azacitidine for Injection, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one year). Azacitidine for Injection 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 for Injection. 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 for Injection doses of 75 mg/m².

Table 1 presents adverse reactions occurring in at least 5% of patients treated with Azacitidine for Injection (subcutaneous) in Studies 1 and 2. It is important to note that duration of exposure was longer for the Azacitidine for Injection-treated group than for the observation group: patients received Azacitidine for Injection for a mean of 11.4 months while mean time in the observation arm was 6.1 months.

Table 2 presents adverse reactions occurring in at least 5% of patients treated with Azacitidine for Injection in Study 4. Similar to Studies 1 and 2 described above, duration of exposure to treatment with Azacitidine for Injection 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 for Injection, 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 for Injection. 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).

Most Commonly Occurring Adverse Reactions (Subcutaneous or Intravenous Route): 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 (Greater Than 2%) Resulting in Clinical Intervention (Subcutaneous or Intravenous Route):

Discontinuation: leukopenia, thrombocytopenia, neutropenia.

Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia.

Dose Reduced: leukopenia, neutropenia, thrombocytopenia.

In clinical studies of either subcutaneous or intravenous Azacitidine for Injection, the following serious adverse reactions occurring at a rate of less than 5% (and not described in Tables 1 or 2) were reported:

Blood and lymphatic system disorders: agranulocytosis, bone marrow failure, pancytopenia, splenomegaly.

Cardiac disorders: atrial fibrillation, cardiac failure, cardiac failure congestive, 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.

6.2 Postmarketing Experience

 The following adverse reactions have been identified during postmarketing use of Azacitidine for Injection. 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)

8.1 Pregnancy

Risk Summary

Based on its mechanism of action and findings in animals, Azacitidine for Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. 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 estimated background risk of major birth defects and miscarriage in the indicated population is unknown. 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 to 4% and 15 to 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/m² (approximately 8% of the recommended human daily dose on a mg/m² 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 to 12 mg/m² (approximately 4% to 16% the recommended human daily dose on a mg/m² basis).

In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4 to 8 (postimplantation) at a dose of 6 mg/m² (approximately 8% of the recommended human daily dose on a mg/m² basis), although treatment in the preimplantation period (on gestation days 1 to 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/m² (approximately 8% the recommended human daily dose on a mg/m² basis) given on gestation day 9, 10, 11 or 12.  In this study azacitidine caused fetal death when administered at 3 to 12 mg/m² 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). 

8.2 Lactation

Risk Summary

There is no information on the presence of azacitidine or its metabolites in human milk, the effects on a breast-fed child, or the effects on milk production.  Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for azacitidine in animal studies [see Nonclinical Toxicology (13.1)] and the potential for serious adverse reactions in a nursing child from azacitidine, advise patients not to breastfeed during treatment with azacitidine and for 1 week after the final dose. 

8.3 Females And Males Of Reproductive Potential

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

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating Azacitidine for Injection.

Contraception

Females

Azacitidine for Injection can cause fetal harm.  Advise females of reproductive potential to use effective contraception during treatment with Azacitidine for Injection and for 6 months after the final dose [see Use in Specific Populations (8.1)  and Clinical Pharmacology (12.3)].

Males

Based on genotoxicity findings, advise males 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 Nonclinical Toxicology (13.1)]. 

Infertility

Based on animal data, azacitidine could have an effect on male or female fertility [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

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 less than 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 (2.5) and Warnings and Precautions (5.3)].

8.6 Renal Impairment

Severe renal impairment (creatinine clearance [CLcr] less than 30 mL/min) has no major effect on the exposure of azacitidine after multiple subcutaneous administrations.  Therefore, azacitidine can be administered to patients with renal impairment without Cycle 1 dose adjustment [see Clinical Pharmacology (12.3)].

8.7 Gender

There were no clinically relevant differences in safety and efficacy based on gender.

8.8 Race

Greater than 90% of all patients in all trials were Caucasian. Therefore, no comparisons between Caucasians and non-Caucasians were possible.

10  Overdosage

One case of overdose with Azacitidine for Injection was reported during clinical trials. A patient experienced diarrhea, nausea, and vomiting after receiving a single intravenous dose of approximately 290 mg/m², 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 for Injection overdosage.

11  Description

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:

9dca4f01-figure-01 - azacitidine 1

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.

12.1 Mechanism Of Action

Azacitidine for Injection is a pyrimidine nucleoside analog of cytidine. Azacitidine for Injection 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.

12.3 Pharmacokinetics

The area under the curve (AUC) and peak concentration (C_max) of subcutaneous administration of azacitidine in patients with cancer were approximately dose proportional within the dose range of 25 mg/m² (0.33 times the lowest approved recommended dosage) to 100 mg/m² (the maximum approved recommended dosage). The mean and standard deviation (SD) of C_maxwas 750 ± 403 ng/mL after a single subcutaneous administration of 75mg/m² azacitidine. Multiple dosing at the recommended dose-regimen does not result in drug accumulation.

Absorption

Azacitidine is rapidly absorbed after subcutaneous administration with a median time to C_max (T_max) of 0.5 hour. The bioavailability of subcutaneous azacitidine relative to intravenous azacitidine is approximately 89%, based on AUC.

Distribution

Mean volume of distribution following intravenous dosing is 76 ± 26 L.

Elimination

Mean apparent subcutaneous clearance is 167 ± 49 L/hour and mean half-life after subcutaneous administration is 41 ± 8 minutes.

Excretion

Published studies indicate that urinary excretion is the primary route of elimination of azacitidine and its metabolites. Following intravenous administration of radioactive azacitidine, the cumulative urinary excretion was 85% of the radioactive dose.  Fecal excretion accounted for less than 1% of administered radioactivity over 3 days.  Mean excretion of radioactivity in urine following subcutaneous administration of ¹⁴C-azacitidine was 50%.  The mean elimination half-lives of total radioactivity (azacitidine and its metabolites) were similar after intravenous and subcutaneous administrations, about 4 hours.

Specific Populations

The effects of hepatic impairment, gender, age, or race on the pharmacokinetics of azacitidine have not been studied.

Patients with Renal Impairment

The exposure of azacitidine increased by approximately 70% after single and 41% after multiple subcutaneous administrations of 75 mg/m²/day azacitidine in patients with cancer and severe renal impairment (CLcr less than 30 mL/min) relative to patients with cancer and normal renal function (CLcr greater than 80 mL/min).  This increase in exposure was not correlated with an increase in adverse events.  The exposure was similar to exposure in patients with normal renal function receiving 100 mg/m²[see Use in Specific Populations (8.6)].

Drug-Drug Interactions

No formal clinical drug interaction studies with azacitidine have been conducted.

An in vitro study of azacitidine incubation in human liver fractions indicated that azacitidine may be metabolized by the liver.  Whether azacitidine metabolism may be affected by known microsomal enzyme inhibitors or inducers has not been studied.

An in vitro study with cultured human hepatocytes indicated that azacitidine at concentrations up to 100 µM (intravenous C_max = 10.6 µM) does not cause any inhibition of cytochrome P450 (CYP) 2B6 and 2C8.  The potential of azacitidine to inhibit other CYP enzymes is not known.

In vitro studies with human cultured hepatocytes indicated that azacitidine at concentrations of 1.0 µM to 100 µM does not induce CYP 1A2, 2C19, or 3A4/5. 

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 to 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 to 30 mg/m² (approximately 20 to 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  Clinical Studies

Myelodysplastic Syndromes (MDS)

Study 1 was a randomized, open-label, controlled trial carried out in 53 U.S. sites that 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.

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 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.

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)

9dca4f01-figure-02 - azacitidine 2

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.

15  References

• 1.“OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html   

16  How Supplied/Storage And Handling

Azacitidine for Injection is supplied as a lyophilized powder in 100 mg single-dose vials packaged in cartons of 1 vial (NDC 68001-313-56).

Storage

Store unreconstituted vials at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

Discard unused portion.

Handling and Disposal

Azacitidine for Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

Sterile, Nonpyrogenic, Preservative-free.

This vial stopper is not made with natural rubber latex.

17  Patient Counseling Information

Hepatic Toxicity in Patients with Severe Pre-Existing Hepatic Impairment

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

Renal Toxicity

Instruct patients to inform their physician about any underlying renal disease [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1)] .

Advise females of reproductive potential to avoid pregnancy during treatment with Azacitidine for Injection. Advise females of reproductive potential to use effective contraception during treatment with Azacitidine for Injection and for 6 months 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 1 week after the final dose [see Use in Specific Populations (8.2)].

Infertility

Advise males and females 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 – January 2018