Azacitidine (Page 2 of 5)

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 CONTRAINDICATIONS

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 WARNINGS AND PRECAUTIONS

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 1: Most Frequently Observed Adverse Reactions (Greater Than or Equal To 5% in All Subcutaneous Azacitidine for Injection-Treated Patients; Studies 1 and 2)
Number (%) of Patients
Body System All Azacitidine for
Injection b
Observationc
Adverse reactiona (N=220) (N=92)
a Multiple terms of the same preferred terms for a patient are only counted once within each treatment group.
b Includes adverse reactions from all patients exposed to Azacitidine for Injection, including patients after crossing over from observations.
c Includes adverse reactions from observation period only; excludes any adverse events after crossover to Azacitidine for Injection.

Blood and lymphatic system disorders

Anemia

153 (70)

59 (64)

Anemia aggravated

12 (6)

5 (5)

Febrile neutropenia

36 (16)

4 (4)

Leukopenia

106 (48)

27 (29)

Neutropenia

71 (32)

10 (11)

Thrombocytopenia

144 (66)

42 (46)

Gastrointestinal disorders

Abdominal tenderness

26 (12)

1 (1)

Constipation

74 (34)

6 (7)

Diarrhea

80 (36)

13 (14)

Gingival bleeding

21 (10)

4 (4)

Loose stools

12 (6)

0

Mouth hemorrhage

11 (5)

1 (1)

Nausea

155 (71)

16 (17)

Stomatitis

17 (8)

0

Vomiting

119 (54)

5 (5)

General disorders and administration site conditions

Chest pain

36 (16)

5 (5)

Injection site bruising

31 (14)

0

Injection site erythema

77 (35)

0

Injection site granuloma

11 (5)

0

Injection site pain

50 (23)

0

Injection site pigmentation changes

11 (5)

0

Injection site pruritus

15 (7)

0

Injection site reaction

30 (14)

0

Injection site swelling

11 (5)

0

Lethargy

17 (8)

2 (2)

Malaise

24 (11)

1 (1)

Pyrexia

114 (52)

28 (30)

Infections and infestations

Nasopharyngitis

32 (15)

3 (3)

Pneumonia

24 (11)

5 (5)

Upper respiratory tract infection

28 (13)

4 (4)

Injury, poisoning, and procedural complications

Post procedural hemorrhage

13 (6)

1 (1)

Metabolism and nutrition disorders

Anorexia

45 (21)

6 (7)

Musculoskeletal and connective tissue disorders

Arthralgia

49 (22)

3 (3)

Chest wall pain

11 (5)

0

Myalgia

35 (16)

2 (2)

Nervous system disorders

Dizziness

41 (19)

5 (5)

Headache

48 (22)

10 (11)

Psychiatric disorders

Anxiety

29 (13)

3 (3)

Insomnia

24 (11)

4 (4)

Respiratory, thoracic and mediastinal disorders

Dyspnea

64 (29)

11 (12)

Skin and subcutaneous tissue disorders

Dry skin

11 (5)

1 (1)

Ecchymosis

67 (31)

14 (15)

Erythema

37 (17)

4 (4)

Rash

31 (14)

9 (10)

Skin nodule

11 (5)

1 (1)

Urticaria

13 (6)

1 (1)

Vascular disorders

Hematoma

19 (9)

0

Hypotension

15 (7)

2 (2)

Petechiae

52 (24)

8 (9)

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).

Table 2: Most Frequently Observed Adverse Reactions (Greater Than or Equal To 5% in the Azacitidine for Injection-Treated Patients and the Percentage with NCI CTC Grade 3/4 Reactions; Study 4)
Number (%) of Patients
Any Grade Grade 3/4
Best Best
Azacitidine Supportive Azacitidine Supportive
Body System for Injection Care Only for Injection Care Only
Adverse Reactiona (N=175) (N=102) (N=175) (N=102)
a Multiple reports of the same preferred term from a patient were only counted once within each treatment.

Blood and lymphatic system disorders

Anemia

90 (51)

45 (44)

24 (14)

9 (9)

Febrile neutropenia

24 (14)

10 (10)

22 (13)

7 (7)

Leukopenia

32 (18)

2 (2)

26 (15)

1 (1)

Neutropenia

115 (66)

29 (28)

107 (61)

22 (22)

Thrombocytopenia

122 (70)

35 (34)

102 (58)

29 (28)

Gastrointestinal disorders

Abdominal pain

22 (13)

7 (7)

7 (4)

0

Constipation

88 (50)

8 (8)

2 (1)

0

Dyspepsia

10 (6)

2 (2)

0

0

Nausea

84 (48)

12 (10)

3 (2)

0

Vomiting

47 (27)

7 (7)

0

0

General disorders and administration site conditions

Fatigue

42 (24)

12 (12)

6 (3)

2 (2)

Injection site bruising

9 (5)

0

0

0

Injection site erythema

75 (43)

0

0

0

Injection site hematoma

11 (6)

0

0

0

Injection site induration

9 (5)

0

0

0

Injection site pain

33 (19)

0

0

0

Injection site rash

10 (6)

0

0

0

Injection site reaction

51 (29)

0

1 (1)

0

Pyrexia

53 (30)

18 (18)

8 (5)

1 (1)

Infections and infestations

Rhinitis

10 (6)

1 (1)

0

0

Upper respiratory tract infection

16 (9)

4 (4)

3 (2)

0

Urinary tract infection

15 (9)

3 (3)

3 (2)

0

Investigations

Weight decreased

14 (8)

0

1 (1)

0

Metabolism and nutrition disorders

Hypokalemia

11 (6)

3 (3)

3 (2)

3 (3)

Nervous system disorders

Lethargy

13 (7)

2 (2)

0

1 (1)

Psychiatric disorders

Anxiety

9 (5)

1 (1)

0

0

Insomnia

15 (9)

3 (3)

0

0

Renal and urinary disorders

Hematuria

11 (6)

2 (2)

4 (2)

1 (1)

Respiratory, thoracic and mediastinal disorders

Dyspnea

26 (15)

5 (5)

6 (3)

2 (2)

Dyspnea exertional

9 (5)

1 (1)

0

0

Pharyngolaryngeal pain

11 (6)

3 (3)

0

0

Skin and subcutaneous tissue disorders

Erythema

13 (7)

3 (3)

0

0

Petechiae

20 (11)

4 (4)

2 (1)

0

Pruritus

21 (12)

2 (2)

0

0

Rash

18 (10)

1 (1)

0

0

Vascular disorders

Hypertension

15 (9)

4 (4)

2 (1)

2 (2)

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.

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