Azacitidine

Sandoz Inc

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Azacitidine for Injection safely and effectively. See full prescribing information for Azacitidine for Injection. AZACITIDINE for injection for SC or IV useInitial U.S. Approval: 2004INDICATIONS AND USAGEAzacitidine for Injection is a nucleoside metabolic inhibitor indicated for the treatment of patients with the following FAB myelodysplastic syndrome (MDS) subtypes: Refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL). (1)DOSAGE AND ADMINISTRATION •The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology values, is Azacitidine for Injection 75 mg/m2 daily for 7 days to be administered by subcutaneous (SC) injection or intravenous (IV) infusion. Premedicate for nausea and vomiting. (2.1) •Repeat cycles every 4 weeks (2.2). After 2 cycles, may increase dose to 100 mg/m2 if no beneficial effect is seen and no toxicity other than nausea and vomiting has occurred (2.2). Patients should be treated for a minimum of 4 to 6 cycles. Complete or partial response may require additional treatment cycles (2.2). •Continue treatment as long as the patient continues to benefit (2.2). •Patients should be monitored for hematologic response and renal toxicities, with dosage delay or reduction as appropriate (2.3, 2.4, 2.5). DOSAGE FORMS AND STRENGTHS •Lyophilized powder in 100 mg single-use vials (3). CONTRAINDICATIONS •Advanced malignant hepatic tumors (4.1). •Hypersensitivity to azacitidine or mannitol (4.2). WARNINGS AND PRECAUTIONS •Anemia, neutropenia and thrombocytopenia. Perform complete blood counts (CBC) prior to each treatment cycle and as needed to monitor response and toxicity. (5.1). •Hepatotoxicity: Use with caution in patients with severe preexisting liver impairment (5.2). •Renal abnormalities. Monitor patients with renal impairment for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys (5.3). •Monitor liver chemistries and serum creatinine prior to initiation of therapy and with each cycle (5.4). •Azacitidine for Injection may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be apprised of the potential hazard to a fetus. (5.5, 8.1). •Men should be advised not to father a child while receiving Azacitidine for Injection (5.6, 13.1). Side EffectsMost common adverse reactions (>30%) by SC route are: nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia and ecchymosis. Most common adverse reactions by IV route also included petechiae, rigors, weakness and hypokalemia (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS •No formal clinical assessments of drug-drug interactions between Azacitidine for Injection and other agents have been conducted (7). USE IN SPECIFIC POPULATIONS •Nursing Mothers: Discontinue drug or nursing taking into consideration importance of drug to mother (8.3). •Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function (8.5).

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 AZACITIDINE INDICATIONS AND USAGE
  • 1.1 Myelodysplastic Syndromes (MDS)
• 2 AZACITIDINE DOSAGE AND ADMINISTRATION
  • 2.1 First Treatment Cycle
  • 2.2 Subsequent Treatment Cycles
  • 2.3 Dosage Adjustment Based on Hematology Laboratory Values
  • 2.4 Dosage Adjustment Based on Renal Function and Serum Electrolytes
  • 2.5 Use in Geriatric Patients
  • 2.6 Preparation of Azacitidine for Injection
  • 2.7 Instructions for Subcutaneous Administration
  • 2.8 Instructions for Intravenous Administration
• 3 DOSAGE FORMS AND STRENGTHS
• 4 AZACITIDINE CONTRAINDICATIONS
  • 4.1 Advanced Malignant Hepatic Tumors
  • 4.2 Hypersensitivity to Azacitidine or Mannitol
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Anemia, Neutropenia and Thrombocytopenia
  • 5.2 Severe Pre-existing Hepatic Impairment
  • 5.3 Renal Abnormalities
  • 5.4 Monitoring Laboratory Tests
  • 5.5 Use in Pregnancy
  • 5.6 Use in Males
• 6 AZACITIDINE ADVERSE REACTIONS
  • 6.1 Overview
  • 6.2 Adverse Reactions in Clinical Trials
  • 6.3 Postmarketing Experience
• 7 DRUG INTERACTIONS
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Gender
  • 8.7 Race
• 10 OVERDOSAGE
• 11 AZACITIDINE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
• 15 REFERENCES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
• Principal Display Panel

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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 DOSAGE AND ADMINISTRATION

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. Patients should be premedicated for nausea and vomiting.

2.2 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. 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.

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.

2.3 Dosage Adjustment Based on Hematology Laboratory Values

• •For patients with baseline (start of treatment) WBC ≥3.0 x10⁹/L, ANC ≥1.5 x10⁹/L, and platelets ≥75.0 x10⁹/L, adjust the dose as follows, based on nadir counts for any given cycle:

• •For patients whose baseline counts are WBC <3.0 x10⁹/L, ANC<1.5 x10⁹/L, or platelets <75.0 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.

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 >25% above the nadir and rising. If a >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.

2.4 Dosage Adjustment Based on Renal Function and Serum Electrolytes

If unexplained reductions in serum bicarbonate levels to <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)].

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, 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 )].

2.6 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-use 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.

2.7 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 (2ºC -  8ºC, 36ºF  -  46ºF) for up to 8 hours. When Azacitidine for Injection is reconstituted using refrigerated (2ºC  -  8ºC, 36ºF  -  46ºF) water for injection, the reconstituted product may be stored under refrigerated conditions (2ºC -  8ºC, 36ºF  -  46ºF) for up to 22 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 1 hour at 25°C (77°F) or for up to 8 hours between 2°C and 8°C (36°F and 46°F); when reconstituted with refrigerated (2ºC  - 8ºC, 36ºF -  46ºF) water for injection, it may be stored for 22 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 - 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 -  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-use 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 or Mannitol

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

5 WARNINGS AND PRECAUTIONS

5.1 Anemia, Neutropenia and Thrombocytopenia

Treatment with Azacitidine for Injection is associated with anemia, neutropenia and thrombocytopenia. Complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle. After administration of the recommended dosage for the first cycle, dosage for subsequent cycles should be reduced or delayed based on nadir counts and hematologic response [see Dosage and Administration (2.3)].

5.2 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)].

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 Abnormalities

Renal abnormalities 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 <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. If unexplained reductions in serum bicarbonate <20 mEq/L or elevations of BUN or serum creatinine occur, the dosage should be reduced or held [see Dosage and Administration (2.4)].

Patients with renal impairment should be closely monitored for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys [see Dosage and Administration (2.4, 2.5)].

Safety and effectiveness of Azacitidine for Injection in patients with MDS and renal impairment have not been studied as these patients were excluded from the clinical trials.

5.4 Monitoring Laboratory Tests

Complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each cycle. Liver chemistries and serum creatinine should be obtained prior to initiation of therapy.

5.5 Use in Pregnancy

Azacitidine for Injection may cause fetal harm when administered to a pregnant woman. Azacitidine caused congenital malformations in animals. Women of childbearing potential should be advised to avoid pregnancy during treatment with Azacitidine for Injection. There are no adequate and well-controlled studies in pregnant women using Azacitidine for Injection. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

5.6 Use in Males

Men should be advised to not father a child while receiving treatment with Azacitidine for Injection. In animal studies, pre-conception treatment of male mice and rats resulted in increased embryofetal loss in mated females [see Nonclinical Toxicology (13)].

6 ADVERSE REACTIONS

6.1 Overview

Adverse Reactions Described in Other Labeling Sections: anemia, neutropenia, thrombocytopenia, elevated serum creatinine, renal failure, renal tubular acidosis, hypokalemia, hepatic coma [see Warnings and Precautions (5.1, 5.2, 5.3)].

Most Commonly Occurring Adverse Reactions (SC or IV Route): nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by IV route also included petechiae, rigors, weakness and hypokalemia.

Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (SC or IV Route):

Discontinuation: leukopenia, thrombocytopenia, neutropenia.

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

Dose Reduced: leukopenia, neutropenia, thrombocytopenia.

6.2 Side Effects 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 (SC administration), Studies 2 and 3 were single arm studies (one with SC administration and one with IV administration), and Study 4 was an international randomized trial (SC 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 IV 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 (SC) 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 SC 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 SC 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 IV and SC studies. Adverse reactions that appeared to be specifically associated with the IV 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 SC or IV Azacitidine for Injection, the following serious adverse reactions occurring at a rate of < 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.

6.3 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)

7 DRUG INTERACTIONS

No formal clinical assessments of drug-drug interactions between Azacitidine for Injection and other agents have been conducted [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D [see Warning and Precautions (5.5)]

Azacitidine for Injection may cause fetal harm when administered to a pregnant woman. Azacitidine was teratogenic in animals. There are no adequate and well controlled studies with Azacitidine for Injection in pregnant women. Women of childbearing potential should be advised to avoid pregnancy during treatment with Azacitidine for Injection. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Female partners of male patients receiving Azacitidine for Injection should not become pregnant [see Nonclinical Toxicology (13.1)].

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 - 12 mg/m² (approximately 4% - 16% the recommended human daily dose on a mg/m² basis).

In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4 - 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 - 3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after a single IP dose of 3 – 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 - 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).

8.3 Nursing Mothers

It is not known whether azacitidine or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for azacitidine in animal studies and the potential for serious adverse reactions in nursing infants from Azacitidine for Injection, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into consideration the importance of the drug to the mother.

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 < 65 years of age and patients 65 years of age and older.

Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function [see Dosage and Administration (2.5) and Warnings and Precautions (5.3)].

8.6 Gender

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

8.7 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 IV 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: