Azacitidine Injection

Name: Azacitidine Injection

Why is this medication prescribed?

Azacitidine is used to treat myelodysplastic syndrome (a group of conditions in which the bone marrow produces blood cells that are misshapen and does not produce enough healthy blood cells). Azacitidine is in a class of medications called demethylation agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells in the bone marrow.

Other uses for this medicine

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

In case of emergency/overdose

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include:

  • diarrhea
  • nausea
  • vomiting

What other information should I know?

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your body's response to azacitidine.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Warnings and precautions

Anemia, Neutropenia and Thrombocytopenia

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)].

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)].

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.

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. If unexplained reductions in serum bicarbonate less than 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 may be at increased risk for renal toxicity. Also, azacitidine and its metabolites are primarily excreted by the kidney. Therefore, these patients should be closely monitored for toxicity  [see Dosage and Administration (2.4, 2.5)]. Patients with MDS and renal impairment were excluded from the clinical studies.

Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, Azacitidine for Injection can cause fetal harm when administered to a pregnant woman. In animal studies, azacitidine caused adverse developmental effects 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.

Advise females of reproductive potential to use effective contraception during treatment with Azacitidine for Injection and for 1 week 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 (8.1 and 8.3) and Clinical Pharmacology (12.3)]. 

Adverse reactions

The following adverse reactions are described in other labeling sections:

• Anemia, neutropenia and thrombocytopenia [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)]

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.

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 5.0% 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 (69.5)

  59 (64.1)

      Anemia aggravated

  12 (5.5)

  5 (5.4)

      Febrile neutropenia

  36 (16.4)

  4 (4.3)

      Leukopenia

  106 (48.2)

  27 (29.3)

      Neutropenia

  71 (32.3)

  10 (10.9)

      Thrombocytopenia

  144 (65.5)

  42 (45.7)

  Gastrointestinal disorders

  

  

      Abdominal tenderness

  26 (11.8)

  1 (1.1)

      Constipation

  74 (33.6)

  6 (6.5)

      Diarrhea

  80 (36.4)

  13 (14.1)

      Gingival bleeding

  21 (9.5)

  4 (4.3)

      Loose stools

  12 (5.5)

  0

      Mouth hemorrhage

  11 (5.0)

  1 (1.1)

      Nausea

  155 (70.5)

  16 (17.4)

      Stomatitis

  17 (7.7)

  0

      Vomiting

  119 (54.1)

  5 (5.4)

  General disorders and administration site conditions

  

      Chest pain

  36 (16.4)

  5 (5.4)

      Injection site bruising

  31 (14.1)

  0

      Injection site erythema

  77 (35.0)

  0

      Injection site granuloma

  11 (5.0)

  0

      Injection site pain

  50 (22.7)

  0

      Injection site pigmentation changes

  11 (5.0)

  0

      Injection site pruritus

  15 (6.8)

  0

      Injection site reaction

  30 (13.6)

  0

      Injection site swelling

  11 (5.0)

  0

      Lethargy

  17 (7.7)

  2 (2.2)

      Malaise

  24 (10.9)

  1 (1.1)

      Pyrexia

  114 (51.8)

  28 (30.4)

  Infections and infestations

  

  

      Nasopharyngitis

  32 (14.5)

  3 (3.3)

      Pneumonia

  24 (10.9)

  5 (5.4)

      Upper respiratory tract infection

  28 (12.7)

  4 (4.3)

  Injury, poisoning, and procedural complications

  

  

      Post procedural hemorrhage

  13 (5.9)

  1 (1.1)

  Metabolism and nutrition disorders

  

  

      Anorexia

  45 (20.5)

  6 (6.5)

  Musculoskeletal and connective tissue disorders

  

  

      Arthralgia

  49 (22.3)

  3 (3.3)

      Chest wall pain

  11 (5.0)

  0

      Myalgia

  35 (15.9)

  2 (2.2)

  Nervous system disorders

  

  

      Dizziness

  41 (18.6)

  5 (5.4)

      Headache

  48 (21.8)

  10 (10.9)

  Psychiatric disorders

  

  

      Anxiety

  29 (13.2)

  3 (3.3)

      Insomnia

  24 (10.9)

  4 (4.3)

  Respiratory, thoracic and mediastinal disorders

  

  

      Dyspnea

  64 (29.1)

  11 (12.0)

  Skin and subcutaneous tissue disorders

  

  

      Dry skin

  11 (5.0)

  1 (1.1)

      Ecchymosis

  67 (30.5)

  14 (15.2)

      Erythema

  37 (16.8)

  4 (4.3)

      Rash

  31 (14.1)

  9 (9.8)

      Skin nodule

  11 (5.0)

  1 (1.1)

      Urticaria

  13 (5.9)

  1 (1.1)

  Vascular disorders

  

  

      Hematoma

  19 (8.6)

  0

      Hypotension

  15 (6.8)

  2 (2.2)

      Petechiae

  52 (23.6)

  8 (8.7)

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 5.0% 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 (51.4)

  45 (44.1)

  24 (13.7)

  9 (8.8)

     Febrile neutropenia

  24 (13.7)

  10 (9.8)

  22 (12.6)

  7 (6.9)

     Leukopenia

  32 (18.3)

  2 (2.0)

  26 (14.9)

  1 (1.0)

     Neutropenia

  115 (65.7)

  29 (28.4)

  107 (61.1)

  22 (21.6)

     Thrombocytopenia

  122 (69.7)

  35 (34.3)

  102 (58.3)

  29 (28.4)

  Gastrointestinal disorders

  

  

  

  

     Abdominal pain

  22 (12.6)

  7 (6.9)

  7 (4.0)

  0

     Constipation

  88 (50.3)

  8 (7.8)

  2 (1.1)

  0

     Dyspepsia

  10 (5.7)

  2 (2.0)

  0

  0

     Nausea

  84 (48.0)

  12 (11.8)

  3 (1.7)

  0

     Vomiting

  47 (26.9)

  7 (6.9)

  0

  0

  General disorders and administration site conditions

  

  

  

  

     Fatigue

  42 (24.0)

  12 (11.8)

  6 (3.4)

  2 (2.0)

     Injection site bruising

  9 (5.1)

  0

  0

  0

     Injection site erythema

  75 (42.9)

  0

  0

  0

     Injection site hematoma

  11 (6.3)

  0

  0

  0

     Injection site induration

  9 (5.1)

  0

  0

  0

     Injection site pain

  33 (18.9)

  0

  0

  0

     Injection site rash

  10 (5.7)

  0

  0

  0

     Injection site reaction

  51 (29.1)

  0

  1 (0.6)

  0

     Pyrexia

  53 (30.3)

  18 (17.6)

  8 (4.6)

  1 (1.0)

  Infections and infestations

  

  

  

  

     Rhinitis

  10 (5.7)

  1 (1.0)

  0

  0

     Upper respiratory tract infection

  16 (9.1)

  4 (3.9)

  3 (1.7)

  0

     Urinary tract infection

  15 (8.6)

  3 (2.9)

  3 (1.7)

  0

  Investigations

  

  

  

  

     Weight decreased

  14 (8.0)

  0

  1 (0.6)

  0

  Metabolism and nutrition disorders

  

  

  

  

     Hypokalemia

  11 (6.3)

  3 (2.9)

  3 (1.7)

  3 (2.9)

  Nervous system disorders

  

  

  

  

     Lethargy

  13 (7.4)

  2 (2.0)

  0

  1 (1.0)

  Psychiatric disorders

  

  

  

  

     Anxiety

  9 (5.1)

  1 (1.0)

  0

  0

     Insomnia

  15 (8.6)

  3 (2.9)

  0

  0

  Renal and urinary disorders

  

  

  

  

     Hematuria

  11 (6.3)

  2 (2.0)

  4 (2.3)

  1 (1.0)

  Respiratory, thoracic and mediastinal disorders

  

  

  

  

     Dyspnea

  26 (14.9)

  5 (4.9)

  6 (3.4)

  2 (2.0)

     Dyspnea exertional

  9 (5.1)

  1 (1.0)

  0

  0

     Pharyngolaryngeal pain

  11 (6.3)

  3 (2.9)

  0

  0

  Skin and subcutaneous tissue disorders

  

  

  

  

     Erythema

  13 (7.4)

  3 (2.9)

  0

  0

     Petechiae

  20 (11.4)

  4 (3.9)

  2 (1.1)

  0

     Pruritus

  21 (12.0)

  2 (2.0)

  0

  0

     Rash

  18 (10.3)

  1 (1.0)

  0

  0

  Vascular disorders

  

  

  

  

     Hypertension

  15 (8.6)

  4 (3.9)

  2 (1.1)

  2 (2.0)

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).

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.

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)

Nonclinical toxicology

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.

Side Effects

Redness/pain/bruising at the injection site, tiredness, diarrhea, dizziness, trouble sleeping, constipation, nausea, vomiting, mouth sores, dry skin, headache, and loss of appetite may occur. Nausea and vomiting can be severe. In some cases, your doctor may prescribe medication to prevent or relieve nausea and vomiting. Eating several small meals, not eating before treatment, or limiting activity may help lessen some of these effects. If these effects last or worsen, tell your doctor or pharmacist promptly.

People using this medication may have serious side effects. However, your doctor has prescribed this drug because he or she has judged that the benefit to you is greater than the risk ofside effects. Careful monitoring by your doctor may decrease your risk.

Tell your doctor right away if you have any serious side effects, including: easy bleeding/bruising, chest pain, muscle/joint pain, muscle cramps, irregular heartbeat, mental/mood changes (such as anxiety), signs of kidney problems (such as change in the amount of urine), dark urine, yellowing eyes/skin.

This medication can lower the body's ability to fight an infection. Tell your doctor right away if you develop any signs of an infection such as fever, chills, cough, or persistent sore throat.

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

List Azacitidine Vial side effects by likelihood and severity.

Precautions

Before using azacitidine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients (such as mannitol), which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, liver disease (e.g., cancer).

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose. Wash your hands well to prevent the spread of infections.

To lower your risk of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.

This medication is not recommended for use during pregnancy. Also, men using this medication should avoid causing pregnancy during treatment. It is recommended that men and women use effective forms of birth control (e.g., condoms and birth control pills) while using this medication and for some time afterward. Consult your doctor for more details and to discuss reliable forms of birth control.

It is not known whether this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

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