Pronunciation (ay za SYE ti deen)

U.S. Brand Names VidazaTM

Synonyms AZA-CR; 5-Azacytidine; 5-AZC; Ladakamycin; NSC-102816

Therapeutic Category
Antineoplastic Agent, Antimetabolite (Pyrimidine)
Use Treatment of myelodysplastic syndrome (MDS)

Pregnancy Risk Factor D

Pregnancy Implications Embryotoxicity, fetal death, and fetal abnormalities were observed in animal studies. Women of childbearing potential should be advised to avoid pregnancy during treatment. In addition, males should be advised to avoid fathering a child while on azacitidine therapy.

Contraindications Hypersensitivity to azacitidine, mannitol, or any component of the formulation; advanced malignant hepatic tumors; pregnancy

Warnings/Precautions The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. Azacitidine may be hepatotoxic, use caution with hepatic impairment. Progressive hepatic coma leading to death has been reported (rare) in patients with extensive tumor burden, especially those with a baseline albumin <30 g/L. Use caution with renal impairment; dose adjustment may be required.

Adverse Reactions Note: Percentages reported following SubQ administration unless otherwise noted:
>10%: Cardiovascular: Hypotension (7%; I.V. 6% to 66% - incidence may be related to dose and rate of infusion), chest pain (16%), pallor (15%), peripheral edema (19%), pitting edema (14%)
Central nervous system: Pyrexia (52%), fatigue (13% to 36%), headache (22%), dizziness (19%), anxiety (13%), depression (12%), insomnia (11%), malaise (11%), pain (11%)
Dermatologic: Alopecia (I.V. 20%), bruising (30%), petechiae (24%), erythema (17%), skin lesion (14%), rash (14%)
Gastrointestinal: Nausea (70%; more common/more severe with I.V. administration), vomiting (54%; more common/more severe with I.V. administration), mucositis (I.V. 23% to 45%), diarrhea (36%), constipation (34%), anorexia (21%), weight loss (16%), abdominal pain (15%), appetite decreased (13%), abdominal tenderness (12%)
Hematologic: Anemia (70%), thrombocytopenia (66%), leukopenia (48%), neutropenia (32%), febrile neutropenia (16%)
Nadir: Day 10-17
Recovery: Day 28-31
Hepatic: Hepatic enzymes increased (I.V. 37%)
Local: Injection site:
I.V.: Redness, irritation, and induration (80%)
SubQ: Erythema (35%), pain (23%), bruising (14%)
Neuromuscular & skeletal: Weakness (30%), rigors (26%), arthralgia (22%), limb pain (20%), back pain (19%), myalgia (16%)
Respiratory: Cough (30%), dyspnea (5% to 30%), pharyngitis (20%), epistaxis (16%), nasopharyngitis (14%), upper respiratory tract infection (13%), productive cough (11%), pneumonia (11%)
Miscellaneous: Contusion (19%)

5% to 10%: Cardiovascular: Cardiac murmur (10%), tachycardia (9%) peripheral swelling (7%), syncope (6%), chest wall pain (5%), hypoesthesia (5%), postprocedural pain (5%)
Central nervous system: Lethargy (8%)
Dermatologic: Cellulitis (8%), urticaria (6%), dry skin (5%), skin nodule (5%)
Gastrointestinal: Upper abdominal pain (10%), gingival bleeding (9%), oral mucosal petechiae (8%), stomatitis (8%), dyspepsia (7%), hemorrhoids (7%), abdominal distension (6%), loose stools (5%), dysphagia (5%), tongue ulceration (5%)
Genitourinary: Dysuria (8%), urinary tract infection (8%)
Hematologic: Hematoma (9%), postprocedural hemorrhage (6%)
Local: Injection site: Pruritus (7%), granuloma (5%), pigmentation change (5%), swelling (5%)
Neuromuscular & skeletal: Muscle cramps (6%)
Respiratory: Crackles (10%), rhinorrhea (10%), wheezing (9%), breath sounds decreased (8%), pleural effusion (6%), postnasal drip (6%), rhonchi (6%), nasal congestion (5%), atelectasis (5%), sinusitis (5%)
Miscellaneous: Diaphoresis (10%), lymphadenopathy (9%), herpes simplex (9%), night sweats (9%), transfusion reaction (7%), mouth hemorrhage (5%)

<5% (Limited to important or life-threatening): Agranulocytosis, anaphylactic shock, bone marrow depression, CHF, convulsions, dehydration, diverticulitis, hypersensitivity reaction, pyoderma gangrenosum, splenomegaly; myalgia, weakness, and lethargy progressing to somnolence, stupor, or coma (<1%)

Overdose/Toxicology Diarrhea, nausea, and vomiting were reported following a single I.V. dose of 290 mg/m2. Treatment should be supportive.

I.V.: Solutions for injection have very limited stability and must be prepared fresh immediately prior to each dose. Reconstitute vial with 19.9 mL of lactated Ringer's injection, 0.9% sodium chloride, or 5% dextrose to form a 5 mg/mL solution. Mix in 50-250 mL (final concentration 2 mg/mL) lactated Ringer's injection for infusion. Solutions (2 mg/mL) in lactated Ringer's injection are stable for 3 hours; solutions in 5% dextrose in water or 0.9% sodium chloride injection are only stable for 1 hour.

Mechanism of Action Antineoplastic effects may be a result of azacitidine's ability to promote hypomethylation of DNA leading to direct toxicity of abnormal hematopoietic cells in the bone marrow.

Pharmacodynamics/Kinetics

Absorption: SubQ: Rapid and complete

Bioavailability: SubQ: 89%

Distribution: Vd: 76 ?26 L; does not cross blood-brain barrier

Metabolism: Hepatic; hydrolysis to several metabolites

Half-life elimination: ~4 hours

Time to peak concentration: 30 minutes

Excretion: Urine (50% to 85%); feces (minor)

Usual Dosage

I.V. (unlabeled use, doses reported in combination regimens): Children:
Pediatric AML and ANLL: 250 mg/m2 days 4 and 5 every 4 weeks
Pediatric AML induction: 300 mg/m2 days 5 and 6
Adults:

Acute leukemia:
50-150 mg/m2 days 1 through 5 of induction
200 mg/m2 CIVI days 7 through 9 of induction
CML (accelerated phase and blast crisis): 50-150 mg/m2 days 1 through 5 of induction
AML induction: 150 mg/m2 days 3 through 5 and 8 through 10, then
150 mg/m2 days 1 through 5 and 8 through 10 (cycle 2 consolidation)
AML consolidation: 150 mg/m2 CIVI days 1 through 7 for 3 cycles
AML maintenance: 150 mg/m2 days 1 through 3 every 6 weeks
MDS: 75-150 mg/m2 CIVI days 1 through 7 every 4 weeks
SubQ: MDS: 75 mg/m2/day for 7 days repeated every 4 weeks. Dose may be increased to 100 mg/m2/day if no benefit is observed after 2 cycles and no toxicity other than nausea and vomiting have occurred. Treatment is recommended for at least 4 cycles.

Dosage adjustment based on hematology: Adults: SubQ:

For baseline WBC 3.0 x 109/L, ANC 1.5 x 109/L, and platelets 75 x 109/L:牋 Nadir count: ANC <0.5 x 109/L and platelets <25 x 109/L: Administer 50% of dose during next treatment course
Nadir count: ANC 0.5-1.5 x 109/L and platelets 25-50 x 109/L: Administer 67% of dose during next treatment course
Nadir count: ANC >1.5 x 109/L and platelets >50 x 109/L: Administer 100% of dose during next treatment course

For baseline WBC <3 x 109/L, ANC 1.5 x 109/L, or platelets <75 x 109/L: Adjust dose as follows based on nadir counts and bone marrow biopsy cellularity at the time of nadir, unless clear improvement in differentiation at the time of the next cycle:牋 WBC or platelet nadir decreased 50% to 75% from baseline and bone marrow biopsy cellularity at time of nadir 30% to 60%: Administer 100% of dose during next treatment course
WBC or platelet nadir decreased 50% to 75% from baseline and bone marrow biopsy cellularity at time of nadir 15% to 30%: Administer 50% of dose during next treatment course
WBC or platelet nadir decreased 50% to 75% from baseline and bone marrow biopsy cellularity at time of nadir <15%: Administer 33% of dose during next treatment course
WBC or platelet nadir decreased >75% from baseline and bone marrow biopsy cellularity at time of nadir 30% to 60%: Administer 75% of dose during next treatment course
WBC or platelet nadir decreased >75% from baseline and bone marrow biopsy cellularity at time of nadir 15% to 30%: Administer 50% of dose during next treatment course
WBC or platelet nadir decreased >75% from baseline and bone marrow biopsy cellularity at time of nadir <15%: Administer 33% of dose during next treatment course
Note: If a nadir defined above occurs, administer the next treatment course 28 days after the start of the preceding course as long as WBC and platelet counts are >25% above the nadir and rising. If a >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, administer 50% of the scheduled dose.

Dosage adjustment base on serum electrolytes: If serum bicarbonate falls to <20 mEq/L (unexplained decrease): Reduce dose by 50% for next treatment course

Dosage adjustment in renal impairment: If unexplained increases in BUN or serum creatinine occur, delay next cycle until values reach baseline or normal, then reduce dose by 50% for next treatment course.

Administration Premedication for nausea and vomiting is recommended.

SubQ: Doses >50 mg (2 mL) should be divided into 2 syringes and injected into 2 separate sites. Allow refrigerated suspensions to come to room temperature (up to 30 minutes) prior to administration. Resuspend by gently rolling the syringe between the palms for 30 seconds. If azacitidine suspension comes in contact with the skin, immediately wash with soap and water.

I.V.: Short (15 minutes to 2 hours) bolus or continuous (24 hour) infusion. Due to azacitidine's limited stability, for continuous infusions the daily dose should be divided by 12, and a freshly prepared bag, using a freshly reconstituted vial, started every 2 hours.

Monitoring Parameters Liver function tests, electrolytes, CBC, renal function tests (BUN and serum creatinine) should be obtained prior to initiation of therapy. Electrolytes, renal function (BUN and creatinine), CBC should be monitored periodically to monitor response and toxicity. At a minimum, CBC should be repeated prior to each cycle.

Patient Information Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take anything new during treatment unless approved by prescriber. This medication can only be administered by injection (or I.V.); report immediately any pain, burning, swelling at injection/infusion site. Limit oral intake for 4-6 hours before therapy to reduce potential for nausea/vomiting. It is important that you maintain adequate nutrition between treatments (small, frequent meals may help) and adequate hydration (2-3 L/day of fluids), unless advised by prescriber to restrict fluids. You may be susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). May cause nausea, vomiting, or anorexia (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help - if nausea/vomiting are severe, request antiemetic); mouth sores (use soft toothbrush or cotton swabs for mouth care); loss of hair (reversible). Report chest pain or palpitations; sore throat, fever, chills, unusual weakness or fatigue; unusual bruising/bleeding; change in color of urine or stool; difficulty breathing; change in visual acuity; or pain, redness, or swelling at injection site, or any other adverse reactions. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant or cause a pregnancy (males) during therapy. Consult prescriber for instruction on appropriate contraceptive measures. This drug may cause severe fetal defects. Breast-feeding is not recommended.

Dosage Forms Injection, powder for suspension: 100 mg [contains mannitol 100 mg]

References

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