azacitidine


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azacitidine

Vidaza

Pharmacologic class: Pyrimidine antimetabolite

Therapeutic class: Antineoplastic

Pregnancy risk category D

Action

Unclear. Thought to exert antineoplastic effect by causing DNA hypomethylation and direct cytotoxicity on abnormal hematopoietic bone marrow cells. Cytotoxicity causes death of rapidly growing cells, including cancer cells no longer responsive to normal growth control mechanisms.

Availability

Powder for injection (lyophilized): 100-mg single-use vials

Indications and dosages

Treatment of the following myelodysplastic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusion), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia

Adults: For first treatment cycle: 75 mg/m2 subcutaneously or I.V. daily for 7 days; for subsequent treatment cycles, repeat cycle every 4 weeks. Dosage may be increased to 100 mg/m2 if beneficial effect doesn't occur after two cycles and no toxicity (other than nausea and vomiting) develops. Patient should be treated for at least four cycles. Continue therapy as long as patient benefits from it.

Dosage adjustment

• Based on hematologic response (after administration of recommended dosage for first cycle)

• Unexplained serum bicarbonate reduction below 20 mEq/L

• Unexplained blood urea nitrogen or serum creatinine elevation

Off-label uses

• Acute myeloid leukemia

Contraindications

• Hypersensitivity to drug or mannitol

• Advanced malignant hepatic tumor

Precautions

Use cautiously in:

• impaired renal or hepatic function, myelodysplastic syndrome

• pregnant or breastfeeding patients

• children (safety and efficacy not established).

Administration

• Obtain CBC, liver function tests, and serum creatinine level before starting drug.

• For subcutaneous administration, reconstitute with 4 ml sterile water for injection. Inject diluent slowly into vial; invert vial two or three times and rotate gently until uniform suspension appears. Resulting suspension (which will be cloudy) contains azacitidine 25 mg/ml.

• Invert syringe two to three times and gently roll between palms for 30 seconds immediately before administration.

• When giving subcutaneously, divide doses above 4 ml equally in two syringes, and inject subcutaneously in separate sites.

• Administer within 1 hour after reconstitution.

• When giving subcutaneously, rotate sites for each injection (thigh, abdomen, or upper arm). Give new injection at least 1″ from old site and never into tender, bruised, red, or hard area.

• For I.V. administration, reconstitute each vial with 10 ml sterile water for injection. Vigorously shake or roll bottle until all solids have dissolved.

• Prepare I.V. solution by adding reconstituted drug to 50- to 100-ml infusion bag of normal saline solution injection or lactated Ringer's injection.

• Administer I.V. solution over 10 to 40 minutes; administration must be completed within 1 hour of vial reconstitution.

Adverse reactions

CNS: fatigue, headache, confusion, dizziness, anxiety, depression, insomnia, lethargy, weakness, rigors, malaise, hypoesthesia, cerebral hemorrhage

CV: chest pain, cardiac murmur, tachycardia, hypotension, peripheral edema, syncope

EENT: rhinorrhea, epistaxis, sinusitis, nasopharyngitis, pharyngitis, postnasal drip, eye hemorrhage

GI: nausea, vomiting, diarrhea, constipation, anorexia, abdominal pain or tenderness, abdominal distention, dyspepsia, hemorrhoids, dysphagia, gingival bleeding, oral mucosal petechiae, stomatitis, tongue ulcers, mouth hemorrhage

GU: dysuria, urinary tract infection

Hematologic: anemia, thrombocytopenia, leukopenia, neutropenia, febrile neutropenia, lymphadenopathy, aggravated anemia, postprocedural hemorrhage, pancytopenia, bone marrow failure

Musculoskeletal: myalgia, muscle cramps, arthralgia, limb pain, back pain

Respiratory: cough (possibly productive), dyspnea, exertional or exacerbated dyspnea, upper respiratory tract infection, pneumonia, crackles, wheezing, decreased breath sounds, pleural effusion, rhonchi, atelectasis

Skin: lesion, rash, pruritus, herpes simplex, increased sweating, urticaria, dry skin, skin nodule, erythema, pallor, cellulitis

Other: decreased appetite, weight loss, fever, pitting edema, hematoma, night sweats, peripheral swelling, injection-site reactions, tumor lysis syndrome, Sweet's syndrome (acute febrile neutrophilic dermatosis) transfusion reaction, chest-wall pain, postprocedural or other pain, neutropenic sepsis, septic shock

Interactions

Drug-diagnostic tests. Potassium: decreased

Patient monitoring

• Monitor CBC during therapy.

• Monitor liver function tests and serum creatinine frequently.

• Watch for renal tubular acidosis (serum bicarbonate level below 20 mEq/L associated with alkaline urine and hypokalemia, and serum potassium level below 3 mEq/L).

• Monitor patient for signs and symptoms of tumor lysis syndrome (such as irregular heartbeat, shortness of breath, high potassium level, high uric acid level, impaired mental ability, kidney failure).

Patient teaching

Instruct patient to call prescriber immediately if shortness of breath, high potassium level, impaired mental ability, rash, easy bruising or bleeding, or respiratory symptoms develop.

• Advise male patient not to father a child during therapy.

• Caution female of childbearing potential to avoid pregnancy and breastfeeding during therapy.

• As appropriate, review all other significant and life-threatening adverse reactions, especially those related to the tests mentioned above.

azacitidine

A nucleoside analogue that may be used to treat beta-thalassemia, as it stimulates foetal globin production and myelodysplastic syndromes.

Adverse effects
Neutropaenia, thrombocytopaenia, liver failure, renal failure.

azacitidine

Vidaza® Hematology A nucleoside analogue that may be used to treat β-thalassemia as it stimulates fetal globin production and myelodysplastic syndrome Side effects Neutropenia, thrombocytopenia, renal failure, liver failure
References in periodicals archive ?
The compound is currently under development in a multi-national phase III trial in combination with Azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are unfit for intensive induction chemotherapy; Pracinostat is also being tested in an open label phase II study in combination with Azacitidine for the treatment of naive patients with high risk myelodysplastic syndromes (MDS).
"These can improve blood counts, decrease transfusions, reduce the risk of AML, and improve quality of life and survival." Options include azacitidine (Vidaza[R]), decitabine (Dacogen[R]), and lenalidomide (Revlimid[R]).
In addition to advancing the INSPIRE Trial, our Special Protocol Assessment request to the FDA for a Phase 3 combination trial of oral rigosertib plus azacitidine in first-line higher-risk MDS patients is being pursued.
The patient had a complex medical history: right breast cancer (diagnosed 20 years previously, for which the patient had undergone surgical removal, chemotherapy and hormonal therapy), atrophic gastritis and B12 vitamin deficiency, hepatic cirrhosis due to chronic co-infection with hepatitis B and delta viruses (HBV and HDV) diagnosed 30 years previously, and a myelodysplastic syndrome with excess blasts type 1 (RAEB 1) diagnosed one year previously, for which the patient was undergoing treatment with azacitidine (currently at the second course of treatment).
Aprea has commenced a Phase 3 clinical study in myelodysplastic syndromes (MDS) and has completed enrollment in a Phase Ib/II clinical trial in p53 mutated high-risk myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML) with APR-246 and azacitidine. Additional studies in MDS and AML are underway and in planning with other approved agents.
"The medicine- Azacitidine - is not yet available nor approved by the Food and Drug Administration in the Philippines and that its administration would require delicate and special monitoring and experience," his motion read.
It is planning to begin a Phase 3 clinical study in myelodysplastic syndromes (MDS) and is nearing completion of a Phase Ib/II clinical trial in p53 mutated high-risk myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML) with APR-246 and azacitidine. MDS represents a spectrum of hematopoietic stem cell malignancies in which bone marrow fails to produce sufficient numbers of healthy blood cells.
Aprea's drug candidate APR-246 has shown initial positive results in a combination study with standard care azacitidine in patients with TP53 mutant myelodysplastic syndromes (MDS).
Criteria enforced included a requirement for a 99.25 chemotherapy administration procedure code to be greater than or equal to the date of AML diagnosis, minimum 7-day length of stay (LOS) during first treatment, and absence of outpatient administration of azacitidine or decitabine (hypo-methylating agents) within the first 60 days following diagnosis.
Citation: Daniel Pollyea et al., Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia.
Azacitidine (AZA) has been shown to significantly increase OS in a recent phase III study compared with conventional regimens in the treatment of intermediate-2 and high-risk MDS patients with a blast count of 20%-30% (7).