Azacord

A white lyophilized powder or cake in a clear glass vial.
Each vial contains: Azacitidine 100 mg

Antineoplastic.
Pharmacology: Pharmacodynamics: Mechanism of action: Azacitidine is a pyrimidine nucleoside analog of cytidine, believed to exert its antineoplastic effects by DNA hypomethylation and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine.
Clinical Studies: As a form of relatively low-intensity chemotherapy, the DNA methyltransferase inhibitor (DMTI) hypomethylating agent 5-azacytidine has been shown in randomized phase III trials to improve overall survival and quality of life and to decrease the risk of leukemic transformation. Hematologic responses occurred in 60% of patients in the azacitidine arm (10-17% complete response, 16% partial response, 23-36% hematological improvement) compared with an overall 5% response rate (only hematologic improvements) in those receiving supportive care. Additionally, the time to progression to AML or death was improved in those who received azacitidine earlier in the course of disease, suggesting that the drug prolonged the duration of stable disease. Median number of cycles to first response was 3. Data from a randomized trial for higher-risk MDS concluded that azacitidine was superior to conventional care (standard chemotherapy or supportive care) in overall survival. Azacitidine treatment was associated with a median survival of 24.46 months versus 15.02 months for those receiving conventional care, a difference of 9.4 months (p= 0.0001). The hazard ratio for the treatment effect was 0.58 (95% CI: 0.43-0.77) with two-year survival rates of 50.8% with azacitidine compared to 26.2% with conventional care (p <0.0001). The survival benefits of azacitidine were consistent regardless of the conventional care option, cytogenetic subgroups, or age. Azacitidine treatment was associated with a median time to death or transformation to AML of 13.0 months versus 7.6 months for those receiving CCR treatment, an improvement of 5.4 months (p= 0.0025). Azacitidine treatment was also associated with a reduction in cytopenias, and their related symptoms; higher proportion of transfusion independency for longer duration.
Pharmacokinetics: The pharmacokinetics of azacitidine were studied in 6 MDS patients following a single 75 mg/m² subcutaneous (SC) dose and a single 75 mg/m² intravenous (IV) dose. Azacitidine is rapidly absorbed after SC administration; the peak plasma azacitidine concentration of 750 ± 403 ng/ml occurred in 0.5 hour with relative bioavailability of approximately 89% for SC azacitidine. Mean volume of distribution following IV dosing is 76 ± 26 L with mean SC clearance is 167 ± 49 L/hour and mean half-life after SC administration is 41 ± 8 minutes. Published studies indicate that urinary excretion is the primary route of elimination ofazacitidine and its metabolites. Following IV administration of radioactive azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for <1% of administered radioactivity over 3 days.

Azacitidine is indicated for treatment of adult patients with all subtypes of Myelodysplastic syndrome (MDS).

Recommended Dosage: First Treatment Cycle: The recommended starting dose of azacitidine 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.
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 [Precautions], and dosage delay or reduction as described as follows may be necessary.
Dosage Adjustment Based on Hematology Laboratory Values: For patients with baseline (start of treatment) WBC ≥3.0x10⁹/L, ANC ≥1.5x10⁹/L, and platelets ≥75.0x10⁹/L, adjust the dose as in Table 1, based on nadir counts for any given cycle: See Table 1.

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For patients whose baseline counts are WBC <3.0x10⁹/L, ANC <1.5x10⁹/L, or platelets <75.0x10⁹/L, dose adjustments should be based on nadir counts and bone marrow biopsy cellularity at the time of the nadir as shown in Table 2, 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. (See Table 2.)

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If a nadir as defined in the table previously 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.
Route of Administration: Route of administration is subcutaneous or intravenous.
Preparation of AZACITIDINE: Azacitidine is a cytotoxic drug. If reconstituted azacitidine 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 vial is single-use and does not contain any preservatives. Unused portions of each vial should be discarded properly. Do not save any unused portions for later administration.
Instructions for Subcutaneous Administration: Azacitidine 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.
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 (2°-8°C, 36°-46°F) for up to 8 hours. When azacitidine for injection is reconstituted using refrigerated (2°-8°C, 36°-46°F) water for injection, the reconstituted product may be stored under refrigerated conditions (2°- 8°C, 36°-46°F) 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 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).
Suspension Stability: Azacitidine reconstituted 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).
Instructions for Intravenous Administration: Reconstitute the appropriate number of azacitidine 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 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 Administration: Azacitidine 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 vial.
Solution Stability: Azacitidine reconstituted for intravenous administration may be stored at 25°C (77°F), but administration must be completed within 1 hour of reconstitution.

One case of overdose with azacitidine 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 overdosage.

Advanced Malignant Hepatic Tumors: Azacitidine is contraindicated in patients with advanced malignant hepatic tumor.
Hypersensitivity to Azacitidine or Mannitol: Azacitidine is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol.

Anemia, Neutropenia and Thrombocytopenia: Treatment with azacitidine 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 & Administration].
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.
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.
Effects on ability to drive and use machines: No studies of the effects on the ability to drive and use machines have been performed. Patients should be advised that they may experience undesirable effects such as fatigue, during treatment. Therefore, caution should be recommended when driving a car or operating machines.
Renal Abnormalities: Patients with renal impairment should be closely monitored for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys. 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.

Pregnancy: Pregnancy Category D.
Azacitidine is teratogenic in animals. 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). Azacitidine may cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies with Azacitidine in pregnant women. Women of childbearing potential should be advised to avoid pregnancy during treatment with azacitidine. 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 should not become pregnant.
Nursing mothers: It is not known whether azacitidine or its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for azacitidine in animal studies and the potential for serious adverse reactions in nursing infants from azacitidine, a decision should be made to continue drug or not taking into consideration the importance of the drug to the mother.

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. (See Table 3.)

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No formal clinical assessments of drug-drug interactions between azacitidine and other agents have been conducted. An in vitro study of azacitidine incubation in human liver fractions indicated that azacitidine may be metabolized by the liver. An in vitro study with cultured human hepatocytes indicated that azacitidine at concentrations up to 100 μM (IV Cmax = 10.6 μM) does not cause any inhibition of CYP2B6 and CYP2C8. In vitro studies with human cultured hepatocytes indicate that azacitidine at concentrations of 1.0 μM to 100 μM does not induce CYP 1A2, 2C19, or 3A4/5.

Unopened vials: Do not store above 30°C.
Reconstituted suspension: For storage conditions after reconstitution of the medicinal product, see Route of Administration under Dosage & Administration.
Shelf life: 3 years.

Cytotoxic Chemotherapy

L01BC07 - azacitidine ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.

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