AZACITIDINE-SAIDAL

Azacitidine is a pyrimidine nucleoside analogue with anti-neoplastic activity.

It differs from cytosine by the presence of nitrogen in the C5-position, key in its hypomethylating activity. 1, 8, 10 Two main mechanisms of action have been proposed for azacitidine.

One of them is the induction of cytotoxicity.

As an analogue of cytidine, it is able to incorporate into RNA and DNA, disrupting RNA metabolism and inhibiting protein and DNA synthesis.

The other one is through the inhibition of DNA methyltransferase, impairing DNA methylation.

Due to its anti-neoplastic activity and its ability to inhibit methylation in replicating DNA, azacytidine has been used mainly used in the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), two types of cancer characterized by the presence of aberrant DNA methylation. 2, 5, 6, 11, 12 In May 2004, the FDA approved the use of azacitidine administered Subcutaneous for the treatment of MDS of all French-American-British (FAB) subtypes.

In January 2007, the FDA approved the intravenous administration of azacitidine.

The use of oral azacitidine for the treatment of AML in patients in complete remission was approved by the FDA in September 2020.

Azacitidine (for subcutaneous or intravenous use) is indicated for the treatment of adult patients with the following French-American-British (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).

Azacitidine is also indicated for the treatment of pediatric patients aged 1 month and older with newly diagnosed Juvenile Myelomonocytic Leukemia (JMML). 15, 16 Azacitidine (for oral use) is indicated for continued treatment of adult patients with acute myeloid leukemia (AML) who achieved first complete remission or complete remission with incomplete blood count recovery following intensive induction chemotherapy and are not able to complete intensive curative therapy.

The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis, and hypomethylation may restore normal function to genes critical for differentiation and proliferation.

DNA methylation levels in bone marrow granulocytes were reduced in patients with juvenile myelomonocytic leukemia after the first treatment cycle of azacitidine (75 mg/m 2 or 2.5 mg/kg), confirming the DNA-hypomethylating activity of azacitidine.

The use of azacitidine causes anemia, neutropenia and thrombocytopenia in adult patients with myelodysplastic syndrome and pediatric patients with juvenile myelomonocytic leukemia.

Azacitidine may cause renal toxicity, tumor lysis syndrome and embryo-fetal toxicity.

It may also lead to the development of hepatotoxicity in patients with severe pre-existing hepatic impairment.

Azacitidine is rapidly absorbed after subcutaneous administration. 9, 16 In adult patients with myelodysplastic syndrome given a single subcutaneous dose of 75 mg/m of azacitidine, the C max and T max were 750 ng/ml and 0.5 hours, respectively.

Based on the area under the curve, the bioavailability of subcutaneous azacitidine relative to intravenous azacitidine is approximately 89%.

In 21 patients with cancer given subcutaneous azacitidine, the AUC and C max were approximately dose-proportional between and 100 mg/m 2.

Multiple subcutaneous or intravenous doses of azacitidine are not expected to result in drug accumulation.

In patients given an intravenous dose of azacitidine, the volume of distribution is 76 L.

An in vitro study of azacitidine incubation in human liver fractions indicated that cytochrome P450 (CYP) enzymes do not participate in the metabolism of azacitidine.

Azacitidine is metabolized through spontaneous hydrolysis and deamination mediated by cytidine deaminase.

Azacitidine and its metabolites are mainly excreted through urine. 9, 16 In five cancer patients given radioactive azacitidine Intravenous, the cumulative urinary excretion was 85% of the radioactive dose.

Fecal excretion accounted for less than 1% of administered radioactivity over three days.

Following the subcutaneous administration of 14C-azacitidine, the mean excretion of radioactivity in urine was 50%.

The mean half-life of azacitidine after subcutaneous administration is 41 minutes.

The mean elimination half-life of azacitidine and its metabolites was about 4 hours for intravenous and subcutaneous administrations.

Azacitidine has an apparent subcutaneous clearance of 167 L/hour in adults.

In pediatric patients, the geometric mean clearance was 21.8 L/hour.

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One case of overdose with azacitidine was reported during clinical trials.

After receiving a single dose of 290 mg/m of azacitidine Intravenous (almost 4 times the recommended starting dose), a patient experienced diarrhea, nausea, and vomiting.

These adverse events resolved without sequelae, and the correct dose was resumed the following day. In case of overdose, patients should be monitored with appropriate blood counts and receive supportive treatment as necessary.

There is no known specific antidote for azacitidine overdosage.

In mice, the oral LD of azacitidine is 572 mg/kg, while the intravenous LD is approximately 117 mg/kg.

Hypersensitivity to Azacitidine or

Mannitol. 4.1 Advanced Malignant Hepatic Tumors Azacitidine is contraindicated in patients with advanced malignant hepatic tumors. 4.2 Hypersensitivity to Azacitidine or Mannitol Azacitidine is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol.

Do not substitute

Azacitidine for injection for oral azacitidine.

The indications and dosing regimen for

Azacitidine for injection differ from that of oral azacitidine.

The recommended starting dosage for the first treatment cycle, for all patients regardless of baseline hematology values, is Azacitidine for injection 75 mg/m 2 daily for 7 days to be administered by subcutaneous injection or intravenous infusion.

See full prescribing information for schedule for subsequent cycles.

Premedicate for nausea and vomiting.

Continue treatment as long as the patient continues to benefit.

Monitor all patients for hematologic response and for renal toxicity; delay or reduce dosage as appropriate. 2.1 Important Administration Information Do not substitute Azacitidine for injection for oral azacitidine.

Azacitidine for injection differ from that of oral azacitidine 2.2 First Treatment Cycle for Adults The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg/m 2 subcutaneously or intravenously, daily for 7 days.

Premedicate patients for nausea and vomiting.

Obtain complete blood counts, liver chemistries and serum creatinine prior to the first dose. 2.3 Subsequent Treatment Cycles for Adults Repeat cycles every 4 weeks.

The dose may be increased to 100 mg/m 2 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 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.

Monitor patients for hematologic response and renal toxicities, and delay or reduce dosage if necessary.

Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection).

However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information. 2.5 Dosage Adjustment Based on Hematology Laboratory Values For adult patients with baseline (start of treatment) WBC greater than or equal to 3x10 9 /L, ANC greater than or equal to 1.5x10 9 /L, and platelets greater than or equal to 75x10 9 /L, adjust the dose as follows, based on nadir counts for any given cycle: Nadir Counts % Dose in the Next Course ANC (x10 9 /L) Platelets (x10 9 /L) Less than 0.5 Less than 25 50% 0.5 –1.5 25-50 67% Greater than 1.5 Greater than 50 100% For adult patients whose baseline counts are WBC less than 3 x 10 9 /L, ANC less than 1.5 x10 9 /L, or platelets less than 75 x 10 9 /L, base dose adjustments 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 continue the current dose.

Nadir % decrease in counts from baseline Bone Marrow Biopsy Cellularity at Time of Nadir (%) 30-60 15-30 Less than15 % Dose in the Next Course 50-75 100 50 33 Greater than 75 75 50 33 If a nadir as defined in the table above has occurred, give the next course 28 days after the start of the preceding course, provided that both the WBC and the platelet counts are greater than 25% above the nadir and rising.

If a greater than 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, reduce the scheduled dose by 50%.

However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information. 2.6 Dosage Adjustment Based on Serum Electrolytes and Renal Toxicity If unexplained reductions in serum bicarbonate levels to less than 20 mEq/L occur, reduce the dosage by 50% for the next course.

Similarly, if unexplained elevations of BUN or serum creatinine occur, delay the next cycle until values return to normal or baseline and reduce the dose by 50% for the next course. 2.7 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, select the dose carefully and monitor renal function. 2.8 Preparation of Azacitidine for Injection Azacitidine for injection is a hazardous drug.

Follow applicable special handling and disposal procedures.

Azacitidine for injection vial is single-dose and does not contain any preservatives.

Discard unused portions of each vial properly.

Do not save any unused portions for later administration. 2.9 Instructions for Subcutaneous Administration Reconstitute Azacitidine for injection aseptically with 4 mL Sterile Water for Injection, USP to obtain a concentration of 25 mg/mL.

Inject the diluent slowly into the vial.

Vigorously shake or roll the vial until a uniform suspension is achieved.

The suspension will be cloudy.

Do not filter the suspension after reconstitution.

Doing so could remove the active substance.

Preparation for Immediate Subcutaneous Administration

For doses requiring more than 1 vial, divide the dose equally between the syringes (e.g., dose 150 mg = 6 mL, 2 syringes with 3 mL in each syringe) and inject into two separate sites.

Due to retention in the vial and needle, it may not be feasible to withdraw all of the suspension from the vial.

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.

The product must be refrigerated immediately.

Table for suspension stability storage timelines based on the temperature of the diluent for delayed subcutaneous administration.

After removal from refrigerated conditions, the suspension may be allowed to equilibrate to room temperature for up to 30 minutes prior to 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.

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.

Table 2 Suspension Stability: Storage timelines based on the temperature of the diluent for suspension stability storage: Suspension Stability Storage timelines Diluent Storage Temperature/Duration Room temperature (25°C / 77°F) Sterile Water for Injection, USP Store at room temperature at 25°C (77°F) for up to 1 hour or refrigerated at 2°C to 8°C (36°F to 46°F) for up to 8 hours.

Cold (2°C to 8°C / 36°F to 46°F) Sterile Water for Injection, USP Store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 22 hours. 2.10 Instructions for Intravenous Administration Parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Do not use the product if there is evidence of particulate matter or discoloration.

Adult Patients with MDS Reconstitute the appropriate number of Azacitidine for injection vials to achieve the desired dose.

Reconstitute each vial with 10 mL Sterile Water for Injection, USP.

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.

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, USP or Lactated Ringer's Injection, USP.

Azacitidine for injection is incompatible with 5% Dextrose Injection, USP 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.

Azacitidine for injection solution is administered intravenously.

Administer the total dose over a period of 10.

The administration must be completed within 1 hour of reconstitution of the Azacitidine for injection vial.

Azacitidine for injection reconstituted and diluted for intravenous administration may be stored at 25°C (77°F), but administration must be completed within 1 hour of reconstitution.

However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

Azacitidine for injection is supplied as a lyophilized powder in 100 mg single-dose vials packaged in cartons of 1 vial (NDC 83774-102-01).

Store unreconstituted vials at 25º C (77º F); excursions permitted to 15º-30º C (59º-86º F) .

Azacitidine for injection is a hazardous drug.

Follow applicable special handling and disposal procedures.

Based on its mechanism of action and findings in animals, Azacitidine can cause fetal harm when administered to a pregnant woman.

There are no data on the use of azacitidine in pregnant women.

Azacitidine was teratogenic and caused embryo-fetal lethality in animals at doses lower than the recommended human daily dose.

Advise pregnant women of the potential risk to the fetus.

The background rate of major birth defects and miscarriage is unknown for the indicated population.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single IP (intraperitoneal) injection of 6 mg/m 2 (approximately 8% of the recommended human daily dose on a mg/m 2 basis) azacitidine on gestation day 10.

Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day at doses of ~3-12 mg/m 2 (approximately 4%-16% the recommended human daily dose on a mg/m 2 basis).

In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4-8 (postimplantation) at a dose of 6 mg/m 2 (approximately 8% of the recommended human daily dose on a mg/m 2 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 to 12 mg/m 2 (approximately 8% the recommended human daily dose on a mg/m 2 basis) given on gestation day 9, 10, 11 or 12.

In this study azacitidine caused fetal death when administered at 3-12 mg/m on gestation days 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).

Based on its mechanism of action and findings in animals, Azacitidine can cause fetal harm when administered to a pregnant woman.

Verify the pregnancy status of females of reproductive potential prior to initiating azacitidine.

Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment with azacitidine and for 6 months after the last dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment with azacitidine and for 3 months after the last dose.

Based on animal data, azacitidine could have an effect on male or female fertility.

Safety and effectiveness of azacitidine in pediatric patients with MDS have not been established.

Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection).

However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

Of the total number of patients in Studies 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.

Elderly patients are more likely to have decreased renal function.

Monitor renal function in these patients.