Xpreza 100

White lyophilised powder.
Each vial contains 100 mg Azacitidine.
Excipients/Inactive Ingredients: Mannitol.

Pharmacotherapeutic group: Antineoplastic agents, pyrimidine analogues. ATC code: L01BC07.
Pharmacology: Pharmacodynamics: Mechanism of action: Azacitidine is a pyrimidine nucleoside analog of cytidine. Azacitidine is believed to exert its antineoplastic effects by causing hypomethylation of DNA 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 efficacy and safety: Study 1 was a randomized, open-label, controlled trial carried out in 53 U.S. sites compared the safety and efficacy of subcutaneous azacitidine plus supportive care with supportive care alone ("observation") in patients with any of the five FAB subtypes of myelodysplastic syndromes (MDS): refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL). RA and RARS patients were included if they met one or more of the following criteria: required packed RBC transfusions; had platelet counts ≤50.0 x 10⁹/L; required platelet transfusions; or were neutropenic (ANC <1.0 x 10⁹/L) with infections requiring treatment with antibiotics. Patients with acute myelogenous leukemia (AML) were not intended to be included. Supportive care allowed in this study included blood transfusion products, antibiotics, antiemetics, analgesics and antipyretics. The use of hematopoietic growth factors was prohibited. Baseline patient and disease characteristics are summarized in Table 1; the 2 groups were similar.
Azacitidine was administered at a subcutaneous dose of 75 mg/m² daily for 7 days every 4 weeks. The dose was increased to 100 mg/m² if no beneficial effect was seen after 2 treatment cycles. The dose was decreased and/or delayed based on hematologic response or evidence of renal toxicity. Patients in the observation arm were allowed by protocol to cross over to azacitidine if they had increases in bone marrow blasts, decreases in haemoglobin, increases in red cell transfusion requirements, or decreases in platelets, or if they required a platelet transfusion or developed a clinical infection requiring treatment with antibiotics. For purposes of assessing efficacy, the primary endpoint was response rate (as defined in Table 2).
Of the 191 patients included in the study, independent review (adjudicated diagnosis) found that 19 had the diagnosis of AML at baseline. These patients were excluded from the primary analysis of response rate, although they were included in an intent-to-treat (ITT) analysis of all patients randomized. Approximately 55% of the patients randomized to observation crossed over to receive azacitidine treatment. (See Tables 1 and 2.)

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The overall response rate (CR + PR) of 15.7% in azacitidine-treated patients without AML (16.2% for all azacitidine randomized patients including AML) was statistically significantly higher than the response rate of 0% in the observation group (p<0.0001) (Table 3). The majority of patients who achieved either CR or PR had either 2 or 3 cell line abnormalities at baseline (79%; 11/14) and had elevated bone marrow blasts or were transfusion dependent at baseline. Patients responding to azacitidine had a decrease in bone marrow blasts percentage, or an increase in platelets, hemoglobin or WBC. Greater than 90% of the responders initially demonstrated these changes by the 5^th treatment cycle. All patients who had been transfusion dependent became transfusion independent during PR or CR. The mean and median duration of clinical response of PR or better was estimated at 512 and 330 days, respectively; 75% of the responding patients were still in PR or better at completion of treatment. Response occurred in all MDS subtypes as well as in patients with adjudicated baseline diagnosis of AML. (See Table 3.)

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Patients in the observation group who crossed over to receive azacitidine treatment (47 patients) had a response rate of 12.8%.
Study 2, a multi-center, open-label, single-arm study of 72 patients with RAEB, RAEB-T, CMMoL, or AML was also carried out. Treatment with subcutaneous azacitidine resulted in a response rate (CR + PR) of 13.9%, using criteria similar to those described previously. The mean and median duration of clinical response of PR or better was estimated as 810 and 430 days, respectively; 80% of the responding patients were still in PR or better at the time of completion of study involvement. In Study 3, another open-label, single-arm study of 48 patients with RAEB, RAEB-T, or AML, treatment with intravenous azacitidine resulted in a response rate of 18.8%, again using criteria similar to those described previously. The mean and median duration of clinical response of PR or better was estimated as 389 and 281 days, respectively; 67% of the responding patients were still in PR or better at the time of completion of treatment. Response occurred in all MDS subtypes as well as in patients with adjudicated baseline diagnosis of AML in both of these studies. Azacitidine dosage regimens in these 2 studies were similar to the regimen used in the controlled study.
Benefit was seen in patients who did not meet the criteria for PR or better, but were considered "improved." About 24% of azacitidine-treated patients were considered improved, and about 2/3 of those lost transfusion dependence. In the observation group, only 5/83 patients met criteria for improvement; none lost transfusion dependence. In all 3 studies, about 19% of patients met criteria for improvement with a median duration of 195 days.
Study 4 was an international, multicenter, open-label, randomized trial in MDS patients with RAEB, RAEB-T or modified CMMoL according to FAB classification and Intermediate-2 and High risk according to IPSS classification. Of the 358 patients enrolled in the study, 179 were randomized to receive azacitidine plus best supportive care (BSC) and 179 were randomized to receive conventional care regimens (CCR) plus BSC (105 to BSC alone, 49 to low dose cytarabine and 25 to chemotherapy with cytarabine and anthracycline). The primary efficacy endpoint was overall survival.
The azacitidine and CCR groups were comparable for baseline parameters. The median age of patients was 69 years (range was 38-88 years), 98% were Caucasian, and 70% were male. At baseline, 95% of the patients were higher risk by FAB classification: RAEB (58%), RAEB-T (34%), and CMMoL (3%). By IPSS classification, 87% were higher risk: Int-2 (41%), High (47%). At baseline, 32% of patients met WHO criteria for AML.
Azacitidine was administered subcutaneously at a dose of 75 mg/m² daily for 7 consecutive days every 28 days (which constituted one cycle of therapy). Patients continued treatment until disease progression, relapse after response, or unacceptable toxicity. Azacitidine patients were treated for a median of 9 cycles (range 1 to 39), BSC only patients for a median of 7 cycles (range 1 to 26), low dose cytarabine patients for a median of 4.5 cycles (range 1 to 15), and chemotherapy with cytarabine and anthracycline patients for a median of 1 cycle (range 1 to 3, i.e. induction plus 1 or 2 consolidation cycles).
In the Intent-to-Treat analysis, patients treated with azacitidine demonstrated a statistically significant difference in overall survival as compared to patients treated with CCR (median survival of 24.5 months vs. 15.0 months; stratified log-rank p=0.0001). The hazard ratio describing this treatment effect was 0.58 (95% CI: 0.43, 0.77). (See Figure 1.)

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Azacitidine treatment led to a reduced need for red blood cell transfusions (see Table 4 as follows). In patients treated with azacitidine who were RBC transfusion dependent at baseline and became transfusion independent, the median duration of RBC transfusion independence was 13.0 months. (See Table 4.)

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Adult population aged 65 years or older with AML with >30% marrow blasts: The results presented as follows represent the intent-to-treat population studied in AZA-AML-001 (see Indications/Uses for the approved indication).
The efficacy and safety of Azacitidine for injection was studied in an international, multicentre, controlled, open-label, parallel group Phase 3 study in patients 65 years and older with newly diagnosed de novo or secondary AML with >30% bone marrow blasts according to the WHO classification, who were not eligible for HSCT. Azacitidine for injection plus BSC (n=241) was compared to CCR. CCR consisted of BSC alone (n=45), low-dose cytarabine plus BSC (n=158), or standard intensive chemotherapy with cytarabine and anthracycline plus BSC (n=44). Patients were pre-selected by their physician to 1 of the 3 CCRs prior to randomization. Patients received the pre-selected regimen if not randomised to Azacitidine for injection. As part of the inclusion criteria, patients were required to have an ECOG performance status of 0-2 and intermediate- or poor-risk cytogenetic abnormalities. The primary endpoint of the study was overall survival.
Azacitidine for injection was administered at a SC dose of 75mg/m²/day for 7 days, followed by a rest period of 21 days (28 day treatment cycle), for a median of 6 cycles (range: 1 to 28), BSC-only patients for a median of 3 cycles (range: 1 to 20), low-dose cytarabine patients for a median of 4 cycles (range 1 to 25) and standard intensive chemotherapy patients for a median of 2 cycles (range: 1 to 3, induction cycle plus 1 or 2 consolidation cycles).
The individual baseline parameters were comparable between the Azacitidine for injection and CCR groups. The median age of the subjects was 75.0 years (range: 64 to 91 years), 75.2% were Caucasian and 59.0% were male. At baseline 60.7% were classified as AML not otherwise specified, 32.4% AML with myelodysplasia-related changes, 4.1% therapy-related myeloid neoplasms and 2.9% AML with recurrent genetic abnormalities according to the WHO classification.
In the ITT analysis of 488 patients (241 Azacitidine for injection and 247 CCR), Azacitidine for injection treatment was associated with a median survival of 10.4 months versus 6.5 months for those receiving CCR treatment, a difference of 3.8 months, with a stratified log-rank p-value of 0.1009 (two-sided). The hazard ratio for the treatment effect was 0.85 (95% CI= 0.69, 1.03). The one-year survival rates were 46.5% in patients receiving Azacitidine for injection versus 34.3% in patients receiving CCR. (See Figure 2.)

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The Cox PH model adjusted for pre-specified baseline prognostic factors defined a HR for Azacitidine for injection versus CCR of 0.80 (95% CI=0.66, 0.99; p=0.0355).
In addition, although the study was not powered to demonstrate a statistically significant difference when comparing azacitidine to the preselection CCR treatment groups, the survival of Azacitidine for injection treated patients was longer when compared to CCR treatment options BSC alone, low-dose cytarabine plus BSC and were similar when compared to standard intensive chemotherapy plus BSC.
In all pre-specified subgroups age [(<75 years & ≥75 years), gender, race, ECOG performance status (0 or 1 & 2), baseline cytogenetic risk (intermediate & poor), geographic region, WHO classification of AML (including AML with myelodysplasia-related changes), baseline WBC count (≤5 x10⁹/L & >5 x 10⁹/L), baseline bone marrow blasts (≤50% & >50%) and prior history of MDS] there was a trend in OS benefit in favour of Azacitidine for injection. In a few pre-specified subgroups, the OS HR reached statistical significance including patients with poor cytogenetic risk, patients with AML with myelodysplasia-related changes, patients < 75 years, female patients and white patients.
Haematologic and cytogenetic responses were assessed by the investigator and by the IRC with similar results. Overall response rate (complete remission [CR] + complete remission with incomplete blood count recovery [CRi]) as determined by the IRC was 27.8% in the Azacitidine for injection group and 25.1% in the combined CCR group (p=0.5384). In patients who achieved CR or CRi, the median duration of remission was 10.4 months (95% CI=7.2, 15.2) for the Azacitidine for injection subjects and 12.3 months (95% CI=9.0, 17.0) for the CCR subjects. A survival benefit was also demonstrated in patients that had not achieved a complete response for Azacitidine for injection compared to CCR.
Azacitidine for injection treatment improved peripheral blood counts and led to a reduced need for RBC and platelet transfusions. A patient was considered RBC or platelet transfusion dependent at baseline if the subject had one or more RBC or platelet transfusions during the 56 days (8 weeks) on or prior to randomization, respectively. A patient was considered RBC or platelet transfusion independent during the treatment period if the subject had no RBC or platelet transfusions during any consecutive 56 days during the reporting period, respectively.
Of the patients in the Azacitidine for injection group who were RBC transfusion dependent at baseline, 38.5% (95% CI=31.1, 46.2) of these patients became RBC transfusion independent during the treatment period, compared with 27.6% of (95% CI=20.9, 35.1) patients in the combined CCR groups. In patients who were RBC transfusion dependent at baseline and achieved transfusion independence on treatment, the median duration of RBC transfusion independence was 13.9 months in the Azacitidine for injection group and was not reached in the CCR group.
Of the patients in the Azacitidine for injection group who were platelet transfusion dependent at baseline, 40.6% (95% CI=30.9, 50.8) of these patients became platelet transfusion independent during the treatment period, compared with 29.3% of (95% CI=19.7, 40.4) patients in the combined CCR groups. In patients who were platelet transfusion dependent at baseline and achieved transfusion independence on treatment, the median duration of platelet transfusion independence was 10.8 months in the Azacitidine for injection group and 19.2 months in the CCR group.
Health-Related Quality of Life (HRQoL) was assessed using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30). HRQoL data could be analysed for a subset of the full trial population. While there are limitations in the analysis, the available data suggest that patients do not experience meaningful deterioration in quality of life during treatment with Azacitidine for injection.
Pharmacokinetics: The pharmacokinetics of azacitidine were studied in 6 MDS patients following a single 75 mg/m² subcutaneous (SC) dose and a single dose 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. The bioavailability of SC azacitidine relative to IV azacitidine is approximately 89%, based on area under the curve. Mean volume of distribution following IV dosing is 76±26 L. Mean apparent 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 of azacitidine 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. Mean excretion of radioactivity in urine following SC administration of ¹⁴C-azacitidine was 50%. The mean elimination half-lives of total radioactivity (azacitidine and its metabolites) were similar after IV and SC administrations, about 4 hours.
Toxicology: Preclinical safety data: 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 3 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%-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 TA 100 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 system. 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 20-40%, 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 increased in abnormal embryos in mated females when examined on day 2 of gestation.

Xpreza 100 is indicated for treatment of patients with the following myelodysplastic syndrome subtypes: Refractory anaemia (RA); Refractory anaemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions; Refractory anemia with excess blasts; Refractory anemia with excess blasts in transformation (or acute myeloid leukemia with 20-30% bone marrow blasts and multi-lineage dysplasia, according to World Health Organisation (WHO) classification); Adult patients aged 65 years or older who are not eligible for haematopoietic stem cell transplantation (HSCT with AML with >30% marrow blasts according to the WHO classification; Chronic myelomonocytic leukemia.

Xpreza 100 treatment should be initiated and monitored under the supervision of a physician experienced in the use of chemotherapeutic agents. Patients should be premedicated with anti-emetics for nausea and vomiting.
Posology: First treatment Cycle: The recommended starting dose for the first treatment cycle, for all patients regardless of baseline haematology laboratory values, is 75 mg/m² of body surface area, injected subcutaneously or intravenously, daily for 7 days. Patients should be premedicated for nausea and vomiting. Complete blood counts, liver chemistries and serum creatinine should be obtained prior to first dose.
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 (see Precautions) and dosage delay or reduction as described as follows may be necessary.
Dose adjustment due to haematological Laboratory values: For patients with baseline (start of treatment) WBC ≥3.0 x10⁹/L, ANC ≥1.5 x10⁹/L, and platelets ≥75.0 x10⁹/L, adjust the dose as follows, based on nadir counts for any given cycle: See Table 5.

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Patients without reduced baseline blood counts are WBC <3.0 x 10⁹/L and ANC <1.5 x 10⁹/L, and platelets <75.0 x 10⁹/L dose adjustments should be based on nadir counts and bone marrow biopsy cellularity at the time of the nadir as noted as follows, 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 6.)

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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.
Dosage Adjustment Based on Renal Function and Serum Electrolytes: If unexplained reductions in serum bicarbonate levels to <20 mEq/L occur, the dosage should be reduced by 50% on the next course. Similarly, if unexplained elevations of BUN or serum creatinine occur, the next cycle should be delayed until values return to normal or baseline and the dose should be reduced by 50% on the next treatment course.
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, care should be taken in dose selection, and it may be useful to monitor renal function.
Method of administration and Preparation: Reconstituted Xpreza 100 should be injected subcutaneously (insert the needle at a 45-90° angle) using a 25-gauge needle into the upper arm, thigh or abdomen.
Doses greater than 4 mL should be injected into two separate sites.
Injection sites should be rotated. New injections should be given at least 2.5 cm from the previous site and never into areas where the site is tender, bruised, red, or hardened.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Subcutaneous Preparation: Xpreza 100 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.
Preparation for Immediate Subcutaneous Administration: Doses greater than 4 mL should be divided equally into 2 syringes. The product may be held at 25°C 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, and may be held under refrigerated conditions (2ºC-8ºC, 36ºF-46ºF) for up to 8 hours. When azacitidine is reconstituted using refrigerated (2ºC-8ºC, 36ºF-46ºF) water for injection, the reconstituted product may be stored under refrigerated conditions (2ºC-8ºC, 36ºF-46ºF) 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). 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.
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). When Azacitidine for injection is reconstituted using refrigerated (2°C to 8°C) water for injections, the chemical and physical in-use stability of the reconstituted medicinal product has been demonstrated at 2°C to 8°C for 22 hours.
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 Solution Incompatibility: Azacitidine is incompatible with 5% Dextrose solutions, Hespan, or solutions that contain bicarbonate. These solutions have the potential to increase the rate of degradation of Azacitidine and should therefore be avoided.
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 diarrhoea, nausea, and vomiting after receiving a single intravenous 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.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Advanced malignant hepatic tumours (see Precautions).
Breast-feeding (see Use in Pregnancy & Lactation).

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 as described in posology and 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 rarely reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline albumin <30 g/L. Azacitidine is contraindicated in patients with advanced malignant hepatic tumors. (See Contraindications.)
Safety and effectiveness of azacitidine in patients with MDS and hepatic impairment have not been studied as these patients were excluded from the clinical trials.
Renal Abnormalities: Renal abnormalities ranging from elevated serum creatinine to renal failure and death have been reported rarely in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for non-MDS 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 as described in posology and administration.
Patients with renal impairment should be closely monitored for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys. (See Dosage & Administration.)
Safety and effectiveness of azacitidine in patients with MDS and renal impairment have not been studied as these patients were excluded from the clinical trials.
Necrotising Fasciitis: Necrotising fasciitis, including fatal cases, have been reported in patients treated with azacitidine. Azacitidine for injection therapy should be discontinued in patients who develop necrotising fasciitis and appropriate treatment should be promptly initiated.
Tumour lysis syndrome: The patients at risk of tumor lysis syndrome are those with high tumour burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
Information for Patients: Patients should inform their physician about any underlying liver and renal disease. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with azacitidine for injection. For nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into consideration the importance of the drug to the mother. Men should be advised to not father a child while receiving treatment with azacitidine.
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.
Drug Interactions: No formal assessments of drug-drug interactions between azacitidine and other agents have been conducted. (See Pharmacology under Actions.)
Effects on ability to drive and use machines: Azacitidine has minor or moderate influence on the ability to drive and use machines. Fatigue has been reported with the use of azacitidine. Therefore, caution is recommended when driving or operating machines.

Pregnancy: Teratogenic Effects: Pregnancy Category D.
Azacitidine for injection may cause fetal harm when administered to a pregnant woman. Early embryo toxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single IP (intraperitoneal) injection of 6 mg/m² (approximately 8% of the recommended human daily dose on a mg/m² basis) azacitidine on gestation day 10. 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).
In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4-8 (Post implantation) at a dose of 6 mg/m² (approximately 8% of the recommended human daily dose on a mg/m² 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 single IP dose of 3 to 12 mg/m² (approximately 8% the recommended human daily dose mg/m² daily dose on a mg/m² basis) given on gestation days 9, 10, 11 or 12. In this study azacitidine caused fetal death when administered at 3-12 mg/m² on gestation days 9 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). There are no adequate and well-controlled studies in pregnant women using azacitidine. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the foetus.
Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with azacitidine.
Fertility: Men should be advised to not father a child while receiving treatment with azacitidine. (See Precautions for discussion of premating effects of azacitidine exposure on male fertility and embryonic viability.)

Overview: Adverse Reactions Described in Other Monograph Sections: Anemia, neutropenia, thrombocytopenia, elevated serum creatinine, renal failure. Renal tubular acidosis, hepatic coma.
Most Commonly Occurring Adverse Reactions (SC or IV Route): Nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhoea, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by IV route also included petechiae, rigors, weakness and hypokalemia.
Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (SC or IV Route): Discontinuation: leukopenia, thrombocytopenia, neutropenia.
Dose Held: leukopenia, neutropenia and thrombocytopenia; pyrexia, pneumonia, febrile neutropenia.
Dose Reduced: leukopenia, neutropenia and thrombocytopenia.
Adverse Reactions in clinical trials: The data described as follows reflect exposure to azacitidine in 443 MDS patients from 4 clinical studies. Study 1 was a supportive-care controlled trial (SC administration), Studies 2 and 3 were single arm studies (one with SC administration and one with IV administration), and Study 4 was an international randomized trial (SC administration).
In Studies 1, 2 and 3, a total of 268 patients were exposed to azacitidine, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one year). Azacitidine 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 IV 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. 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 doses of 75 mg/m².
Table 7 represents adverse reactions occurring in at least 5% of patients treated with azacitidine (SC) in Studies 1 and 2. It is important to note that duration of exposure was longer for the AZACITIDINE-treated group than for the observation group: patients received azacitidine for a mean of 11.4 months while mean time in the observation arm was 6.1 months. (See Table 7.)

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Table 8 presents adverse reactions occurring in at least 5% of patients treated with AZACITIDINE in Study 4. Similar to Studies 1 and 2 described previously, duration of exposure to treatment with azacitidine was longer (mean 12.2 months) compared with best supportive care (mean 7.5 months). (See Table 8.)

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In Studies 1, 2 and 4 with SC administration of AZACITIDINE, adverse reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhoea, constipation, and injection site erythema/reaction tended to increase in incidence with higher doses of AZACITIDINE. Adverse reactions that tended to be more pronounced during the first 1 to 2 cycles of SC 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 IV and SC studies. Adverse reactions that appeared to be specifically associated with the IV 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 SC or IV AZACITIDINE, the following serious adverse reactions occurring at a rate of <5% (and not described in Tables 7 or 8) were reported: Blood and lymphatic system disorders: agranulocytosis, bone marrow failure, pancytopenia splenomegaly.
Cardiac disorders: atrial fibrillation, cardiac failure, cardiac failure congestive, cardiorespiratory 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: haemoptysis, 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.
Adult population aged 65 years or older with AML with >30% marrow blasts: The most common serious adverse reactions (≥10%) noted from AML >30% within the azacitidine treatment arm included febrile neutropenia (25.0%), pneumonia (20.3%), and pyrexia (10.6%). Other less frequently reported serious adverse reactions in the azacitidine treatment arm included sepsis (5.1%), anaemia (4.2%), neutropenic sepsis (3.0%), urinary tract infection (3.0%), thrombocytopenia (2.5%), neutropenia (2.1%), cellulitis (2.1%), dizziness (2.1%) and dyspnoea (2.1%).
The most commonly reported (≥30%) adverse reactions with azacitidine treatment were gastrointestinal events, including constipation (41.9%), nausea (39.8%) and diarrhea (36.9%) (usually Grade 1-2), general disorders and administration site conditions including pyrexia (37.7%; usually Grade 1-2) and haematological events, including febrile neutropenia (32.2%) and neutropenia (30.1%), (usually grade 3-4).
Table 9 as follows contains adverse reactions associated with azacitidine treatment obtained from the main clinical studies in MDS and AML and post marketing surveillance.
Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to < 1/1000; very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Adverse reactions are presented in the table as follows according to the highest frequency observed in any of the main clinical studies. (See Table 9.)

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No formal clinical drug interaction studies with azacitidine have been conducted.
An in vitro study of azacitidine incubation in human liver fractions indicated that azacitidine may be metabolized by the liver. Whether azacitidine metabolism may be affected by known microsomal enzyme inhibitors or inducers has not been studied.
An in vitro study with cultured human hepatocytes indicated that azacitidine at concentrations upto 100 μM (IV Cmax = 10.6 μM) does not cause any inhibition of CYP2B6 and CYP2C8.
The potential of azacitidine to inhibit cytochrome P450 (CYP) enzymes is not known.
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.

Incompatibilities: This medicinal product must not be mixed with other medicinal products except those mentioned in Special precautions for disposal and other handling as follows.
Special precautions for disposal and other handling: Recommendations for safe handling: Azacitidine for injection is a cytotoxic medicinal product and, as with other potentially toxic compounds, caution should be exercised when handling and preparing azacitidine suspensions. Procedures for proper handling and disposal of anticancer medicinal products should be applied.
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.
Reconstitution procedure: Azacitidine for injection should be reconstituted with water for injections. The shelf life of the reconstituted medicinal product can be extended by reconstituting with refrigerated (2°C to 8°C) water for injections. Details on storage of the reconstituted product are provided as follows.
1. The following supplies should be assembled: Vial(s) of azacitidine; vial(s) of water for injections; non-sterile surgical gloves; alcohol wipes; 5 mL injection syringe(s) with needle(s).
2. 4 mL of water for injections should be drawn into the syringe, making sure to purge any air trapped within the syringe.
3. The needle of the syringe containing the 4 mL of water for injections should be inserted through the rubber top of the azacitidine vial followed by injection of the water for injections into the vial.
4. Following removal of the syringe and needle, the vial should be vigorously shaken until a uniform cloudy suspension is achieved. After reconstitution each mL of suspension will contain 25 mg of azacitidine (100 mg/4 mL). The reconstituted product is a homogeneous, cloudy suspension, free of agglomerates.
The product should be discarded if it contains large particles or agglomerates. Do not filter the suspension after reconstitution since this could remove the active substance. It must be taken into account that filters are present in some adaptors, spikes and closed systems; therefore, such systems should not be used for administration of the medicinal product after reconstitution.
5. The rubber top should be cleaned and a new syringe with needle inserted into the vial. The vial should then be turned upside down, making sure the needle tip is below the level of the liquid. The plunger should then be pulled back to withdraw the amount of medicinal product required for the proper dose, making sure to purge any air trapped within the syringe. The syringe with needle should then be removed from the vial and the needle disposed of.
6. A fresh subcutaneous needle (recommended 25-gauge) should then be firmly attached to the syringe. The needle should not be purged prior to injection, in order to reduce the incidence of local injection site reactions.
7. When more than 1 vial is needed, all the previous steps for preparation of the suspension should be repeated. For doses requiring more than 1 vial, the dose should be equally divided e.g., dose 150 mg=6 mL, 2 syringes with 3 mL in each syringe. Due to retention in the vial and needle, it may not be feasible to withdraw all of the suspension from the vial.
8. The contents of the dosing syringe must be re-suspended immediately prior to administration. The syringe filled with reconstituted suspension should be allowed up to 30 minutes prior to administration to reach a temperature of approximately 20°C-25°C. If the elapsed time is longer than 30 minutes, the suspension should be discarded appropriately and a new dose prepared. To re-suspend, vigorously roll the syringe between the palms until a uniform, cloudy suspension is achieved. The product should be discarded if it contains large particles or agglomerates.
Storage of the reconstituted product: For storage conditions after reconstitution of the medicinal product, see Shelf life under Storage.
Calculation of an individual dose: The total dose, according to the body surface area (BSA) can be calculated as follows: Total dose (mg) = Dose (mg/m²) x BSA (m²).
The following table is provided only as an example of how to calculate individual azacitidine doses based on an average BSA value of 1.8 m². (See Table 10.)

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Unopened vials: Store below 30°C.
Reconstituted suspension: For storage conditions after reconstitution of the medicinal product, see Shelf life as follows.
Shelf life: Unopened powder vial: 2 years.
After reconstitution: When Azacitidine for injection is reconstituted using water for injections that has not been refrigerated, chemical and physical in-use stability of the reconstituted medicinal product has been demonstrated at 25°C for 1 hour and at 2°C to 8°C for 8 hours.
The shelf life of the reconstituted medicinal product can be extended by reconstituting with refrigerated (2°C to 8°C) water for injections. When Azacitidine for injection is reconstituted using refrigerated (2°C to 8°C) water for injections, the chemical and physical in-use stability of the reconstituted medicinal product has been demonstrated at 2°C to 8°C for 22 hours.
From a microbiological point of view, the reconstituted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and must not be longer than 8 hours at 2°C to 8°C when reconstituted using water for injections that has not been refrigerated or not longer than 22 hours when reconstituted using refrigerated (2°C to 8°C) water for injections.

Cytotoxic Chemotherapy

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

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