Azacitidine for injection

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZACITIDINE FOR INJECTION (AZACITIDINE FOR INJECTION)

Composition:

active substance: azacitidine;

1 vial contains azacitidine 100 mg;

excipients: mannitol (E 421).

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white to almost white lyophilized solid or powder.

Pharmacotherapeutic group. Antineoplastic agents. Pyrimidine analogues.

ATC code L01B C07.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Azacitidine is a pyrimidine nucleoside analogue of cytidine. Azacitidine is thought to exert its antineoplastic effects by causing 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 significant suppression of DNA synthesis. Hypomethylation may restore normal function of genes critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause cell death in rapidly dividing cells, including cancer cells that no longer respond to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine.

Pharmacokinetics

The pharmacokinetics of azacitidine were studied in 6 patients with myelodysplastic syndromes (MDS) after a single subcutaneous dose of 75 mg/m² and a single intravenous dose of 75 mg/m².

Absorption

Azacitidine is rapidly absorbed after subcutaneous administration; maximum plasma concentration (Cmax) of azacitidine, 750 ± 403 ng/mL, is reached within 0.5 hours.

Distribution

The bioavailability of azacitidine administered subcutaneously relative to intravenous administration is approximately 89%, based on the area under the curve (AUC). The mean volume of distribution after intravenous administration is 76 ± 26 L. The mean apparent subcutaneous clearance is 167 ± 49 L/h, and the mean half-life after subcutaneous administration is 41 ± 8 minutes. After subcutaneous administration of azacitidine in 21 patients with cancer, AUC and Cmax were approximately dose-proportional over the dose range of 25 to 100 mg/m². Repeated administration at the recommended dosing regimen does not result in accumulation of the drug following either intravenous or subcutaneous administration.

Elimination

Incubation studies of azacitidine in vitro in human liver fractions showed that azacitidine is not metabolized by cytochrome P450 (CYP) enzymes. Azacitidine undergoes spontaneous hydrolysis and cytidine deaminase-mediated deamination.

Published studies indicate that the primary route of elimination of azacitidine and its metabolites is urinary excretion. After intravenous administration of radiolabeled azacitidine to 5 cancer patients, cumulative urinary excretion accounted for 85% of the radioactive dose. Fecal excretion accounted for < 1% of the administered radioactivity over 3 days. The mean excretion of radioactivity in urine after subcutaneous administration of 14C-azacitidine was 50%. The mean half-life of total radioactivity (azacitidine and its metabolites) was similar after intravenous and subcutaneous administration, approximately 4 hours.

Special Populations

The effect of hepatic impairment, gender, age, or race on the pharmacokinetics of intravenous and subcutaneous azacitidine has not been formally studied.

Renal Impairment

In adult cancer patients, the pharmacokinetics of azacitidine were compared in 6 patients with normal renal function (CLcr > 80 mL/min) and 6 patients with severe renal impairment (CLcr < 30 mL/min) after daily subcutaneous administration of azacitidine (days 1 to 5) at a dose of 75 mg/m²/day. Severe renal impairment increased azacitidine exposure by approximately 70% after single-dose and by 41% after multiple-dose subcutaneous administration. This increase in exposure did not correlate with an increased incidence of adverse events. Exposure was similar to that observed in patients with normal renal function receiving azacitidine at a dose of 100 mg/m².

Clinical characteristics

Indications

Injectable azacitidine is indicated for the treatment of adult patients with the following French-American-British (FAB) classification subtypes of myelodysplastic syndromes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if associated with neutropenia or thrombocytopenia or requiring blood transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMML).

Contraindications

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Widespread hepatic malignancies.

Interaction with other medicinal products and other forms of interaction

Formal clinical studies on drug interactions with azacitidine have not been conducted.

In vitro studies

Cytochrome P450 (CYP) enzymes. In vitro studies using azacitidine concentrations up to 100 µM (IV Cmax = 10.6 µM) in human liver microsomes showed that azacitidine does not cause inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP2E1 isoforms at clinically achievable concentrations.

In vitro studies using cultured human hepatocytes indicate that azacitidine at concentrations ranging from 1.0 to 100 µM does not induce CYP1A2, CYP2C19, or CYP3A4/5.

Transport systems. In vitro studies in P-glycoprotein (P-gp) expressing LLC-PK1 cells showed that azacitidine is neither a substrate nor an inhibitor of P-gp. Azacitidine does not inhibit breast cancer resistance protein (BCRP), organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptides (OATP) OATP1B1 and OATP1B3, or organic cation transporter (OCT) OCT2 at clinically relevant concentrations.

Special precautions for use

Risks associated with substitution by other azacitidine formulations

Due to differences in pharmacokinetic parameters, the recommended dose and administration schedule for azacitidine as an injection solution may differ from that of oral azacitidine.

Administration of the injectable solution at doses intended for oral azacitidine may result in fatal adverse reactions. Conversely, treating patients receiving oral azacitidine with doses recommended for the injectable form may be ineffective.

Do not interchange this medicinal product with oral formulations of azacitidine (see section "Method of administration and dosage").

Anaemia, neutropenia, and thrombocytopenia

Azacitidine causes anaemia, neutropenia, and thrombocytopenia in adult patients with MDS, particularly during the first two cycles. Complete blood counts should be performed as needed to monitor treatment response and drug toxicity, but at a minimum prior to each treatment cycle. In adult patients, after the first cycle of azacitidine at the recommended dose, subsequent cycle doses should be reduced or administration delayed based on nadir counts and haematological response.

Hepatotoxicity in patients with severe hepatic impairment

Since azacitidine may be hepatotoxic in patients with severe hepatic impairment, caution is required in patients with pre-existing liver disease. The safety and efficacy of azacitidine in patients with hepatic impairment have not been studied. Progressive hepatic coma with fatal outcome has been reported during treatment in patients with high tumour burden due to metastatic disease, particularly in patients with baseline serum albumin levels < 30 g/L. Azacitidine is contraindicated in patients with extensive hepatic malignancies. Liver function tests should be monitored before initiation of treatment and prior to each cycle. The safety and efficacy of azacitidine in MDS patients with hepatic impairment have not been studied, as such patients were excluded from clinical trials.

Renal impairment

Renal disorders ranging from elevated serum creatinine to renal failure and fatal outcomes have been reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for conditions unrelated to MDS. In 5 patients with chronic myelogenous leukaemia (CML) treated with azacitidine and etoposide, renal tubular acidosis developed, defined as a decrease in serum bicarbonate to < 20 mmol/L associated with alkaline urine and hypokalaemia (serum potassium < 3 mmol/L). If unexplained decreases in serum bicarbonate (< 20 mmol/L) or increases in serum creatinine or blood urea nitrogen occur, dose reduction or delay should be considered. Serum creatinine and electrolytes should be monitored before initiation of therapy and during each cycle. In the event of unexplained serum bicarbonate levels < 20 mmol/L or increased blood urea nitrogen or serum creatinine, dose reduction or discontinuation of the medicinal product should be considered.

Patients with renal impairment may be at increased risk of renal toxicity. Additionally, azacitidine and its metabolites are primarily excreted by the kidneys. Therefore, these patients should be closely monitored for toxicity. Patients with MDS and renal impairment were excluded from clinical trials.

Tumour lysis syndrome

Azacitidine may cause fatal or severe tumour lysis syndrome, including in patients with MDS. Tumour lysis syndrome may occur despite concomitant allopurinol use. Initial risk assessment and appropriate monitoring and treatment should be performed as needed.

Embryo-foetal toxicity

Based on the mechanism of action and data from animal studies, azacitidine may cause foetal harm when administered to a pregnant woman. Azacitidine administered intraperitoneally as a single dose to pregnant rats at approximately 8% of the recommended human daily dose caused foetal death and malformations. Pregnant women should be informed of the potential risk to the foetus. Women of reproductive potential should use effective contraception during treatment with azacitidine and for 6 months after the last dose. Men treated with azacitidine and their female partners of reproductive potential should use effective contraception during treatment and for at least 3 months after completion of therapy.

Use during pregnancy or breastfeeding

Pregnancy

Summary of risks

Based on the mechanism of action and animal study results, azacitidine may pose a risk to the foetus when administered to pregnant women. Data on azacitidine use in pregnant women are lacking. Azacitidine demonstrated teratogenic effects and caused embryonal lethality in animals at doses below the recommended human daily dose (see section "Special precautions for use"). Pregnant women should be informed of the potential risk to the foetus. The background rate of major congenital malformations and miscarriages in the indicated population is unknown.

All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the general population, the estimated background risk of major congenital malformations and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Studies

Early embryotoxicity studies in mice revealed a 44% rate of intrauterine embryonic death (increased resorption) following a single intraperitoneal injection of 6 mg/m² (approximately 8% of the recommended human daily dose on a mg/m² basis) of azacitidine on gestation day 10. Brain development abnormalities were observed in mice treated with azacitidine on day 15 of pregnancy or earlier at doses of 3 to 12 mg/m² (approximately 4–16% of the recommended human daily dose on a mg/m² basis).

Intravenous administration to rats on days 4–8 of pregnancy (post-implantation period) at a dose of 6 mg/m² (approximately 8% of the recommended human daily dose on a mg/m² basis) resulted in marked embryotoxicity, although treatment during the pre-implantation period (days 1–3 of pregnancy) had no adverse effect on embryos. Azacitidine caused multiple foetal developmental abnormalities in rats following a single intravenous dose of 3 to 12 mg/m² (approximately 8% of the recommended human daily dose on a mg/m² basis) on gestation days 9, 10, 11, or 12. In this study, azacitidine caused foetal death when administered at doses of 3 to 12 mg/m² on gestation days 9 and 10; the mean number of live pups per litter decreased to 9% of control at the highest dose on day 9 of gestation. Foetal abnormalities included: CNS abnormalities (exencephaly/encephalocoele), limb abnormalities (micromelia, clubfoot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, oedema, and rib anomalies).

Breastfeeding

There is no information on the presence of azacitidine in human milk, the effects of azacitidine on breastfed infants, or the effects on milk production. Since many drugs are excreted in human milk, and due to the potential carcinogenicity of azacitidine observed in animal studies and the possibility of serious adverse reactions in breastfed infants, breastfeeding is not recommended during treatment with azacitidine and for one week after the last dose.

Women and men of reproductive potential

Based on the mechanism of action and animal study results, azacitidine may cause harm to a foetus when administered to a pregnant woman.

Pregnancy testing

Women of reproductive potential should be tested for pregnancy before initiating azacitidine treatment.

Contraception

Women

Women of reproductive potential should use effective contraception during treatment with azacitidine and for 6 months after the last dose.

Men

Men should be advised to avoid planning conception during treatment and to use effective contraception during treatment and for at least 3 months after completion of therapy.

Fertility

Animal data suggest that azacitidine may impair male or female fertility.

Ability to affect reaction rate when driving or operating machinery

Azacitidine has minor or moderate influence on the ability to drive or operate machinery. Cases of fatigue have been reported with azacitidine use. Therefore, caution is recommended when driving or operating machinery.

Method of Administration and Dosage

The medicinal product should not be substituted with oral azacitidine. Due to differences in exposure, dosage recommendations and administration schedules for oral azacitidine differ from those for injectable azacitidine.

First treatment cycle in adults

The recommended initial dose for the first treatment cycle in all patients, regardless of baseline hematological laboratory parameters, is 75 mg/m² administered subcutaneously or intravenously, once daily for 7 consecutive days.

Patients should receive prophylactic antiemetic premedication to prevent nausea and vomiting.

Prior to the first dose, a complete blood count, liver biochemical tests, and serum creatinine level should be performed.

Subsequent treatment cycles in adults

Repeat cycles every 4 weeks. The dose may be increased to 100 mg/m² if no positive response is observed after 2 treatment cycles, provided there are no signs of toxicity except for nausea and vomiting. At least 4–6 treatment cycles are recommended. Treatment should be continued as long as clinical benefit is observed or until disease progression.

Patients should be monitored for hematological response/toxicity and renal toxicity.

Dosage adjustment based on hematological laboratory parameters

• For adult patients with baseline white blood cell count (at treatment initiation) ≥3 × 10⁹/L, absolute neutrophil count (ANC) ≥1.5 × 10⁹/L, and platelet count ≥75 × 10⁹/L, dosage adjustment should be performed as follows, based on nadir values (lowest counts) for each individual cycle:

Table 1

• For adult patients with a baseline white blood cell count <3 x10⁹/L, ANC <1.5 x10⁹/L, or platelets <75 x10⁹/L, the starting dose should be adjusted based on nadir values and bone marrow biopsy cellularity at nadir, as outlined below, except when clear improvement in differentiation is observed (a higher percentage of mature granulocytes and a higher ANC compared to the beginning of this cycle) at the time of the next cycle; in such cases, continue with the current dose.

Table 2

If the nadir, as defined in the table above, has been reached, the next course should be administered 28 days after the start of the previous course, provided that white blood cell and platelet counts are more than 25% above the nadir and continue to rise. If an increase of more than 25% above the nadir is not observed on day 28, blood counts should be reassessed every 7 days. If a 25% increase above the nadir is not observed by day 42, the planned dose should be reduced by 50%.

Dose adjustment based on renal function and serum electrolyte levels

If unexplained reduction in serum bicarbonate levels to less than 20 mmol/L occurs, the dose should be reduced by 50% in the next cycle. If unexplained elevation of serum creatinine or blood urea nitrogen (BUN) occurs to 2 times or more above baseline values and above the upper limit of normal (ULN), initiation of the next cycle should be delayed until values return to normal or baseline levels, and the dose should be reduced by 50% in the next treatment cycle.

Elderly patients

It is known that azacitidine and its metabolites are substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Since elderly patients are more likely to have decreased renal function, dose selection should be cautious, and renal function should be monitored carefully.

Preparation of azacitidine suspension

Azacitidine is a cytotoxic drug. As with other potentially toxic compounds, caution is required in handling and preparing suspensions.

The vial containing azacitidine is intended for single use and contains no preservatives. Any unused portion remaining in the vial should be properly discarded. Do not store unused portions of the drug for future use.

Instructions for subcutaneous administration of the drug

Azacitidine must be reconstituted under aseptic conditions using 4 mL of sterile water for injection to obtain a concentration of 25 mg/mL. The diluent should be slowly added to the vial. The vial should be shaken or rotated vigorously to obtain a uniform suspension. The suspension will be cloudy. Do not filter the suspension after reconstitution, as filtration may remove the active ingredient.

Preparation for immediate subcutaneous administration

For doses requiring more than one vial, divide the dose equally between syringes (e.g., a 150 mg dose = 6 mL, two syringes with 3 mL each) and administer into two separate injection sites. Due to residual volume in the vial and needle, it may not be possible to withdraw all of the suspension from the vial. The drug may be stored at room temperature for up to 1 hour, but must be administered within 1 hour after reconstitution.

Preparation of the drug for delayed subcutaneous administration

The reconstituted drug may be stored in the vial or drawn into a syringe. For doses requiring more than one vial, divide the dose equally between syringes (e.g., a 150 mg dose = 6 mL, two syringes with 3 mL each) and administer into two separate injection sites. Due to residual volume in the vial and needle, it may not be possible to withdraw all of the suspension from the vial.

The drug must be refrigerated immediately. The table below provides stability storage periods for the suspension depending on the temperature of the diluent for delayed subcutaneous administration.

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

Subcutaneous administration

To obtain a uniform suspension, the syringe contents should be resuspended immediately before administration. To resuspend, rotate the syringe vigorously between the palms until a uniform cloudy suspension is obtained. Administer azacitidine as a subcutaneous suspension. Injection sites should be rotated for each injection (thigh, abdomen, or upper arm). New injections should be administered at least 1 cm away from previous injection sites and never into areas where the skin is irritated, bruised, red, or hardened. After reconstitution, do not filter the suspension.

Table 3

Suspension stability: storage periods based on diluent temperature to ensure suspension stability

Instructions for Intravenous Administration

After reconstitution, the solution should be clear and colourless, free from visible particulate matter.

The parenteral product should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit. Do not use the product if particulate matter or discoloration is observed.

Adult Patients with MDS

Take the required number of vials of the medicinal product to obtain the desired dose. Reconstitute the contents of each vial with 10 mL of sterile water for injections. Shake or rotate the vial vigorously until all solid particles have dissolved. The resulting solution contains 10 mg/mL of azacitidine and should be clear.

Withdraw the required volume of azacitidine solution into a syringe for the desired dose and transfer it into an infusion bag containing 50–100 mL of 0.9% sodium chloride injection or Ringer’s (lactated) solution.

Intravenous Administration

The azacitidine solution should be administered intravenously, with the entire dose infused over 10–40 minutes. The infusion must be completed within 1 hour after reconstitution of the azacitidine vial.

Solution Stability. Azacitidine for injection, once reconstituted and diluted for intravenous administration, may be stored at 25°C, but administration must be completed within 1 hour after reconstitution.

Children

The safety and efficacy of azacitidine in children with MDS have not been established.

Overdose

One case of azacitidine overdose has been reported during clinical studies. The patient experienced diarrhoea, nausea, and vomiting after receiving a single intravenous dose of approximately 290 mg/m², which is nearly 4 times the recommended initial dose.

In the event of overdose, patients should be monitored, appropriate blood tests should be performed, and supportive treatment should be administered as needed. There is no specific antidote for azacitidine overdose.

Adverse Reactions

• Anemia, neutropenia, and thrombocytopenia.
• Hepatotoxicity in patients with severe pre-existing hepatic insufficiency.
• Renal toxicity.
• Tumor lysis syndrome.

These adverse reactions are described in the section "Special Warnings and Precautions for Use".

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to those of another and may not reflect the rates observed in clinical practice.

Myelodysplastic Syndromes

The data below reflect exposure to azacitidine in 443 patients with MDS from 4 clinical trials. Study 1 was a controlled trial with best supportive care (subcutaneous administration), Studies 2 and 3 were single-arm trials (one with subcutaneous and one with intravenous administration), and Study 4 was an international randomized trial (subcutaneous administration).

In Studies 1, 2, and 3, 268 patients received azacitidine, including 116 patients for 6 cycles (approximately 6 months) or longer and 60 patients for more than 12 cycles (approximately one year). Azacitidine was studied primarily in controlled and uncontrolled trials with best supportive care (n = 150 and n = 118, respectively). In the subcutaneous administration trials (n = 220), patients aged 23 to 92 years (median 66.4 years) were enrolled, 68% were men and 94% were women, with MDS or AML. In the intravenous administration trial (n = 48), patients aged 35 to 81 years (median 63.1 years) were enrolled, 65% were women, 100% were women. Most patients received median daily doses of 50 to 100 mg/m².

In Study 4, 175 patients with high-risk MDS (predominantly RAEB and RAEB-T subtypes) received azacitidine, of whom 119 received therapy for 6 or more cycles and 63 received therapy for at least 12 cycles. The median age of this population was 68.1 years (range 42 to 83 years), 74% were men and 99% were women. Most patients received a daily dose of azacitidine of 75 mg/m².

The most common adverse reactions (with subcutaneous or intravenous administration) in adult patients with MDS were: nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, and ecchymosis. The most common adverse reactions with intravenous administration also included petechiae, rigors, asthenia, and hypokalemia.

Adverse reactions leading most frequently (>2%) to clinical intervention (subcutaneous or intravenous administration) in adult patients with MDS:

Discontinuation: leukopenia, thrombocytopenia, neutropenia.

Dose withholding: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia.

Dose reduction: leukopenia, neutropenia, thrombocytopenia.

Table 4 lists adverse reactions that occurred in at least 5% of patients receiving azacitidine (subcutaneously) in Studies 1 and 2. It is important to note that exposure duration was longer in the azacitidine group than in the observation group: patients received azacitidine for a median of 11.4 months, compared to a median of 6.1 months in the observation group.

Table 5 presents adverse reactions occurring in at least 5% of patients who received azacitidine treatment in Study 4. As in Studies 1 and 2 described above, the duration of azacitidine treatment was longer (average 12.2 months) compared to best supportive care (average 7.5 months).

In studies 1, 2, and 4, with subcutaneous administration of azacitidine, adverse reactions such as neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and erythema/injection site reaction tended to increase in frequency with higher doses of azacitidine. Adverse reactions that tended to be more pronounced during the first 1–2 cycles of subcutaneous treatment compared to subsequent cycles included thrombocytopenia, neutropenia, anemia, nausea, vomiting, injection site reaction/erythema/pain/bruising, constipation, petechiae, dizziness, anxiety, hypokalemia, and insomnia. No adverse reactions were observed to increase in frequency over time during treatment.

Overall, adverse reactions were similar in studies of intravenous and subcutaneous administration. Adverse reactions found to be specifically associated with intravenous administration included infusion site reactions (e.g., erythema or pain) and catheter site reactions (e.g., infection, erythema, or hemorrhage).

In clinical trials of azacitidine administered subcutaneously or intravenously, the following serious adverse reactions were reported with an incidence of < 5% (and not described in Tables 4 or 5):

Blood and lymphatic system disorders: agranulocytosis, bone marrow failure, pancytopenia, splenomegaly.

Cardiac disorders: atrial fibrillation, cardiac failure, congestive heart failure, cardiopulmonary failure, arrest, congestive cardiomyopathy.

Eye disorders: ocular hemorrhage.

Gastrointestinal disorders: diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess.

General disorders and administration site conditions: catheter site hemorrhage, general physical health, worsening condition, systemic inflammatory response syndrome.

Hepatobiliary disorders: cholecystitis.

Immune system disorders: anaphylactic shock, hypersensitivity.

Infections and infestations: limb abscess, bacterial infection, cellulitis, blastomycosis, injection site infection, infection, Klebsiella sepsis, neutropenic sepsis, streptococcal pharyngitis, Klebsiella pneumonia, sepsis, septic shock, staphylococcal bacteremia, staphylococcal infection, toxoplasmosis.

Metabolism and nutrition disorders: dehydration.

Musculoskeletal and connective tissue disorders: increased bone pain, muscle weakness, neck pain.

Benign, malignant and unspecified neoplasms (incl. cysts and polyps): skin leukemia.

Nervous system disorders: intracranial hemorrhage, convulsions, intracerebral hemorrhage.

Renal and urinary disorders: back pain, renal failure.

Respiratory, thoracic and mediastinal disorders: hemoptysis, lung infiltration, pneumonitis, respiratory distress.

Skin and subcutaneous tissue disorders: pyoderma gangrenosum, pruritic rash, skin induration.

Surgical and medical procedures: cholecystectomy.

Vascular disorders: orthostatic hypotension.

Post-marketing experience

During post-marketing use of azacitidine, the following adverse reactions have been identified. Because these reactions are reported voluntarily from an undefined population size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

• interstitial lung disease;
• tumor lysis syndrome;
• necrosis at the injection site;
• Sweet’s syndrome (acute febrile neutrophilic dermatosis);
• necrotizing fasciitis (including fatal cases);
• differentiation syndrome;
• pericardial effusion;
• pericarditis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach of children.

Incompatibilities

The intravenous solution is incompatible with 5% dextrose solutions, Gelafundin, or solutions containing bicarbonate. These may potentially increase the degradation rate of azacitidine; therefore, their concomitant use should be avoided. This medicinal product must not be mixed with other medicinal products except as specified in the section “Special precautions for disposal and other handling”.

Packaging. 1 vial in a cardboard box.

Prescription status. Prescription only.

Manufacturer. MSN Laboratories Private Limited.

Manufacturer's address and location of its business operations

Formulations Division, Unit-II, Survey Nos. 1277 and 1319 to 1324, Nandigama (Village), Nandigama (Mandal), Rangareddy District, Telangana, 509228, India.