Azacitidine shilpa

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

Composition:

Active substance: azacitidine;

1 vial contains 100 mg of azacitidine;

Excipients: mannitol (E 421).

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: lyophilized powder, white to almost white.

Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. Pyrimidine analogues. ATC code L01B C07.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

The antineoplastic activity of azacitidine is believed to occur through multiple mechanisms, including cytotoxicity toward abnormal hematopoietic cells in the bone marrow and DNA hypomethylation. The cytotoxic effect may result from several mechanisms, such as inhibition of DNA, RNA, and protein synthesis, incorporation into RNA and DNA, and activation of RNA-damage pathways. Non-proliferating cells are relatively insensitive to azacitidine. Incorporation into DNA leads to inactivation of DNA methyltransferases, resulting in DNA hypomethylation. Hypomethylation of DNA and aberrantly methylated genes involved in pathways regulating and differentiating the normal cell cycle, and normal cell death, may lead to re-expression of genes and restoration of tumor-suppressor functions suppressed in cancer cells. The clinical significance of DNA hypomethylation relative to cytotoxicity or other properties of azacitidine has not been established.

Pharmacokinetics

Absorption

After subcutaneous administration of a single 75 mg/m² dose, azacitidine was rapidly absorbed, with peak plasma concentrations of 750 ± 403 ng/mL reached at 0.5 hours post-dose (first sampling time). Absolute bioavailability of azacitidine following subcutaneous administration compared to intravenous administration (single 75 mg/m² dose) was approximately 89%, based on area under the curve (AUC). The AUC and maximum plasma concentration (Cmax) following subcutaneous administration of azacitidine were approximately dose-proportional over the dose range of 25 to 100 mg/m².

Distribution

Following intravenous administration, the mean volume of distribution was 76 ± 26 L, and systemic clearance was 147 ± 47 L/h.

Biotransformation

Based on in vitro data, metabolism is not mediated by cytochrome P450 (CYP) isoenzymes, UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), or glutathione transferases (GSTs).

Azacitidine undergoes spontaneous hydrolysis and cytidine deaminase-mediated deamination. In human liver S9 fractions, metabolite formation was independent of NADPH, suggesting that metabolism is not mediated by cytochrome P450 isoenzymes. In vitro studies of azacitidine with cultured human hepatocytes indicate that, at concentrations ranging from 1.0 μM to 100 μM (approximately 30 times higher than clinically achieved concentrations), it does not induce CYP 1A2, 2C19, or 3A4/3A5. Inhibition studies of P450 isoenzymes (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) showed no inhibition at concentrations up to 100 μM. Therefore, induction or inhibition of CYP enzymes at clinically achieved plasma concentrations is unlikely.

Elimination

Azacitidine is rapidly cleared from plasma, with a mean elimination half-life (t½) of 41 ± 8 minutes after subcutaneous administration. No accumulation occurs after subcutaneous administration of 75 mg/m² once daily for 7 days. The primary route of elimination of azacitidine and/or its metabolites is renal excretion. After intravenous and subcutaneous administration of 14C-azacitidine, 85% and 50% of the administered radioactivity, respectively, was recovered in urine, while less than 1% was recovered in feces.

Special Populations

The effects of hepatic impairment, gender, age, or race on the pharmacokinetics of azacitidine have not been formally studied.

Renal Impairment

Renal impairment does not have a significant impact on the pharmacokinetic exposure of azacitidine following single and multiple subcutaneous doses. After subcutaneous administration of a single 75 mg/m² dose, mean exposure parameters (AUC and Cmax) in subjects with mild, moderate, and severe renal impairment were increased by 11–21%, 15–27%, and 41–66%, respectively, compared to subjects with normal renal function. However, exposure remained within the same overall range as observed in subjects with normal renal function. Azacitidine can be administered to patients with renal impairment without initial dose adjustment, provided that these patients are monitored for toxicity, as azacitidine and/or its metabolites are primarily eliminated by the kidneys.

Pharmacogenomics

The impact of known polymorphisms in cytidine deaminase on metabolism has not been studied.

Clinical characteristics.

Indications.

Azacitidine is indicated for the treatment of adult patients who are not eligible for hematopoietic stem cell transplantation, with the following disorders:

• Myelodysplastic syndromes (MDS) of intermediate-2 and high risk according to the International Prognostic Scoring System (IPSS);
• Chronic myelomonocytic leukemia (CMML) with 10–29% bone marrow blasts without myeloproliferative disorder;
• Acute myeloid leukemia (AML) with 20–30% blasts and multilineage dysplasia according to the World Health Organization (WHO) classification.

Contraindications. Hypersensitivity to the active substance or to any of the excipients. Advanced malignant hepatic tumors. Breastfeeding.

Special safety precautions.

Recommendations for use

The medicinal product is cytotoxic; therefore, safety measures and precautions must be observed during reconstitution and administration. If reconstituted azacitidine comes into contact with the skin, the skin must be washed immediately and thoroughly with soap and water. If the medicinal product contacts mucous membranes, they should be rinsed immediately and thoroughly with water.

Reconstitution of the medicinal product: detailed instructions are provided in the section "Administration and dosage".

The medicinal product should be reconstituted with water for injections. The solution should not be used if it contains large particles or aggregates. Do not filter the solution after reconstitution, as this may result in loss of the active substance. Note that some adapters and administration systems contain filters. Therefore, such systems should not be used for administering the medicinal product after reconstitution.

The contents of the dosing syringe should be resuspended immediately before administration.

Storage of the reconstituted medicinal product. See section "Administration and dosage*".*

Calculation of individual dose:

total dose based on body surface area (BSA), calculated using the following formula:

Total dose (mg) = dose (mg/m²) × BSA (m²)

Example of calculating individual azacitidine dose based on an average BSA of 1.8 m².

Table 1

Other information on the use of the medicine

A dose exceeding 4 ml should be administered at two separate injection sites.

Injection sites should be rotated. Each new injection site should be at least 2.5 cm away from the previous one. Injection must never be administered into areas of irritated skin, bruised skin, redness, or skin thickening.

Interaction with other medicinal products and other forms of interaction.

Based on in vitro data, metabolism is not mediated by cytochrome P450 (CYP) isoenzymes, UDP-glucuronosyltransferase (UGT), sulfotransferase (SULTs), or glutathione transferase (GST); therefore, interactions related to these metabolizing enzymes in vivo are considered unlikely.

Clinically significant inhibitory or inductive effects of azacitidine on cytochrome P450 enzymes are unlikely.

No formal studies of interactions between azacitidine and other medicinal products have been conducted.

Special precautions for use.

Hematologic toxicity

Treatment with azacitidine is associated with anemia, neutropenia, and thrombocytopenia, particularly during the first 2 cycles. Complete blood counts should be performed as needed to monitor response to treatment and drug toxicity, but at a minimum prior to each treatment cycle. After the first cycle of azacitidine at the recommended dose, the dose should be reduced or administration delayed in subsequent cycles based on nadir counts and hematologic response. Patients should be advised to report immediately any fever. Patients and physicians should also monitor for the development of bleeding symptoms.

Hepatic impairment

Studies in patients with hepatic impairment have not been conducted. Progressive hepatic coma leading to death has been reported during treatment in patients with high tumor burden due to metastatic disease, particularly in patients with a baseline serum albumin level <30 g/L. Azacitidine is contraindicated in patients with extensive hepatic malignancies.

Renal impairment

Renal abnormalities, ranging from elevated serum creatinine levels to renal failure and fatal outcomes, have been reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents. Renal tubular acidosis, defined as a reduction in serum bicarbonate to <20 mmol/L associated with alkaline urine and hypokalemia (serum potassium <3 mmol/L), developed in 5 patients with chronic myelogenous leukemia (CML) treated with azacitidine and etoposide. If unexplained reductions in serum bicarbonate levels (<20 mmol/L) or increases in serum creatinine or blood urea nitrogen (BUN) occur, the dose of azacitidine should be reduced or administration delayed.

Patients should immediately report oliguria or anuria to their healthcare provider. Although no clinically relevant differences in the frequency of adverse reactions have been observed between subjects with normal renal function and those with renal impairment, patients with renal impairment should be closely monitored for signs of toxicity, as azacitidine and/or its metabolites are primarily eliminated via the kidneys.

Laboratory tests

Hepatic function, serum creatinine, and serum bicarbonate should be assessed prior to initiation of therapy and prior to the start of each treatment cycle. A complete blood count should be performed before starting therapy and, as needed, to monitor response and toxicity, but at a minimum prior to each treatment cycle.

Cardiac and pulmonary disorders

Patients with severe congestive heart failure, clinically unstable cardiac disease, or a history of pulmonary disease were excluded from the pivotal registration trial; therefore, the safety and efficacy of the drug in such patients have not been established. Clinical trial data in patients with a history of known cardiovascular or pulmonary disease showed a significantly increased incidence of cardiac disorders with azacitidine use. Therefore, caution is recommended when prescribing the drug to these patients. Assessment of cardiac and pulmonary function may be necessary.

Necrotizing fasciitis

Necrotizing fasciitis, including fatal cases, has been reported in patients treated with azacitidine. Azacitidine should be discontinued in patients diagnosed with necrotizing fasciitis, and appropriate treatment should be initiated immediately.

Tumor lysis syndrome

Patients at risk of tumor lysis syndrome and those with high tumor burden prior to treatment should be carefully monitored and appropriate preventive measures implemented.

Differentiation syndrome

Differentiation syndrome has been reported in patients receiving azacitidine, with an incidence rate currently classified as "not known." Differentiation syndrome may be fatal, and symptoms and clinical signs include respiratory distress, pulmonary infiltrates, fever, rash, pulmonary edema, peripheral edema, rapid weight gain, pleural effusion, pericardial effusion, hypotension, and renal dysfunction (see section "Adverse reactions"). High-dose intravenous corticosteroids and hemodynamic monitoring should be considered at the first sign or symptom suggestive of differentiation syndrome. Temporary discontinuation of injectable azacitidine should be considered until symptoms resolve, and caution should be exercised if treatment is resumed.

Pediatric population

Currently, there are no data on the safety and efficacy of azacitidine in children aged 0–18 years.

Use during pregnancy or breastfeeding.

Females and males of reproductive potential/contraception

Females and males of reproductive potential should use effective contraception during treatment with azacitidine and for 3 months after the end of treatment.

Pregnancy

There are no available data on the use of azacitidine in pregnant women. The potential risk to humans is unknown. Based on animal studies and the mechanism of action of azacitidine, this medicinal product should not be used during pregnancy, especially during the first trimester, unless clearly necessary. In each individual case, the benefits of treatment should be weighed against the potential risks to the fetus.

Breastfeeding

It is unknown whether azacitidine or its metabolites are excreted in human breast milk. Due to the potential for serious adverse reactions in a breastfed child, breastfeeding is contraindicated during treatment.

Fertility

There are no data on the effect of azacitidine on fertility in humans. Adverse effects on fertility have been observed in male animals treated with azacitidine. Males should use effective contraception during treatment and for 3 months after its completion. Male patients should be counselled regarding sperm preservation prior to starting treatment.

Ability to affect the speed of reactions when driving or operating machinery.

Azacitidine may affect the ability to drive or operate machinery. Cases of fatigue and dizziness have been reported with the use of azacitidine.

Dosage and Administration

Treatment with azacitidine should be initiated and supervised by a physician experienced in the use of chemotherapeutic agents. Patients should receive premedication with antiemetic agents to prevent nausea and vomiting.

Dosage

The recommended initial dose for the first treatment cycle in all patients, regardless of baseline hematological laboratory parameters, is 75 mg/m² body surface area administered daily for 7 consecutive days either subcutaneously or intravenously, followed by a 21-day rest period (28-day treatment cycle).

The dose may be increased to 100 mg/m² if no positive response is observed after 2 treatment cycles and in the absence of signs of toxicity, except for nausea and vomiting. At least 4 to 6 treatment cycles are recommended. Additional cycles may be required to achieve a complete or partial response. Treatment may be continued as long as clinical benefit is observed or until disease progression.

Patients should be monitored for hematological response/toxicity and renal toxicity; it may be necessary to delay the start of a new cycle or reduce the dose, as described below.

Laboratory Tests

Liver function, serum creatinine, and serum bicarbonate should be assessed prior to initiation of therapy and before the start of each treatment cycle. A complete blood count should be performed before starting therapy and, if necessary, monitored to assess response and toxicity, but at minimum prior to each treatment cycle.

Dosage Adjustment for Hematological Toxicity

Hematological toxicity is defined as the lowest cell count reached during a given cycle (nadir), specifically when platelet count ≤ 50.0 × 10⁹/L and/or absolute neutrophil count (ANC) ≤ 1 × 10⁹/L.

Improvement is defined as an increase in the cell line(s) affected by hematological toxicity to at least half the difference between the baseline value and the nadir (e.g., improvement value ≥ nadir + (0.5 × [baseline value – nadir])).

Patients without reduced baseline parameters (i.e., white blood cells (WBC) ≥ 3.0 × 10⁹/L and ANC ≥ 1.5 × 10⁹/L, and platelets ≥ 75.0 × 10⁹/L) prior to first treatment

If hematological toxicity occurs after azacitidine administration, the next treatment cycle should not begin until platelet and ANC counts have returned to normal. If improvement is achieved within 14 days, dose adjustment is not required. If improvement is not achieved within 14 days, the dose should be reduced according to Table 2. After dose modifications, the cycle duration should remain 28 days.

Table 2

*Improvement = parameter at improvement ≥ nadir count + (0.5 x [baseline parameter – nadir count])

Patients with reduced baseline blood counts (i.e. WBC < 3.0 × 109/L or ANC < 1.5 × 109/L or platelets < 75.0 × 109/L) prior to first treatment

After administration of azacitidine, if the reduction in WBC, ANC, or platelets compared to pre-treatment values is ≤ 50% or > 50% but with improvement in differentiation of any cell line, the next cycle should not be delayed and dose adjustment is not required.

If the reduction in WBC, ANC, or platelets exceeds 50% compared to pre-treatment values and there is no improvement in cell line differentiation, the start of the next azacitidine treatment cycle should be delayed until platelet and ANC counts return to normal. If improvement is achieved within 14 days, dose adjustment is not required. However, if improvement is not achieved within 14 days, bone marrow cellularity should be assessed. If bone marrow cellularity is > 50%, dose adjustment is not required. If bone marrow cellularity is ≤ 50%, treatment should be delayed and the dose reduced according to Table 3:

Table 3

*Improvement = parameter at improvement ≥ nadir count + (0.5 x [baseline parameter – nadir count])

After dose modifications, the cycle duration should be 28 days.

Special populations

Elderly patients

No specific dose adjustment is recommended for elderly patients. However, since renal function is more likely to be reduced in these patients, monitoring of renal function may be necessary.

Renal impairment

Azacitidine may be administered to patients with renal impairment without adjustment of the initial dose. If unexplained decreases in serum bicarbonate levels to less than 20 mmol/L occur, the dose should be reduced by 50% in the next cycle. If unexplained increases in serum creatinine or blood urea nitrogen (BUN) occur, which are 2 or more times above baseline and above the upper limit of normal (ULN), the start of the next cycle should be delayed until parameters return to normal or baseline levels, and the dose should be reduced by 50% in the next treatment cycle.

Hepatic impairment

No formal studies have been conducted in patients with hepatic impairment. Patients with severe hepatic impairment should be closely monitored for adverse reactions. No specific modifications of the initial dose are recommended before treatment initiation in patients with hepatic impairment; subsequent dose modifications should be based on haematological laboratory parameters. Azacitidine is contraindicated in patients with hepatic tumours with widespread involvement.

Preparation of azacitidine suspension

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

If azacitidine solution comes into contact with the skin, the affected area should be immediately and thoroughly washed with soap and water. If contact occurs with mucous membranes, flush thoroughly with copious amounts of water.

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

Instructions for subcutaneous administration

Reconstitute azacitidine under aseptic conditions using 4 mL of sterile water for injection. Slowly inject the diluent into the vial. Shake or rotate the vial vigorously to obtain a homogeneous suspension. The suspension will be cloudy. The reconstituted suspension contains 25 mg/mL azacitidine. Do not filter the suspension after reconstitution, as the active ingredient may be removed during filtration.

Preparation for immediate subcutaneous administration

Doses exceeding 4 mL should be divided equally into two syringes. The solution may be kept 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 solution may be stored in the vial or drawn into a syringe. Doses exceeding 4 mL should be divided equally into two syringes. The solution should be immediately placed in a refrigerator. When azacitidine is reconstituted with sterile water for injection not previously refrigerated, the reconstituted solution may be stored under refrigerated conditions (2–8°C) for up to 8 hours. When azacitidine is reconstituted with sterile water for injection previously refrigerated (2–8°C), the reconstituted solution may be stored under refrigerated conditions (2–8°C) for up to 22 hours. The refrigerated suspension may be removed from the refrigerator and left at room temperature for up to 30 minutes to reach room temperature before administration.

General instructions for subcutaneous administration

To obtain a homogeneous suspension, the syringe contents should be resuspended immediately before administration. To resuspend, rotate the syringe vigorously between the palms until a homogeneous, cloudy suspension is obtained. The azacitidine suspension is administered subcutaneously. Doses exceeding 4 mL should be divided equally into two syringes and administered at two separate injection sites. Injection sites should be rotated (thigh, abdomen, or upper arm). New injections should be administered at least 2.5 cm from previous sites and never into areas where the skin is irritated, bruised, red, or hardened. Do not filter the suspension after reconstitution.

Stability of the suspension

Azacitidine reconstituted with sterile water for injection not previously refrigerated for subcutaneous administration may be stored for up to 1 hour at 25°C or up to 8 hours at 2–8°C; when reconstituted with sterile water for injection previously refrigerated (2–8°C), it may be stored for up to 22 hours at 2–8°C.

Instructions for intravenous administration

Dilute the required number of vials to obtain the desired dose. Reconstitute the contents of each vial with 10 mL of sterile water for injection. Shake or rotate the vial vigorously until all solids are dissolved. The resulting solution contains 10 mg/mL azacitidine and should be clear. Visually inspect the parenteral product for particulate matter and discoloration before administration, whenever solution and container permit.

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

Incompatibility with intravenous solutions

Azacitidine is incompatible with 5% dextrose solutions, Hespan, or solutions containing bicarbonate. These solutions may potentially increase the degradation rate of azacitidine; therefore, their use should be avoided.

Intravenous administration

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

Solution stability

The reconstituted product for intravenous administration may be stored at 25°C, but administration to the patient must be completed within 1 hour after reconstitution.

The reconstituted solution/suspension may be stored for 1 hour at 25°C or 8 hours at 2–8°C, or up to 22 hours at 2–8°C if reconstituted with cooled (2–8°C) sterile water for injection.

Children. Not recommended for use in children (under 18 years of age), as the safety and efficacy of the drug in this patient population have not been established.

Overdose.

One case of azacitidine overdose has been reported in 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 higher than the recommended initial dose.

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

Adverse Reactions

Adult patients with MDS, CMML, and AML with 20–30% bone marrow blasts

Adverse reactions that were probably or possibly related to azacitidine occurred in 97% of patients.

The most common serious adverse reactions (> 2%) observed in clinical studies were febrile neutropenia (8.0%) and anemia (2.3%). Other serious adverse reactions included infections such as neutropenic sepsis and pneumonia (sometimes fatal), thrombocytopenia, hypersensitivity reactions, and hemorrhagic events (e.g., intracranial hemorrhage, gastrointestinal and intracranial bleeding).

The most frequently reported adverse reactions during azacitidine therapy were hematologic reactions (71.4%), including thrombocytopenia, neutropenia, and leukopenia (usually grade 3–4), gastrointestinal events (60.6%), such as nausea and vomiting (usually grade 1–2), and injection site reactions (77.1%; usually grade 1–2).

Adult patients aged 65 years and older with AML with > 30% bone marrow blasts

The most common serious adverse reactions (≥ 10%) reported in the azacitidine treatment group during clinical studies were febrile neutropenia (25.0%), pneumonia (20.3%), and pyrexia (10.6%).

Other serious adverse reactions less frequently observed in the azacitidine treatment group included sepsis, anemia, neutropenic sepsis, urinary tract infections, thrombocytopenia, neutropenia, cellulitis, dizziness, and dyspnea.

The most frequently reported adverse reactions during azacitidine therapy were gastrointestinal disorders (≥ 30%), including constipation, nausea, and diarrhea (usually grade 1–2), general disorders and administration site conditions, including pyrexia (usually grade 1–2), and hematologic events, including febrile neutropenia and neutropenia (usually grade 3–4).

Table 4 below provides information on adverse reactions associated with azacitidine use.

The frequency of adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data). Within each frequency category, adverse effects are listed in descending order of severity.

Table 4

* Rarely, fatal cases have been reported.

Description of selected adverse reactions

Hematologic adverse reactions

The most commonly reported hematologic adverse reactions during treatment were thrombocytopenia, neutropenia, and leukopenia, usually of grade 3–4. The risk of these reactions is higher during the first 2 cycles, after which they occur less frequently as hematologic function recovers in patients. Most hematologic adverse reactions were managed by routine monitoring of complete blood counts, delaying the start of the next cycle, prophylactic use of antibiotics and/or growth factor support (e.g., G-CSF) in neutropenia, and blood transfusions for anemia or thrombocytopenia, as needed.

Infections

Myelosuppression may lead to neutropenia and an increased risk of infection. Serious infections, such as neutropenic sepsis (0.8%) and pneumonia (2.5%), some with fatal outcomes, have been reported in patients receiving azacitidine. Infections may be managed with prophylactic antibiotics and/or growth factor support (e.g., G-CSF) in neutropenia.

Bleeding

Bleeding may occur in patients receiving azacitidine. Serious adverse reactions such as gastrointestinal hemorrhage (0.8%) and intracranial hemorrhage (0.5%) have been reported. Patients should be monitored for signs and symptoms of bleeding, particularly those with pre-existing or treatment-related thrombocytopenia.

Hypersensitivity

Serious hypersensitivity reactions (0.25%) have been reported in patients receiving azacitidine. In the event of an anaphylactic-like reaction, treatment should be discontinued immediately and appropriate symptomatic therapy initiated.

Skin and subcutaneous tissue disorders

Most skin and subcutaneous tissue adverse reactions are injection-site-related. None of these adverse reactions led to temporary or permanent discontinuation of azacitidine or dose reduction in the pivotal study. Most reactions occurred during the first 2 cycles, with a decrease in frequency in subsequent cycles. Skin reactions such as rash/inflammation/itching at the injection site, rash, erythema, and skin damage may require management with concomitant medications such as antihistamines, corticosteroids, and nonsteroidal anti-inflammatory drugs (NSAIDs).

These skin reactions should be differentiated from soft tissue infections, which occasionally occur at the injection site. During post-marketing use, soft tissue infections including cellulitis and necrotizing fasciitis have been reported, rarely resulting in fatal outcomes.

Gastrointestinal disorders

The most frequently reported treatment-related gastrointestinal adverse reactions included constipation, diarrhea, nausea, and vomiting. These adverse reactions were managed symptomatically.

Renal disorders

Cases of increased serum creatinine levels, hematuria, renal tubular acidosis, renal failure, and fatal outcomes have been reported in patients treated with azacitidine.

Hepatic disorders

Progressive hepatic coma and fatal outcomes have been reported in patients with high tumor burden due to metastatic disease and pre-existing hepatic impairment during treatment.

Cardiovascular disorders

Data from studies in patients with known cardiovascular or pulmonary disease in their medical history showed a statistically significant increase in cardiac events in patients with newly diagnosed AML treated with azacitidine.

Elderly patients

Safety data on the use of azacitidine in elderly patients (≥ 85 years) are limited.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of the reach of children.

Incompatibilities. The intravenous solution is incompatible with 5% dextrose solutions, Hespan, or solutions containing bicarbonate. These may potentially increase the degradation rate of azacitidine; therefore, concomitant use should be avoided. Do not mix with other medicinal products except those specified in the section "Dosage and administration".

Packaging. 100 mg of lyophilisate for injection solution in a vial. 1 vial in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Shilpa Medicare Limited, India

Manufacturer's address and place of business.

Unit 4, Pharmaceutical Formulations SEZ, Plots S-20 to S-26, Pharma SEZ, TSIIC, Green Industrial Park, Polepalli, Jadcherla, Mahbubnagar, Telangana, 509301, India