Azapan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZAPAN

Composition:

Active substance: azacitidine;

1 vial contains azacitidine 100 mg;

Excipient: mannitol (E 421).

Pharmaceutical form. Lyophilisate for solution for injection.

Main physico-chemical properties: lyophilized powder from white to almost white.

Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. Pyrimidine analogues. ATC code L01BC07.

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 cycle may lead to re-expression of genes and restoration of tumor-suppressor functions 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 dose of 75 mg/m², azacitidine was rapidly absorbed, with peak plasma concentrations of 750 ± 403 ng/mL reached at 0.5 hours post-dose (first sampling time point). The absolute bioavailability of azacitidine following subcutaneous administration relative to intravenous administration (single dose of 75 mg/m²) 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 of 1.0 μM to 100 μM (approximately 30 times higher than clinically achieved concentrations), it does not induce CYP 1A2, 2C19, or 3A4/3A5. In inhibition studies of P450 isoenzymes (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) at concentrations up to 100 μM, no inhibition occurred. 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 after 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 in subjects with normal renal function. Azacitidine may be administered to patients with renal impairment without initial dose adjustment, provided that these patients are closely monitored for toxicity, as azacitidine and/or its metabolites are primarily eliminated by the kidneys.

Pharmacogenomics

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

Clinical characteristics.

Indications.

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

• Intermediate-2 and high-risk myelodysplastic syndromes (MDS) 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;
• AML with >30% bone marrow blasts, according to the WHO classification.

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

Safety precautions.

Recommendations for use

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

Dilution of the medicinal product: detailed instructions are provided in the section "Dosage and method of administration".

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

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

Storage of the diluted medicinal product. See section "Dosage and method of administration*."*

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 calculation of 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 different sites in two separate injections.

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

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 S-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 treatment response and drug toxicity, but at a minimum prior to each treatment cycle. Following the first cycle of azacitidine at the recommended dose, the dose should be reduced or administration delayed for subsequent cycles based on nadir counts and hematologic response. Patients should immediately report any fever. Patients and physicians should also monitor for symptoms of bleeding.

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 decrease in serum bicarbonate to <20 mmol/L associated with alkaline urine pH and hypokalemia (serum potassium <3 mmol/L), developed in 5 patients with chronic myelogenous leukemia (CML) treated with azacitidine and etoposide. If unexplained decreases 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 excreted by the kidneys.

Laboratory tests

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

Cardiac and pulmonary diseases

Patients with severe congestive heart failure, clinically unstable cardiac disease, or a history of pulmonary disease were excluded from the pivotal registration study; 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 treatment. Therefore, caution is recommended when prescribing this agent to these patients. Assessment of cardiac and pulmonary function may be necessary.

Necrotizing fasciitis

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

Tumor lysis syndrome

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

Pediatric population

There are currently no data on the safety and efficacy of azacitidine in children aged

0–18 years.

Use during pregnancy or breastfeeding.

Women of reproductive potential / contraception in men and women

Women of reproductive potential and men should use effective contraception during treatment with azacitidine and for 3 months after completion 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 needed. In each individual case, the benefits of treatment should be weighed against the potential risk 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 the 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. Men should use effective contraception during treatment and for 3 months after treatment ends. Male patients should be counselled regarding sperm preservation prior to starting treatment.

Ability to affect reaction rate 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 prophylactic antiemetic medication to prevent nausea and vomiting.

Dosage

The recommended starting dose for the first treatment cycle in all patients, regardless of baseline laboratory hematological parameters, is 75 mg/m² body surface area administered as a subcutaneous injection daily for 7 consecutive days, 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 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; delay of the next treatment cycle or dose reduction may be necessary, as described below.

Laboratory Tests

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

Dosage Adjustment for Hematological Toxicity

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

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

Patients without reduced baseline parameters (i.e., leukocytes (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 be initiated only after platelet count and ANC have returned to normal. If improvement is achieved within 14 days, no dose adjustment is required. If improvement is not achieved within 14 days, the dose should be reduced according to Table 2. After dose modifications, the treatment cycle duration should remain 28 days.

Table 2

*Improvement = value at improvement ≥ nadir count + (0.5 x [baseline value – 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

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

If the reduction in WBC, ANC, or platelets is > 50% compared to the pre-treatment value 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 modification is not required. However, if improvement is not achieved within 14 days, bone marrow cellularity must be assessed. If bone marrow cellularity is > 50%, dose modification 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 value 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, reduced renal function is more likely in this patient population, and therefore monitoring of renal function may be necessary.

Renal impairment

Azacitidine can be administered to patients with renal impairment without adjustment of the initial dose. 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 increases in serum creatinine or blood urea nitrogen (BUN) occur by 2 or more times above baseline 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.

Hepatic impairment

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

Preparation of azacitidine suspension

Azapan is a cytotoxic medicinal product. As with other potentially toxic compounds, caution is required when handling 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 does not contain preservatives. Any unused portion of the medicinal product remaining in the vial should be properly disposed of. Do not store any unused portion of the medicinal product for later use.

Instructions for subcutaneous administration

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

Preparation for immediate subcutaneous administration

Doses exceeding 4 mL should be divided equally into 2 syringes. The product may be kept at room temperature for up to 1 hour, but must be administered within 1 hour after reconstitution.

Preparation for delayed subcutaneous administration

The reconstituted product may be stored in the vial or drawn into a syringe. Doses exceeding 4 mL should be divided equally into 2 syringes. The product should be placed immediately in a refrigerator. When reconstituted with sterile water for injections not stored refrigerated, the reconstituted suspension may be stored under refrigerated conditions (2–8 °C) for up to 8 hours. If reconstituted with sterile water for injections stored refrigerated (2–8 °C), the reconstituted suspension may be stored under refrigerated conditions (2–8 °C) for up to 22 hours. The refrigerated suspension may be removed from the refrigerator and allowed to sit at room temperature for up to 30 minutes prior to administration to reach room temperature.

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 uniform cloudy suspension is obtained. Administer azacitidine suspension subcutaneously. Doses exceeding 4 mL should be divided equally into 2 syringes and administered at 2 separate sites. Injection sites should be rotated with each injection (thigh, abdomen, or upper arm). New injections should be administered at least 2.5 cm away from previous injection sites and never into areas where the skin is irritated, bruised, erythematous, or hardened. After reconstitution, do not filter the suspension.

Stability of the suspension

Azacitidine reconstituted with sterile water for injections not refrigerated 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 injections refrigerated (2–8 °C), it may be stored for up to 22 hours at 2–8 °C.

Children. The medicinal product should not be used in children (under 18 years of age) as the safety and efficacy in this patient population have not been established.

Overdose.

One case of azacitidine overdose was 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 higher than the recommended initial dose.

In case of overdose, patients 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 probably or possibly related to azacitidine treatment 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 (0.8%) and pneumonia (2.5%; sometimes fatal), thrombocytopenia (3.5%), hypersensitivity reactions (0.25%), and hemorrhagic events (e.g., intracranial hemorrhage (0.5%), gastrointestinal (0.8%), and intracranial bleeding (0.5%)).

The most commonly 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, 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 clinical studies in the azacitidine treatment group 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 (5.1%), anemia (4.2%), neutropenic sepsis (3.0%), urinary tract infections (3.0%), thrombocytopenia (2.5%), neutropenia (2.1%), cellulitis (2.1%), dizziness (2.1%), and dyspnea (2.1%).

The most commonly reported adverse reactions during azacitidine therapy were gastrointestinal disorders (≥ 30%), 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 hematologic manifestations, including febrile neutropenia (32.2%) and neutropenia (30.1%; usually grade 3–4).

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

The frequency of adverse reactions is defined as: 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 group, adverse effects are listed in decreasing order of severity.

Table 4

* fatal outcomes have rarely been reported

Description of individual adverse reactions

Haematological adverse reactions

The most frequently reported (≥ 10%) haematological adverse reactions during treatment were thrombocytopenia, neutropenia, febrile neutropenia, and leukopenia, usually of grade 3–4. The risk of these reactions is higher during the first 2 cycles, after which their frequency decreases as haematological function recovers in patients. Most haematological adverse reactions were managed by routine monitoring of complete blood counts and delaying the start of the next cycle, prophylactic use of antibiotics and/or growth factor support (e.g., G-CSF) for neutropenia, and blood transfusions for anaemia or thrombocytopenia, as necessary.

Infections

Myelosuppression may lead to neutropenia and an increased risk of infection. Serious infections such as sepsis (including neutropenic sepsis) and pneumonia, sometimes resulting in death, have been reported in patients treated with azacitidine. Infections may be managed by prophylactic use of antibiotics and/or growth factor support (e.g., G-CSF) for neutropenia.

Bleeding

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

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 decreasing 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 non-steroidal 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 leading to fatal outcomes.

Gastrointestinal disorders

The most commonly reported treatment-related gastrointestinal adverse reactions were constipation, diarrhoea, nausea, and vomiting. These adverse reactions were managed symptomatically.

Renal disorders

Cases of increased serum creatinine levels, haematuria, 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 tumour burden due to liver metastases and a history of hepatic insufficiency during treatment.

Cardiovascular disorders

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

Elderly patients

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

Paediatric population

Data on the safety and efficacy of azacitidine therapy in children are limited.

In a study involving children receiving azacitidine therapy (28 patients, aged 1 month to 18 years), the most commonly reported adverse reactions in the paediatric population were fever, haematological events (including anaemia, thrombocytopenia, and febrile neutropenia), and gastrointestinal manifestations, including constipation and vomiting.

According to data from another study (involving 7 patients aged 2 to 12 years), the most frequently reported events were neutropenia, nausea, leukopenia, thrombocytopenia, diarrhoea, and increased ALT levels. Febrile neutropenia and neutropenia leading to treatment interruption were observed in two patients.

Based on available study data, no new adverse reactions have been reported in children receiving azacitidine therapy. The overall safety profile in children corresponds to that observed in adult patients.

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

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, their concomitant use should be avoided. Do not mix with other medicinal products except those specified in the section "Instructions for use and handling".

Packaging. Lyophilisate in vials sealed with a rubber stopper and an aluminium cap with a flip-off component. One vial per cardboard box.

Prescription status. Prescription only.

Manufacturer. Panacea Biotec Pharma Ltd./Panacea Biotec Pharma Ltd.

Manufacturer's address and location of operation. Malpur, Baddi, Solan, 173205, India/Malpur, Baddi, Solan, 173205, India.