Azacitidine-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZACITIDINE-VISTA (AZACITIDINE-VISTA)

Composition:

Active substance: azacitidine;

1 vial contains 100 mg of azacitidine;

Excipient: mannitol (E 421).

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: lyophilized powder of white or almost white color.

Pharmacotherapeutic group. Antineoplastic agents. Pyrimidine analogues.

ATC code L01B C07.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

The antineoplastic activity of azacitidine is believed to result from multiple mechanisms, including cytotoxicity toward abnormal hematopoietic cells in the bone marrow and DNA hypomethylation. The cytotoxic effect may result from multiple 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 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 a peak plasma concentration 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 75 mg/m² dose) was approximately 89%, based on the area under the plasma concentration–time curve (AUC). 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

After 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-glucuronosyltransferase (UGT), sulfotransferase (SULT), or glutathione transferase (GST).

Azacitidine undergoes spontaneous hydrolysis and deamination, mediated by cytidine deaminase. In human S9 liver fractions, metabolite formation was independent of NADPH [reduced nicotinamide adenine dinucleotide phosphate], suggesting that metabolism is not mediated by cytochrome P450 isoenzymes. In vitro studies of azacitidine in cultured human hepatocytes indicate that at concentrations of 1.0 to 100 μM (approximately 30 times higher than clinically achieved concentrations), it does not induce CYP 1A2, 2C19, 3A4, or 3A5. In inhibition studies of P450 isoenzymes (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4), no inhibition occurred 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 via urinary excretion. After intravenous and subcutaneous administration of 14C-azacitidine, 85% and 50% of the administered radioactivity, respectively, were 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 effect 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 patients with mild, moderate, and severe renal impairment were increased by 11–21%, 15–27%, and 41–66%, respectively, compared to patients with normal renal function. However, exposure remained within the same overall range as in patients with normal renal function. Azacitidine may 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 cytidine deaminase polymorphisms 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 syndrome (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;
• AML with > 30% bone marrow blasts, according to the classification.

Contraindications

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

Advanced malignant hepatic tumors.

Breastfeeding period.

Special safety precautions

The medicinal product is cytotoxic; therefore, safety precautions must be observed and care taken during its reconstitution and administration. Appropriate handling and disposal procedures for antineoplastic agents should be followed.

If reconstituted azacitidine comes into contact with the skin, the skin should be immediately and thoroughly washed with soap and water. If the medicinal product contacts mucous membranes, they should be immediately and thoroughly rinsed with water.

Reconstitution of the medicinal product. For detailed instructions, see 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 reconstituted medicinal product. See section "Administration and dosage". Calculation of individual dose

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

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

Table 1

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

The 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 one. Injection sites must never be areas of irritated skin, bruising, redness, or thickening.

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 medicinal product for future use.

Interaction with other medicinal products and other forms of interaction

In vitro data indicate that metabolism is not mediated by cytochrome P450 (CYP) isoenzymes, UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), 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

Risks associated with substitution by other azacitidine dosage forms

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

Administration of the medicinal product as an injection solution at doses intended for oral azacitidine may result in fatal adverse reactions. Conversely, treating patients taking oral azacitidine with doses recommended for injectable azacitidine may be ineffective.

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

Hematologic toxicity (anemia, neutropenia, thrombocytopenia)

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 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 (see section "Method of administration and dosage"). Patients should be advised to report promptly any fever. Patients and physicians should also monitor for symptoms of bleeding.

Hepatic impairment

Since azacitidine may be potentially hepatotoxic in patients with severe hepatic impairment, caution should be exercised in patients with pre-existing liver disease. Clinical studies in patients with hepatic impairment have not been conducted. Cases of progressive hepatic coma with fatal outcome have been reported during treatment in patients with high tumor 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 (see section "Contraindications"). Liver function tests should be monitored before initiation of treatment and prior to each cycle. Patients should inform their physician of any pre-existing liver disease.

Renal impairment

Renal abnormalities ranging from elevated serum creatinine to renal failure and fatal outcomes have been observed in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents. Renal tubular acidosis, defined as decreased serum bicarbonate to < 20 mmol/L associated with alkaline urine reaction and hypokalemia (serum potassium < 3 mmol/L), developed in 5 patients with chronic myeloid leukemia (CML) treated with azacitidine and etoposide. If unexplained decreases in serum bicarbonate (< 20 mmol/L) or increases in serum creatinine or blood urea nitrogen occur, the dose of azacitidine should be reduced or administration delayed (see section "Method of administration and dosage").

Patients should report oliguria and anuria to their healthcare provider immediately. Although no clinically relevant differences in the frequency of adverse reactions have been observed between patients 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 (see section "Method of administration and dosage").

Tumor lysis syndrome

Patients at risk of tumor lysis syndrome and those with high tumor burden prior to treatment require careful monitoring and appropriate preventive measures.

Embryo-fetal toxicity

Due to its mechanism of action and findings from animal studies, azacitidine can cause fetal harm when administered to a pregnant woman. Single-dose intraperitoneal administration of azacitidine to pregnant rats at approximately 8% of the recommended human daily dose resulted in fetal death and malformations. Pregnant women should be informed of the potential risk to the fetus. Women of reproductive potential should use effective contraception during treatment and for at least 6 months after completion of therapy. Men undergoing treatment with azacitidine and their female partners of reproductive potential should use effective contraception during treatment and for 3 months after its completion.

Laboratory tests

Liver function, serum creatinine, and serum bicarbonate should be assessed prior to initiation of therapy and before each treatment cycle. A complete blood count should be performed prior to initiation of therapy and as needed to monitor response and toxicity, but at minimum before each treatment cycle (see section "Adverse reactions").

Cardiac and pulmonary diseases

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

Necrotizing fasciitis

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

Differentiation syndrome

Cases of differentiation syndrome (frequency unknown) have been reported in patients receiving azacitidine. 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"). At the first sign or symptom suggestive of differentiation syndrome, high-dose intravenous corticosteroids and hemodynamic monitoring should be considered. Temporary discontinuation of injectable azacitidine may be required until symptoms resolve; if treatment is resumed, caution is advised.

Use during pregnancy or breastfeeding

Contraception

Women of reproductive potential should use effective contraception during treatment and for at least 6 months after completion of therapy. Men are advised to use effective contraception during treatment and for 3 months after its completion.

Pregnancy

There are no data on the use of azacitidine in pregnant women. Animal studies have shown reproductive toxicity. The potential risk to humans is unknown. Given the findings from 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 risk to the fetus.

Breastfeeding

It is unknown whether azacitidine or its metabolites are excreted in human milk. Due to the potential for serious adverse reactions in the breastfed infant, 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 are advised to avoid fathering a child during treatment. Men should be counselled regarding sperm cryopreservation prior to starting therapy.

Ability to affect reaction speed when driving or operating machinery

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

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 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. A minimum of 6 treatment cycles is 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 occurs.

Patients should be monitored for hematological response/toxicity and renal toxicity; delay in initiating a new cycle or dose reduction may be necessary, as described below.

Azacitidine-Vista must not be used interchangeably with oral azacitidine. Due to differences in exposure, dosing and administration recommendations for oral azacitidine differ from those for injectable azacitidine. Healthcare professionals are advised to verify the drug name, dose, and route of administration.

Laboratory Tests

Liver function, serum creatinine, and serum bicarbonate should be assessed prior to initiation of therapy and before each treatment cycle. A complete blood count should be performed before starting therapy and, if necessary, monitored to assess 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 cycle (nadir), when platelet count ≤ 50.0 × 10⁹/L and/or absolute neutrophil count (ANC) ≤ 1 × 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 ≥ nadir + (0.5 × [baseline value – nadir])).

Patients without reduced baseline parameters (i.e., white blood cells [WBC] ≥ 3 × 10⁹/L and ANC ≥ 1.5 × 10⁹/L, platelets ≥ 75.0 × 10⁹/L) prior to first treatment

If hematological toxicity occurs after azacitidine administration, the next treatment cycle should not be initiated until 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 (see Table 2). After dose modifications, the cycle duration should remain 28 days.

Table 2

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

Patients with reduced baseline blood counts (i.e. WBC < 3 × 10⁹/L or ANC < 1.5 × 10⁹/L, or platelets < 75 × 10⁹/L) prior to first treatment

After administration of azacitidine, if the reduction in WBC or ANC, or platelet count compared to pre-treatment values is ≤ 50% or greater than 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 or ANC, or platelet count 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 must 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 (see Table 3).

Table 3

* Improvement = parameter during improvement ≥ nadir value + (0.5 × [baseline parameter – nadir value]).

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

Special populations

Elderly patients

No specific dose adjustment is recommended for elderly patients. However, elderly patients are more likely to have decreased renal function; 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 elevation of serum creatinine or blood urea nitrogen (BUN) occurs at 2 times or more above baseline and above the upper limit of normal (ULN), the start of the next cycle should be delayed until values return to normal or baseline, 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 adjustments of the initial dose are recommended for patients with hepatic impairment; subsequent dose modifications should be based on haematological laboratory parameters. Azacitidine is contraindicated in patients with extensive liver tumour burden.

Instructions for subcutaneous administration of the medicinal product

Azacitidine should be reconstituted under aseptic conditions using 4 ml of sterile water for injection. The diluent should be slowly injected into the vial. The vial should be shaken or rotated vigorously to obtain a homogeneous suspension. The suspension will be cloudy. The resulting suspension contains 25 mg/ml azacitidine. The suspension should not be filtered after reconstitution, as the active substance may be removed by filtration.

Preparation for immediate subcutaneous administration

Doses exceeding 4 ml should be divided into equal parts in two syringes. The product may be kept at room temperature for up to 1 hour, but should be administered within 1 hour after reconstitution.

Preparation of the medicinal product 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 into equal parts in two syringes. The product should be placed immediately in a refrigerator. When azacitidine is reconstituted with water for injection not stored refrigerated, the reconstituted solution may be stored under refrigerated conditions (2–8 °C) for up to 8 hours. When the product is reconstituted with water for injection stored 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 left outside the refrigerator 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, the syringe should be rotated vigorously between the palms until a homogeneous, cloudy suspension is obtained. Azacitidine suspension is administered subcutaneously. Doses exceeding 4 ml should be divided into equal parts in 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 a previous site and never into areas where the skin is irritated, bruised, red, or hardened. The suspension should not be filtered after reconstitution.

Stability of the suspension

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

Instructions for intravenous administration

Take the required number of vials of the medicinal product to achieve the desired dose. Reconstitute the contents of each vial with 10 ml of sterile water for injection. The vial should be shaken or rotated vigorously until all solid particles dissolve. The resulting solution contains 10 mg/ml azacitidine and should be clear. The parenteral solution should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Draw the required amount of azacitidine solution into a syringe for the desired dose and transfer it into a 50–100 ml infusion bag containing 0.9% sodium chloride for 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 increase the degradation rate of azacitidine; therefore, their use should be avoided.

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.

Stability of the solution

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 when the solution is reconstituted with refrigerated (2–8 °C) water for injection.

Children

Not recommended for use in children (under 18 years of age), as the safety and efficacy of azacitidine in this patient population have not been established. Available data are presented in the sections “Pharmacokinetics”, “Pharmacodynamics” and “Adverse reactions”, but dosage recommendations cannot be provided.

Overdose

Symptoms. One case of azacitidine overdose has been reported in clinical trials. 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.

Treatment. In case of overdose, the patient should be monitored, necessary blood tests should be performed, and supportive treatment should be administered if required. There is no specific antidote for azacitidine overdose.

Adverse Reactions

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

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

The most common serious adverse reactions observed in clinical studies were febrile neutropenia (8%) 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., intracerebral hemorrhage) (0.5%), gastrointestinal hemorrhage (0.8%), and intracranial hemorrhage (0.5%).

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

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

The most common serious adverse reactions (≥ 10%) observed in clinical studies were febrile neutropenia (25%), pneumonia (20.3%), and hyperthermia (10.6%). Other adverse reactions included sepsis (5.1%), anemia (4.2%), neutropenic sepsis (3%), urinary tract infections (3%), thrombocytopenia (2.5%), neutropenia (2.1%), cellulitis (2.1%), dizziness (2.1%), and dyspnea (2.1%). The most common (≥ 30%) treatment-emergent adverse reactions with azacitidine were gastrointestinal disorders, including constipation (41.9%), nausea (39.8%), and diarrhea (36.9%) (usually grade 1–2), general disorders such as hyperthermia (37.7%, usually grade 1–2), and hematologic abnormalities, including febrile neutropenia (32.2%) and neutropenia (30.1%) (usually grade 3–4).

Table 4 presents adverse reactions associated with azacitidine treatment from pivotal clinical trials in MDS and AML, as well as post-marketing experience.

The frequency of adverse reactions is defined according to the following categories: 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 category, adverse events are listed in order of decreasing severity.

Table 4

* Fatal cases have been rarely reported.

Description of selected adverse reactions

Haematological adverse reactions

Haematological adverse reactions were the most frequently reported (≥ 10%) during treatment, including anaemia, thrombocytopenia, neutropenia, febrile neutropenia, and leucopenia, usually of grade 3–4. The risk of these reactions is higher during the first 2 cycles, after which they occur less frequently as haematological function recovers in patients. Most haematological 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 factors (e.g., granulocyte colony-stimulating factor [G-CSF]) for neutropenia, and blood transfusions for anaemia or thrombocytopenia, as necessary.

Infections

Myelosuppression may lead to neutropenia and increased risk of infection. Serious infections such as neutropenic sepsis and pneumonia, some with fatal outcomes, have occurred in patients receiving azacitidine. Infections can be managed with antibacterial agents and/or growth factors (e.g., G-CSF) for neutropenia.

Haemorrhage

Bleeding may occur in patients receiving azacitidine. Serious adverse reactions such as gastrointestinal haemorrhage and intracranial haemorrhage 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 have occurred in patients receiving azacitidine. In the event of an anaphylactic reaction, treatment must be discontinued immediately and appropriate symptomatic therapy initiated.

Skin and subcutaneous tissue adverse reactions

Most skin and subcutaneous tissue adverse reactions were injection site-related. In clinical studies, none of these adverse reactions led to discontinuation or dose reduction of azacitidine. Most reactions occurred during the first 2 cycles and decreased in frequency in subsequent cycles. Skin reactions such as rash, inflammation, pruritus, erythema, and skin damage at the injection site 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 may 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 adverse reactions

The most commonly reported treatment-related gastrointestinal adverse reactions were constipation, diarrhoea, nausea, and vomiting. These adverse reactions were managed symptomatically with antiemetics for nausea and vomiting, antidiarrhoeals for diarrhoea, and laxatives and/or stool softeners for constipation.

Renal adverse reactions

Renal function disorders have occurred in patients treated with azacitidine, ranging from increased serum creatinine and haematuria to renal tubular acidosis, renal failure, and fatal outcomes.

Hepatic adverse reactions

In patients with high tumour burden and a history of hepatic insufficiency, progressive hepatic coma with fatal outcome has occurred during treatment.

Cardiovascular adverse reactions

Data from studies in patients with pre-existing cardiovascular or pulmonary disease showed a statistically significant increase in cardiac events in patients with newly diagnosed AML treated with azacitidine.

Elderly patients

Safety data for azacitidine use in patients aged 85 years and older are limited.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and 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 to protect from light at a temperature not exceeding 30 ºC. Keep out of reach of children.

Incompatibilities

The intravenous solution is incompatible with 5% dextrose solutions, Gelopran, 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 "Method of administration and dosage".

Packaging

100 mg of powder in clear 20 ml vials. 1 vial in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Nang Kuang Pharmaceutical Co., Ltd.

Manufacturer's address and place of business

No. 1001, 1001-1, Zhongshan Rd., Xinhua Dist., Tainan City, Taiwan (R.O.C.)