Onureg^® (Tablets) Instructions for Use

Marketing Authorization Holder

Bristol-Myers Squibb (France)

Manufactured By

Excella, GmbH & Co. KG (Germany)

ATC Code

L01BC07 (Azacitidine)

Active Substance

Azacitidine (Rec.INN registered by WHO)

Dosage Forms

	Onureg®	Film-coated tablets 200 mg: 7 or 14 pcs.
		Film-coated tablets 300 mg: 7 or 14 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets pink, oval, engraved with “200” on one side and “ONU” on the other side.

Excipients: mannitol (E421), silicified microcrystalline cellulose (E460, E551), croscarmellose sodium (E468), magnesium stearate (E570).

Film coating composition – Opadry II pink: hypromellose (E464), titanium dioxide (E171), lactose monohydrate, macrogol (E1521), triacetin (E1518), red iron oxide (E172).

7 pcs. – blister (1) – cardboard packs with leaflet.
7 pcs. – blister (2) – cardboard packs with leaflet.

Film-coated tablets brown, oval, engraved with “300” on one side and “ONU” on the other side.

Excipients: mannitol (E421), silicified microcrystalline cellulose (E460, E551), croscarmellose sodium (E468), magnesium stearate (E570).

Film coating composition – Opadry II brown: hypromellose (E464), titanium dioxide (E171), lactose monohydrate, macrogol (E1521), triacetin (E1518), yellow iron oxide (E172), red iron oxide (E172), black iron oxide (E172).

7 pcs. – blister (1) – cardboard packs with leaflet.
7 pcs. – blister (2) – cardboard packs with leaflet.

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agents; antimetabolites; pyrimidine analogues

Pharmacological Action

Antineoplastic agent, a pyrimidine nucleoside analogue of cytidine. The antineoplastic effect of azacitidine is believed to be due to DNA hypomethylation and a direct cytotoxic effect on abnormal hematopoietic cells in the bone marrow.

The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause significant suppression of DNA synthesis. Hypomethylation can restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells, which are no longer responsive to normal growth control mechanisms. Non-proliferating cells are accordingly insensitive to azacitidine.

Pharmacokinetics

After subcutaneous administration, Azacitidine is rapidly absorbed. C_max in blood plasma is reached in 0.5 h and is 750 ± 403 ng/ml. The bioavailability of azacitidine after subcutaneous administration relative to intravenous administration is 89%. After intravenous administration, the mean V_d is 76 ± 26 L. After subcutaneous administration, the mean T_1/2 is 41 ± 8 min. Azacitidine and its metabolites are excreted primarily by the kidneys.

Indications

Myelodysplastic syndromes of the following subtypes (according to FAB classification): refractory anemia, refractory anemia with ringed sideroblasts (accompanied by neutropenia, thrombocytopenia, and requiring blood transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, chronic myelomonocytic leukemia.

ICD codes

Dosage Regimen

Administered subcutaneously or intravenously.

For the first therapy cycle, the recommended initial dose, regardless of hematological parameters, is 75 mg/m² subcutaneously or intravenously, daily for 7 days. Premedication should be administered to prevent nausea and vomiting.

Subsequent therapy cycles should be conducted every 4 weeks. The dose can be increased to 100 mg/m² if there is no therapeutic effect after the first 2 therapy cycles and in the absence of toxicity manifestations (except for nausea and vomiting). It is recommended to conduct 4-6 therapy cycles. In case of complete or partial effectiveness of the drug, additional therapy cycles can be conducted. Treatment can be continued as long as a therapeutic response is observed.

Before conducting repeated therapy cycles, the absolute neutrophil count (ANC) and platelet count should be monitored, as well as toxic reactions (especially renal), and the drug dose should be adjusted accordingly.

In patients with baseline leukocyte count <3.0×10⁹/L, ANC <1.5×10⁹/L, or platelets <75.0×10⁹/L, dose adjustment should be based on the nadir value and the cellular composition of the bone marrow biopsy during the nadir.

In case of an unexplained decrease in serum bicarbonate to a level <20 mEq/L during the next therapy cycle, the dose of azacitidine should be reduced by 50%.

In case of an unexplained increase in blood urea nitrogen (BUN) or serum creatinine during the next therapy cycle, the dose of azacitidine should be reduced by 50% and maintained at this level until these parameters return to baseline (pre-treatment) or normal values.

Adverse Reactions

From the hematopoietic system: anemia, febrile neutropenia, leukopenia, neutropenia, thrombocytopenia, agranulocytosis, pancytopenia, splenomegaly.

From the cardiovascular system: arterial hypotension, atrial fibrillation, heart failure, cardiac arrest, cardiomyopathy, orthostatic hypotension.

From the digestive system: nausea, vomiting, frequent loose stools, dyspepsia, constipation, oral cavity hemorrhages and bleeding, diverticulitis, stomatitis, gastrointestinal bleeding, melena, perirectal abscess, cholecystitis.

General disorders: chest pain, increased body temperature, malaise, systemic inflammatory response syndrome.

Infections: nasopharyngitis, pneumonia, urinary tract infection, lower limb abscesses, bacterial infection, cellulitis, blastomycosis, sepsis caused by Klebsiella spp., neutropenic sepsis, streptococcal pharyngitis, pneumonia caused by Klebsiella spp., sepsis, septic shock, staphylococcal bacteremia, staphylococcal infection, toxoplasmosis.

From the CNS: dizziness, headache, anxiety, insomnia, lethargy, cerebral hemorrhage, seizures, intracranial hemorrhages.

From the organ of vision: eye hemorrhage.

From metabolism: weight loss, hypokalemia, dehydration.

From the musculoskeletal system: arthralgia, myalgia, bone pain, muscle weakness, neck pain.

From the urinary system: hematuria, lower back pain, renal failure.

From the respiratory system: dyspnea, pharyngolaryngeal pain, hemoptysis, pulmonary infiltration, pneumonitis, respiratory distress.

Dermatological reactions: dry skin, ecchymoses, erythema, petechiae, hematomas, rash, pruritus, pyoderma gangrenosum, skin induration.

Allergic reactions: urticaria, anaphylactic shock, hypersensitivity reactions.

Contraindications

Progressive malignant liver tumors, hypersensitivity to azacitidine.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy.

Experimental studies in animals have revealed a teratogenic effect of azacitidine.

Male patients are not recommended to conceive during treatment with azacitidine.

Use in Hepatic Impairment

Contraindicated in progressive malignant liver tumors.

Since Azacitidine is potentially hepatotoxic in patients with severe pre-existing liver dysfunction, caution is required when treating patients with liver disease.

Use in Renal Impairment

Azacitidine and its metabolites are excreted primarily by the kidneys, so the risk of toxic reactions may be higher in patients with impaired renal function.

Geriatric Use

Since impaired renal function is more likely in elderly patients, dose selection in such cases should be made with caution and preferably under the control of renal function.

Special Precautions

A complete blood count should be performed before starting therapy, and liver and kidney function should be assessed. Blood cell count analysis should be performed regularly to assess clinical response and toxic effects, but at a minimum, before each administration of azacitidine. After administration of the recommended dose during the first therapy cycle, the dose for subsequent cycles should be adjusted based on nadir values and hematologic response.

Since Azacitidine is potentially hepatotoxic in patients with severe pre-existing liver dysfunction, caution is required when treating patients with liver disease. In patients with a significant tumor burden due to metastases, rare cases of progression to hepatic coma and fatal outcome have been reported during treatment with azacitidine, especially in patients with a baseline albumin level of less than 30 g/L. Azacitidine is contraindicated in patients with severe malignant liver tumors.

The safety and efficacy of azacitidine in patients with myelodysplastic syndrome and impaired liver function have not been established.

Rarely, in patients receiving intravenous Azacitidine in combination with other chemotherapeutic agents for other diseases (not myelodysplastic syndromes), renal abnormalities were observed – ranging from increased serum creatinine to renal failure and death. Furthermore, in some cases, in patients receiving Azacitidine in combination with etoposide, renal tubular acidosis was observed, which was manifested by a sharp decrease in serum bicarbonate to less than 20 mEq/L and was accompanied by alkaline urine and hypokalemia (serum potassium <3 mEq/L). In case of an unexplained decrease in serum bicarbonate to less than 20 mEq/L or an increase in BUN or serum creatinine, the dose should be reduced or not changed (not increased).

Azacitidine and its metabolites are excreted primarily by the kidneys, so the risk of toxic reactions may be higher in patients with impaired renal function. Since impaired renal function is more likely in elderly patients, dose selection in such cases should be made with caution and preferably under the control of renal function.

The safety and efficacy of azacitidine in patients with myelodysplastic syndrome and impaired renal function have not been established.

Drug Interactions

Drug interactions of azacitidine have not been studied.

In vitro studies on human hepatocyte culture have shown that Azacitidine at concentrations from 1 to 100 µM does not cause induction of CYP1A2, CYP2C19, CYP3A4 isoenzymes.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.