Vidaza (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Celgene International, Sarl. (Switzerland)

Manufactured By

Baxter Oncology, GmbH (Germany)

Labeled By

PHARMSTANDARD-UfaVITA, JSC (Russia)

Or

BAXTER ONCOLOGY, GmbH (Germany)

Quality Control Release

CELGENE INTERNATIONAL, Sarl. (Switzerland)

Or

PHARMSTANDARD-UfaVITA, JSC (Russia)

ATC Code

L01BC07 (Azacitidine)

Active Substance

Azacitidine (Rec.INN registered by WHO)

Dosage Form

Vidaza

Lyophilizate for preparation of suspension for subcutaneous administration 100 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilizate for preparation of suspension for subcutaneous administration in the form of a powder or porous mass of white color; the prepared suspension is white.

Excipients: mannitol – 100 mg.

Vials of colorless glass with a capacity of 30 ml (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agents; pyrimidine analogues

Pharmacological Action

Antitumor drug. Antimetabolite. The antitumor action of azacitidine is due to various mechanisms, including cytotoxicity against pathologically altered hematopoietic cells of the bone marrow and DNA hypomethylation.

The mechanisms involved in the realization of the cytotoxic action of azacitidine include inhibition of DNA, RNA and protein synthesis, incorporation of the drug into DNA and RNA, and activation of DNA damage pathways. Non-proliferating cells are practically insensitive to azacitidine.

Incorporation of azacitidine into DNA leads to inactivation of DNA methyltransferase, resulting in DNA hypomethylation. DNA hypomethylation in aberrantly methylated genes, present in the regulatory cycle of normal cells, their differentiation and cell death, can cause gene re-expression and restoration of tumor growth suppression properties in the cancer cells themselves.

The clinical significance of the DNA hypomethylation mechanism compared to the cytotoxic and other effects of azacitidine has not yet been established.

The clinical efficacy and safety of Vidaza was confirmed by the results of a multicenter randomized phase III study. In patients with myelodysplastic syndrome, chronic myelomonocytic leukemia and acute myeloid leukemia, therapy with Vidaza was superior to conventional standard therapy in all efficacy criteria, including survival and overall response rate.

Pharmacokinetics

Absorption

After subcutaneous administration, Azacitidine is rapidly absorbed, reaching C_max 750±403 ng/ml 0.5 hours after administration. The absolute bioavailability of azacitidine after subcutaneous administration is 89% relative to this indicator after intravenous administration based on AUC results.

Metabolism

Results of in vitro studies have shown that cytochrome P450 isoenzymes, UDP-glucuronyltransferase, sulfotransferase and glutathione transferase are not involved in the metabolism of azacitidine. Azacitidine is metabolized by spontaneous hydrolysis and deamination, which is induced by cytidine deaminase.

Excretion

Azacitidine is rapidly eliminated from the body, its T_1/2 after subcutaneous administration is 41±8 min. Most of azacitidine (50-85%) and/or its metabolites are excreted by the kidneys. Less than 1% of the drug is excreted through the intestines. There are no data on the penetration of azacitidine into breast milk.

Pharmacokinetics in special clinical cases

The influence of impaired liver or kidney function, as well as age, gender or race on the pharmacokinetic parameters of azacitidine has not been studied.

Indications

Treatment of adult patients who cannot undergo hematopoietic stem cell transplantation

• Myelodysplastic syndrome (MDS) with high or intermediate-2 risk according to the IPSS (International Prognostic Scoring System);
• Acute myeloid leukemia;
• Chronic myelomonocytic leukemia without signs of MDS.

ICD codes

Dosage Regimen

The drug Vidaza is administered subcutaneously into the shoulder, thigh or abdomen. Injection sites should be alternated. The site for the next injection should be more than 2.5 cm from the previous one. Vidaza should not be injected into damaged, reddened, hardened or painful areas of the skin (including areas of skin with hemorrhages).

It is recommended to prescribe antiemetic drugs before administering Vidaza.

The recommended initial dose of the drug Vidaza during the first cycle of therapy for all patients, regardless of baseline hematological parameters, is 75 mg/m² of body surface area and is administered daily for 7 days followed by a 21-day break (28-day therapeutic cycle).

At least 6 therapeutic cycles should be performed. Treatment is continued as long as its effectiveness persists or until symptoms of disease progression appear.

During patient monitoring, the response in terms of blood counts and possible manifestations of toxicity, in particular from the blood and kidneys, are assessed, which may require delaying the next course of treatment or adjusting the drug dose. Below are the options for modifying the dose of the drug Vidaza when various types of toxicity develop.

Dose modification when symptoms of hematological toxicity are detected

Hematological toxicity is considered to be the maximum decrease in the number of cells during a given treatment cycle (nadir), if the platelet count decreases to 50×10⁹/L and below and/or the absolute neutrophil count (ANC) decreases to 1×10⁹/L and below.

Recovery is considered to be an increase in the number of cells in the cell line(s) by at least half the difference between the baseline number of cells and the nadir (i.e., the number of cells at recovery > nadir + (0.5×([baseline count – nadir])).

Patients with baseline (before starting Vidaza therapy) white blood cell counts >3×10 ⁹/L, absolute neutrophil count >1.5×10 ⁹/L, platelet count >75×10 ⁹/L

If these patients develop symptoms of hematological toxicity during treatment with Vidaza, the next cycle of treatment with the drug is delayed until the platelet count and absolute neutrophil count recover to baseline values. If the duration of the recovery period does not exceed 14 days, no modification of the drug dose is required. If the blood cell count does not increase to the required level within 14 days, the drug dose should be reduced according to the recommendations below. When using a modified dose, the duration of the therapy cycle should be restored to 28 days.

* Recovery = count ≥ nadir count + (0.5 × [Baseline count – nadir count])

Patients with baseline (before starting Vidaza therapy) white blood cell counts <3×10 ⁹/L, absolute neutrophil count <1.5×10 ⁹/L, platelet count <75×10 ⁹/L.

If before the next course of treatment with Vidaza there is a decrease in the white blood cell count or absolute neutrophil count or platelet count less than or equal to 50% of their baseline values, or more than 50%, but in the presence of signs of improved differentiation of any cell line, the administration regimen of Vidaza and its dose should not be changed.

For patients whose blood cell count does not exceed the 50% threshold from the baseline level in the absence of signs of improved differentiation of cell lines, the next course of treatment with Vidaza should be delayed until the absolute neutrophil and platelet counts recover. If the recovery process took no more than 14 days, no correction of the Vidaza dose is required. If the blood cell count does not reach the desired level within 14 days, it is necessary to determine the bone marrow cellularity. With a cellularity index > 50%, no change in the drug dose is required. If bone marrow cellularity is ≤ 50%, administration of Vidaza should be delayed and the dose reduced according to the recommendations in the table

* Recovery = count ≥ nadir count + (0.5 × [Baseline count – nadir count])

After dose modification, the cycle duration should be restored to 28 days.

An example of calculating an individual dose of azacitidine is presented in the table below

Features of use in specific patient groups

No special studies have been conducted in patients with impaired renal function. Patients with severe renal failure require careful monitoring to control adverse events. It is not necessary to change the initial dose of the drug in patients with impaired renal function (for example, baseline serum creatinine level or blood urea concentration is 2 times the ULN or bicarbonate concentration is less than 20 mmol/L). Subsequent dose modification is based on the results of the study of hematological parameters and renal function indicators. If the serum bicarbonate concentration decreases unexplainedly to less than 20 mmol/L, the dose of the drug for the next therapy cycle should be reduced by 50%. If the serum creatinine concentration or blood urea nitrogen concentration increases unexplainedly by 2 or more times from baseline or above the ULN, the next cycle of therapy should be delayed until these parameters return to normal or baseline values, and the dose of the drug in the next cycle should be reduced by 50%.

No special studies have been conducted in patients with impaired liver function. Patients with severe hepatic insufficiency require careful monitoring for timely detection of adverse events. This category of patients does not require changing the initial dose of the drug. Subsequent dose modification will depend on the results of the blood test.

Elderly patients do not require a special dosage regimen. Since this category of patients has a higher likelihood of impaired renal function, it is recommended to monitor renal function during treatment.

It is not recommended to prescribe Vidaza to children and adolescents under 18 years of age due to insufficient clinical experience.

Rules for preparing the solution and performing injections

The contents of the vial with the drug should be dissolved in 4 ml of water for injections to a concentration of 25 mg/1 ml. After adding water for injections to the vial, it must be shaken vigorously until a homogeneous white suspension is obtained. If the required dose exceeds 100 mg, 2 vials of the drug are used.

Immediately before administration, it is necessary to re-suspend the contents of the syringe. To do this, vigorously roll the syringe between your palms until a homogeneous white suspension is obtained. The temperature of the suspension during injection should be 20-25°C (-13°F). Do not use the drug if it contains large particles.

For subcutaneous injection, it is recommended to use a 25-gauge needle, and the needle should be inserted under the skin of the shoulder, thigh or abdomen at an angle of 45-90°. No more than 4 ml of the dissolved drug should be injected into one area. Doses greater than 4 ml should be administered into 2 different areas.

The Vidaza suspension should be prepared immediately before use. The prepared suspension should be stored at a temperature of 25°C (77°F) for no more than 45 minutes or at a temperature from 2°C (35.6°F) to 8°C (46.4°F) for no more than 8 hours. It is necessary that before administration the temperature of the suspension in the syringe reaches 20-25°C (-13°F) (but not more than within 30 minutes). If these time limits are exceeded, the prepared suspension must be disposed of appropriately and a new suspension must be prepared.

Adverse Reactions

Most often hematological reactions (71.4%), including thrombocytopenia, neutropenia and leukopenia (usually grade 3-4 severity); gastrointestinal complications (60.6%), including nausea and vomiting (usually grade 1-2 severity) or local reactions at the injection site (77.1%; severity grade 1-2); serious adverse reactions – febrile neutropenia (8%), anemia (2.3%), as well as – neutropenic sepsis, pneumonia, thrombocytopenia and bleeding (e.g., intracranial).

Definition of frequency of adverse reactions: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10 000, <1/1000), very rare (<1/10 000); unknown (cannot be estimated from the available data).

From the hematopoietic system very common – neutropenia, febrile neutropenia, leukopenia, thrombocytopenia, anemia; common – pancytopenia.

From the digestive system very common – diarrhea, constipation, nausea, vomiting, abdominal pain, anorexia; common – gastrointestinal bleeding, hemorrhoidal bleeding, stomatitis, gum bleeding, dyspepsia.

From the liver and biliary tract uncommon – hepatic failure, progressive hepatic coma.

From the nervous system very common – dizziness, headache; common – intracranial bleeding, drowsiness,

From the psyche confusion, anxiety, insomnia.

From the cardiovascular system common – increase or decrease in blood pressure, hematomas.

From the respiratory system very common – dyspnea; common – exertional dyspnea, pain in the larynx and pharynx; rare – interstitial lung diseases.

From the urinary system common – hematuria, renal failure, increased creatinine concentration; uncommon – renal tubular acidosis.

From the skin and subcutaneous tissue very common – petechiae, itching, rash, ecchymoses; common – purpura, alopecia, erythema, maculopapular rash.

From the musculoskeletal system very common – arthralgia; common – bone pain, myalgia.

From the organ of vision : common – intraocular bleeding, conjunctival hemorrhage.

Infections very common – pneumonia, nasopharyngitis; common – neutropenic sepsis, upper respiratory tract and urinary tract infections, cellulitis, sinusitis, pharyngitis, rhinitis, herpes simplex.

From the immune system uncommon – hypersensitivity reactions.

From metabolism very common – anorexia, common – hypokalemia; rare – tumor lysis syndrome.

Local reactions very common – pain and redness, nonspecific reactions at the injection site; common – bleeding, hemorrhage, hematoma, induration, inflammation, rash, itching, skin discoloration, nodule formation and tenderness at the injection site; rare – tissue necrosis at the injection site.

Other very common – weakness, fever, chest pain; common – weight loss.

Contraindications

• Extensive liver metastases;
• Pregnancy;
• Lactation (breastfeeding period);
• Childhood (lack of data on efficacy and safety);
• Hypersensitivity to azacitidine or other components of the drug.

With caution the drug should be used in patients with cardiovascular diseases, lung diseases, with impaired renal and liver function, including extensive metastatic liver lesions.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and breastfeeding.

Men and women of reproductive potential should use effective methods of contraception during treatment and for 3 months after its completion. Men should be advised to consider the possibility of preserving samples of their own sperm before starting treatment.

Use in Hepatic Impairment

Use with caution in patients with impaired liver function.

No specific studies have been conducted in patients with impaired liver function. Patients with severe hepatic insufficiency should be carefully monitored for the timely detection of adverse events. This category of patients does not require modification of the initial drug dose. Subsequent dose modification will depend on the results of blood tests.

During treatment with azacitidine, cases of hepatic coma with a fatal outcome have been observed in patients with extensive metastatic liver lesions, especially when the serum albumin level is less than 30 g/L.

Use in Renal Impairment

Use with caution in patients with impaired renal function.

No specific studies have been conducted in patients with impaired renal function. Patients with severe renal failure should be carefully monitored to control adverse events. It is not necessary to change the initial dose of the drug in patients with impaired renal function (for example, baseline serum creatinine or blood urea concentration is twice the upper limit of normal (ULN) or bicarbonate concentration is less than 20 mmol/L). Subsequent dose modification is based on the results of hematological parameters and renal function tests. For an unexplained decrease in serum bicarbonate to less than 20 mmol/L, the drug dose for the next therapy cycle should be reduced by 50%. For an unexplained increase in serum creatinine or blood urea nitrogen to twice or more the baseline values or above the ULN, the next therapy cycle should be delayed until these parameters return to normal or baseline values, and the drug dose in the next cycle should be reduced by 50%.

Pediatric Use

Contraindicated in children (lack of data on efficacy and safety).

Geriatric Use

Elderly patients do not require a special dosage regimen. Since elderly patients are more likely to have impaired renal function, monitoring of renal function is recommended during treatment.

Special Precautions

Treatment with Vidaza should be carried out under the supervision of a physician experienced in the use of anticancer drugs.

The safety and efficacy of Vidaza in patients suffering from severe congestive heart failure, other significant cardiovascular or pulmonary diseases have not been established.

Before starting therapy and before the start of each cycle, the results of liver function tests and serum creatinine, as well as complete blood count data, should be obtained. Regular blood tests are indicated for monitoring the efficacy and safety of treatment.

The most frequent adverse effects during treatment with azacitidine were hematological reactions, including thrombocytopenia, neutropenia, and leukopenia (usually grade 3-4). The highest risk of developing these reactions is noted during the first two therapy cycles, after which they occur less frequently in patients with recovered hematological parameters. Most hematological reactions resolve with a delay of the next treatment cycle, prophylactic administration of antibiotics and/or colony-stimulating factor for neutropenia, and blood transfusions for anemia or thrombocytopenia.

A complete blood count should be performed to monitor treatment efficacy and possible adverse reactions at least before each treatment cycle. After the first treatment cycle, the dosage for subsequent treatment is calculated based on baseline parameters and their dynamics during treatment.

Medical personnel and the patient should be instructed on the need to monitor body temperature (fever) and symptoms that allow diagnosing bleeding.

Myelosuppression may lead to neutropenia and an increased risk of infection. Serious adverse reactions such as neutropenic sepsis (0.8%) and pneumonia (2.5%) have been observed in patients during treatment with azacitidine. In case of infectious complications, etiotropic treatment and colony-stimulating factor for neutropenia may be prescribed.

Patients receiving azacitidine treatment may develop bleeding, including those classified as serious adverse reactions, such as gastrointestinal (0.8%) and intracranial bleeding (0.5%). It is necessary to monitor symptoms that allow diagnosing bleeding, especially in patients with baseline thrombocytopenia or thrombocytopenia that occurred during treatment.

Hypersensitivity reactions classified as serious (0.25%) have been observed in patients treated with azacitidine. In case of anaphylactic reactions, azacitidine treatment should be stopped immediately and symptomatic treatment should be prescribed.

Most adverse reactions of the skin and subcutaneous tissue were noted at the injection site. Most of these reactions occurred during the first two treatment cycles, with a tendency to decrease with continued treatment. Such local adverse reactions as rash, inflammation, itching at the injection site, erythema may require the prescription of antihistamines, corticosteroids, and NSAIDs.

During treatment with azacitidine, cases of hepatic coma with a fatal outcome have been observed in patients with extensive metastatic liver lesions.

In rare cases, renal function disorders have been observed in patients treated with azacitidine, including various conditions from increased creatinine levels and renal tubular acidosis to the development of renal failure, including fatal outcomes.

For an unexplained decrease in serum bicarbonate, an unexplained increase in serum creatinine or blood urea concentration, the next therapy cycle should be delayed until these parameters return to normal or baseline values, and the drug dose in the next cycle should be reduced. Since Azacitidine and its metabolites are excreted primarily by the kidneys, patients with renal failure should be carefully monitored for adverse events.

Constipation, diarrhea, nausea, and vomiting were most frequently observed during treatment with azacitidine. These adverse reactions were controlled with symptomatic means: antiemetics for nausea and vomiting, antidiarrheals for diarrhea, and laxatives for constipation.

Vidaza is a cytotoxic drug and, like other toxic substances, should be handled with caution. Any unused or consumable material should be disposed of in accordance with local requirements.

If the reconstituted azacitidine solution comes into contact with the skin, wash it immediately and thoroughly with soap and water. If it comes into contact with the mucous membrane, rinse it thoroughly with water.

Effect on the ability to drive vehicles and operate machinery

Studies on the effect on the ability to drive vehicles and use machinery have not been conducted. Given the possibility of weakness during treatment with Vidaza, patients should exercise particular caution when driving a car and operating machinery.

Overdose

Symptoms one case of azacitidine overdose was reported during a clinical trial. The patient experienced diarrhea, nausea, and vomiting after a single intravenous administration of the drug at a dose of 290 mg/m², which is almost 4 times higher than the recommended initial dose.

Treatment it is recommended to monitor the level of relevant blood cells and prescribe supportive treatment if necessary. There is no specific antidote for azacitidine overdose.

Drug Interactions

No targeted clinical studies of the interaction of azacitidine with other drugs have been conducted. Data from in vitro studies indicate that the involvement of cytochrome P450 isoenzymes, UDP-glucuronosyltransferase, sulfotransferase, and glutathione transferase in the metabolism of azacitidine is unlikely. Therefore, in vivo interaction with these metabolizing enzymes is not considered clinically significant.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life is 4 years.

Dispensing Status

The drug is dispensed by prescription.

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.