Vaidase, lyophilizate 100 mg 200 mg

Pharmacodynamics

Antitumor drug. Antimetabolite. Azacitidine’s antitumor action is due to a variety of mechanisms, including cytotoxicity against pathologically altered hematopoietic cells in the bone marrow and DNA hypomethylation. The mechanisms involved in 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.

Nonproliferating cells are almost insensitive to azacitidine. Incorporation of azacitidine into DNA leads to inactivation of DNA methyltransferase, resulting in DNA hypomethylation. DNA hypomethylation in aberrantly methylated genes, which are also 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 cancer cells themselves. The clinical significance of the mechanism of DNA hypomethylation compared to the cytotoxic and other effects of azacitidine has not yet been established.

The clinical efficacy and safety of Vaidase has been confirmed by the results of a multicenter randomized phase III study. In patients with myelodysplastic syndrome, chronic myelomonocytic leukemia and acute myeloleukemia, therapy with Vaidase was superior to current conventional therapy in all efficacy criteria, including life expectancy and overall treatment response rate.

Pharmacokinetics

Intake

. After p/c administration, azacitidine is rapidly absorbed, reaching C_max 750±403 ng/mL 0.5 h after administration. Absolute bioavailability of azacitidine by infusion is 89% relative to this value by infusion based on the results of AUC determination.

Metabolism

The results of in vitro studies showed that cytochrome P450 system isoenzymes, UDP-glucuronyltransferase, sulfotransferase and glutathione transferase are not involved in metabolism of azacitidine. Azacytidine is metabolized by spontaneous hydrolysis and deamination, which is induced by cytidine deaminase.

Excretion

Azacitidine is rapidly excreted from the body, its T_1/2 after p/q administration is 41±8 minutes. Most of azacitidine (50-85%) and/or its metabolites are excreted by the kidneys. Less than 1% of the drug is excreted through the intestine. There are no data on excretion of azacitidine in breast milk.

Pharmacokinetics in special clinical cases

The effect of hepatic or renal dysfunction, as well as age, sex or race on the pharmacokinetic parameters of azacitidine has not been studied.

Indications

Treatment of adult patients in whom a hematopoietic stem cell transplant cannot be performed:

Active ingredient

Composition

Active substances:

Azacytidine 100 mg.

Associates:

Mannitol – 100 mg.

How to take, the dosage

The drug Vaidaza is injected p/u into the shoulder, thigh or abdomen. The injection sites should be alternated. The next injection site should be more than 2.5 cm from the previous one. Vaidaza should not be injected into damaged, hyperemic, thickened or painful areas of skin (including areas of skin with hemorrhages).

The administration of anti-emetics is recommended before Vaidaza is administered.

The recommended starting dose of Vaidaza for the first cycle of therapy for all patients, regardless of hematologic baseline values, is 75 mg/m2 body surface and is given daily for 7 days followed by a break of 21 days (a 28-day therapy cycle).

A minimum of 6 therapeutic cycles must be performed. Treatment continues as long as it remains effective or until symptoms of disease progression appear.

At follow-up, patients are evaluated for blood count response and possible toxicities, particularly in the blood and kidneys, which may require delaying the next course of treatment or adjusting the dose of the drug. Below are options for modifying the dose of Vaidaza if various types of toxicity develop.

Dose modification when symptoms of hematologic toxicity are detected

Hematologic toxicity is defined as the maximum decrease in cell count during a given treatment cycle (nadir) if the platelet count decreases to 50×109/l or lower and/or the absolute neutrophil count (ANR) decreases to 1×109/l or lower.

The increase in cell count(s) in cell line(s) by at least half the difference between baseline cell count and nadir (i.e. cell count in recovery > nadir + (0.5×([baseline count – nadir])) is considered a recovery.

Patients with baseline (before Vaidase 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 hematologic toxicity during treatment with Vaidase, the next cycle of treatment with the drug is postponed until the platelet count and absolute neutrophil count return to baseline values. If the recovery period does not exceed 14 days, no modification of the drug dose is required. If blood cell counts have not risen to the required level within 14 days, the dose should be reduced according to the recommendations below. If a modified dose is used, the therapy cycle should be restored to 28 days.

* Recoveries = number (q-number) ≥ minimum q-number + (0.5 × [Baseline q-number – minimum q-number])

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

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

Patients whose blood cell counts have not exceeded 50% of the threshold from baseline with no signs of improved cellular differentiation, the next course of treatment with Vaidase should be delayed until the absolute neutrophil and platelet counts recover. If the recovery process took no more than 14 days, Vaidaza dosage adjustment is not required. If blood cell count did not reach the desired level within 14 days, determination of bone marrow cell saturation is necessary. If the cell saturation > 50%, no change in the drug dose is required. If bone marrow cell saturation is ≤ 50%, Vaidase should be delayed and the dose reduced according to the recommendations in the table:

* Recovery = quantity (quantity) ≥ minimum quantity + (0.5 × [Initial Quantity – Minimum Quantity]).

After dose modification, the cycle length must be restored to 28 days.

An example of an individual dose calculation for azacitidine is shown in the table below:

Interaction

There have been no targeted clinical studies on the interaction of azacitidine with other drugs. In vitro studies indicate that the participation of cytochrome P450 system isoenzymes, UDP-glucuronyltransferase, sulfotransferase and glutathione transferase in metabolism of azacitidine is unlikely. Therefore, in vivo interactions with these enzymes involved in metabolism do not appear to be clinically significant.

Special Instructions

Treatment with Vaidaza should be done under the supervision of a physician experienced in the use of antineoplastic drugs.

The safety and effectiveness of Vaidaza in patients with severe congestive heart failure, other significant cardiovascular or pulmonary disease has not been established.

Before initiating therapy and before each cycle, liver function tests and serum creatinine should be obtained, as well as gross blood counts. Regular blood tests are indicated to monitor the efficacy and safety of treatment.

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

An extensive blood test 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 values and their dynamics during treatment.

The medical staff and patient should be instructed to monitor for body temperature (fever) and symptoms to diagnose bleeding.

Myelosuppression can lead to neutropenia and an increased risk of infection. Serious adverse reactions such as neutropenia-associated sepsis (0.8%) and pneumonia (2.5%) have been reported in patients treated with azacitidine. In case of infectious complications it is possible to prescribe etiotropic treatment and colony-stimulating factor against neutropenia.

Patients treated with azacitidine may develop bleeding, including those classified as serious adverse reactions, such as gastrointestinal (0.8%) and intracranial bleeding (0.5%). Bleeding symptoms should be controlled, especially in patients with baseline thrombocytopenia or thrombocytopenia secondary to treatment.

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

The majority of adverse reactions from the skin and subcutaneous fat were noted at the injection site. Most such reactions occurred during the first two cycles of treatment, with a tendency to decrease as treatment continued. Local adverse reactions such as rash, inflammation, itching at the injection site, erythema may require prescription of antihistamines, corticosteroids and NSAIDs.

In patients with advanced metastatic liver lesions there have been cases of hepatic coma with fatal outcome during treatment with azacitidine.

In patients treated with azacitidine there have been rare cases of renal dysfunction with conditions ranging from increased creatinine levels and renal tubular acidosis to development of renal failure, including death.

If there is an unexplained decrease in serum bicarbonate levels, an unexplained increase in serum creatinine or blood urea concentrations, the next cycle of therapy should be delayed until these parameters are restored to normal or baseline values, and the drug dose should be reduced in the next cycle. Because azacitidine and its metabolites are excreted primarily by the kidneys, patients with renal impairment should be monitored closely to control adverse events.

In treatment with azacitidine, constipation, diarrhea, nausea and vomiting were the most frequently reported adverse reactions. These adverse reactions were managed with symptomatic medications: antiemetics for nausea and vomiting, anti-diarrheals for diarrhea, and laxatives for constipation.

Vaidaza is a cytotoxic medication that, like other toxic substances, should be handled with caution. Any unused or consumable material must be disposed of according to local requirements.

If reconstituted azacitidine solution comes in contact with the skin, immediately rinse thoroughly with soap and water. If mucous membranes come in contact, rinse thoroughly with water.

Impact on the ability to drive vehicles and other mechanisms requiring increased attention

There have been no studies on the effect on the ability to drive vehicles and use mechanisms. Because of the possibility of weakness during treatment with Vaidaza, patients should exercise special caution when driving and operating machinery.

Contraindications

With caution: the drug should be used in patients with cardiovascular disease, lung disease, renal and hepatic impairment, including extensive metastatic liver disease.

Side effects

Most common: hematologic reactions (71.4%), including thrombocytopenia, neutropenia, and leukopenia (usually of grade 3-4 severity); gastrointestinal complications (60.6%), including nausea and vomiting (usually of grade 1-2 severity) or local injection site reactions (77.1% severity 1-2); serious adverse reactions include febrile neutropenia (8%), anemia (2.3%), and neutropenic sepsis, pneumonia, thrombocytopenia, and bleeding (e.g., intracranial).

Determine the frequency of adverse reactions:

Overdose

Symptoms: one case of azacitidine overdose was reported in a clinical trial. The patient experienced diarrhea, nausea and vomiting after a single intravenous injection of 290 mg/m2, which is almost 4 times the recommended starting dose.

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

Pregnancy use

The drug is contraindicated in pregnant and breastfeeding women.

Men and women of childbearing age should use effective contraception during treatment and for 3 months after completion of treatment. Men should be advised to consider conserving their own sperm samples before starting treatment.