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Vidaza® [Azacitidine]

Baxter Oncology GmbH
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Clinical Pharmacology

Pharmacodynamics

Antitumor drug. An antimetabolite. The antitumor effect of azacitidine is due to a variety of mechanisms, including cytotoxicity against pathologically altered hematopoietic bone marrow cells and DNA hypomethylation. The mechanisms involved in the implementation of the cytotoxic effect of Azacitidine include inhibition of DNA, RNA and protein synthesis, incorporation of the drug into DNA and RNA, as well as activation of DNA damage pathways. Non-proliferating cells are practically not sensitive to Azacitidine. The incorporation of Azacitidine into DNA leads to the inactivation of DNA methyltransferase, resulting in DNA hypomethylation. DNA hypomethylation in aberrantly methylated genes, which is 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 in comparison with 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, Vidaza therapy was superior to modern traditional therapy in all criteria of effectiveness, including longevity and overall response rate to treatment.

Pharmacokinetics

Suction

After s / c injection, Azacitidine is rapidly absorbed, reaching Cmax 750 ± 403 ng / ml 0.5 h after injection. The absolute bioavailability of azacitidine when s / c administration is 89% relative to this indicator when the / in the introduction on the basis of the results of the determination of AUC.

Metabolism

The results of an in vitro study showed 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.

Removal

Azacitidine is rapidly excreted from the body, its T1/2 after s / c injection is 41 ± 8 minutes Most of the 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 entry of azacitidine into breast milk.

Pharmacokinetics in special clinical situations

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

Indications

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

  • Myelodysplastic syndrome (MDS) with a high or intermediate-2 degree of risk in accordance with the IPSS scale (International Predictive Scoring System);
  • acute myeloid leukemia;
  • chronic myelomonocytic leukemia with no signs of MDS.

Composition

1 bottle contains:

Active substances: Azacitidine 100 mg.

Excipients: mannitol - 100 mg.

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Vidaza® [Azacitidine]

Dosage and Administration

The drug Vidaza injected s / c in the shoulder, hip or abdomen. Injection sites should be alternated. The place for the next injection should be more than 2.5 cm from the previous one. Vidaza should not be injected into damaged, flushed, compacted or painful areas of the skin (including in areas of skin with hemorrhages).

Before the introduction of Vidaza recommended antiemetic drugs.

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

Must be at least 6 therapeutic cycles. Treatment is continued until its effectiveness is maintained or until the onset of symptoms of disease progression.

During the observation of patients, the response from the blood indicators and possible manifestations of toxicity, in particular from the blood and kidneys, which may require a delay in the next course of treatment or dose adjustment of the drug, are evaluated. The possibilities of modifying the dose of the drug Vidaza during the development of various types of toxicity are presented below.

Dose modification for detecting symptoms of hematological toxicity

Hematologic toxicity is considered the maximum reduction in the number of cells during a given treatment cycle (nadir), if the number of platelets decreases to 50 × 109/ l and below and / or the absolute number of neutrophils (AChN) is reduced to 1 × 109/ l and below.

Recovery is the increase in the number of cells in the cell line (s) by at least half the difference between the initial number of cells and the nadir (i.e., the number of cells during recovery> nadir + (0.5 × ([initial number is nadir]).

Patients with baseline (before the start of Vidaza therapy) leukocyte counts> 3 × 10 9/ l, absolute neutrophil count> 1.5 × 10 9/ l, platelet count> 75 × 10 9/ l

If, during the treatment with Vaidaza, these patients develop symptoms of hematologic toxicity, the next cycle of drug treatment is delayed until the number of platelets and the absolute number of neutrophils are restored to their original values. If the duration of the recovery period does not exceed 14 days, modification of the dose of the drug is not required. If the number of blood cells has not increased to the required level within 14 days, the dose of the drug should be reduced according to the recommendations set out below. When using a modified dose, the duration of the cycle of therapy should be restored to 28 days.

Blood cell count % of the initial dose for the next cycle, if recovery * of blood cell count required more than 14 days
Absolute Neutrophil Count Platelet count
≤1×109/ l ≤50×109/ l 50%
>1×109/ l >50×109/ l 100%

* Recovery = quantity (qty) ≥ minimum qty + (0.5 × [Original qty - minimum qty])

Patients with baseline (prior to the start of Vidaza therapy) leukocyte counts <3 10="" sup="">9/ l, absolute neutrophil count <1.5 10="" sup="">9/ l, platelet count <75 10="" sup="">9/ l.

If before the next course of treatment with Vidaza, there is a decrease in the number of leukocytes or the absolute number of neutrophils or platelets less than or equal to 50% of their initial values, or more than 50%, but if there are signs of improvement in the differentiation of any cell germ, the dosage regimen of Vidaza and its dose must change.

Patients whose blood cell count has not exceeded 50% of the threshold from the initial level in the absence of signs of improvement in the differentiation of cell germs, the next course of treatment with Vidaza should be delayed until the absolute number of neutrophils and platelets is restored. If the recovery process took no more than 14 days, the dose adjustment of Vidaza is not required.If the number of blood cells has not reached the desired level within 14 days, a determination of the cellular saturation of the bone marrow is necessary. When the cell saturation index> 50% does not require a change in the dose of the drug. If the bone marrow cell saturation is ≤ 50%, administration of the drug Vaidaza should be delayed, and the dose should be reduced according to the recommendations given in the table:

Cellular bone marrow saturation % of the initial dose for the next cycle, if recovery * of blood cell count required more than 14 days
  Recovery * ≤21 days Recovery *> 21 days
15-50% 100% 50%
< 15% 100% 33%

* Recovery = quantity (qty) ≥ minimum qty + (0.5 × [Original qty - minimum qty]).

After modifying the dose, the cycle time should be restored to 28 days.

An example of the calculation of the individual dose of azacitidine is presented in the table below:

m2 body surfaces 100% of the recommended starting dose (75 mg / m2) 50% of the recommended starting dose (37.5 mg / m2) 33% of the recommended starting dose (25 mg / m2)
  Daily dose Solution volume Daily dose Solution volume Daily dose Solution volume
1,4 105 mg 4.2 ml ** 52.5 mg 2.1 ml * 35 mg 1.4 ml *
1,5 112.5 mg 4.5 ml ** 56.25 mg 2.25 ml * 37.5 mg 1.5 ml *
1,6 120 mg 4.8 ml ** 60 mg 2.4 ml * 40 mg 1.6 ml *
1,7 127.5 mg 5.1 ml ** 63.75 mg 2.55 ml * 42.5 mg 1.7 ml *
1,8 135 mg 5.4 ml ** 67.5 mg 2.7 ml * 45 mg 1.8 ml *
1,9 142.5 mg 5.7 ml ** 71.25 mg 2.85 ml * 47.5 mg 1.9 ml *
* 1 bottle containing 100 mg of Azacitidine
** 2 vials containing 100 mg azacitidine

Features of use in certain groups of patients

In patients with impaired renal function special studies have been conducted. Patients with severe renal failure require careful monitoring to control adverse events. There is no need to change the initial dose of the drug in patients with impaired renal function (for example, the initial serum creatinine level or the concentration of urea in the blood is 2 times higher than VGN or the concentration of bicarbonate is less than 20 mmol / l). Subsequent dose modification is based on the results of a study of hematological parameters and indicators of renal function. With an unexplained decrease in serum bicarbonate concentration of less than 20 mmol / l, the dose of the drug for the next cycle of therapy should be reduced by 50%. With an inexplicable increase in serum creatinine concentration or blood urea nitrogen concentration 2 or more times from baseline or above VGN, the next cycle of therapy should be postponed until these parameters are restored to normal or baseline values, and the dose of the drug in the next cycle should be reduced by 50%.

In patients with impaired liver function special studies have been conducted. Patients with severe hepatic insufficiency require careful monitoring for the timely detection of adverse events. This category of patients is not required to change the initial dose of the drug. Subsequent modification of the dose will depend on the results of the blood test.

Elderly patients no special dosing regimen is required. Since in this category of patients the likelihood of impaired renal function is higher, it is recommended to monitor renal function during treatment.

It is not recommended to appoint Vaidazu children and adolescents under 18 years old due to lack of clinical experience.

Terms of solution preparation and injection

The contents of the drug bottle should be dissolved in 4 ml of water for injection to a concentration of 25 mg / 1 ml. After adding water to the vial for injection, it is necessary to shake it vigorously until a homogeneous white suspension is obtained. With the required dose in excess of 100 mg, 2 bottles of the drug are used.

Immediately before the introduction, it is necessary to re-translate the contents of the syringe into a suspension. To do this, you should energetically roll the syringe between the palms until a homogeneous white suspension is obtained. The temperature of the suspension during the injection should be 20-25 ° C. Do not use the drug if it contains large particles.

It is recommended to use a 25 gauge needle to perform a sc injection, and the needle should be inserted under the skin of the shoulder, thigh, or abdomen at an angle of 45-90 °. In one area should be injected no more than 4 ml of the dissolved drug.Doses of more than 4 ml should be administered in 2 different areas.

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

Adverse reactions

Most often: hematological reactions (71.4%), including thrombocytopenia, neutropenia and leukopenia (usually 3-4 degrees of severity); gastrointestinal complications (60.6%), including nausea and vomiting (usually 1-2 degrees of severity) or local reactions at the injection site (77.1%; severity of 1-2); serious adverse reactions include febrile neutropenia (8%), anemia (2.3%), and sepsis on the background of neutropenia, pneumonia, thrombocytopenia, and bleeding (for example, intracranial).

Determination of the frequency of adverse reactions:

  • very often (≥1 / 10);
  • often (≥1 / 100, <1/10);
  • infrequently (≥1 / 1000, <1/100);
  • rarely (≥1 / 10,000, <1/1000);
  • very rarely (<1/10 000);
  • unknown (it is impossible to estimate according to the available data).

From the hemopoietic system: very often - neutropenia, febrile neutropenia, leukopenia, thrombocytopenia, anemia; often pancytopenia.

From the digestive system: very often - diarrhea, constipation, nausea, vomiting, abdominal pain, anorexia; often - gastrointestinal bleeding, hemorrhoidal bleeding, stomatitis, bleeding gums, dyspepsia.

Liver and biliary tract: infrequently - liver failure, progressive hepatic coma.

From the nervous system: very often - dizziness, headache; often - intracranial bleeding, drowsiness.

From the psyche: confusion, anxiety, insomnia.

Since the cardiovascular system: often - increase or decrease in blood pressure, hematoma.

On the part of the respiratory system: very often, shortness of breath; often - shortness of breath on exertion, pain in the larynx and pharynx; rarely - interstitial lung disease.

From the urinary system: often - hematuria, renal failure, increasing the concentration of creatinine; infrequently - renal tubular acidosis.

On the part of the skin and subcutaneous fat: very often - petechiae, itching, rash, ecchymosis; often - purpura, alopecia, erythema, spotted rash.

From the musculoskeletal system: very often - arthralgia; often - bone pain, myalgia.

On the part of the organ of vision: often - intraocular bleeding, bleeding into the conjunctiva.

Infections: very often - pneumonia, nasopharyngitis; often - sepsis on the background of neutropenia, infections of the upper respiratory tract and urinary tract, inflammation of the subcutaneous tissue, sinusitis, pharyngitis, rhinitis, herpes simplex.

On the part of the immune system: infrequently - hypersensitivity reactions.

Metabolism: very often - anorexia, often - hypokalemia; rarely - tumor lysis syndrome.

Local reactions: very often - pain and redness, nonspecific reactions at the injection site; often - bleeding, hemorrhage, hematoma, induration, inflammation, rash, itching, discoloration of the skin, nodule formation and soreness at the injection site; rarely, tissue necrosis at the site of administration.

Other: very often - weakness, fever, pain in the chest; often - weight loss.

Carefully: the drug should be used in patients with cardiovascular diseases, lung diseases, with impaired renal and hepatic function, including extensive metastatic lesions of the liver.

Drug interactions

There has been no targeted clinical studies of the interaction of azacitidine with other drugs.Data from in vitro studies indicate that the participation of cytochrome P450 isoenzymes, UDP glucuronyl transferase, sulfotransferase, and glutathione transferase in azacitidine metabolism is unlikely. In this regard, the in vivo interaction with these enzymes involved in metabolism does not seem to be clinically significant.

Pregnancy and Lactation

The drug is contraindicated during pregnancy and during breastfeeding.

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

Special instructions

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

The safety and efficacy of Vidaza in patients with severe congestive heart failure, other severe cardiovascular or pulmonary diseases has not been established.

Before the start of therapy and before the start of each cycle, the results of the study of the functional activity of the liver and creatinine of the blood serum, as well as the data of the complete blood count, should be obtained. Regular blood tests are indicated to monitor the effectiveness and safety of the treatment.

The most common side effects in the treatment with Azacitidine were hematological reactions, including thrombocytopenia, neutropenia and leukopenia (usually 3–4 degrees of severity). The greatest risk of these reactions occurring during the first two cycles of therapy, after which they occur with less frequency in patients with recovered hematological parameters. Most hematological reactions are resolved by delaying the next treatment cycle, prophylactic antibiotics and / or colony-stimulating factor in neutropenia and blood transfusions in anemia or thrombocytopenia.

A full blood count should be performed to monitor the effectiveness of treatment and possible adverse reactions at least before each treatment cycle. After the first treatment cycle, the dosage for the subsequent treatment is calculated on the basis of baseline indicators and their dynamics during the treatment process.

Medical personnel and the patient should receive instructions on the need to control body temperature (fever) and symptoms that allow to diagnose bleeding.

Myelosuppression can lead to neutropenia and an increased risk of infection. In patients treated with azacitidine, serious adverse reactions were noted, such as sepsis during neutropenia (0.8%) and pneumonia (2.5%). In the case of infectious complications, it is possible to prescribe etiotropic treatment and colony-stimulating factor in neutropenia.

Patients receiving treatment with azacitidine may develop bleeding, incl. categorized as serious adverse reactions, such as gastrointestinal (0.8%) and intracranial hemorrhage (0.5%). It is necessary to control the symptoms that allow to diagnose bleeding, especially in patients with initial thrombocytopenia or thrombocytopenia that occurred during treatment.

In patients treated with azacitidine, hypersensitivity reactions were categorized as serious (0.25%). In the event of anaphylactic reactions, treatment with Azacitidine should be immediately stopped and symptomatic treatment prescribed.

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

Cases of development of hepatic coma with a lethal outcome were observed during treatment with azacitidine in patients with common liver metastatic lesions.

In patients treated with azacitidine, renal dysfunction was rarely observed, including various conditions ranging from an increase in creatinine and renal-canal acidosis to the development of renal failure, including fatal.

With an inexplicable decrease in serum bicarbonate levels, an inexplicable increase in serum creatinine level or blood urea concentration, the next therapy cycle should be postponed until these parameters are restored to normal or baseline values, and the dose of the drug in the next cycle should be reduced. Since Azacitidine and its metabolites are excreted primarily by the kidneys, and patients with renal insufficiency should be carefully monitored to control adverse events.

The treatment with azacitidine most often marked constipation, diarrhea, nausea and vomiting. These adverse reactions were stopped with the help of symptomatic means: antiemetic - for nausea and vomiting, antidiarrheal - for diarrhea, and laxatives - for constipation.

Vidaza is a cytotoxic drug that, like other toxic substances, should be handled with care. Any unused or consumable must be disposed of according to local regulations.

Upon contact of the reconstituted azacitidine solution with the skin, immediately wash it thoroughly with soap and water. In case of contact with mucous membrane, rinse thoroughly with water.

Impact on the ability to drive vehicles and other mechanisms that require high concentration of attention

Studies on the impact on the ability to drive and use of mechanisms have not been conducted. Given the possibility of developing weakness during the treatment with Vidaza, patients should take special care when driving and working with mechanisms.

Overdosage

Symptoms: A single case of azacitidine overdose was reported during a clinical trial. The patient had diarrhea, nausea and vomiting after a single intravenous drug at a dose of 290 mg / m2, which exceeds the recommended initial dose by almost 4 times.

Treatment: It is recommended to monitor the level of relevant blood cells and prescribe, if necessary, supportive treatment. There is no specific antidote for an Azacitidine overdose.

  • Brand name: Vidaza
  • Active ingredient: Azacitidine
  • Dosage form: Lyophilisate for the preparation of suspensions for subcutaneous injection.
  • Manufacturer: Baxter Oncology GmbH
  • Country of Origin: Switzerland

Studies and clinical trials of Azacitidine (Click to expand)

  1. A phase II study of 5-day intravenous azacitidine in patients with myelodysplastic syndromes
  2. Treatment of acute myelogenous leukemia with outpatient azacitidine
  3. Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia
  4. Azacitidine for the treatment of lower risk myelodysplastic syndromes : A retrospective study of 74 patients enrolled in an Italian named patient program
  5. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome : A dose and schedule finding study
  6. Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer
  7. Activity of azacitidine in chronic myelomonocytic leukemia
  8. Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes
  9. Azacitidine for the treatment of patients with acute myeloid leukemia : Report of 82 patients enrolled in an Italian compassionate program
  10. Effects of azacitidine compared with conventional care regimens in elderly (≥75 years) patients with higher-risk myelodysplastic syndromes
  11. Successful treatment of relapsed AML after allogeneic stem cell transplantation with azacitidine
  12. Match unrelated bone marrow transplantation in a case of high risk myelodysplastic syndrome treated with azacitidine and concomitant 1α-25-dihydroxyvitamin D3, as differentiating agent
  13. Practical use of azacitidine in higher-risk myelodysplastic syndromes: An expert panel opinion
  14. Thrice weekly azacitidine does not improve hematological responses in lower-risk myelodysplastic syndromes: A study of the Hoosier Oncology Group
  15. P060 Effect of azacitidine on PI-PLC-beta1 expression and Akt activation in a patient affected by high-risk myelodysplastic syndrome (MDS)
  16. P150 Karyotype does not predict response to azacitidine in patients with myelodysplastic syndrome
  17. P151 Azacitidine in combination with EPO+G-CSF and valproic acid rapidly determines hematological improvement in pretreated non responsive IPSS INT-1 MDS patients
  18. P152 G-CSF increases hematological response and survival among patients with myelodysplasia treated with azacitidine
  19. P153 Clinical effects of 5-azacitidine five days/monthly schedule in three symptomatic low-risk (IPSS: 0-1) myelodysplastic patients
  20. C031 Maintenance treatment with 5-azacitidine for patients with high risk myelodysplastic syndrome (MDS) or acute myeloid leukemia following MDS (MDS-AML) in complete remission (CR) after induction chemotherapy
  21. C033 Quantification of phosphoinositidephospholipase C (PI-PLC) beta 1 gene promoter methylation predicts the responsiveness to azacitidine in myelodysplastic syndromes

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