Composition, form of production and packaging
Lyophilizate for the preparation of concentrate for the preparation of a solution for infusions in the form of a compact or pulverulent mass of white color.
decitabine 50 mg
Excipients: potassium dihydrogen phosphate - 68 mg, sodium hydroxide - 11.6 mg; sodium hydroxide solution 1M or hydrochloric acid solution 1M-qs (used when pH adjustment of the lyophilizate is necessary).
129.6 mg - glass bottles with a capacity of 20 ml (1) - blisters (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2012.
Antitumor drug, antimetabolite. Decitabine (5-aza-2'-deoxycytidine) is an analogue of the cytosine nucleoside, which selectively inhibits the activity of DNA methyltransferase in small doses, which leads to hypomethylation of promoters of suppressor genes, their reactivation, induction of cell differentiation or "aging" of cells followed by their programmed death. In high concentrations (> 10 -4 M) decitabine has a pronounced cytotoxic effect.
Complete (PE) or partial (CHE) effect was observed in patients from all risk groups by IPSS classification. However, in patients with intermediate-2 and high-risk, the beneficial effect was more pronounced (Table 1).
Table 1. Dependence of effectiveness on the degree of risk
Degree of risk for IPSS Dakogen Maintenance therapy
The total frequency of the effect (PE + FE) Median time to transition to AML * or death (days) Total frequency of effect (PE + PE) Median time to transition to AML or death (days)
all patients 15/89 (17%) 340 0/81 219
intermediate-2 and high 11/61 (18%) 335 0/57 189
Intermediate-2 8/38 (21%) 371 0/36 263
High 3/23 (13%) 260 0/21 79
* - AML - acute myelogenous leukemia
The pharmacokinetics of decitabine was studied in 14 oncological patients who received the drug at a dose of 15 mg / m 2 by a 3-hour IV infusion at a constant rate every 8 hours for 3 consecutive days.
The pharmacokinetics of decitabine corresponds to the multicameral model of the distribution of T 1/2 in the terminal elimination phase of about 0.78 hours. The maxin the plasma of the cut is 77 ng / ml, the AUC is 157 ng ? h / ml. Cumulation of the drug with this scheme of application was not observed. When Dacogen was administered to 23 patients with a 1-hour infusion, similar data on pharmacokinetics were obtained daily for 5 consecutive days.
After intravenous administration of oncological patients with Vd, decitabine in the equilibrium state is approximately 70 l / m 2 , which indicates the penetration of the drug into peripheral tissues. Binding of the drug with blood plasma proteins is extremely low (<1%). In addition, decitabine binds poorly to P-glycoprotein.
In cells, decitabine is sequentially phosphorylated with phosphokinases to the corresponding triphosphate, which is inserted into DNA by a DNA polymerase. In vitro data indicate that P450 is not involved in the metabolism of decitabine. The main way of metabolism of decitabine is most likely associated with deamination of cytidine deaminase in the liver, as well as in granulocytes, intestinal epithelium and in blood plasma. Until now, the metabolites of decitabine in vivo have not been uniquely identified. However, a high overall clearance and a slight excretion of unchanged substance with urine (<1% of the administered dose) suggest a significant metabolism of the substance in vivo.
Possible pharmacokinetic drug interaction with other drugs exposed in cells to sequential phosphorylation by intracellular phosphokinases (for example, with cytarabine) and / or metabolism by enzymes involved in the inactivation of decitabine (eg, with cytidine deaminase).
After intravenous administration of cancer patients, the clearance of the active substance from the plasma is approximately 130 l / h on the average? m 2 . The individual spread of this indicator is approximately 50%. In an unchanged form, apparently, only a small part of the introduced decitabine is excreted.
Pharmacokinetics in special clinical cases
The pharmacokinetics of decitabine in groups of patients with impaired renal and hepatic function has not been studied.
Studies of the dependence of pharmacokinetics on the sex, age and race of the patient were not conducted.
Myelodysplastic syndrome (MDS) of all types in previously treated and untreated patients, including:
- primary and secondary;
- all types according to the French-American-British classification of FAB and intermediate-1, intermediate-2 and high risk according to the international IPSS risk assessment scale.
Dakogen should be administered under the supervision of a doctor who has experience in treating patients with myelodysplastic syndrome.
Dacogen is administered by intravenous infusion. A central venous catheter is not required.
Dacogen is dissolved in 10 ml of sterile water for injection. Immediately after preparation, the preparation is diluted with infusion solutions (0.9% sodium chloride solution, 5% dextrose solution or Ringer's lactate solution).
Premedication for the prevention of nausea and vomiting is usually not recommended, although it can be carried out if necessary.
It is recommended that a minimum of 4 treatment cycles be performed, but longer treatment may be required to achieve full or partial effect. After achieving the full effect, a minimum of 2 subsequent treatment cycles should be performed. The experience of more than 8 treatment cycles is limited. In each treatment cycle, the Dacogen is administered at a fixed dose of 15 mg / m 2 by a continuous 3-hour IV infusion every 8 hours for 3 days (ie, only 9 doses per cycle). This cycle is repeated every 6 weeks, depending on the clinical effect and toxicity. The total daily dose should not exceed 45 mg / m 2 , and the total dose per cycle - 135 mg / m 2 . If the next dose is missed, treatment should be resumed as soon as possible.
If after 4 cycles of treatment the hematologic indices (platelet count and absolute neutrophil count) do not return to the baseline level, as well as in the case of progression of the disease (increase in the number of blast cells in the bone marrow or peripheral blood), the patient may be found to have no response to treatment, and Alternative therapy should be considered.
Correction of dose
It takes more than 6 weeks to restore hematological parameters (neutrophils to 1000 / ml or more, platelets to 50000 / ОјL and more), and the beginning of the next cycle is postponed for up to 2 weeks and the dose is reduced according to the following scheme:
- It takes less than 8 weeks for recovery: the dose of Dacogen for the next cycle is reduced to 11 mg / m 2 every 8 hours for 3 days (33 mg / m 2 / day for 3 days).
- It takes more than 8 weeks to recover: a check should be performed to detect the progression of the disease. In the absence of disease progression (ie, when the full effect, partial effect, hematologic improvement or stabilization of the disease is identified), the dose of Dacogen for the next cycle is reduced to 11 mg / m 2 every 8 hours for 3 days (33 mg / m 2 / day within 3 days).
With the development of myelosuppression or its complications, Dakogen therapy may be discontinued or the dose reduced as described above. Therapy can be resumed only after the removal of active and uncontrolled infection.
If any of the following biochemical changes occur, Dacogen application is resumed only after normalization to baseline or normal range: serum creatinine> 2 mg / dl;the level of ALT and total bilirubin is more than 2 times higher than ULN.
Preparation of the infusion solution and the rules for handling the drug
The contents of the vial are for single use only.
Avoid contact with the skin and wear protective goggles. Standard procedures for handling antitumor drugs should be followed.
Dacogen under aseptic conditions is dissolved in 10 ml of sterile water for injection. After dissolution, each 1 ml of the resulting solution contains about 5.0 mg of decitabine at pH 6.8-7.
Immediately after preparation, the preparation is diluted with infusion solutions (0.9% sodium chloride solution, 5% dextrose solution or Ringer's solution with lactate) to a final concentration of 0.1-1 mg / ml.
If the infusion solution is not expected to be used within 15 minutes after preparation, the lyophilizate is aseptically dissolved in 10 ml of sterile water for injection and then diluted with a cold infusion solution (2 В° to 8 В° C) and stored at a temperature of 2 В° to 8 В° РЎ no more than 7 hours.
The most important and frequent side effects of decitabine are myelosuppression and its consequences.
Results of clinical trials
The safety of decitabine was studied in 170 patients with myelodysplastic syndrome. Side effects observed in> 5% of patients receiving Dacogen in this study are presented in Table 2.
Table 2. Side effects observed in> 5% of patients receiving decitabine
MEDDRA system / organ Decitabine 15 mg / m 2 (n = 83) * maintenance therapy (n = 81)
Infections and colonization
pneumonia ** 22 14
urinary tract infection 7 2
sinusitis 5 2
septic shock ****
Blood and lymphatic system
neutropenia ** 90 72
thrombocytopenia ** 89 79
anemia 82 74
febrile neutropenia 29 6
leukopenia 28 14
headache 28 14
From the respiratory system
nosebleeds 14 19
From the digestive system
nausea 42 16
diarrhea 34 16
vomiting 25 9
fever 53 28
* 89 patients were included in this group, but only 83 received treatment
** Including lethal cases
*** registered in patients receiving decitabine in clinical studies of MDS and hematological and non-hematological tumors, including lethal cases
**** registered in patients who received decitabine in clinical studies of MDS and hematological and non-hematological tumors.
- lactation period;
- hypersensitivity to decitabine.
With caution and under the control of the condition, the drug should be used in patients with impaired hepatic function to detect symptoms of toxicity (transaminase activity more than 2 times higher than normal, serum bilirubin> 25.7 Ојmol / L) or kidney (serum creatinine> 177 Ојmol / l). The possibility of using the drug in these patients is not established.
PREGNANCY AND LACTATION
Dacogen is contraindicated in pregnancy and lactation (breastfeeding).
The dacogen has a teratogenic effect. Effects of Dacogen in pregnant women in specially planned and controlled studies have not been studied.
During Dakogen treatment, women of reproductive age and men should use adequate contraceptive methods. Women should avoid pregnancy (including when treated with a drug of the sexual partner). If it is necessary to prescribe the drug during pregnancy, and if the pregnancy has occurred during the treatment period, women should be informed about the harm of the drug for the fetus. Decitabine disrupts fertility in men and has a mutagenic effect.
It is not known whether decitabine or its metabolites are excreted in breast milk. Dacogen during breastfeeding is contraindicated, so if you need to use Dacogen during lactation, breastfeeding should be discontinued.
In experimental studies, it has been shown that decitabine has a teratogenic effect in rats and mice.
APPLICATION FOR FUNCTIONS OF THE LIVER
Use with caution in patients with impaired renal function.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Use with caution in patients with impaired hepatic function.
APPLICATION FOR CHILDREN
Safety and efficacy of the drug in children are not established.
APPLICATION IN ELDERLY PATIENTS
Older patients are prescribed the drug at the same dose as the younger patient. Correction of the dose is carried out according to the above scheme.
Dacogen can strengthen the myelosuppression present in patients with MDS and its consequences. The myelosuppression caused by Dacogen is reversible. In the presence of myelosuppression or its complications, the use of Dacogen may be suspended or the dose may be reduced.
Before starting treatment, the liver function and the creatinine concentration in the blood are evaluated.
It should be done regularly, before each treatment cycle, and according to the indications, a complete analysis of the cellular composition of the blood, including the number of platelets.
Because of the possibility of developing infertility as a result of Dacogen, men are advised to get advice on the possibility of preserving sperm before starting treatment.
Use in Pediatrics
Safety and efficacy of the drug in children are not established.
Impact on the ability to drive vehicles and manage mechanisms
Studies of the influence of decitabine on the ability to manage motor vehicles and mechanisms have not been carried out. In the presence of weakness, fatigue, dizziness, anemia, the patient should exercise caution when driving vehicles and other activities that require a high concentration of attention and speed of psychomotor reactions.
No cases of direct overdose of decitabine have been reported.
Symptoms: early clinical studies and literature have described the enhancement of myelosuppression, including prolonged neutropenia and thrombocytopenia when used at doses that are higher than currently recommended. Toxicity, most likely, will be manifested by pronounced adverse reactions, mainly myelosuppression.
Treatment: there is no specific antidote. Conducting maintenance therapy.
Decitabine-induced myelosuppression may be exacerbated by other antitumor drugs.
The effect of concomitant therapy on decitabine
Since the binding of decitabine to blood plasma proteins in vitro is extremely low (<1%), it is unlikely that it will be replaced by other drugs. Possible pharmacokinetic drug interaction with other drugs exposed in cells to sequential phosphorylation by intracellular phosphokinases (for example, with cytarabine) and / or metabolism by enzymes involved in the inactivation of decitabine (eg, with cytidine deaminase).
In vitro data suggest that decitabine is a weak substrate for P-glycoprotein (P-gp) and therefore most often does not interact with P-gp inhibitors.
Effect of decitabine on concomitant therapy
Since the binding of decitabine to plasma proteins in vitro is extremely low (<1%), it is unlikely that it will displace protein-bound drugs from the plasma. Decitabine is a weak inhibitor of the basic isoenzymes of the human cytochrome P450 system: the IC50 values вЂ‹вЂ‹for CYP1A2, 2C8, 2C9, 2C19, 2D6 and 3A4 were more than 5700 ng / ml. These values вЂ‹вЂ‹are higher than C max of decitabine in the blood plasma of patients (<100 ng / ml) who received the recommended dose of the drug.Similarly, decitabine at concentrations up to 2280 ng / ml, i.e. significantly exceeding C max in blood plasma when using the recommended dose of the drug does not stimulate the activity of the main isoenzymes of the human cytochrome P450 system (CYP1A2, 2B6, 2C9, 3A4 / 5) in vitro.
Decitabine at concentrations up to 2280 ng / ml is a weak inhibitor of P-gp mediated transport in vitro, and therefore can hardly influence mediated P-gp transport of other drugs.
In the absence of special studies of incompatibility, this drug should not be mixed with other drugs. Dacogen can not be administered through one IV in the catheter with other drugs.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of 15 В° to 30 В° C in the original packaging. Shelf life - 3 years.