DAKOGEN

Active material: Decitabine
When ATH: L01B
CCF: Anticancer drug. Antimetaʙolit
ICD-10 codes (testimony): D06
When CSF: 22.02.03
Manufacturer: JOHNSON & JOHNSON LTD (Russia)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Valium for solution for infusion as a compact or powdery white mass.

Excipients: Potassium dihydrogen phosphate, Sodium hydroxide.

Bottles of colorless glass volume 20 ml (1) – packs cardboard.

Pharmacological action

Anticancer drug, antimetaʙolit. Decitabine – natural nucleoside analogue 2′-deoxycytidine, is specific and potent inhibitor of the enzyme DNA methyltransferase. Methylation and demethylation related to control of gene expression. It has been shown, that lot promotornogo methylation of a gene or close to the plot it inhibits transcription. DNA demethylation restores expression of the gene. Gene activation inhibitors of DNA-methylation, in particular decitabinom, It can be expressed in the differentiation induction, the desired effect in the treatment of mielodisplastičeskih syndromes and other malignancies of the blood, activation of tumor suppression genes and other genes, the effect of which may be extended to many types of tumors.

Fixed DNA enzyme complexes – methyltransferase and 5-AZA-deoksicitidina can cause apoptosis, when the cell exits the cycle of DNA synthesis and cell cycle induced isolation and mitotic block.

Alternative mechanisms, such as overcoming drug resistance, relief immune responses, Induction of apoptosis, can also be the result of decitabina effects.

Decitabine acts in the S-phase of the cell cycle. Cells alone should reach S-phase, to show maximum effect of decitabine.

Pharmacokinetics

Absorption

In patients with later stages of solid tumors with decitabina infusion dose 100 mg / m² during 1 h drug concentration in plasma during infusion increased, and then decreased dwuhfazno; middle C_max in plasma is 0.459± 0.100 mg/ml, average AUC – 408± 88 NG x h/ml. In patients with advanced solid tumors with 72-hour infusions in a dose of decitabina 20, 25 or 30 mg / m²/SUT AUC is 543 ± 158, 743± 98 and 743 ± 124 NG x h/ml respectively.

Distribution

V_d decitabina in equilibrium is approximately 4.59 ± 1.42 l/kg..

Linking blood plasma proteins negligibly little (<1%).

Metabolism

The main route of metabolism decitabina is Cytidine deaminirovanie-deaminazoj, which is present mainly in the liver, as well as in granoulozitah, the intestinal epithelium and in plasma. Metabolic studies in vitro suggest, that decitabin is not a substrate of cytochrome P450 isoenzymes human liver.

Deduction

Less 1% decitabina dose presented with urine in an unmodified form. This suggests, that the drug is excreted primarily as metabolites. In patients with later stages of solid tumors with decitabina infusion dose 100 mg / m² during 1 h total clearance of the drug is 126 ± 21 ml/min/kg, that exceeds hepatic blood flow. This testifies to the contribution of vnepečenočnogo metabolism in deducing from an organism of decitabina. The Mean T_1/2 in the Terminal phase of excretion is approximately 35 ± 5 min.

Pharmacokinetics in special clinical situations

Pharmacokinetics of decitabina in patients with the human kidney and liver is not known. Research pharmacokinetics of the dependencies from the floor, the patient's age and race was not held.

Testimony

-all types of myelodysplastic syndrome.

Dosage regimen

The first cycle of treatment

The recommended dose is 15 mg / m² through continuous 3-hour in/infusion in every 8 h for 3 days. Should be premedikatia anti-nausea drugs in standard doses.

Subsequent cycles of treatment

The cycles repeat every 6 weeks. It is recommended that a minimum of 4 treatment cycle, but to achieve partial or full effect may require longer treatment. Treatment can be continued so long, how therapeutic effect persists.

Dose adjustment or postponement of the next introduction is carried out from the General clinical blood analysis.

If the recovery of hematological parameters (the number of neutrophils is ≥ 1000/µl, the number of platelets ≥ 50000/µl) After the previous cycle introduction Dakogena requires more 6 Sun., the beginning of the next cycle of delay and temporarily reduce the dose according to the following algorithm:

is the restore requires more 6, but less 8 Sun.: Introduction Dakogena lay for up to 2 Sun., then resume treatment at a dose of 11 mg / m² every 8 no (33 mg / m²/d, kursovaya dose – 99 mg / m²);

is the restore requires more 8, but less 10 Sun.: should conduct a survey to determine the progression of the disease. In the absence of disease progression introduction Dakogena lay still on 2 Sun., then resume treatment at a dose of 11 mg / m² every 8 no (33 mg / m²/d, kursovaya dose – 99 mg / m²). In subsequent cycles, you can save the dose or increase the, depending on the clinical indications.

If you have any of the following forms of toxicity application Dakogena resume only after its elimination: 1) content of serum creatinine >177 mmol / l; 2) level of ALT and total bilirubin ≥ 2 times the VGN; 3) acute infection, exacerbation of chronic infection, uncontrolled infection process.

Elderly patients drug administered in the same dose, that and more young patients. Correction doses are on the above diagram.

Preparation infuzing solution and rules for the treatment of drug

Dakogen – cytotoxic drug and, as with any potentially toxic drug, caution should be exercised in the preparation infuzing solution and treatment.

In aseptic conditions Dakogen dissolved in 10 ml of sterile water for injection; 1 ml of the resulting solution contains approximately 5.0 mg decitabina at pH 6.8-7.0. Immediately after cooking the drug dilute infusion solutions (0.9% sodium chloride, 5% solution dekstrozy or solution periods with lactatom) prior to the final concentration 0.1-1.0 mg/ml and impose no later, than 15 minutes after this.

If the solution for the infusions do not intend to use during the 15 minutes after cooking, the valium in aseptic conditions dissolved in 10 ml of sterile water for injection and then diluted with cold infusion solution (0.9% sodium chloride, 5% solution dekstrozy or solution periods with lactatom) prior to the final concentration 0.1-1.0 mg/ml decitabina and stored at a temperature between 2° and 8° c for no more 7 hours before the introduction.

Should comply with the rules for the treatment and disposal of anticancer drugs.

Side effect

Currently analyzed data about side effects in clinical trials Dakogena 2 phase, as well as comparative data on standard therapy based on the results of clinical studies 3 phase. Since the conditions for clinical trials vary widely, the frequency of side effects, registered in the study of one drug, cannot be directly compared with results from studies of other drugs, and these values may not reflect real results directly use of drugs in clinical practice. However, data on side effects in clinical studies provide the basis for forecasting the picture side effects, that can be seen in clinical practice in connection with the use of the drug, and allow you to estimate the frequency of their occurrence.

Table. The most common side effects, observed at ≥ 10% patients, receiving Dakogen in 2 and 3 phases of clinical trials

Contraindications

- Pregnancy;

- Lactation;

-hypersensitivity to decitabinu.

FROM caution use in patients with human liver and kidneys.

Pregnancy and lactation

Category D. Dakogen is contraindicated for use in pregnancy and lactation (breast-feeding).

Dakogen has teratogenic effects. Effects of Dakogena in pregnant women in specially designed and controlled studies have examined the.

Women of reproductive age during treatment Dakogenom, and partners of men, receiving Dakogen, pregnancy should be avoided. If necessary, the appointment of drugs in pregnancy, and, If the pregnancy occurred during treatment, women should be informed about the dangers of the drug to the fetus.

During treatment Dakogenom and over 2 months after the end of men, and women are encouraged to be sure to use adequate contraception. In preclinical studies decitabin caused significant weight reduction and violation of testicular histology, significant reduction of spermatozoa, decreased frequency and frequency increased pregnancy loss fertilized egg before its implantation.

Unknown, whether the decitabin is allocated or its metabolites in breast milk in humans. Because many drugs are highlighted with breast milk and because of the risk of serious side effects in infants decitabina, If necessary, use during lactation should decide the issue of termination of breastfeeding.

Cautions

Data on application of Dakogena in patients with impaired liver and kidneys are very small. Decitabin not displayed with urine in any significant number. The drug undergoes metabolism in the liver to Active, but without the participation of the izofermentov zitohroma r450. There are no data on the efficacy and safety of Dakogena content in patients with serum creatinine >177 mmol / l, activity transaminaz more than 2 times higher bilirubin levels and the VGN in the serum >25.7 mmol / l.

Application of Dakogena accompanied by the development of neutropenia and thrombocytopenia. After the first cycle of treatment in a recommended dose for the subsequent cycles of the dose should be adjusted or loop defer depending on the minimum number of committed blood cells (nadir) and effects on haematological parameters.

Physicians should consider the need for an early application of growth factors and/or antimicrobial, antifungal or antiviral drugs for the treatment of the alleged infection in patients, with its signs mielosupression period. Mielosuprescia and reinforcement of neutropenia in the first and second cycles of treatment by themselves do not necessarily indicate the progression of mielodisplastičeskogo syndrome.

Should undertake general clinical blood analysis with frequency, necessary to monitor therapeutic and toxic effects, but possibly less, eg, before each treatment cycle. Before treatment should evaluate liver function and content of serum creatinine.

Decitabina carcinogenicity studies were not conducted.

Use in Pediatrics

The safety and efficacy of the children have not been established.

Overdose

Symptoms: the introduction of the drug at high doses (eg, 300 mg / m²/ day for 3 days, cycles on 6 weeks) accompanied by enhanced mielosupressiei, including deferred neutropenia and thrombocytopenia. Patients, treated with high doses of Dakogen, There was also a weak or moderately expressed reversible increased creatinine in the serum.

Treatment: There is no specific antidote. Simptomaticescuu and supportive therapy.

Drug Interactions

Specific drug interaction studies with other drugs Dakogena has not been.

Decitabin metabolised Cytidine-deaminazoj, However, the ability to interact with other substrates for this enzyme is small, tk. K_m (Michaelis constant) for decitabina relatively high (250 M). Since tying with blood plasma proteins negligibly little (<1%), You cannot expect interaction, caused by the displacement of drugs from bonding with blood plasma proteins.

It can be expected, that called decitabinom mielosuprescia will intensify under the influence of other anticancer drugs. Known, that monotherapy with tamoxifen is accompanied by thrombocytopenia (content of platelets <100 000/ l) and thromboembolic complications, This effect is reinforced by the simultaneous application of other anticancer drugs. One patient, receiving decitabin in combination with with tamoxifen, There was severe thrombocytopenia (40 000/l) with symptoms of bleeding and subdural hematoma. You should compare the benefits and risks of combined use of decitabina and tamoxifen. You must monitor patients, receiving combination therapy, to identify bleeding and/or symptoms of thromboembolism.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be kept out of the reach of children at a temperature between 15° to 30° c in its original packaging. Shelf life - 3 year.