Dacogen (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Johnson & Johnson, LLC (Russia)

Manufactured By

BSP Pharmaceuticals S.p.A. (Italy)

Packaging and Quality Control Release

JANSSEN PHARMACEUTICA, NV (Belgium)

Contact Information

JANSSEN, pharmaceutical division of Johnson & Johnson LLC

ATC Code

L01BC08 (Decitabine)

Active Substance

Decitabine (Rec.INN registered by WHO)

Dosage Form

Dacogen

Lyophilizate for preparation of concentrate for preparation of solution for infusion 50 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilizate for preparation of concentrate for preparation of solution for infusion in the form of a compact or powdery mass of white color.

Excipients: potassium dihydrogen phosphate – 68 mg, sodium hydroxide – 11.6 mg.

If necessary for pH adjustment, 1M sodium hydroxide solution q.s. or 1M hydrochloric acid solution q.s. are used.

129.6 mg – glass vials with a capacity of 20 ml (1) – blisters (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Antitumor drug, antimetabolite. Decitabine (5-aza-2′-deoxycytidine) is an analog of the nucleoside cytosine, which in low doses selectively inhibits the activity of DNA methyltransferase, leading to hypomethylation of promoter regions of suppressor genes, their reactivation, induction of cellular differentiation or to cell “senescence” with subsequent programmed cell death. In high concentrations (>10^-4 M), Decitabine has a pronounced cytotoxic effect.

Complete response (CR) or partial response (PR) was observed in patients from all risk groups according to the IPSS classification. However, in patients with intermediate-2 and high risk, the favorable effect was more pronounced (Table 1).

Table 1. Dependence of efficacy on risk degree

* – AML – acute myeloid leukemia

Pharmacokinetics

The pharmacokinetics of decitabine was studied in 14 cancer patients who received the drug at a dose of 15 mg/m² by 3-hour intravenous infusion at a constant rate every 8 hours for 3 consecutive days.

Distribution

The pharmacokinetics of decitabine corresponds to a multi-compartment distribution model. T_1/2 in the terminal elimination phase is approximately 0.78 hours. C_max in plasma is 77 ng/ml, AUC is 157 ng ^_× h/ml. No accumulation of the drug was observed with the specified administration regimen. When Dacogen was administered to 23 patients by 1-hour infusion daily for 5 consecutive days, similar pharmacokinetic data were obtained.

After IV administration to cancer patients, the V_d of decitabine at steady state is approximately 70 L/m², indicating penetration of the drug into peripheral tissues. Binding of the drug to plasma proteins is extremely low (<1%). Furthermore, Decitabine binds poorly to P-glycoprotein.

Metabolism

In cells, Decitabine undergoes sequential phosphorylation by phosphokinases to the corresponding triphosphate, which is incorporated into DNA by DNA polymerase. In vitro data indicate that cytochrome P450 is not involved in the metabolism of decitabine. The main pathway of decitabine metabolism is likely associated with deamination by cytidine deaminase in the liver, as well as in granulocytes, intestinal epithelium, and plasma. To date, metabolites of decitabine in vivo have not been unequivocally identified. However, the high total clearance and insignificant excretion of the unchanged substance in urine (<1% of the administered dose) suggest substantial metabolism of the substance in vivo.

Pharmacokinetic drug interaction is possible with other drugs undergoing sequential phosphorylation by intracellular phosphokinases in cells (e.g., cytarabine) and/or metabolism by enzymes involved in the inactivation of decitabine (e.g., cytidine deaminase).

Excretion

After IV administration to cancer patients, the clearance of the active substance from plasma averages approximately 130 L/h × m². The individual variation of this indicator is approximately 50%. Apparently, only a small part of the administered decitabine is excreted unchanged.

Pharmacokinetics in special clinical cases

The pharmacokinetics of decitabine in groups of patients with impaired renal or hepatic function has not been studied.

No studies have been conducted on the dependence of pharmacokinetics on patient sex, age, or race.

Indications

Myelodysplastic syndrome (MDS) of all types in previously treated and untreated patients, including:

• Primary and secondary;
• All types according to the French-American-British (FAB) classification and intermediate-1, intermediate-2 and high risk according to the International Prognostic Scoring System (IPSS).

ICD codes

Dosage Regimen

Dacogen should be administered under the supervision of a physician experienced in the treatment of 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 injections. Immediately after preparation, the drug 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 may be performed if necessary.

It is recommended to conduct at least 4 treatment cycles, however, longer treatment may be required to achieve a complete or partial response. After achieving a complete response, at least 2 subsequent treatment cycles should be conducted. Experience with more than 8 treatment cycles is limited. In each treatment cycle, Dacogen is used at a fixed dose of 15 mg/m² by continuous 3-hour IV infusion every 8 hours for 3 days (i.e., a total of 9 doses per cycle). This cycle is repeated every approximately 6 weeks, depending on the clinical response and toxicity. The total daily dose should not exceed 45 mg/m², and the total dose per cycle should not exceed 135 mg/m². If a dose is missed, treatment should be resumed as soon as possible.

If after 4 treatment cycles the hematological parameters (platelet count and absolute neutrophil count) have not returned to baseline levels, and also in case of disease progression (increase in the number of blast cells in the bone marrow or peripheral blood), the patient may be considered non-responsive to treatment, and the possibility of alternative therapy should be considered.

Dose adjustment

If recovery of hematological parameters (neutrophils to 1000/mL or more, platelets to 50,000/µL or more) requires more than 6 weeks, then the start of the next cycle is delayed for up to 2 weeks and the dose is reduced according to the following scheme:

• Recovery requires less than 8 weeks: the dose of Dacogen for the next cycle is reduced to 11 mg/m² every 8 hours for 3 days (33 mg/m²/day for 3 days).
• Recovery requires more than 8 weeks: an examination should be performed to detect disease progression. In the absence of disease progression (i.e., upon detection of complete response, partial response, hematological improvement, or disease stabilization), the dose of Dacogen for the next cycle is reduced to 11 mg/m² every 8 hours for 3 days (33 mg/m²/day for 3 days).

If myelosuppression or its complications develop, therapy with Dacogen may be discontinued or the dose reduced, as indicated above. Therapy may be resumed only after resolution of active and uncontrolled infection.

In the presence of any of the following biochemical changes, Dacogen administration is resumed only after they have normalized to baseline levels or the normal range: serum creatinine > 2 mg/dL; ALT and total bilirubin levels more than 2 times the upper limit of normal (ULN).

Preparation of the infusion solution and handling instructions

The contents of the vial are intended for single use only.

Contact of the solution with the skin should be avoided and protective goggles should be used. Standard procedures for handling antineoplastic drugs should be followed.

Dacogen is dissolved under aseptic conditions in 10 ml of sterile water for injections. After dissolution, each 1 ml of the resulting solution contains approximately 5.0 mg of decitabine at pH 6.8-7.

Immediately after preparation, the drug is diluted with infusion solutions (0.9% sodium chloride solution, 5% dextrose solution, or Ringer’s lactate solution) to a final concentration of 0.1-1 mg/ml.

If the infusion solution is not intended to be used within 15 minutes after preparation, then the lyophilisate is dissolved under aseptic conditions in 10 ml of sterile water for injections and then diluted with a cold infusion solution (from 2°C (35.6°F) to 8°C (46.4°F)) and stored at a temperature from 2°C (35.6°F) to 8°C (46.4°F) for no more than 7 hours.

Adverse Reactions

The most important and frequent side effects of decitabine are myelosuppression and its consequences.

Results of clinical studies

The safety of decitabine was studied in 170 patients with myelodysplastic syndrome. Adverse effects observed in >5% of patients receiving Dacogen in this study are presented in Table 2.

Table 2. Adverse effects observed in >5% of patients receiving Decitabine

* this group included 89 patients, but only 83 received treatment

** including fatal cases

*** reported in patients receiving Decitabine in clinical studies of MDS and hematological and non-hematological tumors, including fatal cases

**** reported in patients receiving Decitabine in clinical studies of MDS and hematological and non-hematological tumors.

Contraindications

• Pregnancy;
• Lactation period;
• Hypersensitivity to decitabine.

With caution and under control of the condition to detect symptoms of toxicity, the drug should be used in patients with impaired liver function (transaminase activity more than 2 times higher than normal, serum bilirubin content >25.7 µmol/L) or renal function (serum creatinine >177 µmol/L). The possibility of using the drug in such patients has not been established.

Use in Pregnancy and Lactation

Dacogen is contraindicated for use during pregnancy and lactation (breastfeeding).

Dacogen has a teratogenic effect. The effects of Dacogen in pregnant women have not been studied in specially designed and controlled studies.

During treatment with Dacogen, women of reproductive age and men should use adequate methods of contraception. Women should avoid pregnancy (including when the sexual partner is being treated with the drug). If it is necessary to prescribe the drug during pregnancy, or if pregnancy occurs during treatment, women should be informed about the harm of the drug to the fetus. Decitabine impairs fertility in men and has a mutagenic effect.

It is not known whether Decitabine or its metabolites are excreted in breast milk. Dacogen is contraindicated during breastfeeding, therefore, if it is necessary to use Dacogen during lactation, breastfeeding should be discontinued.

In experimental studies, it was shown that Decitabine has a teratogenic effect in rats and mice.

Use in Hepatic Impairment

Use with caution in patients with impaired liver function.

Use in Renal Impairment

Use with caution in patients with impaired renal function.

Pediatric Use

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

Geriatric Use

Elderly patients are prescribed the drug in the same dose as younger patients. Dose adjustment is carried out according to the above scheme.

Special Precautions

Dacogen may enhance the myelosuppression present in MDS patients and its consequences. 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, liver function and serum creatinine concentration should be assessed.

A complete blood cell count, including platelet count, should be performed regularly, before each treatment cycle, and as indicated.

Due to the possibility of infertility resulting from the use of Dacogen, men are advised to receive counseling on the possibility of sperm cryopreservation before starting treatment.

Use in pediatrics

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

Effect on ability to drive vehicles and operate machinery

No studies have been conducted on the effect of decitabine on the ability to drive vehicles and operate machinery. In the presence of weakness, fatigue, dizziness, anemia, the patient should exercise caution when driving vehicles and other activities requiring high concentration and speed of psychomotor reactions.

Overdose

No cases of direct overdose with decitabine have been reported.

Symptoms in early clinical studies and in the literature, increased myelosuppression, including prolonged neutropenia and thrombocytopenia, has been described when using doses exceeding those currently recommended. Toxicity is most likely to manifest as pronounced adverse reactions, mainly myelosuppression.

Treatment there is no specific antidote. Supportive care should be provided.

Drug Interactions

Myelosuppression caused by decitabine may be enhanced by other antineoplastic drugs.

Effect of concomitant therapy on Decitabine

Since the binding of decitabine to plasma proteins in vitro is extremely low (<1%), it is unlikely that it will be displaced by other drugs. Pharmacokinetic drug interaction is possible with other drugs undergoing sequential phosphorylation by intracellular phosphokinases in cells (e.g., cytarabine) and/or metabolism by enzymes involved in the inactivation of decitabine (e.g., cytidine deaminase).

In vitro data indicate that Decitabine is a weak substrate for P-glycoprotein (Pgp) and therefore most often does not interact with Pgp 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 plasma. Decitabine is a weak inhibitor of the major human cytochrome P450 isoenzymes: IC50 values for CYP1A2, 2C8, 2C9, 2C19, 2D6 and 3A4 exceeded 5700 ng/ml. These values are higher than the C_max of decitabine in the plasma of patients (<100 ng/ml) receiving the recommended doses of the drug. Similarly, Decitabine at concentrations up to 2280 ng/ml, i.e., significantly exceeding the C_max in plasma when using the recommended dose of the drug, does not stimulate the activity of the major human cytochrome P450 isoenzymes (CYP1A2, 2B6, 2C9, 3A4/5) in vitro.

Decitabine at concentrations up to 2280 ng/ml is a weak inhibitor of Pgp-mediated transport in vitro, and therefore is unlikely to affect the Pgp-mediated transport of other drugs.

Pharmaceutical incompatibility

In the absence of specific incompatibility studies, this drug should not be mixed with other drugs. Dacogen should not be administered through the same IV catheter with other drugs.

Storage Conditions

The drug should be stored out of the reach of children at a temperature from 15°C (59°F) to 30°C (86°F) in the original packaging.

Shelf Life

Shelf life – 3 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.