Decinjet

INSTRUCTION for medical use of the medicinal product DECINJET (DECINJET)

Composition:

active substance: decitabine;

1 vial contains 50 mg of decitabine;

excipients: potassium dihydrogen phosphate, sodium hydroxide, hydrochloric acid concentrated.

Pharmaceutical form. Powder for concentrate for solution for infusion.

Main physicochemical characteristics: lyophilized mass or powder, white to almost white in color.

Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. Pyrimidine analogues. Decitabine. ATC code L01B C08.

Pharmacological Properties

Pharmacodynamics

Decitabine (5-aza-2’-deoxycytidine) is a deoxynucleoside analog of cytidine that, at low doses, selectively inhibits the activity of DNA methyltransferases, leading to hypomethylation of the gene promoter region and subsequent reactivation of tumor suppressor genes, induction of cellular differentiation or cellular senescence followed by programmed cell death.

Pharmacokinetics

Population pharmacokinetic parameters of decitabine were obtained from 3 clinical studies involving 45 patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), using a 5-day treatment schedule. In each study, pharmacokinetic parameters were assessed on day 5 of the first treatment cycle.

Distribution

The pharmacokinetics of decitabine following intravenous administration as a 1-hour infusion were described by a linear two-compartment model, characterized by rapid elimination of the active substance from the central compartment and relatively slow distribution from the peripheral compartment. Pharmacokinetic parameters for a typical patient (body weight 70 kg / body surface area 1.73 m²) are presented in Table 1.

Table 1

Summary data from population pharmacokinetic analysis in a typical patient receiving daily 1-hour infusions of decitabine at a dose of 20 mg/m² for 5 days every 4 weeks

The total dose per cycle was 100 mg/m².

Decitabine exhibits linear pharmacokinetics after intravenous infusion, with steady-state concentrations being achieved within 0.5 hours. Modeling demonstrated time-independent pharmacokinetic parameters (unchanged from cycle to cycle), and no accumulation was observed with these dosing regimens. Binding of decitabine to plasma proteins is negligible (< 1%). The Vdss (mean volume of distribution at steady state) of decitabine in oncology patients is high, indicating extensive distribution of the drug into peripheral tissues. No dependence on age, creatinine clearance, total bilirubin levels in blood, or disease stage was observed.

Biological transformation

Intracellularly, decitabine is activated through sequential phosphorylation by phosphokinases to its corresponding triphosphate, which is then incorporated into DNA by DNA polymerase. In vitro metabolism studies and human mass balance studies have demonstrated that the cytochrome P450 system is not involved in decitabine metabolism. The primary metabolic pathway is most likely deamination by cytidine deaminase in the liver, kidneys, intestinal epithelium, and blood. Human mass balance studies showed that unchanged decitabine in plasma accounts for approximately 2.4% of the total radioactivity in plasma. The major circulating metabolites are considered to lack pharmacological activity. The presence of these metabolites in urine, along with high total clearance and low urinary excretion of unchanged active substance (~4% of the dose), indicates that decitabine undergoes extensive in vivo metabolism. In vitro studies indicate that decitabine, at concentrations 20 times higher than the maximum therapeutic plasma concentration (Cmax), does not inhibit or induce CYP450 enzymes. Therefore, CYP-mediated metabolic interactions with other drugs are not expected, and it is unlikely that decitabine will interact with drugs metabolized via these pathways. Additionally, in vitro data show that decitabine is a weak substrate of P-glycoprotein.

Elimination

Mean plasma clearance after intravenous administration in oncology patients was > 200 L/h, with moderate inter-subject variability (coefficient of variation (CV) approximately 50%). Excretion of the active substance in unchanged form plays a minor role in the elimination of decitabine.

Results from mass balance studies with radiolabeled 14C-decitabine in cancer patients showed that 90% of the decitabine dose (4% in unchanged form) is excreted in urine.

Special patient populations

The impact of renal or hepatic impairment, sex, age, or race on the pharmacokinetics of decitabine has not been formally studied. Pharmacokinetic data in special patient populations were obtained from three clinical trials mentioned above and one Phase I trial in patients with MDS (n = 14; administered at a dose of 15 mg/m² as 3-hour infusions every 8 hours for 3 days).

Elderly patients

Population pharmacokinetic analysis showed that the pharmacokinetics of decitabine are independent of age (range studied: 40 to 87 years, mean age: 70 years).

Sex

Population pharmacokinetic analysis did not reveal any clinically significant differences in decitabine pharmacokinetics between women and men.

Racial origin

The majority of patients enrolled in the studies were Caucasian. However, according to population pharmacokinetic analysis, there was no apparent effect of race on decitabine concentrations.

Hepatic impairment

The pharmacokinetics of decitabine has not been formally studied in patients with hepatic impairment. Results from mass balance studies and in vitro studies described above indicate that CYP enzymes are unlikely to be involved in decitabine metabolism. Additionally, some data from population pharmacokinetic analysis suggest no significant dependence of pharmacokinetic parameters on total bilirubin levels, despite a wide range of total bilirubin values. Therefore, hepatic dysfunction is not expected to affect decitabine concentrations.

Renal impairment

The pharmacokinetics of decitabine has not been formally studied in patients with renal impairment. Population pharmacokinetic analysis based on limited data did not reveal a significant dependence of pharmacokinetic parameters on normalized creatinine clearance, a marker of kidney function. Therefore, renal dysfunction is not expected to affect decitabine concentrations.

Preclinical safety data

Formal carcinogenicity studies with decitabine have not been conducted. Published scientific literature indicates that decitabine has carcinogenic properties. In vitro and in vivo studies provide sufficient evidence that decitabine exerts genotoxic effects. According to scientific literature, decitabine has adverse effects on all aspects of the reproductive cycle, including fertility, embryonic and fetal development, and postnatal development. Repeated-dose toxicity studies in rats and rabbits showed that the primary manifestation of toxicity was myelosuppression, including effects on bone marrow, which was reversible after discontinuation of treatment. Gastrointestinal toxicity was also observed in male rats, and testicular atrophy did not resolve during the planned recovery periods. Administration of decitabine to neonatal/young rats showed a similar overall toxicity profile as in adult rats. Neurobehavioral development and reproductive capacity were not affected during treatment of neonatal/young rats at doses causing myelosuppression.

Clinical Characteristics

Indications.

Decitabine is indicated for the treatment of adult patients with newly diagnosed de novo or secondary acute myeloid leukemia (AML) who, according to WHO classification, are not suitable for standard induction chemotherapy.

Contraindications.

Hypersensitivity to decitabine or to any of the excipients of the medicinal product.

Breastfeeding period (see section "Use during pregnancy or breastfeeding").

Special precautions

Contact of the medicinal product with skin should be avoided, and gloves must be worn. Standard procedures for handling cytotoxic medicinal products should be followed.

Decitabine must not be administered by infusion through the same intravenous access line/system used for other medicinal products.

Disposal. The contents of the vial are intended for single use only. Any unused medicinal product or waste material must be disposed of in accordance with local requirements.

Interaction with other medicinal products and other forms of interactions

Specific interaction studies between decitabine and other medicinal products have not been conducted.

Potential interactions may exist with medicinal products that are also activated via sequential phosphorylation (involving intracellular kinases) and/or metabolized by enzymes involved in decitabine inactivation (e.g., cytidine deaminase). Such agents should be administered concomitantly with decitabine with caution.

Effect of other medicinal products on decitabine

CYP-mediated interactions between decitabine and other medicinal products are not expected, as decitabine metabolism is not mediated by the cytochrome CYP450 system, but occurs via oxidative deamination.

Effect of decitabine on other medicinal products

Since the plasma protein binding of decitabine in vitro is low (< 1%), it is unlikely that decitabine will displace other medicinal products from their plasma protein binding sites. In vitro studies indicate that decitabine is a weak inhibitor of P-gp-mediated transport; therefore, an effect on P-gp-mediated transport of other medicinal products is not expected (see section "Pharmacokinetics").

Special Warnings and Precautions for Use

Myelosuppression

Myelosuppression and its complications, including infections and hemorrhages observed in patients with MDS, may be exacerbated during treatment with decitabine. Therefore, there is an increased risk of developing severe infections (of any etiology: bacterial, fungal, or viral) with potentially fatal outcomes (see section "Adverse Reactions"). Patients should be monitored for signs and symptoms of infection, and appropriate treatment should be initiated immediately if necessary.

It is known that during clinical trials, most patients had pre-existing myelosuppression of grade 3–4 severity. Worsening of myelosuppression was observed in the majority of patients who had grade 2 myelosuppression at the start of treatment, more frequently than in patients with baseline grade 1 or 0 myelosuppression. Myelosuppression caused by decitabine is reversible. Complete blood counts and platelet counts should be monitored regularly based on clinical indications and before each treatment cycle. If myelosuppression or its complications occur, decitabine therapy may be interrupted or supportive treatment initiated as recommended (see sections "Dosage and Administration" and "Adverse Reactions").

Respiratory, Thoracic, and Mediastinal Disorders

Cases of interstitial lung disease (ILD), including pulmonary infiltrates, organizing pneumonia, and pulmonary fibrosis, without signs of infectious etiology, have been reported in patients receiving decitabine. A careful evaluation of patients presenting with acute onset or unexplained worsening of pulmonary symptoms should be performed to exclude ILD. If ILD is confirmed, appropriate treatment should be initiated (see section "Adverse Reactions").

Hepatic Function Impairment

The use of decitabine in patients with hepatic impairment has not been studied. Caution should be exercised when administering decitabine to patients with impaired liver function; such patients require close monitoring (see sections "Dosage and Administration", "Pharmacokinetics").

Renal Function Impairment

The use of decitabine in patients with severe renal impairment has not been studied. Caution should be exercised when administering decitabine to patients with severe renal impairment (creatinine clearance < 30 mL/min); these patients require close monitoring (see section "Dosage and Administration").

Cardiac Disorders

Patients with a history of severe congestive heart failure or clinically unstable cardiac disease were excluded from clinical trials; therefore, the safety and efficacy of decitabine in these patients have not been established. During the post-marketing period, cases of cardiomyopathy with decompensated heart function have been reported, sometimes reversible upon discontinuation of treatment, dose reduction, or corrective therapy. Patients, especially those with a history of cardiac disease, should be monitored for signs and symptoms of heart failure.

Differentiation Syndrome

Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported in patients receiving decitabine. Differentiation syndrome may have a fatal outcome (see section "Adverse Reactions"). If symptoms or signs suggestive of differentiation syndrome occur, immediate treatment with high-dose intravenous corticosteroids and hemodynamic monitoring should be considered. Temporary discontinuation of Decinget should be considered until symptoms resolve, and caution is advised if treatment is resumed.

Excipients

This medicinal product contains 0.5 mmol of potassium per vial. After reconstitution and dilution of the solution for intravenous infusion, this medicinal product contains less than 1 mmol (39 mg) of potassium per dose, i.e., it is practically potassium-free.

This medicinal product contains 0.29 mmol of sodium per vial. After reconstitution and dilution of the solution for intravenous infusion, this medicinal product contains between 0.6 mmol and 6 mmol of sodium per dose (depending on the infusion diluent). This should be taken into account when prescribing to patients on a sodium-restricted diet.

Use during Pregnancy or Breastfeeding

Women of Childbearing Potential/Contraception in Men and Women

Due to the genotoxic potential of decitabine (see section "Non-Clinical Safety Data"), women of childbearing potential are advised to use effective contraception and to avoid becoming pregnant during treatment with decitabine and for 6 months after completion of treatment.

Men must use effective contraception and avoid fathering a child during treatment with decitabine and for 3 months after the last dose of decitabine (see section "Non-Clinical Safety Data").

The concomitant use of decitabine and hormonal contraceptives has not been studied.

Pregnancy

There are insufficient data on the use of this medicinal product in pregnant women. Studies have shown teratogenic effects of decitabine in rats and mice (see section "Non-Clinical Safety Data"). The potential risk in humans is unknown. Based on animal data and the mechanism of action, decitabine should not be used in pregnant women or in women of childbearing potential who are not using effective contraception. A pregnancy test should be performed in all women of childbearing potential before starting treatment.

If a woman uses decitabine during pregnancy or becomes pregnant while receiving treatment, she should be informed of the potential risk to the fetus.

Breastfeeding

It is unknown whether decitabine or its metabolites are excreted in human breast milk. Decitabine is contraindicated in women who are breastfeeding; therefore, if treatment with this medicinal product is necessary, breastfeeding must be discontinued (see section "Contraindications").

Fertility

There are no data on the effect of decitabine on human fertility. Animal studies have demonstrated effects of decitabine on male fertility and its mutagenic potential. Given the risk of infertility associated with decitabine treatment, men should consider sperm cryopreservation, and women of childbearing potential should consider oocyte cryopreservation prior to starting decitabine therapy.

Ability to Affect Reaction Speed When Operating Vehicles or Machinery

Decitabine has a moderate influence on the ability to drive vehicles and operate machinery. Patients should be informed that adverse reactions such as anemia may occur during treatment. Therefore, patients should be advised to take precautions when driving a car or operating machinery.

Method of Administration and Dosage

Decitabine should be administered under the supervision of a physician experienced in the use of chemotherapeutic agents.

Dosage

In each treatment cycle, decitabine is recommended to be administered at a dose of 20 mg/m² body surface area as an intravenous infusion over more than 1 hour for 5 consecutive days (i.e., a total of 5 doses per cycle). The daily dose should not exceed 20 mg/m², and the total dose per cycle should not exceed 100 mg/m². If a scheduled dose is missed, treatment should be resumed as soon as possible. Cycles should be repeated every 4 weeks, depending on the patient's clinical response and observed toxicity. Patients should be treated for a minimum of 4 cycles; however, complete or partial remission may take longer than 4 cycles. Treatment may be continued as long as there is evidence of response, clinical benefit, or disease stability, i.e., in the absence of clear disease progression.

If after 4 treatment cycles hematological parameters (such as platelet count or absolute neutrophil count) have not recovered to pre-treatment levels or if the disease progresses (increased number of blast cells in peripheral blood or worsening of bone marrow blast cell parameters), the patient may be considered non-responsive to treatment. Alternative therapy should be considered.

Premedication for the prevention of nausea and vomiting is not recommended as a routine procedure, but may be used if necessary.

Treatment of Myelosuppression and Associated Complications

Myelosuppression and myelosuppression-related adverse effects (thrombocytopenia, anemia, neutropenia, and febrile neutropenia) are common in both treated and untreated patients with AML. Complications of myelosuppression include infections and bleeding.

Treatment may be delayed at the physician’s discretion if the patient develops any of the following complications:

• Febrile neutropenia (temperature ≥ 38.5 °C, absolute neutrophil count < 1000/µL);
• Active viral, bacterial, or fungal infection (e.g., requiring intravenous antimicrobial agents or systemic supportive therapy);
• Bleeding (gastrointestinal, urogenital, pulmonary with platelet count < 25,000/µL, or hemorrhagic lesions of the central nervous system).

Resumption of treatment should begin after improvement or stabilization with appropriate management (anti-infective therapy, blood transfusions, or growth factors). In clinical studies, approximately one-third of patients receiving decitabine required treatment delay. Dose reduction is not recommended.

Special Patient Populations

Patients with Hepatic Impairment. Studies in patients with hepatic impairment have not been conducted; therefore, the need for dose adjustment has not been established. If liver function deteriorates, patients should be closely monitored (see sections "Pharmacological Properties" and "Special Warnings and Precautions for Use").

Patients with Renal Impairment. Studies in patients with renal impairment have not been conducted; therefore, the need for dose adjustment has not been established (see sections "Pharmacological Properties" and "Special Warnings and Precautions for Use").

Method of Administration

Decitabine should be administered by intravenous infusion, not necessarily through a central venous catheter.

The medicinal product should be reconstituted under aseptic conditions with 10 mL of sterile water for injection. After reconstitution, the final concentration of the solution is 5 mg/mL at a pH of 6.7 to 7.3. Within 15 minutes of reconstitution, the concentrate (in 10 mL of sterile water for injection) should be diluted with cold (2–8 °C) infusion fluid (9 mg/mL (0.9%) sodium chloride solution or 5% glucose solution) to a final decitabine concentration of 0.15–1 mg/mL. The prepared diluted solution for intravenous infusion may be stored at 2–8 °C for up to 3 hours, followed by up to 1 hour at room temperature (20–25 °C) prior to administration.

From a microbiological standpoint, the product should be used within the recommended time frame. The user is responsible for ensuring adherence to the recommended storage conditions and times, as well as for performing reconstitution under aseptic conditions.

Decitabine should not be administered via the same intravenous access line or infusion system as other medicinal products.

Children

The safety and efficacy of the medicinal product in children (under 18 years of age) have not been established. Data are lacking.

Overdose

There is no direct experience of overdose in humans, and no specific antidote exists for overdose. However, clinical studies and scientific publications have reported enhanced myelosuppression, including prolonged neutropenia and thrombocytopenia, following doses exceeding the current therapeutic dose by 20 times. Toxicity is likely to manifest as an exacerbation of adverse reactions, primarily myelosuppression. Management of overdose should be supportive.

Adverse Reactions

The most common adverse reactions (≥ 35 %) reported during decitabine treatment were pyrexia, anemia, and thrombocytopenia.

The most common adverse reactions of grade 3–4 severity (≥ 20 %) were pneumonia, thrombocytopenia, neutropenia, febrile neutropenia, and anemia.

In clinical studies, adverse reactions with fatal outcome occurred in 30 % of patients receiving decitabine and in 25 % of patients in the control group, arising during treatment or within 30 days after the last dose of the drug.

In the decitabine group, a higher frequency of treatment discontinuation due to adverse reactions was observed in women (43 %) compared to men (32 %).

Adverse reactions observed in 293 patients with MDS who received decitabine are summarized in Table 2. The table includes data from clinical studies and post-marketing experience. Adverse reactions are listed by frequency. Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10 000, < 1/1000), very rare (< 1/10 000), and not known (frequency cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Table 2

Adverse reactions associated with decitabine

a Common terminology criteria for adverse reaction grading of the U.S. National Cancer Institute.

b Except for pneumonia, urinary tract infections, sepsis, septic shock, and sinusitis.

c The most frequently reported "other infections" during the DACO-016 study were oral herpes, oral candidiasis, pharyngitis, upper respiratory tract infections, pertussis, bronchitis, and nasopharyngitis.

d Including infectious enterocolitis.

e Including bleeding associated with thrombocytopenia, some with fatal outcome.

f Including preferred terms: hypersensitivity, drug hypersensitivity, anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, anaphylactoid shock.

g The incidence of hyperbilirubinemia of any grade and grade 3–4 observed in clinical trials of AML and myelodysplastic syndrome (MDS) was 11% and 2%, respectively.

* Including adverse reactions with fatal outcome.

NA — not applicable.

Description of selected adverse reactions

Hematologic adverse reactions

The most common hematologic adverse reactions associated with decitabine treatment reported were febrile neutropenia, thrombocytopenia, neutropenia, anemia, and leukopenia.

In patients receiving decitabine, severe adverse reactions related to bleeding, some with fatal outcome, such as CNS hemorrhage (2%) or gastrointestinal hemorrhage (2%), have been observed due to severe thrombocytopenia.

Management of hematologic adverse reactions should be performed by monitoring quantitative blood counts and, if necessary, early initiation of supportive therapy. Supportive measures include prophylactic use of antibiotics and/or administration of growth factors (particularly granulocyte colony-stimulating factor — G-CSF) in case of neutropenia, and blood transfusions for anemia or thrombocytopenia according to institutional guidelines (for situations when decitabine administration should be delayed, see section "Dosage and administration").

Infections and infestations

Severe adverse reactions related to infections with potentially fatal outcomes such as septic shock, sepsis, pneumonia, and other infections (viral, bacterial, and fungal) have been observed in patients receiving decitabine.

Gastrointestinal disorders

Cases of enterocolitis, including neutropenic colitis and cecitis, have been reported during decitabine treatment. Enterocolitis may lead to septic complications and can be fatal.

Respiratory, thoracic, and mediastinal disorders

Cases of interstitial lung disease (including pulmonary infiltrates, organizing pneumonia, and pulmonary fibrosis) without signs of infectious etiology have been reported in patients receiving decitabine.

Differentiation syndrome

Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported in patients receiving decitabine. Differentiation syndrome can be fatal, and symptoms and clinical manifestations include respiratory distress, pulmonary infiltrates, fever, rash, pulmonary edema, peripheral edema, rapid weight gain, pleural effusion, pericardial effusion, arterial hypotension, and renal dysfunction. Differentiation syndrome may occur with or without concomitant leukocytosis. Capillary leak syndrome and coagulopathy may also occur (see section "Special precautions").

Reporting suspected adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the drug. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store below 25 °C. Keep out of reach of children.

Incompatibilities. This medicinal product must not be mixed with other medicinal products except those specified in the section "Dosage and administration."

Packaging.

Powder for concentrate for solution for infusion in a vial, 1 vial in a cardboard box or 1 vial in a protective plastic overwrap within a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Yugia Pharma Specialities Limited.

Manufacturer's address and location of operations.

Survey Nos. 550, 551 & 552, Kothur Village, Shamirpet Mandal, Medchal – Malkajgiri, Medchal District, Telangana, 500101 – India.