Decitex

Drug product: Each vial contains Decitabine 50 mg.
Excipients/Inactive Ingredients: Dimethyl sulfoxide.
Diluent: Monobasic potassium phosphate, sodium hydroxide, water for injection.

Pharmacotherapeutic group: Antineoplastic and Immunomodulating Agent, Pyrimidine Analogues. ATC Code: L01BC08.
Pharmacology: Pharmacodynamics: Mechanism of action: Decitabine (5-aza-2'-deoxycytidine) is a cytosine nucleoside analogue that selectively inhibits DNA methyltransferases at low doses, resulting in gene promoter hypomethylation that can result in reactivation of tumor suppressor genes, induction of cellular differentiation or cellular senescence followed by programmed cell death.
Pharmacokinetics: The population pharmacokinetic (PK) parameters of decitabine were reported from 3 clinical studies [DACO-017 (n=11), DACO-020 (n=11) and DACO-016 (n=23)] utilizing the 5-Day regimen (20 mg/m² x 1-hour x 5 days every 4 weeks) and 1 study, DACO-018 (n=12), utilizing the 3-Day regimen (15 mg/m² x 3-hours every 8 hours x 3 days every 6 weeks) in MDS or AML patients. In the 5-Day regimen, decitabine PK was evaluated on the fifth day of the first treatment cycle. Total dose per cycle was 100 mg/m². In the 3-Day regimen, decitabine PK was evaluated after the first dose of each dosing day of the first treatment cycle. Total dose per cycle was 135 mg/m².
Distribution: The pharmacokinetics of decitabine following intravenous administration as a 1-hour (5-Day regimen) or 3-hour (3-Day regimen) infusion was described by a linear two-compartment model, characterized by rapid elimination of the drug from the central compartment and by relatively slow distribution from the peripheral compartment. For a typical patient (weight 70 kg/body surface area 1.73 m²) the decitabine PK parameters are listed in Table 1 as follows. (See Table 1.)

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Decitabine exhibits linear PK and following the intravenous infusion, steady-state concentrations are reached within 0.5 hour. Based on reported model simulation, PK parameters were independent of time (i.e., did not change from cycle to cycle) and no accumulation was reported with this dosing regimen. Plasma protein binding of decitabine is negligible (<1%). Decitabine Vd_ss in cancer patients is large indicating distribution of the drug into peripheral tissues. There was no evidence of dependencies on age, creatinine clearance, total bilirubin, or disease.
Metabolism: Intracellularly, decitabine is activated through sequential phosphorylation via phosphokinase activities to the corresponding triphosphate, which is then incorporated by the DNA polymerase. In light of in vitro metabolism reported data, the human mass balance study results indicated that the cytochrome P450 system is not involved in the metabolism of decitabine. The primary route of metabolism is likely through deamination by cytidine deaminase in the liver, kidney, intestinal epithelium, and blood. Reported results from the human mass balance study showed that unchanged decitabine in plasma accounted for approximately 2.4% of total radioactivity in plasma. The major circulating metabolites are not believed to be pharmacologically active. The presence of these metabolites in urine together with the high total body clearance and low urinary excretion of unchanged drug in the urine (~4% of the dose) indicate that decitabine is appreciably metabolized in vivo. In addition, in vitro reported data show that decitabine is a poor P-gp substrate.
Elimination: Reported mean plasma clearance following intravenous administration in cancer subjects was >200 L/h with moderate inter-subject variability (Coefficient of Variation [CV] is approximately 50%). Excretion of unchanged drug appears to play only a minor role in the elimination of decitabine.
Reported results from a mass balance study with radioactive ¹⁴C-decitabine in cancer patients showed that 90% of the administered dose of decitabine (4% unchanged drug) is excreted in the urine.
Special populations: The effects of renal or hepatic impairment, gender, age or race on the pharmacokinetics of decitabine have not been formally reported. Information on special populations was derived from reported pharmacokinetic data from the 4 studies noted previously.
Elderly: Reported population pharmacokinetic analysis showed that decitabine PK are not dependent on age (range studied 40 to 87 years; median 70 years).
Hepatic impairment: The PK of decitabine have not been formally reported in patients with hepatic impairment. Reported results from a human mass balance study and in vitro experiments mentioned previously indicated that the CYP enzymes are unlikely to be involved in the metabolism of decitabine. In addition, the limited reported data from the population PK analysis indicated no significant PK parameter dependencies on total bilirubin concentration despite a wide range of total bilirubin levels. Thus, decitabine exposure is not likely to be affected in patients with impaired hepatic function.
Renal impairment: The PK of decitabine have not been formally reported in patients with renal insufficiency. The population PK analysis on the limited reported decitabine data indicated no significant PK parameter dependencies on normalized creatinine clearance, an indicator of renal function. Thus, decitabine exposure is not likely to be affected in patients with impaired renal function.
Gender: Reported population PK analysis of decitabine did not show any clinically relevant difference between men and women.
Race: Most of the patients reported were Caucasian. However, the reported population PK analysis of decitabine indicated that race had no apparent effect on the exposure to decitabine.

Decitabine is indicated for: the treatment of adult patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British (FAB) subtypes and Intermediate-1, Intermediate-2, and High-Risk International Prognostic Scoring System (IPSS) groups; the treatment of adult patients with newly diagnosed de novo or secondary acute myeloid leukemia (AML), according to the World Health Organization (WHO) classification who are not candidates for standard induction chemotherapy.
The efficacy of decitabine has not been fully reported in patients under the age of 65 years.

MODE OF ADMINISTRATION: Decitabine must be initiated under the supervision of physicians experienced in the use of chemotherapeutic agents. Complete blood and platelet count should be performed regularly, as clinically indicated and prior to each treatment cycle.
Decitabine is administered by intravenous infusion. A central venous catheter is not required. For instructions on reconstitution and dilution of the medicinal product before administration, see Instructions for Use and Handling and Disposal under Cautions for Usage.
RECOMMENDED DOSE: There are 2 regimens recommended for decitabine administration. A 5-Day dosing regimen in the treatment of AML, and a 3-Day or 5-Day dosing regimen in the treatment of MDS. With either regimen, it is recommended that patients be treated for a minimum of 4 cycles; however, a response may take longer than 4 cycles to be obtained. Treatment may be continued as long as the patient shows response, continues to benefit or exhibits stable disease, i.e., in the absence of overt progression.
If after 4 cycles, the patient's hematological values (e.g., platelet count or absolute neutrophil count), have not returned to pre-treatment levels or if disease progression occurs (peripheral blast counts are increasing or bone marrow blast counts are worsening), the patient may be considered to be a non-responder and alternative therapeutic options to decitabine should be considered.
Pre-medication for the prevention of nausea and vomiting is not routinely recommended but may be administered if required.
Treatment Regimen in Acute Myeloid Leukemia: In a treatment cycle, decitabine is administered at a dose of 20 mg/m² body surface area by intravenous infusion over 1 hour repeated daily for 5 consecutive days (i.e., a total of 5 doses per treatment cycle). The total daily dose must not exceed 20 mg/m² and the total dose per treatment cycle must not exceed 100 mg/m². The cycle should be repeated every 4 weeks depending on the patient's clinical response and observed toxicity. If a dose is missed, treatment should be resumed as soon as possible. It is possible to use this regimen in an outpatient setting.
Treatment Regimen in Myelodysplastic Syndromes: 3-Day Dosing Treatment Regimen in MDS: In a treatment cycle, decitabine is administered for 3 consecutive days at a fixed dose of 15 mg/m² body surface area over a 3-hour period every 8 hours (i.e., a total of 9 doses per treatment cycle). This cycle is repeated approximately every 6 weeks depending on the patient's clinical response and observed toxicity. The total daily dose must not exceed 45 mg/m² and the total dose per treatment cycle must not exceed 135 mg/m². If a dose is missed, treatment should be resumed as soon as possible.
5-Day Dosing Treatment Regimen in MDS: In a treatment cycle, decitabine is administered at a dose of 20 mg/m² body surface area by intravenous infusion over 1 hour repeated daily for 5 consecutive days (i.e., a total of 5 doses per treatment cycle). The total daily dose must not exceed 20 mg/m² and the total dose per treatment cycle must not exceed 100 mg/m². The cycle should be repeated every 4 weeks depending on the patient's clinical response and observed toxicity. If a dose is missed, treatment should be resumed as soon as possible. It is possible to use this regimen in an outpatient setting.
Management of Myelosuppression and Associated Complications: Myelosuppression and adverse events related to myelosuppression (thrombocytopenia, anemia, neutropenia, and febrile neutropenia) are common in both treated and untreated patients with AML and MDS. Complications of myelosuppression include infections and bleeding. Treatment may be modified in patients experiencing myelosuppression and associated complications as described as follows: In AML: Treatment may be delayed at the discretion of the treating physician, if the patient experiences myelosuppression-associated complications, such as those described as follows: Febrile neutropenia (temperature ≥38.5°C and absolute neutrophil count <1000/μL).
Active viral, bacterial or fungal infection (i.e., requiring intravenous anti-infectives or extensive supportive care).
Hemorrhage (gastrointestinal, genito-urinary, pulmonary with platelets <25000/μL or any central nervous system hemorrhage).
Treatment with decitabine may be resumed once these conditions have improved or have been stabilized with adequate treatment (anti-infective therapy, transfusions, or growth factors).
Dose reduction is not recommended.
In MDS: 5-Day Dosing Regimen: Dose reduction is not recommended in this clinical setting to optimize patient benefit, dose should be delayed as follows: Dose Regimen Modifications in the First 3 Cycles: During the first cycles of treatment, Grade 3 and 4 cytopenias are common and may not represent progression of MDS. Pre-treatment cytopenias may not improve until after Cycle 3.
For the first 3 cycles, to optimize patient benefit in the setting of moderate neutropenia (absolute neutrophil count <1000/μL), all attempts should be made to maintain full dose treatment at the standard treatment cycle interval. Concomitant antimicrobial prophylaxis as per institutional guidelines can be administered until recovery of granulocytes to above 500/μL. Clinicians should also consider the need for early administration of growth factors during this time for the prevention or treatment of infections in patients with MDS.
Similarly, to optimize patient benefit in the setting of moderate thrombocytopenia (platelet count <25000/μL), all attempts should be made to maintain full dose treatment at the standard treatment cycle interval with concomitant administration of platelet transfusions in case of bleeding events.
Dose Regimen Modifications After Cycle 3: Dose should be delayed in case of the following toxicities considered to be at least possibly related to the treatment: Severe myelosuppression-associated complications (infections not resolving with adequate anti-infective therapy, bleeding not resolving with adequate treatment).
Prolonged myelosuppression defined as a hypocellular marrow (5% or less cellularity) without evidence of disease progression for 6 weeks or more after the start of a course of therapy.
If recovery (absolute neutrophil count >1000/μL and platelets >50000/μL) requires more than 8 weeks, the patient should be discontinued from the treatment of drug and assessed for disease progression (by bone marrow aspirate) within 7 days after the end of 8 weeks. For patients who have been treated for at least 6 cycles, and who continue to derive benefit from the therapy, a prolonged delay beyond 8 weeks can be allowed, in the absence of progression, at the discretion of the treating physician.
3-Day Dosing Regimen: Dose Regimen Modifications in the First 3 Cycles: During the first cycles of treatment, Grade 3 and 4 cytopenias are common and may not represent progression of MDS. Pre-treatment cytopenias may not improve until after Cycle 3.
For the first 3 cycles, to optimize patient benefit in the setting of moderate neutropenia (absolute neutrophil count <1000/μL), all attempts should be made to maintain full dose treatment at the standard treatment cycle interval. Concomitant antimicrobial prophylaxis as per institutional guidelines can be administered until recovery of granulocytes to above 500/μL.
Clinicians should also consider the need for early administration of growth factors during this time for the prevention or treatment of infections in patients with MDS.
Similarly, to optimize patient benefit in the setting of moderate thrombocytopenia (platelet count <25000/μL), all attempts should be made to maintain full dose treatment at the standard treatment cycle interval with concomitant administration of platelet transfusions in case of bleeding events.
Dose Regimen Modifications After Cycle 3: If hematologic recovery (absolute neutrophil count >1000/μL and platelets >50000/μL) from a previous decitabine treatment cycle, with persistent cytopenia(s) being considered related to drug administration, requires more than 6 weeks, then the next cycle of decitabine therapy should be delayed and dosing reduced by the algorithm as follows. All dose reductions that occur should remain in effect for the duration of the chemotherapy; there should be no dose re-escalation.
Recovery requiring more than 6 weeks, but less than 8 weeks - decitabine dosing to be delayed for up to 2 weeks and the dose reduced to 11 mg/m² every 8 hours (33 mg/m²/day, 99 mg/m²/cycle) upon restarting therapy.
Recovery requiring more than 8 weeks, but less than 10 weeks - the decitabine dose should be delayed up to 2 more weeks and the dose reduced to 11 mg/m² every 8 hours (33 mg/m²/day, 99 mg/m²/cycle) upon restarting therapy, then maintained in subsequent cycles as clinically indicated.
Recovery requiring more than 10 weeks - Patient should be discontinued from the treatment of drug and assessed for disease progression (by bone marrow aspirates) within 7 days after the end of 10 weeks. However, for patients who have been treated for at least 6 cycles, and who continue to derive benefit from the therapy, a prolonged delay beyond 10 weeks can be allowed, in the absence of progression, at the discretion of the treating physician.
Special populations: Pediatrics: The safety and effectiveness in pediatric patients with MDS have not been reported.
Treatment of pediatric patients with AML is not recommended because decitabine was not reported to be effective in this patient population.
Hepatic impairment: Studies in patients with hepatic impairment have not been reported. The need for dosage adjustment in patients with hepatic impairment has not been evaluated. If worsening hepatic function occurs, patients should be carefully monitored (see PRECAUTIONS and Pharmacology: Pharmacokinetics under Actions).
Renal impairment: Studies in patients with renal impairment have not been reported; however, data from reported clinical trials that included patients with mild-moderate impairment indicated no need for dosage adjustment. Patients with severe renal impairment were excluded from these reported trials (see Pharmacology: Pharmacokinetics under Actions).

OVERDOSE AND TREATMENT: There is no reported direct experience of human overdose and no specific antidote. However, early clinical study data in published literature at doses greater than 20 times higher than the current therapeutic doses, reported increased myelosuppression including prolonged neutropenia and thrombocytopenia. Toxicity is likely to manifest as exacerbations of adverse reactions, primarily myelosuppression (see ADVERSE REACTIONS). Treatment for overdose should be supportive.

Known hypersensitivity to decitabine or any of the excipients (see Description).
Lactation (see USE IN PREGNANCY & LACTATION).

Notification of Ministry of Public Health: This drug may cause serious hazard. Must use only under physician supervision.

Myelosuppression: Myelosuppression and complications of myelosuppression, including infections and bleeding that occur in patients with MDS or AML may be exacerbated with decitabine treatment. Myelosuppression caused by decitabine is reversible. Complete blood count and platelet counts should be performed regularly, as clinically indicated and prior to each treatment cycle. In the presence of myelosuppression or its complications, treatment with decitabine may be interrupted, the dose reduced or supportive measures instituted as recommended in RECOMMENDED DOSE under Dosage & Administration and ADVERSE REACTIONS.
Cardiac disease: Patients with a history of severe congestive heart failure or clinically unstable cardiac disease were excluded from reported clinical studies and therefore the safety and efficacy of decitabine in these patients has not been reported.
Effects on Ability to Drive and Use Machines: No reported studies of the effects on the ability to drive or use machines with decitabine have been performed. Patients should be advised that they may experience undesirable effects, such as anemia, during treatment. Therefore, caution should be recommended when driving a car or operating machines.
Hepatic impairment: The use of decitabine in patients with hepatic impairment has not been reported. Caution should be exercised in the administration of decitabine to patients with hepatic impairment or in patients who develop signs or symptoms of hepatic impairment. Patients should be monitored closely (see RECOMMENDED DOSE under Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Renal impairment: The use of decitabine in patients with severe renal impairment has not been reported. Caution should be exercised in the administration of decitabine to patients with severe renal impairment (Creatinine Clearance [CrCl] <30 mL/min) and these patients should be monitored closely (see RECOMMENDED DOSE under Dosage & Administration).

Pregnancy: Women of childbearing potential should be advised to use effective contraceptive measures and avoid becoming pregnant while being treated with decitabine. The time period following treatment with decitabine where it is safe to become pregnant is unknown. There are no adequate data on the use of decitabine in pregnant women. Reported studies have shown that decitabine is teratogenic in rats and mice. The potential risk for humans is unknown. Based on reported results from animal studies and its mechanism of action, decitabine should not be used during pregnancy, unless clearly necessary. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving decitabine, the patient should be apprised of the potential hazard to the fetus.
Use in Males: Men should be advised to not father a child while receiving decitabine, and for 3 months following completion of treatment.
Fertility: Female patients of childbearing potential should be advised to seek consultation regarding oocyte cryopreservation prior to initiation of treatment with decitabine. Because of the possibility of infertility as a consequence of decitabine therapy, men should be advised to seek advice on conservation of sperm prior to any treatment.
Breast-feeding: It is not known whether decitabine or its metabolites are excreted in breast milk. Decitabine is contraindicated during lactation; therefore if treatment with decitabine is required, breast-feeding must be discontinued (see CONTRAINDICATIONS).

Clinical study data: Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of decitabine based on the reported comprehensive assessment of the available adverse event information. A causal relationship with decitabine cannot be reliably established in individual cases. Further, because clinical trials are reported under widely varying conditions, adverse reaction rates reported in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The most important and frequently occurring adverse reactions in both the 5-Day and 3-Day regimens are myelosuppression and those occurring as a consequence of myelosuppression.
Adverse reactions: The safety of decitabine was evaluated in 682 subjects from reported AML and MDS clinical studies (D-0007, DACO-016, DACO-017, DACO-020, EORTC-06011 and ID03-0180). In these reported clinical studies, decitabine was administered with the 5-Day or 3-Day dosing regimen. Adverse reactions reported during these reported clinical studies are summarized as follows in Table 2. The adverse reactions are listed by frequency category. Frequency categories are defined as follows: Very common (≥1/10), Common (≥1/100 to <1/10) and Uncommon (≥1/1000 to <1/100).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 2.)

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Description of selected adverse reactions: Hematologic adverse reactions: The most commonly reported hematologic adverse reactions associated with decitabine treatment included febrile neutropenia, thrombocytopenia, neutropenia, anemia and leucopenia.
Serious infection-related adverse reactions such as septic shock, sepsis, and pneumonia were reported in patients receiving decitabine.
Serious bleeding-related adverse reactions such as CNS hemorrhage (1%) and gastrointestinal hemorrhage (2%), in the context of severe thrombocytopenia, were reported in patients receiving decitabine.
Hematological adverse reactions should be managed by routine monitoring of complete blood counts and supportive treatments as required. Supportive treatments include, administration of prophylactic antibiotics and/or growth factor support (e.g. G-CSF) for neutropenia and transfusions for anaemia or thrombocytopenia according to institutional guidelines. For situations where decitabine administration should be delayed, see RECOMMENDED DOSE under Dosage & Administration.
Postmarketing Data: In addition to the adverse reactions reported during reported clinical studies and listed previously, the following adverse reactions have been reported during reported postmarketing experience. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In the table, the frequencies are provided according to the following convention: Very common ≥ 1/10; Common ≥ 1/100 and < 1/10; Uncommon ≥ 1/1000 and < 1/100; Rare ≥ 1/10000 and < 1/1000; Very rare < 1/10000, including isolated reports. (See Table 3.)

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No formal clinical drug interaction studies with decitabine have been reported.
There is the potential for a drug-drug interaction with other agents which are also activated by sequential phosphorylation (via intracellular phosphokinase activities) and/or metabolized by enzymes implicated in the inactivation of decitabine (e.g., cytidine deaminase). Therefore, caution should be exercised if these drugs are combined with decitabine.
Impact of co-administered drugs on decitabine: CYP450-mediated metabolic drug interactions are not anticipated as decitabine metabolism is not mediated by this system but by oxidative deamination. Displacement of decitabine from its plasma protein binding by co-administered drugs is unlikely given the negligible in vitro plasma protein binding (<1%) of decitabine. In vitro reported data indicated that decitabine is a poor P-glycoprotein (P-gp) substrate and is therefore not prone to interaction with P-gp inhibitors.
Impact of decitabine on co-administered drugs: Given its low in vitro plasma protein binding (<1%), decitabine is unlikely to displace co-administered drugs from their plasma protein binding. In vitro reported studies show that decitabine does not inhibit nor induce CYP450 enzymes up to more than 20-fold of the therapeutic maximum observed plasma concentration (C_max). Thus, CYP-mediated metabolic drug interactions are not anticipated and is unlikely to interact with agents metabolized through these pathways. Decitabine has been reported to be a weak inhibitor of P-gp mediated transport in vitro and is therefore also not expected to affect P-gp mediated transport of co-administered drugs (see Pharmacology: Pharmacokinetics under Actions).

Instructions for Use and Handling and Disposal: This medicinal product is for single use only. Skin contact with the solution should be avoided and protective gloves must be worn. Standard procedures for dealing with anticancer agents should be adopted.
DECITEX should be aseptically reconstituted with 10 mL of accompanied diluent only. Immediately after reconstitution, the solution should be further diluted with 0.9% Sodium Chloride Solution, 5% Dextrose Solution or Lactated Ringer's Solution to a final drug concentration of 0.1 to 1.0 mg/mL. The diluted solution can be stored at 2°C to 8°C for 7 hours.
Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. Decitabine should not be infused through the same intravenous access/line with other medicinal products.

Do not store above 30°C.

Targeted Cancer Therapy

L01BC08 - decitabine ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.

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