Decita

Each vial contains: Decitabine 50 mg.
Decitabine for Injection contains decitabine (5-aza-2'-deoxycitidine), an analogue of the natural nucleoside 2'-deoxycytidine. Decitabine is a fine, white powder with the molecular formula of C₈H₁₂N₄O₄ and a molecular weight of 228.21. Its chemical name is 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one.
Excipients/Inactive Ingredients: Excipients of decitabine for injection include potassium dihydrogen phosphate, sodium hydroxide and water for injection (removed after lyophilization).

ATC classification: Antimetabolites.
Pharmacology: Pharmacodynamics/Pharmacokinetics: Mechanism of action: Decitabine is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated into DNA. Non-proliferating cells are relatively insensitive to decitabine. Pharmacokinetic parameters were evaluated in patients. Eleven patients received 20 mg/m² infused over 1 hour intravenously (treatment Option 2). Fourteen patients received 15 mg/m² infused over 3 hours (treatment Option 1). PK parameters are shown in Table 1. Plasma concentration-time profiles after discontinuation of infusion showed a biexponential decline. The CL of decitabine was higher following treatment Option 2. Upon repeat doses there was no systemic accumulation of decitabine or any changes in PK parameters. Population PK analysis (N=35) showed that the cumulative AUC per cycle for treatment Option 2 was 2.3-fold lower than the cumulative AUC per cycle following treatment Option 1. (See Table 1.)

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Decitabine for Injection is indicated for treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

Recommended Dose: There are two regimens for Decitabine for Injection administration. With either regimen it is recommended that patients be treated for a minimum of 4 cycles; however, a complete or partial response may take longer than 4 cycles. Complete blood counts and platelet counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each cycle. Liver chemistries and serum creatinine should be obtained prior to initiation of treatment.
Treatment Regimen-Option 1: Decitabine for Injection is administered at a dose of 15 mg/m² by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days. This cycle should be repeated every 6 weeks. Patients may be premedicated with standard anti-emetic therapy.
If hematologic recovery (ANC ≥1,000/μL and platelets ≥50,000/μL) from a previous Decitabine for Injection treatment cycle requires more than 6 weeks, then the next cycle of Decitabine for Injection therapy should be delayed and dosing temporarily reduced by following this algorithm: Recovery requiring more than 6, but less than 8 weeks: Decitabine for Injection dosing to be delayed for up to 2 weeks and the dose temporarily reduced to 11 mg/m² every 8 hours (33 mg/m²/day, 99 mg/m²/cycle) upon restarting therapy.
Recovery requiring more than 8, but less than 10 weeks: Patient should be assessed for disease progression (by bone marrow aspirates); in the absence of progression, the Decitabine for Injection 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 or increased in subsequent cycles as clinically indicated.
Treatment Regimen-Option 2: Decitabine for Injection is administered at a dose of 20 mg/m² by continuous intravenous infusion over 1 hour repeated daily for 5 days. This cycle should be repeated every 4 weeks. Patients may be premedicated with standard anti-emetic therapy.
If myelosuppression is present, subsequent treatment cycles of Decitabine for Injection should be delayed until there is hematologic recovery (ANC ≥1,000/μL and platelets ≥50,000/μL).
Patients with Non-hematologic Toxicity: Following the first cycle of Decitabine for Injection treatment, if any of the following non-hematologic toxicities are present, Decitabine for Injection treatment should not be restarted until the toxicity is resolved: serum creatinine ≥2 mg/dL; SGPT, total bilirubin ≥2 times ULN; and active or uncontrolled infection.
Instructions for Intravenous Administration: Decitabine for Injection is a cytotoxic drug and caution should be exercised when handling and preparing Decitabine for Injection.
Procedures for proper handling and disposal of antineoplastic drugs should be applied. Several guidances on this subject have been published.
Decitabine for Injection should be aseptically reconstituted with 10 mL of Sterile Water for Injection; upon reconstitution, each mL contains approximately 5.0 mg of decitabine at pH 6.7-7.3. Immediately after reconstitution, the solution should be further diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final drug concentration of 0.1-1.0 mg/mL. Unless used within 15 minutes of reconstitution, the diluted solution must be prepared using cold (2˚C-8˚C) infusion fluids and stored at 2˚C-8˚C (36˚F-46˚F) for up to a maximum of 4 hours until administration.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if there is evidence of particulate matter or discoloration.

Symptoms and treatment of Overdose: There is no known antidote for overdosage with Decitabine for Injection. Higher doses are associated with increased myelosuppression including prolonged neutropenia and thrombocytopenia. Standard supportive measures should be taken in the event of an overdose. Decitabine has moderate influence on the ability to drive and use machines. Patients should be advised that they may experience undesirable effects such as anaemia during treatment. Therefore, caution should be recommended when driving a car or operating machines.

None.

Myelosuppression and complications of myelosuppression, including infections and bleeding that occur in patients with MDS may be exacerbated with Decitabine treatment. Therefore patients are at increased risk for severe infections (due to any pathogen such as bacterial, fungal and viral), with potentially fatal outcome. Patients should be monitored for signs and symptoms of infection and treated promptly.
In clinical studies, the majority of patients had baseline Grade 3/4 myelosuppression. In patients with baseline Grade 2 abnormalities, worsening of myelosuppression was seen in most patients and more frequently than in patients with baseline Grade 1 or 0 abnormalities. Myelosuppression caused by Decitabine is reversible. Complete blood 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 and/or supportive measures instituted.
Respiratory, thoracic and mediastinal disorders: Cases of interstitial lung disease (ILD) (including pulmonary infiltrates, organising pneumonia and pulmonary fibrosis) without signs of infectious aetiology have been reported in patients receiving decitabine. Careful assessment of patients with an acute onset or unexplained worsening of pulmonary symptoms should be performed to exclude ILD. If ILD is confirmed, appropriate treatment should be initiated.
Cardiac disease: Patients with a history of severe congestive heart failure or clinically unstable cardiac disease were excluded from clinical studies and therefore the safety and efficacy of Decitabine in these patients has not been established.
Excipients: This medicine contains 0.5 mmol potassium per vial. After reconstitution and dilution of the solution for intravenous infusion, this medicine contains less than 1 mmol (39 mg) of potassium per dose, i.e. essentially 'potassium-free'.
This medicine contains 0.29 mmol sodium per vial. After reconstitution and dilution of the solution for intravenous infusion, this medicine contains between 0.6-6 mmol sodium per dose depending on the infusion fluid for dilution. To be taken into consideration by patients on a controlled sodium diet.
Hepatic impairment: Use in patients with hepatic impairment has not been established. Caution should be exercised in the administration of Decitabine to patients with hepatic impairment and patients should be monitored closely.
Renal impairment: Use in patients with severe renal impairment has not been studied. 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.

Women of childbearing potential/Contraception in males and females: Women of childbearing potential must 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. Men should use effective contraceptive measures and be advised to not father a child while receiving Decitabine, and for 3 months following completion of treatment.
The use of decitabine with hormonal contraceptives has not been studied.
Pregnancy: There are no adequate data on the use of Decitabine in pregnant women. Studies have shown that decitabine is teratogenic in rats and mice. The potential risk for humans is unknown. Based on results from animal studies and its mechanism of action, Decitabine should not be used during pregnancy and in women of childbearing potential not using effective contraception. If Decitabine is used during pregnancy, or if a patient becomes pregnant while receiving this medicinal product, the patient should be apprised of the potential hazard to the foetus.
Breast-feeding: It is not known whether decitabine or its metabolites are excreted in breast milk. Decitabine is contraindicated during breast-feeding; therefore if treatment with this medicine is required, breast-feeding must be discontinued.
Fertility: No human data on the effect of decitabine on fertility are available. In non-clinical animal studies, decitabine alters male fertility and is mutagenic. Because of the possibility of infertility as a consequence of Decitabine therapy, men should seek advice on conservation of sperm and female patients of childbearing potential should seek consultation regarding oocyte cryopreservation prior to initiation of treatment.

Clinical Studies Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed 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 practice.
Most Commonly Occurring Adverse Reactions: neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia.
Adverse Reactions Most Frequently (≥1%) Resulting in Clinical Intervention in the Phase 3 Trials in the Decitabine for Injection Arm: Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardio-respiratory arrest, increased blood bilirubin, intracranial hemorrhage, abnormal liver function tests.
Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile neutropenia.
Dose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia, depression, pharyngitis.
Discussion of Adverse Reactions Information: Decitabine for Injection was studied in 3 single-arm studies (N=66, N=98, N=99) and 1 controlled supportive care study (N=83 Decitabine for Injection, N=81 supportive care). The data described as follows reflect exposure to Decitabine for Injection in 83 patients in the MDS trial. In the trial, patients received 15 mg/m² intravenously every 8 hours for 3 days every 6 weeks. The median number of Decitabine for Injection cycles was 3 (range 0 to 9).
Tables 2a and 2b present all adverse events regardless of causality occurring in at least 5% of patients in the Decitabine for Injection group and at a rate greater than supportive care. (See Tables 2a, 2b, 3a and 3b.)

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Serious Adverse Events that occurred in patients receiving Decitabine for Injection regardless of causality, not previously reported in Tables 2a, 2b, 3a and 3b include: Blood and Lymphatic System Disorders: myelosuppression, splenomegaly.
Cardiac Disorders: myocardial infarction, cardio-respiratory arrest, cardiomyopathy, atrial fibrillation, supraventricular tachycardia.
Gastrointestinal Disorders: gingival pain, upper gastrointestinal hemorrhage.
General Disorders and Administrative Site Conditions: chest pain, catheter site hemorrhage.
Hepatobiliary Disorders: cholecystitis.
Infections and Infestations: fungal infection, sepsis, bronchopulmonary aspergillosis, peridiverticular abscess, respiratory tract infection, pseudomonal lung infection, Mycobacterium avium complex infection.
Injury, Poisoning and Procedural Complications: post procedural pain, post procedural hemorrhage.
Nervous System Disorders: intracranial hemorrhage.
Psychiatric Disorders: mental status changes.
Renal and Urinary Disorders: renal failure, urethral hemorrhage.
Respiratory, Thoracic and Mediastinal Disorders: hemoptysis, lung infiltration, pulmonary embolism, respiratory arrest, pulmonary mass.
Allergic Reaction: Hypersensitivity (anaphylactic reaction) to Decitabine for Injection has been reported in a Phase 2 trial.

Drug interaction studies with decitabine have not been conducted. In vitro studies in human liver microsomes suggest that decitabine is unlikely to inhibit or induce cytochrome P450 enzymes. In vitro metabolism studies have suggested that decitabine is not a substrate for human liver cytochrome P450 enzymes. As plasma protein binding of decitabine is negligible (<1%), interactions due to displacement of more highly protein bound drugs from plasma proteins are not expected.

Instruction for use: Decitabine for Injection is a cytotoxic drug and caution should be exercised when handling and preparing Decitabine for Injection.
Decitabine for Injection should be aseptically reconstituted with 10 mL of Sterile Water for Injection; upon reconstitution, each mL contains approximately 5.0 mg of decitabine at pH 6.7-7.3. Immediately after reconstitution, the solution should be further diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final drug concentration of 0.1-1.0 mg/mL. Unless used within 15 minutes of reconstitution, the diluted solution must be prepared using cold (2˚C-8˚C) infusion fluids and stored at 2˚C-8˚C (36˚F-46˚F) for up to a maximum of 4 hours until administration.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if there is evidence of particulate matter or discoloration.
Reconstituted and diluted solution: Within 15 minutes of reconstitution, the concentrate (in 10 mL of sterile water for injections) must be further diluted with cold (2°C-8°C) infusion fluids. This prepared diluted solution for intravenous infusion can be stored at 2°C-8°C for up to a maximum of 3 hours, followed by up to 1 hour at room temperature (20°C-25°C) before administration.
From a microbiological point of view, the product should be used within the time period recommended above. It is the responsibility of the user to follow the recommended storage times and conditions and ensure that reconstitution has taken place in aseptic conditions.

Store at temperatures not exceeding 30°C

Cytotoxic Chemotherapy

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

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