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DACOGEN is a brand name for Decitabine, supplied as a powder. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: DACOGEN® (decitabine) is indicated for the treatment of adult patients with de novo or secondary Myelodysplastic Syndrome (MDS), untreated or previously treated with chemotherapy, who are not considered candidates for hematopoietic stem cell transplantation, including: Intermediate-1, intermediate-2 and high-risk…
Verbatim from this product's HC label. Tap a section to expand.
1 Dosing Considerations DACOGEN must be administered under the supervision of a qualified physician experienced in the use of chemotherapeutic agents. Patients may be premedicated with standard anti-emetic therapy. A mild to moderate increase in nausea, vomiting and diarrhea was reported in patients receiving DACOGEN.
(See ADVERSE REACTIONS). Two dosing regimens are recommended. 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 may be delayed at the discretion of the treating physician, if patients experience hematological or non-hematological adverse reactions (see Recommended Dose and Dosage Adjustment).
, platelet counts 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 DACOGEN should be considered.
Dosage should be modified in the presence of hematological and non-hematological toxicities. 2 Recommended Dose and Dosage Adjustment Recommended Dose There are two possible treatment regimens for DACOGEN.
Option 1:
In Patient (3-Day Dosing Regimen) DACOGEN is administered at a dose of 15 mg/m2 body surface area by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 consecutive days. This cycle should be repeated every 6 weeks depending on the patient’s clinical response and observed toxicity.
Option 2:
Out Patient (5-Day Dosing Regimen) DACOGEN is administered at a dose of 20 mg/m2 body surface area by continuous intravenous infusion over 1 hour repeated daily for 5 consecutive days. This cycle should be repeated every 4 weeks depending on the patient’s clinical response and observed toxicity.
Dosage Adjustment If patients experience toxicities as described below DACOGEN dosage should be adjusted. DACOGEN® Product Monograph Page 6 of 44 Non-Hematologic Toxicity DACOGEN treatment should be delayed subsequent to any the following non-hematologic toxicities and should not be restarted until toxicities resolve: Serum creatinine ≥ 2 mg/dL SGPT, total bilirubin ≥ 2 times ULN Active or uncontrolled infection Hematologic Toxicity Myelosuppression and adverse events related to myelosuppression (thrombocytopenia, anemia, neutropenia, and febrile neutropenia) are common in both treated and untreated patients.
1 Adverse Reaction Overview The safety of DACOGEN in MDS adult patients was studied in a single-arm study (N = 99) and a controlled supportive care trial (N = 83 DACOGEN, N = 81 supportive care). In the controlled supportive care trial, patients received 15 mg/m2 DACOGEN by body surface area intravenously every 8 hours for 3 days every 6 weeks.
In the single-arm MDS study (N=99) DACOGEN was dosed at 20 mg/m2 intravenously infused by body surface area, over one hour daily for 5 consecutive days of a 4-week cycle. Patients with a history of uncontrolled cardiac disease or congestive heart failure, renal dysfunction or, hepatic dysfunction were excluded.
The safety profile of DACOGEN using the 3-day and 5-day regimens are similar in that the most common adverse reactions were blood and lymphatic systems disorders: mainly myelosuppression (neutropenia, thrombocytopenia, anemia, and febrile neutropenia).
The incidence of these adverse reactions were lower in patients treated with the 5-day regimen. In the first two treatment cycles, there was an increased risk of febrile neutropenia and increased requirements for transfusion which were not seen in later cycles.
Dose-related, but transient cytopenias, were reported early in the treatment regimen following the initial DACOGEN infusions. Serious infection-related adverse reactions such as septic shock, sepsis, and pneumonia were reported in patients receiving DACOGEN.
Serious bleeding-related adverse reactions such as central nervous system (CNS) haemorrhage (1%) and gastrointestinal (GI) haemorrhage (2%), in the context of severe thrombocytopenia, were reported in patients receiving decitabine.
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. Cases of myelosuppression, cardiac arrest, infections, hypersensitivity (anaphylaxis) and intracranial hemorrhage have been reported in patients receiving decitabine.
General DACOGEN administration should only be administered by healthcare professionals experienced with cancer chemotherapeutic drugs. DACOGEN is a cytotoxic drug and caution should be exercised while handling and disposal of DACOGEN.
See DOSAGE AND ADMINISTRATION; SPECIAL HANDLING INSTRUCTIONS. There is a risk of DACOGEN degradation at room temperature if not used within 15 minutes of reconstitution. Therefore, DACOGEN should be diluted with cold recommended infusion fluids and stored at 2-8°C for a maximum of 4 hours until administration (see DOSAGE AND ADMINISTRATION, Administration, Reconstitution, STORAGE, STABILITY AND DISPOSAL).
Route of Administration Dosage Form / Strength/Composition Non-medicinal Ingredients Intravenous infusion Single-use clear colorless glass vials containing 50 mg lyophilized powder for solution for infusion, with a potency of 5 mg/mL upon reconstitution.
Potassium dihydrogen phosphate, sodium hydroxide DACOGEN® Product Monograph Page 9 of 44 Carcinogenesis and Mutagenesis Carcinogenicity studies with decitabine have not been conducted. Decitabine is mutagenic in vitro and in vivo studies.
(See NON-CLINICAL TOXICOLOGY). Cardiovascular No thorough clinical QT/QTc study have been conducted. 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 DACOGEN in these patients has not been established.
Patients with history of severe congestive heart failure or clinically unstable cardiac disease should be closely monitored. (See NON-CLINICAL TOXICOLOGY). Driving and Operating Machinery Patients should be advised that they may experience fatigue, dizziness, confusional state, and blurred vision due to anemia during treatment.
Due caution should be exercised when driving or operating a vehicle or potentially dangerous machinery. Hematologic Hemorrhage Serious bleeding-related adverse reactions (AR) such as central nervous system (CNS) haemorrhage (1%) and gastrointestinal (GI) haemorrhage (2%), were reported due to severe thrombocytopenia in patients receiving DACOGEN.
DACOGEN is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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Complications of myelosuppression include infections and bleeding. Treatment may be delayed at the discretion of the treating physician, if the patient experiences myelosuppression- associated complications, such as those described below.
Treatment with DACOGEN may be resumed once these conditions have improved or have been stabilized with adequate treatment (anti-infective therapy, transfusion, or growth factors). , requiring intravenous anti-infectives or extensive supportive care) Hemorrhage (gastrointestinal, genito-urinary, pulmonary with platelets < 25,000/μL or any central nervous system hemorrhage).
(See WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS).
Option 1:
In Patient (3-Day Dosing Regimen) If hematologic recovery (ANC at least 1,000/μL and platelets at least 50,000/μL) from a previous DACOGEN treatment cycle requires more than 6 weeks, the next cycle of DACOGEN therapy should be delayed and DACOGEN dose temporarily should be reduced by following this algorithm: If DACOGEN treatment is required for more than 6, but less than 8 weeks – DACOGEN dosing should be delayed for up to 2 weeks and the dose should be temporarily reduced to 11 mg/m2 by surface area every 8 hours (33 mg/m2/day, 99 mg/m2/cycle) upon restarting therapy.
If DACOGEN treatment is required for more than 8, but less than 10 weeks - bone marrow aspirate should be performed to assess for disease progression. In the absence of progression, DACOGEN dose should be delayed up to 2 more weeks and the dose should be reduced to 11 mg/m2 by surface area every 8 hours (33 mg/m2/day, 99 mg/m2/cycle) upon restarting therapy, then the dose should be maintained or increased in subsequent cycles as clinically indicated.
Option 2:
Out Patient (5-Day Dosing Regimen) Dose reduction is not recommended for the 5-day dosing regimen. If hematologic recovery (ANC at least 1,000/μL and platelets at least 50,000/μL) from a previous DACOGEN treatment cycle requires more than 4 weeks, DACOGEN therapy should be delayed to the next cycle.
DACOGEN® Product Monograph Page 7 of 44 Pediatrics (< 18 years of age):
There is no safety and efficacy data available from children. MDS occurs rarely in children.
Geriatrics (> 65 years of age):
No overall differences in safety or effectiveness were observed between patient 65 years and older as compared to younger subjects. However, in older individuals (75 years and older) catheter related infections (5% in patients 65 and older vs.
24% in patients 75 years and older) were reported more frequently in a phase 3 clinical trial.
Renal Impairment:
Patients with renal impairment were excluded from the trials. Decitabine is mainly excreted (90%) in the urine. DACOGEN should be used with caution in renal impairment and these patients should be monitored closely for toxicity including worsening of renal function.
Serum creatinine should be obtained prior to initiation of treatment if non-hematologic toxicities are present. DACOGEN treatment should not be restarted until serum creatinine ≥ 2 mg/dL. (See […]
2 Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.
Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Myelodysplastic Syndrome (MDS) Option 1:
In Patient (3-Day Dosing Regimen) A Phase 3 (D-0007), randomized open-label, multicenter, controlled trial was conducted with DACOGEN plus supportive care vs. supportive care alone in 170 adult patients with MDS. 83 patients received DACOGEN intravenously infused at a dose of 15 mg/m2 per body surface area over a 3-hour period, every 8 hours, for 3 consecutive days.
This cycle was repeated every 6 weeks, depending on the patient’s clinical response and toxicity. The median number of cycles completed was 3 for the DACOGEN and for Supportive Care treatment arms (range 1 to 9). DACOGEN® Product Monograph Page 13 of 44 The most common adverse reactions in patients who received DACOGEN were: neutropenia (90%), thrombocytopenia (89%), anaemia (82%), fatigue (48%), pyrexia (53%), nausea (42%), cough (40%), petechiae (39%), constipation (35%), diarrhoea (34%), and hyperglycaemia (33%).
Pyrexia, cough, headache, staphylococcal infection, and pneumonia occurred consistently throughout treatment. Fungal infections and bacteremia appeared as early events, as did febrile neutropenia, rigor and hyperbilirubinemia. The overall incidence of death was similar (71% DACOGEN vs.
68% Supportive Care) for the two treatment arms during the study period or during long term follow-up. The major causes of death on study in both study arms were disease progression (MDS/AML) and infection. Fewer patients died on study in the DACOGEN arm (14%) than in the Supportive Care arm (22%).
The situation was reversed in the long-term follow-up period (57% DACOGEN vs. 46% Supportive Care). Serious adverse reactions (SARs) were experienced by 69% of the DACOGEN patients and 56% of the Supportive Care patients. SARs occurred most commonly in the SOC categories of blood and lymphatic system disorders, general disorders and administrative sites conditions, infections and infestations and cardiac disorders.
The most common SARs in the DACOGEN arm that occurred in more than one patient and at an incidence numerically greater than in the Supportive Care arm were: febrile neutropenia (25%), pneumonia (17%), pyrexia (14%), and catheter-related infections (5%).
The highest incidence of Grade 3 and/or Grade 4 SARs in the DACOGEN arm occurred with neutropenia (87%), thrombocytopenia (85%), febrile neutropenia (23%) and leukopenia (22%). In the first two treatment cycles, there was an increased risk of febrile neutropenia and increased requirements for transfusion which were not seen in later cycles.
Ten percent of patients discontinued due to toxicity. Adverse reactions for permanent discontinuation were due to thrombocytopenia (2%), neutropenia (1%), cardiopulmonary arrest (1%), pneumonia NOS (1%), lymphadenopathy (1%), elevated total bilirubin (1%), elevated SGPT (1%), Mycobacterium avium complex infection (1%), subarachnoid hemorrhage (1%), cardio-respiratory arrest (1%), increased blood bilirubin (1%), intracranial hemorrhage (1%), and abnormal liver function tests (1%).
Approximately one - third of patients receiving DACOGEN required dose delay or dose reduction. The adverse reactions most frequently resulting in permanent discontinuation were thrombocytopenia (2%), neutropenia (1%), cardiopulmonary arrest (1%), pneumonia NOS (1%), MAC infection (1%), subarachnoid hemorrhage (1%), lymphadenopathy (1%), elevated total bilirubin (1%), and elevated SGPT (1%).
Adverse reactions leading to temporarily dose suspension were neutropenia (2%), pulmonary congestion (1%), atrial […]
Patients receiving DACOGEN should be monitored closely for signs and symptoms of serious bleeding-related adverse events. (See ADVERSE REACTIONS). Myelosuppression Complete blood and platelet counts should be performed regularly, as clinically indicated and prior to each treatment cycle.
g. G- CSF) for neutropenia and red blood cell or platelet transfusions or antimicrobial agents for the prevention and treatment of myelosuppression or infections may be instituted according to institutional guidelines. (See WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests, DOSAGE AND ADMINISTRATION).
Increased risk of febrile neutropenia, worsening of neutropenia from Grade 3 to Grade 4 (in 85% patients) and increased requirements for transfusion occurred in the first two treatment cycles. Myelosuppression and complications of myelosuppression, including infections and bleeding that occur in patients with MDS may be exacerbated with DACOGEN treatment.
The highest incidence of Grade 3 and/or Grade 4 ARs with neutropenia (87%), thrombocytopenia (85%), febrile neutropenia (23%) and leukopenia (22%) occurred with DACOGEN. Additionally, eight patients had fatal events due to infection and/or bleeding that were considered at least possibly related to DACOGEN treatment.
Fungal infections and bacteremia appeared as early events, as do febrile neutropenia, rigor and hyperbilirubinemia. (See ADVERSE REACTIONS). Hepatic There are no data in patients with hepatic impairment because these patients were excluded from the trials.
Hyperbilirubinemia appeared as an early event. DACOGEN should be used with caution and liver function tests should be monitored closely during DACOGEN treatment (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics). DACOGEN® Product Monograph Page 10 of 44 Immune Hypersensitivity Hypersensitivity reactions including serious anaphylactic reactions have been reported with DACOGEN.
Skin and subcutaneous events and petechiae also appeared early, but diminish more slowly than other early events. DACOGEN treatment should be discontinued for serious adverse reactions. Supportive treatment should be initiated promptly.
(See ADVERSE REACTIONS).
Infections and Infestations:
Serious infection-related adverse reactions such as septic shock, sepsis, and pneumonia were reported in patients receiving DACOGEN. Infections were reported with higher frequency early in treatment during Cycles 1 and 2. Fungal infections and bacteremia appeared as early events, as did febrile neutropenia.
Patients should be monitored for signs and symptoms of infection and supportive prophylactic antibiotics and treatment should be initiated promptly. (See ADVERSE REACTIONS). Monitoring and Laboratory Tests Complete blood and platelet counts should be performed to monitor response and toxicity as needed, but at a minimum prior to each dose.
Liver chemistries and serum creatinine should be obtained prior to initiation of treatment and if signs and symptoms of liver/renal toxicities are suspected. (See Hematologic, ADVERSE REACTIONS). Renal Patients with renal impairment were excluded from the trials.
Decitabine is mainly excreted (90%) in the urine. DACOGEN should be used with caution and these patients should be monitored closely. (See ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics). 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 […]