Posology : מינונים

4.2.     Posology and Method of Administration
DACOGEN administration must be initiated under the supervision of physicians experienced in the use of chemotherapeutic agents.



Posology
There are 2 regimens recommended for DACOGEN 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.

Pre-medication for the prevention of nausea and vomiting is not routinely recommended but may be administered if required

MDS
There are two regimens for Dacogen administration for MDS. 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.

In the AML Phase 3 study, the median time to response (complete remission [CR] or CR with incomplete platelet recovery [CRp]) was 4.3 months. In MDS, the median time to response (CR+PR) in the Phase 2 MDS studies with the 5-Day dosing regimen was 3.5 cycles. In the Phase 3 MDS study with the 3-Day dosing regimen, the median time to response was 3 cycles. 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 counts or absolute neutrophil count [ANC]), 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.

4.2.1 Treatment Regimen – Option 1
Dacogen is administered at a dose of 15 mg/m2 body surface 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.

4.2.2 Treatment Regimen – Option 2
Dacogen 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.

4.2.3 Patients with Non-hematologic Toxicity

Following treatment with either DACOGEN regimen, if the following non-hematological toxicities occur, the next cycle of DACOGEN therapy should be withheld until levels return to within the normal range or baseline:


-Serum creatinine greater than or equal to 2 mg/dL. Serum glutamate pyruvate transaminase (SGPT) or alanine aminotransferase (ALT) or, total bilirubin greater than or equal to 2 times the upper limit of normal (ULN).

-Active viral or bacterial infection that is not controlled by concomitant anti-infective therapy.

AML
In a treatment cycle, Dacogen 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.
If a dose is missed, treatment should be resumed as soon as possible.

The cycle should be repeated every 4 weeks depending on the patient's clinical response and observed toxicity. It is recommended that patients be treated for a minimum of 4 cycles; however, a complete or partial remission 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 haematological values (e.g., 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.

Management of myelosuppression and associated complications

Myelosuppression and adverse events related to myelosuppression (thrombocytopenia, anaemia, 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 below: 

In AML
Treatment may be delayed at the discretion of the treating physician, if the patient experiences myelosuppression-associated complications, such as those described below: 
•    Febrile neutropenia (temperature ≥ 38.5°C and absolute neutrophil count < 1,000/μL)
•    Active viral, bacterial or fungal infection (i.e., requiring intravenous anti-infectives or extensive supportive care)
•    Haemorrhage (gastrointestinal, genito-urinary, pulmonary with platelets < 25,000/μL or any central nervous system haemorrhage)

Treatment with DACOGEN may be resumed once these conditions have improved or have been stabilized with adequate treatment (anti-infective therapy, transfusions, or growth factors).


In clinical studies, approximately one-third of patients receiving DACOGEN required a dose-delay. Dose reduction is not recommended.


In MDS
3-Day Dosing Regimen
Dose Regimen Modifications in the First 3 Cycles
During the first cycles of treatment, Grade 3-4 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 <25,000/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 Modifications After Cycle 3
If hematologic recovery (absolute neutrophil count ≥ 1,000/μL and platelets ≥ 50,000/μL) from a previous Dacogen treatment cycle with persistent cytopenia(s) being considered related to drug administration, requires more than 6 weeks, then the next cycle of Dacogen therapy should be delayed and dosing reduced by the algorithm below. 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, but less than 8 weeks − Dacogen 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, but less than 10 weeks – the Dacogen 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 the drug and assessed for disease progression (by bone marrow aspirate) 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 direction of the treating physician.


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 <25,000/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 >1,000/µL and platelets >50,000/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.

Special Populations:
Paediatric population
The safety and efficacy of Dacogen in children aged < 18 years have not yet been established. No data are available.

Hepatic impairment
Studies in patients with hepatic impairment have not been conducted. The need for dose adjustment in patients with hepatic impairment has not been evaluated. Dacogen should be used with caution in these 
 patients. If worsening hepatic function occurs, patients should be carefully monitored (see sections 4.4 and 5.2).

Renal impairment
Studies in patients with renal impairment have not been conducted. Dacogen should be used with caution in these patients.

The need for dose adjustment in patients with renal impairment has not been evaluated (see section 4.4 and 5.2).

The use of Dacogen in patients with renal or hepatic impairment has not been established. Caution should be exercised in the administration of Dacogen to patients with hepatic or renal impairmentand patients should be monitored closely for signs of toxicity.

Geriatric Use
Of the total number of MDS patients exposed to Dacogen in the controlled clinical trial, 61 of 83 patients were age 65 and over, while 21 of 83 patients were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Method of Administration

DACOGEN 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 Section 6.6.