Posology : מינונים

5.          DOSAGE AND ADMINISTRATION

5.1         Premedication and Special Considerations

•        Premedicate adults with acetaminophen 650 mg orally and diphenhydramine 50 mg orally or intravenously 1 hour prior to MYLOTARG dosing and 1 mg/kg methylprednisolone or an equivalent dose of an alternative corticosteroid within 30 minutes prior to infusion of MYLOTARG.
•        Premedicate pediatric patients 1 month and older with acetaminophen 15 mg/kg (maximum of 650 mg) and diphenhydramine 1 mg/kg (maximum of 50 mg), 1 hour prior to MYLOTARG dosing and 1 mg/kg methylprednisolone orally or intravenously within 30 minutes prior to infusion of MYLOTARG; additional doses of acetaminophen and diphenhydramine may be administered every 4 hours after the initial pretreatment dose. Repeat with the same dose of methylprednisolone or an equivalent corticosteroid for any sign of an infusion reaction, such as fever, chills, hypotension, or dyspnea during the infusion or within 4 hours afterwards [see Warnings and Precautions (8.2)].


•       Use appropriate measures to prevent tumor lysis syndrome.

•       For patients with hyperleukocytosis (leukocyte count greater than or equal to 30 Gi/L), cytoreduction is recommended prior to administration of MYLOTARG.

5.2         Recommended Dosage

Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen)
Adults

The recommended dose of MYLOTARG in adults is 3 mg/m2. A treatment course including MYLOTARG in combination therapy for adults with newly-diagnosed de novo CD33-positive AML consists of 1 induction cycle and 2 consolidation cycles [see Clinical Studies (14.1)].

For the induction cycle, the recommended dose of MYLOTARG is 3 mg/m 2 (up to one 5 mg vial) on Days 1, 4 and 7 in combination with daunorubicin and cytarabine. For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle.
For the consolidation cycles, the recommended dose of MYLOTARG is 3 mg/m 2 on Day 1 (up to one 5 mg vial) in combination with daunorubicin and cytarabine.

Pediatric Patients 1 Month and Older

The recommended dose of MYLOTARG in pediatric patients 1 month and older is: •   3 mg/m2 for patients with body surface area (BSA) greater than or equal to 0.6 m2 •   0.1 mg/kg for patients with BSA less than 0.6 m2

For Induction 1, MYLOTARG is given once in combination with standard chemotherapy. No MYLOTARG is given in the second induction cycle [see Clinical Studies (14.1)].

No MYLOTARG is given in the first or third intensification cycles. For Intensification 2, MYLOTARG is given once in combination with standard chemotherapy. Consider the risks and potential benefits before giving MYLOTARG during Intensification 2 [see Adverse Reactions (9.1)].


Newly-Diagnosed CD33-positive AML (Single-agent Regimen)
A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy [see Clinical Studies (14.1)].

For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m 2 (not limited to one 5 mg vial) as a single agent on Day 1, and 3 mg/m2 (not limited to one 5 mg vial) on Day 8.

For continuation, the recommended dose of MYLOTARG is 2 mg/m 2 (not limited to one 5 mg vial) as a single agent on Day 1 every 4 weeks.

Relapsed or Refractory CD33-positive AML (Single-agent Regimen)


The recommended dose of MYLOTARG as a single agent for treatment for adults and pediatric patients 2 years and older with relapsed or refractory CD33-positive AML is 3 mg/m 2 (up to one 5 mg vial) on Days 1, 4 and 7. Treatment in the relapsed or refractory setting consists of a single course of MYLOTARG [see
Clinical Studies (14.1)].

5.3    Dosage Modifications for Toxicities

Monitor blood counts frequently through resolution of cytopenias. Monitor blood counts and chemistries at least three times per week through recovery from treatment-related toxicities. Management of some adverse reactions [see Warnings and Precautions (8) and Adverse Reactions (9)] may require dose interruptions or permanent discontinuation of MYLOTARG, Table 1, shows the dose modification guidelines for hematologic and nonhematologic toxicities.

Table 1. Dosage Modifications for Hematologic and Nonhematologic Toxicities Hematologic and                              Recommended Action
Nonhematologic
Toxicities
For patients receiving MYLOTARG in combination therapy
Persistent                   • Adults: If platelet count does not recover to greater than or thrombocytopenia               equal to 100 Gi/L within 14 days following the planned start date of the consolidation cycle (14 days after hematologic recovery following previous cycle), discontinue
MYLOTARG (do not administer MYLOTARG in the consolidation cycles).
• Pediatrics: Patients should have a platelet count of 75 Gi/L before the next cycle (induction or intensification).
Persistent neutropenia       • Adults: If neutrophil count does not recover to greater than 0.5 Gi/L within 14 days following the planned start date of the consolidation cycle (14 days after hematologic recovery following previous cycle), discontinue MYLOTARG (do not administer MYLOTARG in the consolidation cycles).
• Pediatrics: Patients should have a neutrophil count of 1 Gi/L before the next cycle (induction or intensification).
For all patients receiving MYLOTARG (Monotherapy or in Combination)
VOD                          • Discontinue MYLOTARG [see Warnings and Precautions (8.1)].
Total bilirubin greater than • Delay treatment with MYLOTARG until recovery of total 2 × ULN, or AST and/or         bilirubin to less than or equal to 2 × ULN and AST and ALT
ALT greater than               to less than or equal to 2.5 × ULN prior to each dose.
2.5 × ULN                    • Omit scheduled dose if delayed more than 2 days between sequential infusions.
Infusion-related reactions   • Interrupt the infusion and institute appropriate medical management.
• Administer acetaminophen, diphenhydramine and/or methylprednisolone, if needed [see Dosage and
Administration (5.1)].
• Provide supportive care measures as needed.
• For mild, moderate or severe infusion-related reactions, once symptoms resolve, consider resuming the infusion at no more than half the rate at which the reaction occurred. Repeat the
Table 1. Dosage Modifications for Hematologic and Nonhematologic Toxicities Hematologic and                          Recommended Action
Nonhematologic
Toxicities procedure above in the event of recurrence of symptoms.
• Permanently discontinue MYLOTARG upon occurrence of a severe infusion reaction or for any life-threatening infusion reaction [see Warnings and Precautions (8.2)].
Other severe or life-    • Delay treatment with MYLOTARG until recovery to a threatening non-             severity of no more than mild.
hematologic toxicities   • Omit scheduled dose if delayed more than 2 days between sequential infusions.
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; VOD=veno-occlusive disease; ULN=upper limit of normal.

5.4        Instructions for Reconstitution, Dilution, and Administration 
Use appropriate aseptic technique for the reconstitution and dilution procedures. Protect the reconstituted and diluted MYLOTARG solution from light.

Reconstitution

•       MYLOTARG is a cytotoxic drug. Follow applicable special handling and disposal procedures.
•       Calculate the dose (mg) and number of vials of MYLOTARG required.
•       Prior to reconstitution, allow drug product vials to reach room temperature (up to 30°C) for approximately 5 minutes.
•       Reconstitute each vial with 5 mL of Sterile Water for Injection, to obtain a concentration of 1 mg/mL of MYLOTARG that delivers at least 4.5 mL (4.5 mg).
•       Gently swirl the vial to aid dissolution. DO NOT SHAKE.
•       Inspect the reconstituted solution for particulates and discoloration. The reconstituted solution may contain small white to off-white, opaque to translucent, and amorphous to fiber-like particles.
•       MYLOTARG contains no bacteriostatic preservatives.
•       If the reconstituted solution cannot be used immediately, it may be stored in the original vial for up to 16 hours in a refrigerator (2°C to 8°C) or up to 3 hours at room temperature (up to 30°C).. PROTECT FROM LIGHT. DO NOT FREEZE.

* The minimum amount that can be extracted is 4.5 mg/vial.

Dilution

•    Calculate the required volume of the reconstituted solution needed to obtain the appropriate dose according to patient body surface area. Withdraw this amount from the vial(s) using a syringe.
PROTECT FROM LIGHT. Discard any unused reconstituted solution left in the vial.
Doses must be mixed to a concentration between 0.075 mg/mL to 0.234 mg/mL according to the following instructions:
• Doses less than 3.9 mg must be prepared for administration by syringe. Add the reconstituted MYLOTARG solution to a syringe with 0.9% Sodium Chloride Injection to a final concentration between 0.075 mg/mL to 0.234 mg/mL. PROTECT FROM LIGHT.
• Doses greater than or equal to 3.9 mg are to be diluted in a syringe or a polyvinyl chloride (PVC) with di(2-ethylhexyl)phthalate (DEHP), non-PVC polyolefin, or ethylene vinyl acetate intravenous infusion 
bag in an appropriate volume of 0.9% Sodium Chloride Injection to ensure a final concentration between 0.075 mg/mL to 0.234 mg/mL. PROTECT FROM LIGHT.
•        Gently invert the infusion container to mix the diluted solution. DO NOT SHAKE.
•        Following dilution with 0.9% Sodium Chloride Injection, MYLOTARG solution should be infused immediately. If not used immediately, the diluted solution may be stored up to 18 hours in a refrigerator (2°C to 8°C) and for up to 6 hours at room temperature (up to 30°C). The allowed time at room temperature (up to 30°C) includes the time required for preparation of the diluted solution, equilibration, if needed, and the 2 hours needed to administer to the patient. PROTECT FROM LIGHT and DO NOT FREEZE.

Administration

•       Use an in-line 0.2 micron polyethersulfone (PES) filter for infusion of MYLOTARG.
•       Protect the intravenous bag from light using a light-blocking cover during infusion. The infusion line does not need to be protected from light.
•       Infuse the diluted solution over 2 hours using an infusion set made of polyvinyl chloride (PVC) with DEHP, PVC non-DEHP, polyethylene, or polyurethane. The infusion must be completed prior to the end of the allowed 6-hour storage of the diluted solution at room temperature (up to 30°C).
•       Do not mix MYLOTARG with, or administer as an infusion with, other medicinal products.

6.         DOSAGE FORMS AND STRENGTHS

For injection: 5 mg as a white to off-white lyophilized cake or powder in a single-dose vial for reconstitution and further dilution.