Posology : מינונים

5. DOSAGE AND ADMINISTRATION
5.1           Recommended Dosage
The recommended dosage of ZEPZELCA is 3.2 mg/m2 by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity.
Initiate treatment with ZEPZELCA only if absolute neutrophil count (ANC) is at least 1,500 cells/mm 3 and platelet count is at least 100,000/mm3.

5.2           Dosage Modifications for Adverse Reactions
The recommended dose reductions for adverse reactions are listed in Table 1. Permanently discontinue ZEPZELCA in patients who are unable to tolerate 2 mg/m2 or require a dose delay greater than two weeks.

Table 1: Dose Reduction for ZEPZELCA for Adverse Reactions
Dose Reduction                             Total Dose
First                                      2.6 mg/m2 every 21 days
Second                                     2 mg/m2 every 21 days

Discontinue ZEPZELCA if patients are unable to tolerate 2 mg/m 2 every 21 days.

Dosage modifications for ZEPZELCA for adverse reactions are presented in Table 2.

Table 2: Dosage Modifications for ZEPZELCA for Adverse Reactions


Adverse Reaction                        Severitya                                Dosage Modification 
Neutropeniab                            Grade 4                                  • Withhold ZEPZELCA until Grade ≤ 1 [see Warnings and Precautions               or                                   • Resume ZEPZELCA at a reduced (7.1)]                                                                             dose Any grade febrile neutropenia
Thrombocytopenia                        Grade 3 with bleeding                    • Withhold ZEPZELCA until platelet ≥ 100,000/mm3
[see Warnings and Precautions               or
(7.1)]                                                                           • Resume ZEPZELCA at reduced dose Grade 4
Hepatotoxicity                        Grade 2                                     • Withhold ZEPZELCA until Grade ≤ 1 [see Warnings and Precautions                                                     • Resume ZEPZELCA at same dose (7.2)]


Grade ≥ 3                                   • Withhold ZEPZELCA until Grade ≤ 1 • Resume ZEPZELCA at reduced dose or permanently discontinue

Rhabdomyolysis                        Grade 2                                     • Withhold ZEPZELCA until Grade ≤ 1 [see Warnings and Precautions                                                     • Resume ZEPZELCA at same dose (7.4)]
Grade ≥ 3                                   • Permanently discontinue ZEPZELCA.
Other Adverse Reactions               Grade 2                                     • Withhold ZEPZELCA until Grade ≤ 1 [see Postmarketing (8.2)]                                                         • Resume ZEPZELCA at same dose Grade ≥ 3                                   • Withhold ZEPZELCA until Grade ≤ 1 • Resume ZEPZELCA at reduced dose or permanently discontinue

 a
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.
b
Patients with isolated Grade 4 neutropenia (neutrophil count less than 500 cells/mm 3) may receive G-CSF prophylaxis rather than undergo lurbinectedin dose reduction.

5.3            Premedication
Consider administering the following pre-infusion medications for antiemetic prophylaxis [see Adverse Reactions (8.1)]: •   Corticosteroids (dexamethasone 8 mg intravenously or equivalent) •   Serotonin antagonists (ondansetron 8 mg intravenously or equivalent) 
5.4            Preparation, Administration and Storage
ZEPZELCA is a hazardous drug. Follow applicable special handling and disposal procedures.
Preparation
•   Inject 8 mL of Sterile Water for Injection USP into the vial, yielding a solution containing 0.5 mg/mL lurbinectedin. Shake the vial until complete dissolution.
•   Visually inspect the solution for particulate matter and discoloration. The reconstituted solution is a clear, colorless or slightly yellowish solution, essentially free of visible particles.
•   Calculate the required volume of reconstituted solution as follows: Volume (mL) = Body Surface Area (m2) x Individual Dose (mg/m2)
0.5 mg/mL

•   For administration through a central venous line, withdraw the appropriate amount of reconstituted solution from the vial and add to an infusion container containing at least 100 mL of diluent (0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP).
•   For administration through a peripheral venous line, withdraw the appropriate amount of reconstituted solution from the vial and add to an infusion container containing at least 250 mL of diluent (0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP).
Administration
•   Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is observed, do not administer.
•   ZEPZELCA can be administered with or without an in-line filter. If infusion lines containing in-line filters are utilized for administration of ZEPZELCA, Polyethersulfone (PES) in-line filters with pore sizes of 0.22 micron are recommended.
o    Do not use in-line nylon membrane filters when the reconstituted ZEPZELCA solution is diluted using 0.9% Sodium Chloride Injection, USP. Adsorption of ZEPZELCA to the Nylon membrane filters has been observed when 0.9% Sodium Chloride Injection, USP is used as the diluent.
•   Compatibility with other intravenous administration materials and the diluted ZEPZELCA solution has been demonstrated in the following materials: o    Polyolefin containers (polyethylene, polypropylene and mixtures).
o    Polyvinyl Chloride (PVC) (non-DEHP-containing), polyurethane and polyolefin infusion sets (polyethylene, polypropylene and polybutadiene).
o    Implantable venous access systems with titanium and plastic resin ports and with polyurethane or silicone intravenous catheters.
•   Do not co-administer ZEPZELCA and other intravenous drugs concurrently within the same intravenous line.
Storage of Infusion Solution
•   If not used immediately after reconstitution or dilution, the ZEPZELCA solution can be stored prior to administration for up to 24 hours following reconstitution, including infusion time, at either room temperature/ ambient light or under refrigeration at
2ºC-8ºC (36ºF-46ºF) conditions.