Posology : מינונים

3. DOSAGE AND ADMINISTRATION

3.1 Patient Selection
Unresectable or Metastatic HER2-Low Breast Cancer
Select patients for treatment of unresectable or metastatic HER2-low breast cancer with ENHERTU based on HER2 expression (IHC 1+ or IHC 2+/ISH-) [see Clinical Studies (14.2)].


Unresectable or Metastatic HER2-Mutant NSCLC
Select patients for the treatment of unresectable or metastatic HER2-mutant NSCLC with ENHERTU based on the presence of activating HER2 (ERBB2) mutations in tumor or plasma specimens [see Clinical Studies (14.3)]. If no mutation is detected in a plasma specimen, test tumor tissue.

Locally Advanced or Metastatic Gastric Cancer

Select patients with locally advanced or metastatic gastric cancer based on HER2 protein overexpression or HER2 gene amplification. Reassess HER2 status if it is feasible to obtain a new tumor specimen after prior trastuzumab-based therapy and before treatment with ENHERTU.

3.2 Recommended Dosage and Schedules

Do not substitute ENHERTU for or with trastuzumab or ado-trastuzumab emtansine.
Slow or interrupt the infusion rate if the patient develops infusion-related symptoms.
Permanently discontinue ENHERTU in case of severe infusion reactions.

Premedication
ENHERTU is highly emetogenic [see Adverse Reactions (7.1)] which includes delayed nausea and/or vomiting.
Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting.
Recommended Dosage for Metastatic Breast Cancer

The recommended dosage of ENHERTU is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Recommended Dosage for Unresectable or Metastatic HER2-Mutant NSCLC

The recommended dosage of ENHERTU is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Recommended Dosage for Locally Advanced or Metastatic Gastric Cancer

The recommended dosage of ENHERTU is 6.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.


3.3 Dosage Modifications
Management of adverse reactions may require temporary interruption, dose reduction, or treatment discontinuation of ENHERTU as described in Tables 1 and 2.

Do not re-escalate the ENHERTU dose after a dose reduction is made.

If a planned dose is delayed or missed, administer as soon as possible; do not wait until the next planned cycle. Adjust the schedule of administration to maintain a 3-week interval between doses. Administer the infusion at the dose and rate the patient tolerated in the most recent infusion.

Table 1: Dosage Reduction Schedule
Dose Reduction Schedule                    Breast Cancer and NSCLC                    Gastric Cancer 
Recommended starting dose                                 5.4 mg/kg                            6.4 mg/kg First dose reduction                                      4.4 mg/kg                            5.4 mg/kg Second dose reduction                                     3.2 mg/kg                            4.4 mg/kg Requirement for further dose reduction               Discontinue treatment                Discontinue treatment 
Table 2: Dosage Modifications for Adverse Reactions
Adverse Reaction                    Severity                        Treatment Modification Interstitial Lung     Asymptomatic ILD/pneumonitis        Interrupt ENHERTU until resolved to Disease               (Grade 1)                           Grade 0, then: (ILD)/pneumonitis                                         • if resolved in 28 days or less from date of onset, maintain dose.
[see Warnings and                                         • if resolved in greater than 28 days Precautions (6.1)].                                           from date of onset, reduce dose one level (see Table 1).
• consider corticosteroid treatment as soon as ILD/pneumonitis is suspected
.
Symptomatic ILD/pneumonitis         • Permanently discontinue ENHERTU.
(Grade 2 or greater)                • Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected .
Neutropenia           Grade 3 (less than 1.0 to 0.5 x        •   Interrupt ENHERTU until resolved to 109/L)                                     Grade 2 or less, then maintain dose.


Adverse Reaction                        Severity                                    Treatment Modification [see Warnings and         Grade 4 (less than 0.5 x 109/L)                 •    Interrupt ENHERTU until resolved to Precautions (6.2)].                                                            Grade 2 or less.
•    Reduce dose by one level (see
Table 1).
Febrile                   Absolute neutrophil count of less               •    Interrupt ENHERTU until resolved.
Neutropenia               than 1.0 x 109/L and temperature                •    Reduce dose by one level (see greater than 38.3°C or a sustained                   Table 1).
[see Warnings and         temperature of 38°C or greater for
Precautions (6.2)].       more than one hour


Thrombocytopenia          Grade 3 (platelets less than 50 to 25           •    Interrupt ENHERTU until resolved to x 109/L)                                             Grade 1 or less, then maintain dose.
[see Adverse
Reactions (7.1)]
Grade 4 (platelets less than 25 x               •    Interrupt ENHERTU until resolved to 109/L)                                               Grade 1 or less.
•    Reduce dose by one level (see
Table 1).
Left Ventricular          LVEF greater than 45% and                       •    Continue treatment with ENHERTU.
Dysfunction               absolute decrease from baseline is
10% to 20%
[see Warnings and
Precautions (6.3)]                              And absolute              •    Continue treatment with ENHERTU.
decrease from             •    Repeat LVEF assessment within 3 baseline is less               weeks.
than 10%
And absolute              •    Interrupt ENHERTU.
LVEF 40% to decrease from             •    Repeat LVEF assessment within 3 baseline is 10% to             weeks.
45%
20%                       •    If LVEF has not recovered to within
10% from baseline, permanently discontinue ENHERTU.
•    If LVEF recovers to within 10% from baseline, resume treatment with
ENHERTU at the same dose.
LVEF less than 40% or absolute                  •    Interrupt ENHERTU.
decrease from baseline is greater               •    Repeat LVEF assessment within 3 than 20%                                             weeks.
•    If LVEF of less than 40% or absolute decrease from baseline of greater than 20% is confirmed, permanently discontinue ENHERTU.
Symptomatic congestive heart                    •    Permanently discontinue ENHERTU.
failure (CHF)
Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v.5.0).


3.4 Preparation and Administration
In order to prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is ENHERTU (trastuzumab deruxtecan) and not trastuzumab or ado-trastuzumab emtansine.

Reconstitute and further dilute ENHERTU prior to intravenous infusion. Use appropriate aseptic technique.
ENHERTU (trastuzumab deruxtecan) is a cytotoxic drug. Follow applicable special handling and disposal procedures.

Reconstitution

•   Reconstitute immediately before dilution.
•   More than one vial may be needed for a full dose. Calculate the dose (mg), the total volume of reconstituted ENHERTU solution required, and the number of vial(s) of ENHERTU needed [see Dosage and Administration (3.2)].
•   Reconstitute each 100 mg vial by using a sterile syringe to slowly inject 5 mL of Sterile Water for Injection, USP into each vial to obtain a final concentration of 20 mg/mL.
•   Swirl the vial gently until completely dissolved. Do not shake.
•   If not used immediately, store the reconstituted ENHERTU vials in a refrigerator at 2ºC to 8ºC for up to 24 hours from the time of reconstitution, protected from light. Do not freeze.
•
•   The product does not contain a preservative. Discard unused ENHERTU after 24 hours refrigerated.

Dilution

•   Withdraw the calculated amount from the vial(s) using a sterile syringe. .
•   Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be clear and colorless to light yellow. Do not use if visible particles are observed or if the solution is cloudy or discolored.
•
•   Dilute the calculated volume of reconstituted ENHERTU in an intravenous infusion bag containing 100 mL of 5% Dextrose Injection, USP. DO NOT use Sodium Chloride Injection, USP. ENHERTU is compatible with an infusion bag made of polyvinylchloride or polyolefin (copolymer of ethylene and polypropylene).
•   Gently invert the infusion bag to thoroughly mix the solution. Do not shake.
•   Cover the infusion bag to protect from light.
•   Discard any unused portion left in the vials.

Administration

If not used immediately, store the diluted ENHERTU in a refrigerator at 2ºC to 8ºC for up to 24 hours or at room temperature for up to 4 hours including preparation and infusion time.

•   Protect from light. Do not freeze.
•   The maximum time from reconstitution of the vial through the end of administration should not exceed 24 hours.
•   If the prepared infusion solution was stored refrigerated (2ºC to 8ºC), allow the solution to reach room temperature prior to administration. Cover the infusion bag to protect from light.
•   Administer ENHERTU as an intravenous infusion only with an infusion set made of polyolefin or polybutadiene
•   Administer ENHERTU with a 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter.
•   Do NOT administer as an intravenous push or bolus.
•   Cover the infusion bag to protect from light during administration.
•   Do not mix ENHERTU with other drugs or administer other drugs through the same intravenous line.
•   First infusion: Administer infusion over 90 minutes.
•   Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated.


4   DOSAGE FORMS AND STRENGTHS
For injection: 100 mg of trastuzumab deruxtecan as a white to yellowish white lyophilized powder in a single-dose vial for reconstitution and further dilution