Posology : מינונים

5         DOSAGE AND ADMINISTRATION

5.1 Recommended Dosage
• Administer ELZONRIS at 12 mcg/kg intravenously over 15 minutes once daily on days 1 to 5 of a 21- day cycle. The dosing period may be extended for dose delays up to day 10 of the cycle. Continue treatment with ELZONRIS until disease progression or unacceptable toxicity. The dose is calculated based on the patient’s actual weight.
• Prior to the first dose of the first cycle, ensure serum albumin is greater than or equal to 3.2 g/dL before administering ELZONRIS.
• Premedicate patients with an H1-histamine antagonist (e.g., diphenhydramine hydrochloride), H2- histamine antagonist (e.g., famotidine), corticosteroid (e.g., 50 mg intravenous methylprednisolone or equivalent) and acetaminophen (or paracetamol) approximately 60 minutes prior to each ELZONRIS infusion.
• Administer Cycle 1 of ELZONRIS in the inpatient setting with patient observation through at least 24 hours after the last infusion.
•      Administer subsequent cycles of ELZONRIS in the inpatient setting or in a suitable outpatient ambulatory care setting that is equipped with appropriate monitoring for patients with hematopoietic malignancies undergoing treatment. Observe patients for a minimum of 4 hours following each infusion.

5.2      Dosage Modifications
Monitor vital signs and check albumin, transaminases, and creatinine prior to preparing each dose of ELZONRIS. See Table 1 for recommended dose modifications and Table 2Table 2 for CLS management guidelines.
Table 1. Recommended ELZONRIS Dosage Modifications
Parameter             Severity Criteria                           Dosage Modification Serum albumin < 3.5 g/dL or reduced ≥
Serum albumin         0.5 g/dL from value measured prior to       See CLS Management Guidelines (Table 2) initiation of the current cycle
Body weight increase ≥ 1.5 kg over
See CLS Management Guidelines (Table
Body weight           pretreatment weight on prior treatment
2Table 2) day
Aspartate aminotransferase                                                  Withhold ELZONRIS until transaminase ALT or AST increase > 5 times the
(AST) or alanine                                                  elevations are ≤ 2.5 times the upper limit of upper limit of normal aminotransferase                                                  normal.
(ALT)
Serum creatinine > 1.8 mg/dL (159           Withhold ELZONRIS until serum creatinine Serum creatinine      micromol/L) or creatinine clearance < 60    resolves to ≤ 1.8 mg/dL (159 micromol/L) or mL/minute                                   creatinine clearance ≥ 60 mL/minute.
Systolic blood        Systolic blood pressure ≥ 160 mmHg or       Withhold ELZONRIS until systolic blood pressure              ≤ 80 mmHg                                   pressure is < 160 mmHg or > 80 mmHg.
Withhold ELZONRIS until heart rate is
Heart rate            Heart rate ≥ 130 bpm or ≤ 40 bpm
< 130 bpm or > 40 bpm.
Body                                                              Withhold ELZONRIS until body temperature Body temperature ≥ 38°C temperature                                                       is < 38°C.
Withhold ELZONRIS until resolution of any mild or moderate hypersensitivity reaction.
Hypersensitivity      Mild or moderate
Resume ELZONRIS at the same infusion reactions rate.
Severe or life-threatening                  Discontinue ELZONRIS permanently.


Table 2. CLS Management Guidelines
Time of               CLS                        Recommended                                  ELZONRIS Dosing Presentation          Sign/Symptom               Action                                       Management Prior to first dose
Administer ELZONRIS when serum albumin ≥ 3.2 of ELZONRIS in        Serum albumin < 3.2 g/dL g/dL.
cycle 1

Serum albumin < 3.5 g/dL            Administer 25g intravenous albumin (q12h or more
Interrupt
Serum albumin reduced by            frequently as practical) until
During                                                                                        ELZONRIS dosing ≥ 0.5 g/dL from the albumin         serum albumin is ≥ 3.5 g/dL
ELZONRIS                                                                                      until the relevant value measured prior to             AND not more than 0.5 g/dL dosing                                                                                        CLS sign/symptom ELZONRIS dosing initiation of       lower than the value measured has resolved1.
the current cycle                   prior to dosing initiation of the current cycle.


Administer 25g intravenous albumin (q12h or more frequently as practical), and manage fluid status as indicated clinically (e.g., generally with
A predose body weight that is        intravenous fluids and increased by ≥ 1.5 kg over the       vasopressors if hypotensive and previous day’s predose weight        with diuretics if normotensive or hypertensive), until body weight increase has resolved (i.e., the increase is no longer ≥ 1.5 kg greater than the previous day’s predose weight).

Administer 25g intravenous albumin (q12h, or more frequently as practical) until serum albumin is ≥ 3.5 g/dL.
Administer 1 mg/kg of methylprednisolone (or an equivalent) per day, until resolution of CLS sign/symptom
Edema, fluid overload and/or or as indicated clinically.
hypotension
Aggressive management of fluid status and hypotension if present, which could include intravenous fluids and/or diuretics or other blood pressure management, until resolution of CLS sign/symptom or as clinically indicated.
1
If ELZONRIS dose is held:
• ELZONRIS administration may resume in the same cycle if all CLS signs/symptoms have resolved and the patient did not require measures to treat hemodynamic instability • ELZONRIS administration should be held for the remainder of the cycle if CLS signs/symptoms have not resolved or the patient required measures to treat hemodynamic instability (e.g., required administration of intravenous fluids and/or vasopressors to treat hypotension) (even if resolved), and
• ELZONRIS administration may only resume in the next cycle if all CLS signs/symptoms have resolved, and the patient is hemodynamically stable.

5.3     Preparation for Administration
Assure the following components required for dose preparation and administration are available prior to thawing ELZONRIS:
• One infusion syringe pump
• One empty 10 mL sterile vial
• 0.9% Sodium Chloride Solution for Injection
• Three 10 mL sterile syringes
• One 1 mL sterile syringe
• One mini-bifuse Y-connector or equivalent
• Microbore tubing
• One 0.2 micron polyethersulfone in-line filter


•     Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Thawed ELZONRIS appearance should be a clear, colorless liquid that may contain a few white to translucent particles.
•     Prior to dose preparation allow vials to thaw at 25 °C or below for up to 1 hour in the outer carton, and verify thaw visually. Thawed vials may be held at room temperature for approximately 1 hour prior to dosage preparation. Do not force thaw. Do not refreeze vial once thawed.
•     Use aseptic technique for preparation of the ELZONRIS dose.
•     A 2-step process is required for preparation of the final ELZONRIS dose: - Step 1 - Prepare 10 mL of 100 mcg/mL ELZONRIS
- Using a sterile 10 mL syringe, transfer 9 mL of 0.9% Sodium Chloride Solution for Injection to an empty sterile 10 mL vial.
- Gently swirl the ELZONRIS vial to mix the contents, remove the cap, and using a sterile 1 mL syringe, withdraw 1 mL of thawed ELZONRIS from the product vial.
- Transfer the 1 mL of ELZONRIS into the 10 mL vial containing the 0.9% Sodium Chloride Solution for Injection. Gently invert the vial at least 3 times to mix the contents.
Do not shake vigorously.
- Following dilution the final concentration of ELZONRIS is 100 mcg/mL.
- Step 2 – Prepare the ELZONRIS infusion set.
- Calculate the required volume of diluted ELZONRIS (100 mcg/mL) according to patient’s weight.
- Draw up the required volume into a new syringe (if more than 10 mL of diluted ELZONRIS (100 mcg/mL) is required for the calculated patient dose, repeat step 1 with a second vial of ELZONRIS). Label the ELZONRIS syringe.
- Prepare a separate syringe with at least 3 mL of 0.9% Sodium Chloride Solution for Injection to be used to flush the administration set once the ELZONRIS dose is delivered.
- Label the 0.9% Sodium Chloride Solution for Injection flush syringe.
- Connect the 0.9% Sodium Chloride Solution for Injection flush syringe to one arm of the Y-connector or equivalent and ensure the clamp is closed.
- Connect the product syringe to the other arm of the Y-connector or equivalent and ensure the clamp is closed.
- Connect the terminal end of the Y-connector or equivalent to the microbore tubing.
- Remove the cap from the supply side of the 0.2 micron filter and attach it to the terminal end of the microbore tubing.
- Unclamp the arm of the Y-connector or equivalent connected to the 0.9% Sodium Chloride Solution for Injection flush syringe. Prime the Y-connector or equivalent up to the intersection (do not prime the full infusion set with 0.9% Sodium Chloride Solution for Injection). Re-clamp the Y-connector or equivalent line on the 0.9% Sodium Chloride Solution for Injection flush arm.
- Remove the cap on the terminal end of the 0.2 micron filter and set it aside. Unclamp the arm of the Y-connector or equivalent connected to the product syringe, and prime the entire infusion set, including the filter. Recap the filter, and re-clamp the Y-connector or equivalent line on the product side. The infusion set is now ready for delivery for dose administration.
•     Administer ELZONRIS within 4 hours. During this 4-hour window, the prepared dose should remain at 25 °C.
•     Do not reuse excess ELZONRIS. Any excess material should be thrown away immediately following infusion.

5.4     Administration

•     Establish venous access and maintain with sterile 0.9% Sodium Chloride Solution for Injection.
•     Administer the prepared ELZONRIS dose via infusion syringe pump over 15 minutes. The total infusion time will be controlled using a syringe pump to deliver the entire dose and the 0.9% Sodium Chloride Solution for Injection flush over 15 minutes.


•     Insert the ELZONRIS syringe into the syringe pump, open the clamp on the ELZONRIS side of the Y- connector or equivalent and deliver the prepared ELZONRIS dose.
•     Once the ELZONRIS syringe has been emptied, remove it from the pump and place the 0.9% Sodium Chloride Solution for Injection flush syringe in the syringe pump.
•     Open the clamp on the 0.9% Sodium Chloride Solution for Injection flush side of the Y-connector or equivalent and resume infusion via the syringe pump at the pre-specified flow to push remaining ELZONRIS dose out of the infusion line to complete delivery.