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preparation of rituximab or ruxience

1. Using aseptic technique, withdraw the necessary amount of rituximab or Ruxience and dilute to a final concentration of 1 to 4 mg/mL into an infusion bag containing either 0.9% Sodium Chloride, USP, or 5% Dextrose in Water, USP. It is recommended that a dilution of 2 mg/mL be used for ease in calculating dose. Gently invert the bag to mix the solution. Discard any unused portion left in the vial. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.  
2. DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. Rituximab or Ruxience can be diluted with 5% dextrose or normal saline. In general they should not be infused with other fluids or medications, but nurses may consult with a pharmacist to check for y-site compatibility with other medications if needed.  
3. If the subject tolerated the first infusion well, subsequent study drug infusions can be administered at an initial rate of 100 mg/hr and increased by 100 mg/hr increments at 30-minute intervals to a maximum of 400 mg/hr as tolerated. Such an infusion schedule is listed below. If the subject did not tolerate the first infusion well, the above guidelines for the first infusion should be followed for subsequent infusions.  
| Time                                                                       | Infusion Rate   | Dose in 30 minutes   | Cumulative Dose   |
|----------------------------------------------------------------------------|-----------------|----------------------|-------------------|
| (Minutes)                                                                  | (mg/h)          | (mg)                 | (mg)              |
| 0-30                                                                       | 100             | 50                   | 50                |
| 31-60                                                                      | 200             | 100                  | 150               |
| 61-90                                                                      | 300             | 150                  | 300               |
| 91-120                                                                     | 400             | 200                  | 500               |
| 121-150                                                                    | 400             | 200                  | 700               |
| 151-180                                                                    | 400             | 200                  | 900               |
| 181-195*                                                                   | 400             | 200                  | 1000              |
| Should complete at 195 minutes (3h 15 min) to complete a 1000mg total dose |                 |                      |                   |  
4. Infusion and hypersensitivity reactions may occur. Premedication consisting of acetaminophen and diphenhydramine will be required before each infusion of rituximab or Ruxience. Premedication may attenuate infusion reactions. Since transient hypotension may occur during rituximab or Ruxience infusion, consideration should be given to withholding antihypertensive medications 12 hours before rituximab or Ruxience infusion.  
5. If a hypersensitivity (non-IgE-mediated) or an infusion reaction develops, the infusion rate should be reduced to half that rate, i.e. from 100 mg/h to 50 mg/h. Subjects who experience a moderate to severe infusion related reaction (fever, chills, or hypotension) should have their infusion interrupted immediately and should receive aggressive symptomatic treatment. The infusion should not be restarted before all the symptoms have disappeared and then the infusion can continue at one-half the previous rate.  
6. After the end of infusion, the intravenous line should remain in situ for at least 1 hour in order to be able to administer drugs intravenously if necessary. If there are no adverse events during this period of time, the intravenous line may be removed.  
16.3 APPENDIX C: MOXETUMOMAB PASUDOTOX-TDFK (LUMOXITI™) P**REPARATION AND**
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administration how supplied

LUMOXITI and IV Solution Stabilizer are packaged separately.  
Prior to preparation, LUMOXITI and IV Solution Stabilizer should be stored at 2°C to 8°C
(36°F to 46°F) in original cartons to protect from light.
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lumoxiti (moxetumomab pasudotox-tdfk)

Each single-dose vial supplies LUMOXITI 1 mg/vial (moxetumomab pasudotox-tdfk) for injection as a lyophilized cake or powder for reconstitution and dilution prior to intravenous infusion.  
Multiple vials of LUMOXITI may be required to administer a single dose (See Step 1:
Calculate Dose on next page).  
Reconstitute LUMOXITI vials with Sterile Water for Injection, USP only (not supplied).
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solution stabilizer

Each single-dose vial contains 1 mL IV Solution Stabilizer.  
Only one vial of IV Solution Stabilizer is needed per administration of LUMOXITI,
regardless of the number of vials of LUMOXITI used to prepare the infusion.  
Do not use IV Solution Stabilizer to reconstitute LUMOXITI. Do not flush IV lines with IV Solution Stabilizer.
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storage and handling of reconstituted

| Table 1. Storage Times and Conditions for Reconstituted and Diluted LUMOXITI Solution Reconstituted Solution Diluted LUMOXITI Solution in Infusion Bag After Dilution Administration LUMOXITI does not  contain bacteriostatic  preservatives. Use diluted solution  immediately or after storage at  room temperature (20°C to  25°C; 68°F to 77°F) for up to 4  hours or store refrigerated at  2°C to 8°C (36°F to 46°F) for  up to 24 hours. If the diluted solution is refrigerated  (2°C to 8°C; 36°F to 46°F), allow it  to equilibrate at room temperature  (20°C to 25°C; 68°F to 77°F) for no  more than 4 hours prior to  administration. Use reconstituted solution  immediately.  DO NOT STORE  reconstituted LUMOXITI  vials. Administer diluted solution within  24 hours of reconstitution as a 30-  minute infusion. PROTECT FROM LIGHT.  DO NOT FREEZE. DO NOT SHAKE. PROTECT FROM LIGHT.   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
1: se  
Calculate the dose (mg) and the number of LUMOXITI vials (1 mg/vial) to be reconstituted. The final concentration of the reconstituted LUMOXITI solution is 1 mg/mL.  
Individualize dosing based on the patient's **actual body weight** prior to the first dose of the first treatment cycle.  
A change in dose should only be made between cycles when a change in weight of greater than 10% is observed from the weight used to calculate the first dose of the first treatment cycle. No change in dose should be made during a particular cycle.  
**Do not** round down the dose for partial vials.
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step 2 gather supplies

LUMOXITI 1 mg/vial (number of vials to be reconstituted are based on Step 1)
1 vial of IV Solution Stabilizer (packaged separately)
Alcohol swabs 1 infusion bag containing 50 mL or 100 mL 0.9% Sodium Chloride Injection, USP
Sterile Water for Injection, USP Syringes and needles
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step 3 reconstitution

Reconstitute each LUMOXITI vial with **1.1 mL** Sterile Water for Injection, USP using aseptic technique.  
Direct the Sterile Water for Injection, USP slowly **along the walls** of the LUMOXITI vial and not directly at the lyophilized cake or powder.  
**Do not** reconstitute LUMOXITI vials with the IV Solution Stabilizer. **Gently** swirl the vial until completely dissolved. Invert the vial to ensure all cake or powder in the vial is dissolved. **Do not shake.**
Visually inspect that the reconstituted solution is clear to slightly opalescent, colorless to slightly yellow, and free from visible particles.  
**Do not** use if solution is cloudy, discolored, or contains any particles.  
The resulting 1 mg/mL solution allows a withdrawal volume of 1 mL.  
Note: Use reconstituted solution immediately. Do not store reconstituted LUMOXITI vials. See Table 1 for storage times and conditions for the reconstituted solution.
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step 4 preparation of infusion

Obtain a 50 mL 0.9% Sodium Chloride Injection, USP infusion bag.  
Only one vial of IV Solution Stabilizer is needed per administration of LUMOXITI,
regardless of the number of vials of LUMOXITI used to prepare the infusion.  
Add 1 mL IV Solution Stabilizer to the infusion bag containing 50 mL 0.9% Sodium Chloride Injection, USP.  
Gently invert the bag to mix the solution. **Do not shake.**
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step 5 dilution

Slowly withdraw the required volume of reconstituted LUMOXITI solution needed from each vial, per the calculated dose based on the patient's actual body weight (kg).  
Inject LUMOXITI into the infusion bag containing 50 mL 0.9% Sodium Chloride Injection, USP and 1 mL IV Solution Stabilizer.  
**Gently** invert the bag to mix the solution. Do not shake.  
Discard any partially used or empty vials of LUMOXITI and IV Solution Stabilizer. See **Table 1** for storage times and conditions for the diluted solution.
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step 6 intravenous hydration and

Administer intravenous hydration and premedication to the patient.  
Intravenously administer 1 L of isotonic solution (e.g. 5% Dextrose Injection, USP and 0.45% or 0.9% Sodium Chloride Injection, USP) over 2 to 4 hours before each LUMOXITI infusion. Administer 0.5 L to patients under 50 kg. On day 1 of cycles 2-8, pre-hydration may be started during the rituximab infusion provided it is completed no earlier than 2 hours prior to the LUMOXITI infusion.  
Premedicate 30 to 90 minutes prior to each LUMOXITI infusion with an antihistamine (e.g.  
diphenhydramine), acetaminophen, and a histamine-2 receptor antagonist (e.g. famotidine, or cimetidine), with the exception of day 1 of cycles 2-8, when premedications are to be given prior to Rituxan.
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step 7 administration

Infuse the diluted LUMOXITI solution intravenously using early call back/reverse flow method over 30 +/- 5 minutes.  
**Do not** mix LUMOXITI, or administer as an infusion with other medicinal products. After the infusion, flush the intravenous administration line with of 0.9% Sodium Chloride Injection, USP at the same rate as the infusion. This ensures that the full LUMOXITI dose is delivered.
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step 8 post-infusion medications

Administer post-infusion medications. Intravenously administer 1 L of isotonic solution (e.g. 5% Dextrose Injection, USP and 0.45% or 0.9% Sodium Chloride Injection, USP) over 2 to 4 hours after each LUMOXITI infusion. Administer 0.5 L to patients under 50 kg.  
Consider oral antihistamines and acetaminophen for up to 24 hours following LUMOXITI
infusions.  
Consider oral corticosteroid (e.g. 4 mg dexamethasone) to manage nausea and vomiting. Maintain adequate oral fluid intake. Advise all patients to adequately hydrate with up to 6 L (twelve 8-oz glasses) of oral fluids
(e.g. water, milk, or juice) per 24 hours on Days 1 through 8 of each 28-day treatment cycle. In patients under 50 kg, up to 2 L (eight 8-oz glasses) per 24-hour period is recommended.  
Consider low-dose aspirin on Days 1 through 8 of each 28-day treatment cycle.  
Note: This Healthcare Provider Instructions for Use has been approved by the U.S. Food and Drug Administration.
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16.4 appendix d patient hydration

19C0042 - Moxe-R in HCL
Cycle \#_______ Patient Name________________________________ Patient Study ID _____________________________
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instructions to the patient

1. Complete one form for each Cycle.  
2. You will drink at least 24 cups of fluid each day (1 cup/hour; 1 cup = 8 oz; total of 1.5 gal). **Do not go more than 3 hours without drinking**.  
3. Record the date, number of cups of fluid that you drank, and the time you took them.  
4. Please bring this form to your physician when you go for your next appointment.  
DAY 1  
| Date:         |
|---------------|
| CUPS (#) Time |  
| DAY 2 Date:   |
|---------------|
| CUPS (#) Time |  
Patient Name________________________________ Patient Study ID _____________________________  
| DAY 3 Date:   |             |
|---------------|-------------|
| CUPS (#) Time | DAY 4 Date: |
| CUPS (#) Time | DAY 5 Date: |
| CUPS (#) Time |             |  
19C0042 - Moxe-R in HCL
Cycle \#_______ Patient Name________________________________ Patient Study ID _____________________________  
| DAY 6 Date:   |             |
|---------------|-------------|
| CUPS (#) Time | DAY 7 Date: |
| CUPS (#) Time | DAY 8 Date: |
| CUPS (#) Time |             |  
19C0042 - Moxe-R in HCL
Cycle \#_______  
| 19C0042 - Moxe-R in HCL                                                                                                                                                                                                                                                        |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Cycle #_______ Patient Name________________________________ Patient Study ID _____________________________ Patient's Signature: ___________________________________ Date: ____________________ Staff Signature: ___________________________________ Date: ____________________ |