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2. DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
The recommended dosages for IMFINZI as a single agent and IMFINZI in combination with other therapeutic agents are presented in Table 1.

Administer IMFINZI as an intravenous infusion after dilution as recommended [see Dosage and Administration (2.3)] .
Table 1. Recommended Dosages of IMFINZI

Indication                   Recommended IMFINZI                  Duration of Therapy dosage

Urothelial Carcinoma         Patients with a body weight of       Until disease ≥30 kg:                              progression or
10 mg/kg every 2 weeks               unacceptable toxicity or
1,500 mg every 4 weeks


Patients with a body weight of
<30 kg:
10 mg/kg every 2 weeks

Patients with a body weight of      Until disease
≥30 kg:                             progression,
Unresectable stage III
10 mg/kg every 2 weeks              unacceptable toxicity,
NSCLC                     Or                                  or a maximum of 12 1,500 mg every 4 weeks              months

Patients with a body weight of
<30 kg:
10 mg/kg every 2 weeks or
20 mg/kg every 4 weeks
Patients with a body weight of      Until disease
≥30 kg                              progression or
ES-SCLC                   1,500 mg in combination with        unacceptable toxicity chemotherapy* every 3 weeks
(21 days) for 4 cycles, followed by 1,500 mg every 4 weeks as a single agent

Patients with a body weight of
<30 kg:
20 mg/kg in combination with chemotherapy* every 3 weeks
(21 days) for 4 cycles, followed by 20 mg/kg every 4 weeks as a single agent
Patients with a body weight of       Until disease progression
BTC                      ≥30 kg: or until unacceptable toxicity
1,500 mg in combination with chemotherapy* every 3 weeks

(21 days) followed by 1,500 mg every 4 weeks as a single agent


Patients with a body weight of <30 kg:

20 mg/kg in combination with
 chemotherapy* every 3 weeks
(21 days) followed by 20 mg/kg

every 4 weeks as a single agent


 uHCC                                                                     After Cycle 1 of Patients with a body weight of combination therapy,
≥30 kg:                                   administer IMFINZI as a single agent every 4 weeks until disease
•   IMFINZI 1,500 mg                     progression or unacceptable toxicity following a single dose of
 tremelimumab $ 300 mg at

Day 1 of Cycle 1;
• Continue IMFINZI

1,500 mg as a single
 agent every 4 weeks
Patients with a body weight of

<30 kg:


• IMFINZI 20 mg/kg
 following a single dose of tremelimumab $ 4 mg/kg
 at Day 1 of Cycle 1;

•   Continue IMFINZI
20 mg/kg as a single agent
 every 4 weeks

* Administer IMFINZI prior to   chemotherapy on the same day. When IMFINZI is administered in combination with chemotherapy, refer to the Prescribing Information for appropriate chemotherapeutic agent for dosing information.
$   Administer tremelimumab prior to IMFINZI on the same day. When tremelimumab is administered in combination with IMFINZI, refer to the Prescribing Information for tremelimumab dosing information.
IMFINZI in Combination with Tremelimumab and Platinum-Based Chemotherapy 
The recommended dosage schedule and regimens for IMFINZI for the treatment of metastatic non-small cell lung cancer (NSCLC) are provided in Tables 2 and 3.

Weigh patients prior to each infusion.

Calculate the appropriate dose using Table 3 below based on the patient's weight and tumor histology.

Table 2: Recommended Dosage Schedule
Week*,$
0   1   2    3   4   5    6   7     8   9   10       11   12    13   14   15       16    17   18   19   20   21     22   23   24 Cycle:                1            2            3             4                 5                        6                    7                     8 IMFINZI*,¶            X            X            X             X                 X                        X                    X                     X Tremelimumab¶,#       X            X            X             X                                          X 

Chemotherapy          X            X            X             X                 XÞ                       XÞ                   XÞ                    XÞ 

* continue IMFINZI until disease progression or intolerable toxicity.
$   Note the dosing interval change from every 3 weeks to every 4 weeks starting at cycle 5.
¶   intravenous infusion over 60 minutes [see Dosage and Administration (2.3)].
# if patients receive fewer than 4 cycles of platinum-based chemotherapy, the remaining cycles of tremelimumab (up to a total of 5) should be given after the platinum-based chemotherapy phase, in combination with IMFINZI, every 4 weeks.
Þoptional pemetrexed therapy from week 12 until disease progression or intolerable toxicity for patients with non- squamous disease who received treatment with pemetrexed and carboplatin/cisplatin.


Table 3: Recommended Regimen and Dosage
Tumor          Patient                                 Tremelimumab                  Platinum-based Chemotherapy IMFINZI Dosage
Histology       Weight                                     Dosage*                              Regimen* •        carboplatin & nab-paclitaxel
≥30kg            1,500 mg                        75 mg
Non-                                                                                                      OR Squamous                                                                                   •       carboplatin or cisplatin & <30kg                20 mg/kg                    1 mg/kg pemetrexed
≥30kg            1,500 mg                        75 mg                •        carboplatin & nab-paclitaxel 
Squamous                                                                                                   OR <30kg               20 mg/kg                    1 mg/kg                   •       carboplatin or cisplatin & gemcitabine
* Refer to the Prescribing Information for dosing information.



2.2 Dose Modifications for Adverse Reactions
No dose reductions are recommended. Withhold and/or discontinue IMFINZI or IMFINZI in combination with tremelimumab and platinum-based chemotherapy to manage adverse reactions as described in Table 4.
Table 4. Recommended Treatment Modifications for IMFINZI
Adverse Reactions      Severity1                 Dosage Modification
Pneumonitis [see       Grade 2                   Withhold dose until Grade 1 or resolved Warnings and                                     and corticosteroid dose is less than or Precautions (5.1)]                               equal to prednisone 10 mg per day (or equivalent).
Grade 3 or 4              Permanently discontinue
Hepatitis [see         For ALT or AST            Withhold dose until Grade 1 or resolved Warnings and           greater than 3 but less   and corticosteroid dose is less than or Precautions (5.1)]     than or equal to 8        equal to prednisone 10 mg per day (or times the ULN or Total    equivalent).
bilirubin greater than
1.5 but less than or equal to 5 times the
ULN



ALT or AST greater           Permanently discontinue than 8 times the ULN or total bilirubin greater than 5 times the ULN or Concurrent ALT or
AST greater than 3 times the ULN and total bilirubin greater than 2 times the ULN with no other cause
Colitis or diarrhea [see   Grade 2                      Withhold dose until Grade 1 or resolved Warnings and                                            and corticosteroid dose is less than or Precautions (5.1)]                                      equal to prednisone 10 mg per day (or equivalent).
Grade 3 or 4                 Permanently discontinue
Hyperthyroidism or         Grade 2-4                    Withhold dose until clinically stable thyroiditis [see
Warnings and
Precautions (5.1)]
Adrenal insufficiency      Grade 2-4                    Withhold dose until clinically stable or
Hypophysitis/Hypopitui tarism [see Warnings and Precautions (5.1)]


Type 1 Diabetes            Grade 2-4                    Withhold dose until clinically stable Mellitus [see Warnings and Precautions (5.1)]
Nephritis [see             For Creatinine greater       Withhold dose until Grade 1 or resolved Warnings and               than 1.5 to 3 times the      and corticosteroid dose is less than or Precautions (5.1)]         ULN                          equal to prednisone 10 mg per day (or equivalent).

For Creatinine greater      Permanently discontinue than 3 times the ULN



Rash or dermatitis      Grade 2 for longer          Withhold dose until Grade 1 or resolved (including Pemphigoid) than 1 week or Grade         and corticosteroid dose is less than or [see Warnings and       3                           equal to prednisone 10 mg per day (or Precautions (5.1)]                                  equivalent).


Grade 4                     Permanently discontinue
Infection [see          Grade 3 or 4                Withhold dose until clinically stable Warnings and
Precautions (5.1)]
Infusion-related         Grade 1 or 2               Interrupt or slow the rate of infusion reactions [see Warnings Grade 3 or 4                Permanently discontinue and Precautions (5.2)]


Persistent Grade 2 or     Grade 2 or 3 adverse       Permanently discontinue 3 adverse reaction        reaction that does not
(excluding                recover to Grade 0 or 1 endocrinopathies)         within 12 weeks after last IMFINZI dose
Inability to taper        Inability to reduce to     Permanently discontinue corticosteroid            less than or equal to prednisone 10 mg per day (or equivalent) within 12 weeks after the last IMFINZI dose



Neurological                         Grade 2                           Withhold Toxicities



1National   Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of normal.
2 For   myasthenia gravis permanently discontinue IMFINZI if the adverse reaction does not resolve to ≤ Grade 1 within 30 days or if there are signs of respiratory and/or autonomic insufficiency.


2.3 Preparation and Administration
Preparation
•       Visually inspect drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or visible particles are observed.
•     Do not shake the vial.
•     Withdraw the required volume from the vial(s) of IMFINZI and transfer into an intravenous bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. Do not shake the solution. The final concentration of the diluted solution should be between 1 mg/mL and 15 mg/mL.
•     Discard partially used or empty vials of IMFINZI.


Storage of Infusion Solution
•     IMFINZI does not contain a preservative.
•     Administer infusion solution immediately once prepared. If the infusion solution is not administered immediately and needs to be stored, the time from preparation until the completion of the infusion should not exceed: o 30 days in a refrigerator at 2°C to 8°C o 12 hours at room temperature up to 25°C
•     Do not freeze.
•     Do not shake.


Administration
•   Administer infusion solution intravenously over 60 minutes through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter.
•   Use separate infusion bags and filters for each drug product.

IMFINZI in Combination with Other Products

• Administer all drug products as separate intravenous infusions.
• Do not co-administer other drugs through the same infusion line.

• For platinum-based chemotherapy, refer to Prescribing Information for administration information.

• For pemetrexed therapy, refer to Prescribing Information for administration information.
Combination Regimens: Order of Infusions

IMFINZI in combination with tremelimumab

• Infuse tremelimumab first, followed by IMFINZI on the same day of dosing.
IMFINZI in Combination with Tremelimumab and Platinum-Based Chemotherapy 
• Infuse tremelimumab first, followed by IMFINZI and then platinum-based chemotherapy on the day of dosing.

IMFINZI in Combination with Tremelimumab and Pemetrexed Therapy

• Infuse tremelimumab first, followed by IMFINZI and then pemetrexed therapy on the day of dosing.
Combination Regimens: Infusion Instructions

IMFINZI in Combination with Tremelimumab

• Administer tremelimumab over 60 minutes followed by a 60 minute observation period. Then administer IMFINZI as a separate intravenous infusion over 60 minutes on the same day.

IMFINZI in Combination with Tremelimumab and Platinum-Based Chemotherapy/ Pemetrexed Therapy

Cycle 1
•     Infuse tremelimumab over 1 hour. One to two hours after completion of tremelimumab infusion, infuse IMFINZI over 1 hour. One to two hours after completion of IMFINZI infusion, administer platinum-based chemotherapy.
Subsequent Cycles
•      If there are no infusion reactions during cycle 1, subsequent cycles of IMFINZI can be given immediately after tremelimumab. The time between the end of the IMFINZI infusion and the start of chemotherapy can be reduced to 30 minutes.