Posology : מינונים

5 DOSAGE AND ADMINISTRATION


5.1     Recommended Dosage
The recommended dosages of IMJUDO are presented in Tables 1, 2 and 3.
Administer IMJUDO as an intravenous infusion after dilution as recommended [see Dosage and Administration (5.3)].


IMJUDO in Combination with

Durvalumab

Table 1. Recommended dosage of

IMJUDO

Indication                          Recommended                         Duration of Therapy 
IMJUDO Dosage
Advanced or unresectable            Patients with a body weight of      After Cycle 1 of combination HCC
30 kg and more:                     therapy, administer
•   A single dose of                durvalumab as a single
IMJUDO1 300 mg                  agent every 4 weeks until followed by durvalumab2         disease progression or
1,500 mg at Day 1 of            unacceptable toxicity
Cycle 1;
•   Continue durvalumab
1,500 mg as a single agent every 4 weeks

Patients with a body weight of less than 30 kg:
•   A single dose of
IMJUDO1 4 mg/kg followed by durvalumab2
20 mg/kg at Day 1 of
Cycle 1;
•   Continue durvalumab
20 mg/kg as a single agent every 4 weeks

1   Administer IMJUDO prior to durvalumab on the same day.
2   Refer to the Prescribing Information for durvalumab dosing information
IMJUDO in Combination with Durvalumab and Platinum-Based Chemotherapy 
The recommended dosage schedule and regimens for IMJUDO 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
Week1,
2

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 IMJUDO3,4        X           X             X           X                                     X Durvalumab1,3 X              X             X           X             X                       X                   X                   X Chemotherapy X               X             X           X             X5                      X5                  X5                  X5 1   continue durvalumab until disease progression or intolerable toxicity.
2   dosing interval change from every 3 weeks to every 4 weeks starting at cycle 5.
3   intravenous infusion over 60 minutes [see Dosage and Administration (5.3)].
4   if patients receive fewer than 4 cycles of platinum-based chemotherapy, the remaining cycles of IMJUDO
(up to a total of 5) should be given after the platinum-based chemotherapy phase, in combination with durvalumab, every 4 weeks.
5   optional 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 Histology          Patient Weight            IMJUDO                    Durvalumab            Platinum-based 1 Dosage              Chemotherapy
Dosage                                          Regimen1
Non-Squamous                 30 kg                 75 mg                     1,500 mg              •    carboplatin & nab- paclitaxel
OR
< 30 kg                   1 mg/kg                   20 mg/kg
•    carboplatin or cisplatin & pemetrexed
Squamous                 30 kg                75 mg                  1,500 mg          •   carboplatin & nab- paclitaxel
< 30 kg                1 mg/kg                20 mg/kg              OR •   carboplatin or cisplatin & gemcitabine
1     Refer to the Prescribing Information for dosing information.

5.2      Dosage Modifications for Adverse Reactions

No dose reduction for treatment is recommended. In general, withhold treatment regimen for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue treatment  regimen for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe 
(Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids.

Recommended treatment modifications are presented in Table 4.

Table 4. Recommended Dosage Modifications for Adverse Reactions

Adverse Reaction                     Severity1                   Dosage Modification 
Immune-Mediated Adverse Reactions [see Warnings and Precautions (8.1)] Grade 2                      Withhold2
Pneumonitis                         Grade 3 or 4                 Permanently discontinue Grade 2                      Withhold2
Colitis


Grade 3 or 4                 Permanently discontinue

Intestinal                    Any grade                    Permanently discontinue perforation
ALT or AST increases to more than 3 and up to 8 times the ULN or total bilirubin              Withhold2 increases to more than 1.5 and up to 3 times ULN
Adverse Reaction           Severity1             Dosage Modification 
Hepatitis with no tumor involvement of the liver   ALT or AST increases to more than 8 times ULN or total bilirubin increases to more    Permanently discontinue than 3 times the ULN



AST or ALT is more than 1 and up to 3 times ULN at          Withhold2
Hepatitis with tumor baseline and involvement of the         increases to more liver3                     than 5 and up to 10 times ULN or
AST or ALT is more than 3 and up to 5 times ULN at baseline and increases to more than 8 and up to 10 times ULN


AST or ALT increases to more    Permanently discontinue than 10 times ULN or
Total bilirubin increases to more than 3 times ULN


Endocrinopathies           Grade 3 or 4          Withhold until clinically stable or permanently discontinue depending on severity
Nephritis with Renal       Grade 2 or 3          Withhold2 increased blood
Dysfunction                creatinine
Grade 4 increased blood creatinine      Permanently discontinue
Exfoliative                Suspected SJS,
TEN, or DRESS         Withhold2
Dermatologic               Confirmed SJS, TEN,
or DRESS              Permanently discontinue
Conditions
Myocarditis                Grade 2, 3, or 4      Permanently discontinue Adverse Reaction                      Severity1               Dosage Modification Grade 2                 Withhold2
Neurological Toxicities
Grade 3 or 4            Permanently discontinue

Other Adverse Reactions

Infusion-related reactions [see Grade 1 or 2                  Interrupt or slow the rate of infusion Warnings and Precautions        Grade 3 or 4                  Permanently discontinue 
(8.2)]
ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal
1   Based on National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.
2   Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper.
Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or an inability to reduce corticosteroid dose to 10 mg of prednisone or less per day (or equivalent) within 12 weeks of initiating corticosteroids.
3   If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue durvalumab based on recommendations for hepatitis with no liver involvement.


5.3 Preparation and Administration

Preparation

•   Visually inspect drug product for particulate matter and discoloration. Discard 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 IMJUDO and transfer into an intravenous bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Mix diluted solution by gentle inversion. Do not shake the solution. The maximum final concentration of the diluted solution should not exceed 10 mg/mL.
The total volume of diluent for use with each dose and patient weight is presented in Table 5.

•   Discard partially used or empty vial(s) of IMJUDO.

Table 5. IMJUDO Infusion Conditions
Dose                               Patient                    Maximum diluent Weight                           volume
300 mg                                30 kg                          150 mL 4 mg/kg                             < 30 kg                           80 mL
75 mg                                30 kg                          150 mL 1 mg/kg                             < 30 kg                           80 mL 

Storage of Infusion Solution
•       IMJUDO does not contain a preservative. Administer infusion solution immediately once prepared. If infusion solution is not administered immediately and needs to be stored, the total time from preparation to the start of administration should not exceed:
 o   24 hours in a refrigerator at 2°C to 8°C
 o   24 hours at room temperature up to 30°C
•       Do not freeze.
•       Do not shake.

Administration
•       Administer IMJUDO infusion solution intravenously over 60 minutes through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron filter.

•       Use separate infusion bags and filters for each drug product.

IMJUDO 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 treatment, refer to Prescribing Information for administration information.

Combination Regimens: Order of Infusions

IMJUDO in Combination with Durvalumab
•   Infuse IMJUDO, followed by durvalumab on the same day of dosing.

IMJUDO in Combination with Durvalumab and Platinum-based Chemotherapy 

• Infuse IMJUDO first, followed by durvalumab and then platinum-based chemotherapy on the day of dosing.

IMJUDO in Combination with Durvalumab and Pemetrexed Therapy

•    Infuse IMJUDO first, followed by durvalumab and then pemetrexed treatment on the day of dosing.


Combination Regimens: Infusion Instructions

IMJUDO in Combination with Durvalumab

•    Observe patient for 60 minutes following completion of IMJUDO infusion [see Warnings and Precautions (8.2)]. Then administer durvalumab as a separate intravenous infusion over 60 minutes


IMJUDO in Combination with Durvalumab and Platinum-based Chemotherapy/ Pemetrexed Therapy

Cycle 1:

•    Infuse IMJUDO over one hour. One to two hours after completion of IMJUDO infusion, infuse durvalumab over one hour. One to two hours after completion of durvalumab infusion, administer platinum-based chemotherapy.

Subsequent Cycles:

If there are no infusion reactions during cycle 1, subsequent cycles of durvalumab can be given immediately after IMJUDO. The time between the end of the durvalumab infusion and the start of chemotherapy can be reduced to 30 minutes


6       DOSAGE FORMS AND STRENGTHS
Injection: 25 mg/1.25 mL (20 mg/mL) or 300 mg/15 mL (20 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial.