Posology : מינונים

2             DOSAGE AND ADMINISTRATION
2.1           Patient Selection
Select patients with ESCC for first-line treatment with OPDIVO in combination with fluoropyrimidine- and platinum-based combination chemotherapy or OPDIVO in combination with ipilimumab based on PD-L1 expression [see Clinical Studies (14.12)].


2.2           Recommended Dosage
The recommended dosages of OPDIVO as a single agent are presented in Table 1.


Table 1: Recommended Dosages for OPDIVO as a Single Agent
Recommended OPDIVO              Duration of
Indication
Dosage                     Therapy


3 mg/kg every 2 weeks
(30-minute intravenous infusion)
Advanced renal cell carcinoma                         or
Until disease
240 mg every 2 weeks          progression or
(30-minute intravenous infusion)    unacceptable toxicity or
480 mg every 4 weeks
Esophageal squamous cell carcinoma    (60-minute intravenous infusion) 

Adult patients and pediatric patients age 12 years and older and weighing 50 kg or more:
3 mg/kg every 2 weeks
(30-minute intravenous infusion) or
240 mg every 2 weeks
(30-minute intravenous infusion) or                  Until disease
Unresectable or metastatic melanoma                                      progression or 480 mg every 4 weeks unacceptable
(60-minute intravenous infusion)      toxicity

Pediatric patients age 12 years and older and weighing less than
50 kg:
3 mg/kg every 2 weeks
(30-minute intravenous infusion) or
6 mg/kg every 4 weeks
(30-minute intravenous infusion)


Table 1: Recommended Dosages for OPDIVO as a Single Agent
Recommended OPDIVO                 Duration of
Indication
Dosage                        Therapy
Adult patients and pediatric patients age 12 years and older and weighing 50 kg or more:
3 mg/kg every 2 weeks
(30-minute intravenous infusion) or
240 mg every 2 weeks
(30-minute intravenous infusion)
Until disease or                    recurrence or
Adjuvant treatment of melanoma               480 mg every 4 weeks             unacceptable toxicity for up to 1
(30-minute intravenous infusion)           year
Pediatric patients age 12 years and older and weighing less than
50 kg:
3 mg/kg every 2 weeks
(30-minute intravenous infusion) or
6 mg/kg every 4 weeks
(30-minute intravenous infusion)


Metastatic non-small cell lung cancer


3 mg/kg every 2 weeks

Classical Hodgkin lymphoma              (30-minute intravenous infusion) or                    Until disease progression or
240 mg every 2 weeks unacceptable
(30-minute intravenous infusion)        toxicity
Squamous cell carcinoma of the head and neck



Locally advanced or metastatic urothelial carcinoma


Table 1: Recommended Dosages for OPDIVO as a Single Agent
Recommended OPDIVO                 Duration of
Indication
Dosage                        Therapy


Hepatocellular carcinoma


240 mg every 2 weeks
Until disease
(30-minute intravenous infusion) recurrence or
Adjuvant treatment of urothelial or                    unacceptable carcinoma (UC) toxicity for up to 1
480 mg every 4 weeks year
(60-minute intravenous infusion)
Adult patients and pediatric patients age 12 years and older and weighing 40 kg or more:
3 mg/kg every 2 weeks
Until disease
Microsatellite instability-high (MSI-
(30-minute intravenous infusion)     progression or
H) or mismatch repair deficient unacceptable
(dMMR) metastatic colorectal cancer                     or toxicity
240 mg every 2 weeks
(30-minute intravenous infusion)

Pediatric patients age 12 years and older and weighing less than
40 kg:
3 mg/kg every 2 weeks
(30-minute intravenous infusion)
240 mg every 2 weeks
Until disease
(30-minute intravenous infusion)     progression or
Adjuvant treatment of resected unacceptable esophageal or gastroesophageal                       or toxicity for a total junction cancer
480 mg every 4 weeks          treatment duration of 1 year
(30-minute intravenous infusion)


The recommended dosages of OPDIVO in combination with other therapeutic agents are presented in Table 2. Refer to the respective Prescribing Information for each therapeutic agent administered in combination with OPDIVO for the recommended dosage information, as appropriate.


  Table 2: Recommended Dosages of OPDIVO in Combination with Other
Therapeutic Agents
Indication          Recommended OPDIVO Dosage                       Duration of Therapy 
1 mg/kg every 3 weeks              In combination with ipilimumab for a (30-minute intravenous infusion)            maximum of 4 doses or until with ipilimumab 3 mg/kg             unacceptable toxicity, whichever occurs intravenously                                 earlier over 90 minutes on the same day
Adult patients and pediatric patients age 12 years and older and weighing
50 kg or more:
3 mg/kg every 2 weeks
(30-minute intravenous infusion) or
Unresectable or                  240 mg every 2 weeks metastatic melanoma         (30-minute intravenous infusion)            After completing 4 doses of or                        combination therapy, administer as
480 mg every 4 weeks             single agent until disease progression or (60-minute intravenous infusion)               unacceptable toxicity
Pediatric patients age 12 years and older and weighing less than 50 kg:
3 mg/kg every 2 weeks
(30-minute intravenous infusion) or
6 mg/kg every 4 weeks
(30-minute intravenous infusion)


Neoadjuvant treatment            360 mg every 3 weeks
(30-minute intravenous infusion)       In combination with platinum-doublet of resectable non-small with platinum-doublet chemotherapy           chemotherapy for 3 cycles cell lung cancer on the same day every 3 weeks


360 mg every 3 weeks               In combination with ipilimumab until (30-minute intravenous infusion)          disease progression, unacceptable Metastatic or recurrent     with ipilimumab 1 mg/kg every           toxicity, or up to 2 years in patients non-small cell lung                     6 weeks                         without disease progression cancer                     (30-minute intravenous infusion)
2 cycles of histology-based and histology-based platinum platinum-doublet chemotherapy doublet chemotherapy every 3 weeks


                                    3 mg/kg every 2 weeks
(30-minute intravenous infusion) with ipilimumab 1 mg/kg every 6 weeks
(30-minute intravenous infusion)       In combination with ipilimumab until Malignant pleural                                                      disease progression, unacceptable or mesothelioma                                                          toxicity, or up to 2 years in patients 360 mg every 3 weeks                   without disease progression
(30-minute intravenous infusion) with ipilimumab 1 mg/kg every 6 weeks
(30-minute intravenous infusion)
3 mg/kg every 3 weeks
(30-minute intravenous infusion)         In combination with ipilimumab with ipilimumab 1 mg/kg                        for 4 doses intravenously over 30 minutes on the same day
240 mg every 2 weeks               OPDIVO: Until disease progression, (30-minute intravenous infusion)        unacceptable toxicity, or up to 2 years or
480 mg every 4 weeks
(60-minute intravenous infusion)
Advanced renal cell                                                 Cabozantinib: Until disease progression carcinoma                   Administer OPDIVO in combination or unacceptable toxicity with cabozantinib 40 mg orally once daily without food
3 mg/kg every 2 weeks
(30-minute intravenous infusion) or                          After completing 4 doses of
240 mg every 2 weeks             combination therapy with ipilimumab, (30-minute intravenous infusion)      administer as single agent until disease or                      progression or unacceptable toxicity
480 mg every 4 weeks
(60-minute intravenous infusion)
3 mg/kg every 3 weeks
(30-minute intravenous infusion)         In combination with ipilimumab with ipilimumab 1 mg/kg                        for 4 doses intravenously over 30 minutes on the same day
Adult patients and pediatric patients
Microsatellite              age 12 years and older and weighing instability-high (MSI-H)               40 kg or more: or mismatch repair                3 mg/kg every 2 weeks deficient (dMMR)              (30-minute intravenous infusion) or                           After completing 4 doses of metastatic colorectal combination therapy, administer as cancer                             240 mg every 2 weeks             single agent until disease progression or (30-minute intravenous infusion)               unacceptable toxicity

Pediatric patients age 12 years and older and weighing less than 40 kg:
3 mg/kg every 2 weeks
(30-minute intravenous infusion)

                                 1 mg/kg every 3 weeks
Hepatocellular            (30-minute intravenous infusion)         In combination with ipilimumab carcinoma                    with ipilimumab 3 mg/kg for 4 doses intravenously over 30 minutes on the same day
3 mg/kg every 2 weeks
(30-minute intravenous infusion)            After completing 4 doses of combination therapy, administer as or single agent until disease progression
240 mg every 2 weeks                     or unacceptable toxicity
(30-minute intravenous infusion
Esophageal squamous            240 mg every 2 weeks cell carcinoma                                                   OPDIVO: Until disease progression, (30-minute intravenous infusion) or                     unacceptable toxicity, or up to 2 years
480 mg every 4 weeks
(30-minute intravenous infusion)

Chemotherapy: Until disease
Administer OPDIVO in combination         progression or unacceptable toxicity with fluoropyrimidine- and platinum-containing chemotherapy
3 mg/kg every 2 weeks
(30-minute intravenous infusion) or
360 mg every 3 weeks             In combination with ipilimumab until (30-minute intravenous infusion)        disease progression, unacceptable with ipilimumab 1 mg/kg                   toxicity, or up to 2 years every 6 weeks
(30-minute intravenous infusion)

240 mg every 2 weeks
(30-minute intravenous infusion) with
Gastric cancer,                  fluoropyrimidine- and
Gastroesophageal                  platinum-containing
Until disease progression, unacceptable junction cancer, and         chemotherapy every 2 weeks toxicity, or up to 2 years
Esophageal                                 or adenocarcinoma                   360 mg every 3 weeks
(30-minute intravenous infusion) with fluoropyrimidine- and platinum- containing chemotherapyevery 3 weeks



2.3          Dose Modifications
No dose reduction for OPDIVO is recommended. In general, withhold OPDIVO for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue OPDIVO 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 steroids.

Dosage modifications for OPDIVO or OPDIVO in combination for adverse reactions that require management different from these general guidelines are summarized in Table 3 and Table 4.

When OPDIVO is administered in combination with ipilimumab, withhold or permanently discontinue both ipilimumab and OPDIVO for an adverse reaction meeting these dose modification guidelines.


Table 3: Recommended Dosage Modifications for Adverse Reactions
Dosage
Adverse Reaction                                                   Severity Modification
Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] 
Grade 2                                        a
Withhold
Pneumonitis
Permanently
Grades 3 or 4 discontinue
Colitis                                             Grade 2 or 3                                   a Withhold

For colitis in patients treated with combination                                        Permanently Grade 4 therapy with ipilimumab, see Table 4.                                                   discontinue 
AST/ALT increases to >3 and ≤8 times ULN or                                             a
Withhold
Hepatitis with no tumor involvement of the          Total bilirubin increases to >1.5 liver                                               and ≤3 times ULN.
AST or ALT increases to >8 times
For liver enzyme elevations in patients treated     ULN with combination therapy with ipilimumab, see       or
Table 4.                                                                                Permanently Total bilirubin increases to >3     discontinue times ULN.


Baseline AST/ALT is >1 and ≤3 b   times ULN and increases to >5
Hepatitis with tumor involvement of the liver and ≤10 times ULN or                                             a
Withhold
For liver enzyme elevations in patients treated with combination therapy with ipilimumab, see       Baseline AST/ALT is >3 and ≤5 Table 4.                                            times ULN and increases to >8 and ≤10 times ULN.


Table 3: Recommended Dosage Modifications for Adverse Reactions
Dosage
Adverse Reaction                                                 Severity Modification
Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] AST/ALT increases to >10 times
ULN
Permanently or discontinue
Total bilirubin increases to >3 times ULN.
Withhold until clinically stable or c                                                                     permanently Endocrinopathies                                  Grade 3 or 4 discontinue depending on severity
Grade 2 or 3 increased blood                    a creatinine                           Withhold
Nephritis with Renal Dysfunction
Permanently
Grade 4 increased blood creatinine discontinue
Suspected SJS, TEN, or DRESS         Withhold
Exfoliative Dermatologic Conditions                                                    Permanently Confirmed SJS, TEN, or DRESS discontinue
Permanently
Myocarditis                                       Grades 2, 3, or 4 discontinue

Grade 2                                         a
Withhold
Neurological Toxicities
Permanently
Grade 3 or 4 discontinue
Other Adverse Reactions
Interrupt or slow the
Grade 1 or 2
Infusion-Related Reactions                                                             rate of infusion [see Warnings and Precautions (5.2)]                                                   Permanently Grade 3 or 4 discontinue a
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 last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids.
b
If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO based on recommendations for hepatitis with no liver involvement.
c
Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved.
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


Table 4: Recommended Dosage Modifications for Adverse Reactions in Patients Treated with Combination Therapy
Treatment               Adverse Reaction             Severity         Dosage Modification 
Grade 2                         a
Withhold
Colitis
Permanently
Grade 3 or 4 discontinue
AST/ALT increases to >3 times ULN and ≤5 times ULN
Hepatitis with no tumor     or                                    a
Withhold involvement of the liver
Total bilirubin or                          increases to ≥1.5
Hepatitis with tumor        and ≤3 times ULN.
involvement of the liver/non-HCC               AST or ALT >5 times ULN or              Permanently
Total bilirubin >3        discontinue times ULN.
OPDIVO in combination with                               Baseline AST/ALT ipilimumab is >1 and ≤3 times
ULN and increases to >5 and ≤10 times
ULN or                                    a
Withhold
Baseline AST/ALT
Hepatitis with tumor        is >3 and ≤5 times involvement of the          ULN and increases b liver /HCC                  to >8 and ≤10 times
ULN.
AST/ALT increases to >10 times ULN or                        Permanently
Total bilirubin           discontinue increases to >3 times ULN.
ALT or AST>3                     c
Withhold both times ULN but ≤10        OPDIVO and
OPDIVO in combination with                               times ULN with         cabozantinib until Liver enzyme elevations cabozantinib                                             concurrent total       adverse reactions d bilirubin <2 times    recover to Grades 0-
ULN                            1


                                                                     ALT or AST>10 times ULN or >3             Permanently c times ULN with           discontinue both concurrent total           OPDIVO and bilirubin ≥2 times         cabozantinib
ULN a
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 last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids.
b
If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO in combination with ipilimumab based on recommendations for hepatitis with no liver involvement.
c
Consider corticosteroid therapy for hepatic adverse reactions if OPDIVO is withheld or discontinued when administered in combination with cabozantinib.
d
After recovery, rechallenge with one or both of OPDIVO and cabozantinib may be considered. If rechallenging with cabozantinib with or without OPDIVO, refer to cabozantinib Prescribing Information.
2.4           Preparation and Administration
Visually inspect for particulate matter and discoloration. OPDIVO is a clear to opalescent, colorless to pale-yellow solution. Discard if cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles. Do not shake.
Preparation
•     Withdraw the required volume of OPDIVO and transfer into an intravenous container.
•     Dilute OPDIVO with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL.
The total volume of infusion must not exceed 160 mL.
• For adult and pediatric patients with body weight 40 kg or greater, do not exceed a total volume of infusion of 160 mL.
• For adult and pediatric patients with body weight less than 40 kg, do not exceed a total volume of infusion of 4 mL/kg of body weight.
•     Mix diluted solution by gentle inversion. Do not shake.
•     Discard partially used vials or empty vials of OPDIVO.
•     The product does not contain a preservative.

•     After preparation, store the diluted solution either:
• at room temperature and room light for no more than 8 hours from the time of preparation to end of the infusion. Discard diluted solution if not used within 8 hours from the time of preparation; or
• under refrigeration at 2°C to 8°C (36°F to 46°F) and protected from light for no more than 7 days from the time of preparation to end of infusion. Discard diluted solution if not used within 7 days from the time of preparation.
•     Do not freeze.


Administration
•     Administer the infusion, after dilution, over 30 minutes or 60 minutes depending on the dose (see Tables 1 and 2) through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer).
•     Administer OPDIVO in combination with other therapeutic agents as follows: o With ipilimumab: administer OPDIVO first followed by ipilimumab on the same day.
o With platinum-doublet chemotherapy: administer OPDIVO first followed by platinum- doublet chemotherapy on the same day o With ipilimumab and platinum-doublet chemotherapy: administer OPDIVO first followed by ipilimumab and then platinum-doublet chemotherapy on the same day.
o With fluoropyrimidine- and platinum-containing chemotherapy: administer OPDIVO first followed by fluoropyrimidine- and platinum-containing chemotherapy on the same day.
•     Use separate infusion bags and filters for each infusion.
•     Flush the intravenous line at end of infusion.
•     Do not co-administer other drugs through the same intravenous line.