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2             DOSAGE AND ADMINISTRATION
2.1           Patient Selection
Select patients with ESCC for first-line treatment with YERVOY in combination with nivolumab based on PD-L1 expression [see Clinical Studies (14.7)].
2.2           Recommended Dosage

The recommended dosage of YERVOY as a single agent is presented in Table 1.

Table 1: Recommended Dosages for YERVOY as a Single Agent
Indication              Recommended YERVOY Dosage                 Duration of Therapy Unresectable or metastatic
3 mg/kg every 3 weeks                Maximum of 4 doses melanoma


Table 1: Recommended Dosages for YERVOY as a Single Agent
Indication                 Recommended YERVOY Dosage                    Duration of Therapy (90-minute intravenous infusion)


The recommended dosages of YERVOY 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 YERVOY for recommended dosage information, as appropriate.


Table 2: Recommended Dosages of YERVOY in Combination with Other Therapeutic Agents*
Indication                 Recommended YERVOY Dosage                          Duration of Therapy In combination with nivolumab for a maximum of 4 doses or until unacceptable toxicity,
3 mg/kg every 3 weeks whichever occurs earlier.
Unresectable or                   (90-minute intravenous infusion) metastatic melanoma                                                             After completing 4 doses of with nivolumab 1 mg/kg combination therapy, administer
(30-minute intravenous infusion on the same day)     nivolumab as a single agent until disease progression or unacceptable toxicity.†
In combination with nivolumab for 4 doses.
1 mg/kg every 3 weeks                    After completing 4 doses of
Advanced renal cell with nivolumab 3 mg/kg                 combination therapy, administer carcinoma
(30-minute intravenous infusion on the same day)    nivolumab as single agent until disease progression or unacceptable toxicity†
In combination with nivolumab
Microsatellite                                                                         for 4 doses.
instability-high (MSI-H)                1 mg/kg every 3 weeks or mismatch repair                     with nivolumab 3 mg/kg                    After completing 4 doses of deficient (dMMR)                                                              combination therapy, administer (30-minute intravenous infusion on the same day) metastatic colorectal                                                          nivolumab as single agent until cancer                                                                             disease progression or unacceptable toxicity†
In combination with nivolumab for 4 doses.
3 mg/kg every 3 weeks                    After completing 4 doses of
Hepatocellular with nivolumab 1 mg/kg                 combination therapy, administer carcinoma
(30-minute intravenous infusion on the same day)    nivolumab as single agent until disease progression or unacceptable toxicity†


Table 2: Recommended Dosages of YERVOY in Combination with Other Therapeutic Agents*
Indication                Recommended YERVOY Dosage                          Duration of Therapy In combination with nivolumab until disease progression,
1 mg/kg every 6 weeks                 unacceptable toxicity, or up to 2 years in patients without disease
Metastatic or recurrent        with nivolumab 360 mg every 3 weeks progression† non-small cell lung               (30-minute intravenous infusion) cancer                         and histology-based platinum-doublet chemotherapy every 3 weeks                  2 cycles of histology-based platinum-doublet chemotherapy


1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks            In combination with nivolumab (30-minute intravenous infusion)               until disease progression, Malignant pleural                                                              unacceptable toxicity, or up to or mesothelioma                                                                     2 years in patients without 1 mg/kg every 6 weeks disease progression† with nivolumab 3 mg/kg every 2 weeks
(30-minute intravenous infusion)
1 mg/kg every 6 weeks
(30-minute intravenous infusion)           In combination with nivolumab Esophageal squamous                                                             until disease progression, with nivolumab 3 mg/kg every 2 weeks or        unacceptable toxicity, or up to 2 cell carcinoma
360 mg every 3 weeks                               years
(30-minute intravenous infusion)
*
Refer to the Prescribing Information for the agents administered in combination with YERVOY for recommended dosing information, as appropriate.
†
Refer to the Prescribing Information for nivolumab for dosage information after completing use in combination with YERVOY.


2.3           Recommended Dosage Modifications for Adverse Reactions
No dose reduction for YERVOY is recommended. In general, withhold YERVOY for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue YERVOY for life- threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune- mediated reactions that require systemic immunosuppressive treatment, persistent moderate (Grade 2) or severe (Grade 3) reactions lasting 12 weeks or longer after last YERVOY dose (excluding endocrinopathy), 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 YERVOY or YERVOY in combination with nivolumab for adverse reactions that require management different from these general guidelines are summarized in Table 3.

When YERVOY is administered in combination with nivolumab, withhold or permanently discontinue both YERVOY and nivolumab for toxicity.


Table 3:       Recommended Dosage Modifications for Adverse Reactions Adverse Reaction                    Severity*                  Dosage Modifications Immune-Mediated Adverse Reactions [See Warnings and Precautions (5.1)] Grade 2                    Withholda
Colitis
Grade 3 or 4               Permanently discontinue
AST or ALT increases to more than 3 times and up to 5 times the ULN
Hepatitis with no tumor involvement or
Withholda of the liver                        Total  bilirubin increases to more than 1.5 times or and up to 3 times the
Hepatitis with tumor involvement of ULN the liver/non-HCC                   AST or ALT more than 5 times the ULN or                         Permanently discontinue
Total bilirubin more than
3 times the ULN
Baseline AST/ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to
10 times ULN or                          Withholda
Baseline AST/ALT is
Hepatitis with tumor involvement of   more than 3 and up to 5 the liverb/HCCc                       times ULN and increases to more than 8 and up to
10 times ULN.
AST/ALT increases to more than 10 times ULN or
Permanently discontinue
Total bilirubin increases to more than 3 times
ULN.
Exfoliative Dermatologic Conditions   Suspected SJS, TEN, or      Withhold DRESS
Confirmed SJS, TEN, or      Permanently discontinue
DRESS


Table 3:       Recommended Dosage Modifications for Adverse Reactions Adverse Reaction                  Severity*                 Dosage Modifications d                Grades  3 or 4            Withhold until clinically
Endocrinopathies stable or permanently discontinue depending on severity
Pneumonitis                       Grade 2                   Withholda Grade 3 or 4              Permanently discontinue
Nephritis with Renal Dysfunction  Grade 2 or 3 increased    Withholda blood creatinine
Grade 4 increased blood Permanently discontinue creatinine
Neurological Toxicities           Grade 2                   Withholda Grade 3 or 4              Permanently discontinue
Myocarditis                       Grade 2, 3 or 4           Permanently discontinue 
Ophthalmologic                                   Grade 2, 3, or 4 that does       Permanently discontinue not improve to Grade 1 within 2 weeks while receiving topical therapy or that requires systemic treatment
Other Adverse Reactions
Infusion-Related Reactions [see                  Grade 1 or 2                     Interrupt or slow the rate Warnings and Precautions (5.2)]                                                   of infusion Grade 3 or 4                     Permanently discontinue

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 of normal
*   Based on Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 a
Resume in patients with complete or partial resolution (Grade 0 or 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/ALT are less than or equal to ULN at baseline, withhold or permanently discontinue YERVOY based on recommendations for hepatitis with no liver involvement.
c
This guidance is only applicable to HCC patients who are being treated with YERVOY in combination with nivolumab.
d
Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved.


2.4           Preparation and Administration
•    Do not shake product.
•    Visually inspect for particulate matter and discoloration prior to administration. Discard vial if solution is cloudy, there is pronounced discoloration (solution may have pale- yellow color), or there is foreign particulate matter other than translucent-to-white, amorphous particles.
Preparation of Solution
•    Allow the vial(s) to stand at room temperature for approximately 5 minutes prior to preparation of infusion.
•    Withdraw the required volume of YERVOY and transfer into an intravenous bag.
•    Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to a final concentration ranging from 1 mg/mL to 2 mg/mL. Mix diluted solution by gentle inversion.
•    After preparation, store the diluted solution under refrigeration at 2°C to 8°C for no more than 24 hours from the time of preparation to the time of infusion.
•    Discard partially used or empty vials of YERVOY.
Administration
•    Do not co- administer other drugs through the same intravenous line.
•    Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP after each dose.
•    Administer diluted solution over 30 minutes or 90 minutes depending on the dose, through an intravenous line containing a sterile, non-pyrogenic, low-protein-binding in- line filter.
•    When administered in combination with nivolumab, infuse nivolumab first followed by YERVOY on the same day. When administered with nivolumab and platinum-doublet chemotherapy, infuse nivolumab first followed by YERVOY and then platinum-doublet chemotherapy on the same day. Use separate infusion bags and filters for each infusion.