Posology : מינונים

4.2    Posology and method of administration

Treatment must be initiated and supervised by physicians experienced in the treatment of cancer.
Posology
The recommended dose for adults and pediatric patients 12 years of age and older is 480 mg nivolumab and 160 mg relatlimab every 4 weeks administered as an intravenous infusion over 30 minutes. This dose is established for pediatric patients 12 years of age and older weighing at least 30 kg (see section 5.2).

Treatment with Opdualag should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient. Dose escalation or reduction is not recommended. Dosing delay or discontinuation may be required based on individual safety and tolerability. Guidelines for 
permanent discontinuation or withholding of doses are described in Table 1. Detailed guidelines for the management of immune-related adverse reactions are described in section 4.4.

Table 1:          Recommended treatment modifications for Opdualag
Immune-related         Severity                             Treatment modification adverse reaction
Grade 2 pneumonitis                  Withhold dose(s) until symptoms resolve, Immune-related                                              radiographic abnormalities improve, and pneumonitis                                                 management with corticosteroids is complete Grade 3 or 4 pneumonitis             Permanently discontinue treatment Grade 2 or 3 diarrhoea or colitis    Withhold dose(s) until symptoms resolve and Immune-related                                              management with corticosteroids, if needed, is colitis                                                     complete
Grade 4 diarrhoea or colitis         Permanently discontinue treatment Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) increases to more than 3 and up to
Withhold dose(s) until laboratory values return
5 times upper limit of normal to baseline and management with
(ULN) corticosteroids, if needed, is complete or
Total bilirubin increases to more than 1.5 and up to 3 times ULN
AST or ALT increases to more
Immune-related than 5 times ULN regardless of hepatitis baseline.
or
Total bilirubin increases to more than 3 times ULN                     Permanently discontinue treatment or
Concurrent AST or ALT increase to more than 3 times ULN and total bilirubin increase to more than 2 times ULN
Grade 2 or 3 creatinine elevation    Withhold dose(s) until creatinine returns to Immune-related baseline and management with corticosteroids nephritis and renal is complete dysfunction
Grade 4 creatinine elevation         Permanently discontinue treatment Symptomatic Grade 2 or 3             Withhold dose(s) until symptoms resolve and hypothyroidism, hyperthyroidism,     management with corticosteroids (if needed for hypophysitis                         symptoms of acute inflammation) is complete.
Grade 2 adrenal insufficiency        Treatment should be continued in the presence Grade 3 diabetes                     of hormone replacement therapya as long as no Immune-related symptoms are present endocrinopathies
Grade 4 hypothyroidism
Grade 4 hyperthyroidism
Grade 4 hypophysitis                 Permanently discontinue treatment Grade 3 or 4 adrenal insufficiency
Grade 4 diabetes
Grade 3 rash                         Withhold dose(s) until symptoms resolve and management with corticosteroids is complete
Suspected Stevens-Johnson            Withhold dose(s)
Immune-related skin syndrome (SJS) or toxic epidermal adverse reactions necrolysis (TEN)
Grade 4 rash                         Permanently discontinue treatment (see Confirmed SJS/TEN                    section 4.4)



Immune-related          Severity                              Treatment modification adverse reaction
Grade 2 myocarditis                   Withhold dose(s) until symptoms resolve and Immune-related management with corticosteroids is completeb myocarditis
Grade 3 or 4 myocarditis            Permanently discontinue treatment Grade 3 (first occurrence)          Withhold dose(s)
Grade 4 or recurrent Grade 3;
Other immune-            persistent Grade 2 or 3 despite related adverse          treatment modification; inability to
Permanently discontinue treatment reactions                reduce corticosteroid dose to 10 mg prednisone or equivalent per day
Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5).
a
Recommendation for the use of hormone replacement therapy is provided in section 4.4.
b
The safety of re-initiating Opdualag in patients previously experiencing immune-related myocarditis is not known.

Special populations

Paediatric population
The safety and efficacy of Opdualag in children below 12 years of age have not been established. No data are available (see section 5.2).

Elderly
No dose adjustment is required for elderly patients (≥ 65 years) (see section 5.2).

Renal impairment
No dose adjustment is required in patients with mild or moderate renal impairment (see section 5.2).
Data from patients with severe renal impairment are too limited to draw conclusions on this population.

Hepatic impairment
No dose adjustment is required in patients with mild or moderate hepatic impairment (see section 5.2).
Data from patients with severe hepatic impairment are too limited to draw conclusions on this population.

Method of administration

Opdualag is for intravenous use only. It is to be administered as an intravenous infusion over a period of 30 minutes.

Opdualag must not be administered as an intravenous push or bolus injection.
Opdualag can be used without dilution, or may be diluted with sodium chloride 9 mg/mL (0.9%) solution for injection or glucose 50 mg/mL (5%) solution for injection (see section 6.6).

For instructions on the preparation and handling of the medicinal product before administration, see section 6.6.