Nivolumab and relatlimab
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Lymphocyte Activation Gene-3 Blocker, Programmed Death Receptor-1 Blocking Antibody
Dosing in kidney impairment
Immune-Mediated Adverse Reactions : o Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, immune-mediated nephritis with renal dysfunction, and immune-mediated myocarditis. o Monitor for early identification and management.
Hepatitis resolved in 70% of the 20 patients. Of the 8 patients in whom OPDUALAG was withheld for hepatitis, 6 reinitiated OPDUALAG after symptom improvement; of these, 50% had recurrence of hepatitis. Immune-Mediated Endocrinopathies Adrenal Insufficiency OPDUALAG can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated.
Withhold OPDUALAG depending on severity [see Dosage and Administration ] . Adrenal insufficiency occurred in 4.2% (15/355) of patients receiving OPDUALAG, including Grade 3 (1.4%) and Grade 2 (2.5%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDUALAG in 1.1% and withholding of OPDUALAG in 0.8% of patients.
Approximately 87% (13/15) of patients with adrenal insufficiency received hormone replacement therapy. Systemic corticosteroids were required in 87% (13/15) of patients with adrenal insufficiency. Adrenal insufficiency resolved in 33% of the 15 patients. Of the 3 patients in whom OPDUALAG was withheld for adrenal insufficiency, all 3 reinitiated OPDUALAG after symptom improvement.
Diabetes did not lead to the permanent discontinuation or withholding of OPDUALAG in any patient. Immune-Mediated Nephritis with Renal Dysfunction OPDUALAG can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear alternate etiology. Withhold or permanently discontinue OPDUALAG depending on severity [see Dosage and Administration ] .
Immune-mediated nephritis and renal dysfunction occurred in 2% (7/355) of patients receiving OPDUALAG, including Grade 3 (1.1%) and Grade 2 (0.8%) adverse reactions. Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of OPDUALAG in 0.8% and withholding of OPDUALAG in 0.6% of patients. Systemic corticosteroids were required in 100% (7/7) of patients with nephritis and renal dysfunction.
| * Based on National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. 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 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 | |||
| Adverse Reaction | Severity* | Dose Modification | |
| Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] | |||
| Pneumonitis | Grade 2 | Withholda | |
| Grade 3 or 4 | Permanently discontinue | ||
| Colitis | Grade 2 or 3 | Withholda | |
| Grade 4 | Permanently discontinue | ||
| Hepatitis | AST/ALT increases to more than 3 and up to 8 times ULNorTotal bilirubin increases to more than 1.5 and up to 3 times ULN. | Withholda | |
| AST or ALT increases to more than 8 times ULN regardless of baseline.orTotal bilirubin increases to more than 3 times ULN. | Permanently discontinue | ||
| Endocrinopathiesb | Grade 3 or 4 | Withhold until clinically stable or permanently discontinue depending on severity | |
| Nephritis with Renal Dysfunction | Grade 2 or 3 increased blood creatinine | Withholda | |
| Grade 4 increased blood creatinine | Permanently discontinue | ||
| Exfoliative Dermatologic Conditions | Suspected SJS, TEN, or DRESS | Withhold | |
| Confirmed SJS, TEN, or DRESS | Permanently discontinue | ||
| Myocarditis | Grade 2, 3, or 4 | Permanently discontinue | |
| Neurological Toxicities | Grade 2 | Withholda | |
| Grade 3 or 4 | Permanently discontinue | ||
| Other Adverse Reactions | |||
| Infusion-Related Reactions[see Warnings and Precautions (5.2)] | Grade 1 or 2 | Interrupt or slow the rate of infusion | |
| Grade 3 or 4 | Permanently discontinue | ||
Preparation and administration
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Preparation and Administration OPDUALAG is a fixed-dose combination of nivolumab and relatlimab. Visually inspect the solution in the drug product vial for particulate matter and discoloration prior to administration. OPDUALAG is a clear to opalescent, colorless to slightly yellow solution. Discard the vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white particles.
Preparation
During preparation of the infusion solution, use aseptic technique to assure sterility, as the product does not contain a preservative.
OPDUALAG can be administered diluted or undiluted and administered at a final concentration as specified in Table 2 below.
Withdraw the required volume of OPDUALAG and transfer into an intravenous container. OPDUALAG is compatible with di(2-ethylhexyl)phthalate (DEHP)-plasticized polyvinyl chloride (PVC), ethyl vinyl acetate (EVA), and polyolefin (PO) intravenous bags.
If diluting OPDUALAG prior to administration: - Dilute OPDUALAG solution with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an infusion meeting the final concentration and maximum infusion volume parameters as specified in Table 2 below. - Then mix the diluted solution by gentle inversion.
Do not shake.
Discard partially used vials or empty vials following infusion preparation. [See table below.] Adult patients who weigh less than 40 kg 4 mL/kg Nivolumab: 3 mg/mL to 12 mg/mL Relatlimab: 1 mg/mL to 4 mg/mL Storage of Prepared Solution Store the prepared solution either:
at room temperature and room light for no more than 8 hours from the time of preparation to the end of the infusion. Discard the prepared 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) with protection from light for no more than 24 hours from the time of preparation, which includes the time allowed for equilibration of the infusion bag to room temperature and the duration of the infusion.
Discard the prepared solution if not used within 24 hours from the time of preparation. Do not freeze. Administration
Administer the infusion over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line polyethersulfone (PES), nylon, or polyvinylidene fluoride (PVDF) filter (pore size of 0.2 micrometer to 1.2 micrometer).
Flush the intravenous line at the end of the infusion.
Do not coadminister other drugs through the same intravenous line.
| * Based on National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. 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 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 | |||
| Adverse Reaction | Severity* | Dose Modification | |
| Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] | |||
| Pneumonitis | Grade 2 | Withholda | |
| Grade 3 or 4 | Permanently discontinue | ||
| Colitis | Grade 2 or 3 | Withholda | |
| Grade 4 | Permanently discontinue | ||
| Hepatitis | AST/ALT increases to more than 3 and up to 8 times ULNorTotal bilirubin increases to more than 1.5 and up to 3 times ULN. | Withholda | |
| AST or ALT increases to more than 8 times ULN regardless of baseline.orTotal bilirubin increases to more than 3 times ULN. | Permanently discontinue | ||
| Endocrinopathiesb | Grade 3 or 4 | Withhold until clinically stable or permanently discontinue depending on severity | |
| Nephritis with Renal Dysfunction | Grade 2 or 3 increased blood creatinine | Withholda | |
| Grade 4 increased blood creatinine | Permanently discontinue | ||
| Exfoliative Dermatologic Conditions | Suspected SJS, TEN, or DRESS | Withhold | |
| Confirmed SJS, TEN, or DRESS | Permanently discontinue | ||
| Myocarditis | Grade 2, 3, or 4 | Permanently discontinue | |
| Neurological Toxicities | Grade 2 | Withholda | |
| Grade 3 or 4 | Permanently discontinue | ||
| Other Adverse Reactions | |||
| Infusion-Related Reactions[see Warnings and Precautions (5.2)] | Grade 1 or 2 | Interrupt or slow the rate of infusion | |
| Grade 3 or 4 | Permanently discontinue | ||
| * The concentration range in each group includes 12 mg/mL nivolumab and 4 mg/mL relatlimab as the upper limit, which represents a scenario in which the drug product is infused without dilution. | ||
| Patient Group | Maximum Infusion Volume(mL or mL/kg) | Concentration Range (mg/mL)* |
| Adult patients who weigh at least 40 kg and pediatric patients 12 years of age or older who weigh at least 40 kg | 160 mL | Nivolumab: 3 mg/mL to 12 mg/mLRelatlimab: 1 mg/mL to 4 mg/mL |
| Adult patients who weigh less than 40 kg | 4 mL/kg | Nivolumab: 3 mg/mL to 12 mg/mLRelatlimab: 1 mg/mL to 4 mg/mL |
Contraindications
None. • None. (4)
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary Based on findings in animals and mechanism of action, OPDUALAG can cause fetal harm when administered to a pregnant woman. Administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death ( see Data ). Human IgG4 is known to cross the placenta; therefore, nivolumab and relatlimab have the potential to be transmitted from the mother to the developing fetus. The effects of OPDUALAG are likely to be greater during the second and third trimesters of pregnancy. There are no available data on OPDUALAG in pregnant women to evaluate a drug-associated risk.
Advise the patient of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data OPDUALAG injection for intravenous use contains nivolumab and relatlimab [see Description (11) ] . Nivolumab: One function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining immune tolerance to the fetus.
The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis through delivery, at exposure levels of between 9 and 42 times higher than those observed at the clinical dose of 3 mg/kg (based on AUC). Nivolumab administration resulted in a non-dose-related increase in spontaneous abortion and increased neonatal death. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period.
Relatlimab: There are no available animal data on relatlimab. The effects of a murine surrogate anti-LAG-3 antibody was evaluated in mice using syngeneic and allogeneic breeding models. When anti-LAG-3 antibodies were administered beginning on gestation day 6, there were no maternal or developmental effects in either syngeneic or allogeneic breedings.
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
Supply and cost
Drug shortage status
Recalls (last 24 months)
Therapeutic equivalence (Orange Book)
Price ladder
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