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Nivolumab and relatlimab: Drug information

Nivolumab and relatlimab: Drug information
(For additional information see "Nivolumab and relatlimab: Pediatric drug information" and see "Nivolumab and relatlimab: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Opdualag
Pharmacologic Category
  • Antineoplastic Agent, Anti-LAG-3 Monoclonal Antibody;
  • Antineoplastic Agent, Anti-PD-1 Monoclonal Antibody;
  • Antineoplastic Agent, Immune Checkpoint Inhibitor;
  • Antineoplastic Agent, Monoclonal Antibody
Dosing: Adult

Note: Do not substitute nivolumab/relatlimab with nivolumab.

Melanoma, unresectable or metastatic

Melanoma, unresectable or metastatic: IV: Nivolumab 480 mg and relatlimab 160 mg once every 4 weeks until disease progression or unacceptable toxicity (Tawbi 2022).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

Altered kidney function prior to treatment initiation:

eGFR 30 to 89 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling; however, mild or moderate impairment did not impact nivolumab/relatlimab clearance.

eGFR <30 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling (effects on nivolumab/relatlimab pharmacokinetics are unknown).

Nephritis with kidney dysfunction during treatment (immune-mediated nephritis):

If nivolumab/relatlimab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) or other appropriate therapy for immune-mediated adverse reactions until improvement to ≤ grade 1, then follow with a corticosteroid taper and continue to taper over at least 1 month.

Grade 2 or grade 3 serum creatinine elevation: Withhold nivolumab/relatlimab; resume after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue nivolumab/relatlimab if no complete or partial response within 12 weeks of last nivolumab/relatlimab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 4 serum creatinine elevation: Permanently discontinue nivolumab/relatlimab.

Dosing: Hepatic Impairment: Adult

Hepatic impairment prior to treatment initiation:

Mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1 to 1.5 × ULN and any AST) or moderate (total bilirubin >1.5 to 3 × ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling; however, mild or moderate impairment did not impact nivolumab/relatlimab clearance.

Severe impairment (total bilirubin >3 × ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (effects on nivolumab/relatlimab pharmacokinetics are unknown).

Hepatotoxicity during treatment (immune-mediated hepatitis):

If nivolumab/relatlimab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) or other appropriate therapy for immune-mediated adverse reactions until improvement to ≤ grade 1, then follow with a corticosteroid taper and continue to taper over at least 1 month.

AST, ALT increases to >3 to ≤8 × ULN or total bilirubin >1.5 to ≤3 × ULN: Withhold nivolumab/relatlimab; resume after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue nivolumab/relatlimab if no complete or partial response within 12 weeks of last nivolumab/relatlimab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

AST or ALT >8 × ULN (regardless of baseline) or total bilirubin >3 × ULN: Permanently discontinue nivolumab/relatlimab.

Dosing: Pediatric

(For additional information see "Nivolumab and relatlimab: Pediatric drug information")

Note: Do not substitute nivolumab/relatlimab with nivolumab.

Melanoma, unresectable or metastatic: Children ≥12 years and Adolescents weighing ≥40 kg: IV: Nivolumab 480 mg and relatlimab 160 mg once every 4 weeks until disease progression or unacceptable toxicity.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosage adjustment for toxicity: Children ≥12 years and Adolescents weighing ≥40 kg: IV:

Note: No dosage reductions of nivolumab/relatlimab are recommended.

Immune-mediated adverse reactions (general information): Withhold nivolumab/relatlimab for severe (grade 3) immune-mediated adverse reactions. Permanently discontinue nivolumab/relatlimab for life-threatening (grade 4) immune-mediated adverse reactions, recurrent severe (grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or the inability to reduce corticosteroid dose to prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating corticosteroids. If nivolumab/relatlimab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) until improvement to ≤ grade 1; upon improvement to ≤ grade 1, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants if immune-mediated adverse reaction is not controlled with corticosteroid therapy. Systemic corticosteroids may not be necessary for certain adverse reactions. Hormone replacement therapy may be required for endocrinopathies (if clinically indicated). See table for additional dosage modification guidance.

Nivolumab/Relatlimab Recommended Dosage Modifications for Adverse Reactions

Adverse Reaction

Severity

Management and/or Nivolumab/Relatlimab Dosage Modification

Immune-mediated adverse reactions

Cardiovascular toxicity: Myocarditis

Suspected myocarditis

Withhold nivolumab/relatlimab, promptly initiate high dose corticosteroids, and arrange cardiology consultation with diagnostic workup.

Grade 2, 3, or 4

Permanently discontinue nivolumab/relatlimab.

Dermatologic toxicity

Mild or moderate nonexfoliative rash

May be managed with topical emollients and/or topical corticosteroids.

Exfoliative dermatologic conditions: Suspected Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS)

Withhold nivolumab/relatlimab.

Confirmed SJS, TEN, or DRESS

Permanently discontinue nivolumab/relatlimab.

Endocrinopathies

Grade 2

Depending on clinical severity, consider withholding until symptom improvement with hormone replacement. Resume once acute symptoms have resolved.

Grade 3 or 4

Withhold nivolumab/relatlimab until clinically stable or permanently discontinue depending on severity.

Adrenal insufficiency, ≥ grade 2

Initiate symptomatic management (including hormone replacement as clinically indicated). Depending on the severity, withhold nivolumab/relatlimab.

Diabetes, type 1

Initiate insulin as clinically indicated. Depending on the severity, withhold nivolumab/relatlimab.

Hypophysitis

Withhold or discontinue nivolumab/relatlimab (depending on the severity). Initiate hormone replacement therapy as clinically indicated.

Hyperthyroidism

Withhold or discontinue nivolumab/relatlimab (depending on the severity). Initiate medical management as clinically indicated.

Hypothyroidism

Withhold nivolumab/relatlimab (depending on the severity). Initiate thyroid hormone replacement therapy as clinically indicated.

Thyroiditis

Withhold or discontinue nivolumab/relatlimab (depending on the severity). Initiate medical management as clinically indicated.

GI toxicity: Colitis

Grade 2 or 3

Withhold nivolumab/relatlimab; resume after complete or partial (to grade 0 or 1) resolution after corticosteroid taper.

Permanently discontinue nivolumab/relatlimab if no complete or partial response within 12 weeks of last nivolumab/relatlimab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 4

Permanently discontinue nivolumab/relatlimab.

Neurologic toxicities

Grade 2

Withhold nivolumab/relatlimab; resume after complete or partial (to grade 0 or 1) resolution after corticosteroid taper.

Permanently discontinue nivolumab/relatlimab if no complete or partial response within 12 weeks of last nivolumab/relatlimab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 3 or 4

Permanently discontinue nivolumab/relatlimab.

Ocular disorders: Vogt-Koyanagi-Harada-like syndrome

May require systemic corticosteroids to reduce the risk of permanent vision loss.

Pulmonary toxicity: Pneumonitis

Grade 2

Withhold nivolumab/relatlimab; resume after complete or partial (to grade 0 or 1) resolution after corticosteroid taper.

Permanently discontinue nivolumab/relatlimab if no complete or partial response within 12 weeks of last nivolumab/relatlimab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 3 or 4

Permanently discontinue nivolumab/relatlimab.

Other adverse reactions

Infusion-related reactions

Grade 1 or 2

Interrupt or slow the rate of nivolumab/relatlimab infusion.

Grade 3 or 4

Permanently discontinue nivolumab/relatlimab.

Dosing: Kidney Impairment: Pediatric

Children ≥12 years and Adolescents weighing ≥40 kg: IV:

Altered kidney function prior to treatment initiation:

eGFR 30 to 89 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling; however, mild or moderate impairment did not impact nivolumab/relatlimab clearance.

eGFR <30 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling (effects on nivolumab/relatlimab pharmacokinetics are unknown).

Nephritis with kidney dysfunction during treatment (immune-mediated nephritis):

If nivolumab/relatlimab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) or other appropriate therapy for immune-mediated adverse reactions until improvement to ≤ grade 1, then follow with a corticosteroid taper and continue to taper over at least 1 month.

Grade 2 or grade 3 serum creatinine elevation: Withhold nivolumab/relatlimab; resume after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue nivolumab/relatlimab if no complete or partial response within 12 weeks of last nivolumab/relatlimab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 4 serum creatinine elevation: Permanently discontinue nivolumab/relatlimab.

Dosing: Hepatic Impairment: Pediatric

Children ≥12 years and Adolescents weighing ≥40 kg: IV:

Hepatic impairment prior to treatment initiation:

Mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1 to 1.5 × ULN and any AST) or moderate (total bilirubin >1.5 to 3 × ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling; however, mild or moderate impairment did not impact nivolumab/relatlimab clearance.

Severe impairment (total bilirubin >3 × ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (effects on nivolumab/relatlimab pharmacokinetics are unknown).

Hepatotoxicity during treatment (immune-mediated hepatitis): If nivolumab/relatlimab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) or other appropriate therapy for immune-mediated adverse reactions until improvement to ≤ grade 1, then follow with a corticosteroid taper and continue to taper over at least 1 month.

AST or ALT increases to >3 to ≤8 × ULN or total bilirubin >1.5 to ≤3 × ULN: Withhold nivolumab/relatlimab; resume after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue nivolumab/relatlimab if no complete or partial response within 12 weeks of last nivolumab/relatlimab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

AST or ALT >8 × ULN (regardless of baseline) or total bilirubin >3 × ULN: Permanently discontinue nivolumab/relatlimab.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Adjustment for Toxicity: Adult

Note: No dosage reductions of nivolumab/relatlimab are recommended.

Immune-mediated adverse reactions (general information): Withhold nivolumab/relatlimab for severe (grade 3) immune-mediated adverse reactions. Permanently discontinue nivolumab/relatlimab for life-threatening (grade 4) immune-mediated adverse reactions, recurrent severe (grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or the inability to reduce corticosteroid dose to prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating corticosteroids. If nivolumab/relatlimab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) until improvement to ≤ grade 1; upon improvement to ≤ grade 1, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants if immune-mediated adverse reaction is not controlled with corticosteroid therapy. Systemic corticosteroids may not be necessary for certain adverse reactions. Hormone-replacement therapy may be required for endocrinopathies (if clinically indicated). See table for additional dosage modification guidance.

Nivolumab/Relatlimab Recommended Dosage Modifications for Adverse Reactionsa

Adverse reaction

Severity

Management and/or nivolumab/relatlimab dosage modification

a SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; DRESS = drug rash with eosinophilia and systemic symptoms.

Immune- mediated adverse reactions

Cardiovascular toxicity: Myocarditis

Suspected myocarditis

Withhold nivolumab/relatlimab, promptly initiate high-dose corticosteroids, and arrange cardiology consultation with diagnostic workup.

Grade 2, 3, or 4

Permanently discontinue nivolumab/relatlimab.

Dermatologic toxicity

Mild or moderate nonexfoliative rash

May be managed with topical emollients and/or topical corticosteroids.

Exfoliative dermatologic conditions: Suspected SJS, TEN, or DRESS

Withhold nivolumab/relatlimab.

Confirmed SJS, TEN, or DRESS

Permanently discontinue nivolumab/relatlimab.

Endocrinopathies

Grade 2

Depending on clinical severity, consider withholding until symptom improvement with hormone replacement. Resume once acute symptoms have resolved.

Grade 3 or 4

Withhold nivolumab/relatlimab until clinically stable or permanently discontinue depending on severity.

Adrenal insufficiency, ≥ grade 2

Initiate symptomatic management (including hormone replacement as clinically indicated). Depending on the severity, withhold nivolumab/relatlimab.

Diabetes, type 1

Initiate insulin as clinically indicated. Depending on the severity, withhold nivolumab/relatlimab.

Hypophysitis

Withhold or discontinue nivolumab/relatlimab (depending on the severity). Initiate hormone-replacement therapy as clinically indicated.

Hyperthyroidism

Withhold or discontinue nivolumab/relatlimab (depending on the severity). Initiate medical management as clinically indicated.

Hypothyroidism

Withhold nivolumab/relatlimab (depending on the severity). Initiate thyroid hormone-replacement therapy as clinically indicated.

Thyroiditis

Withhold or discontinue nivolumab/relatlimab (depending on the severity). Initiate medical management as clinically indicated.

GI toxicity: Colitis

Grade 2 or 3

Withhold nivolumab/relatlimab; resume after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue nivolumab/relatlimab if no complete or partial response within 12 weeks of last nivolumab/relatlimab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 4

Permanently discontinue nivolumab/relatlimab.

Neurologic toxicities

Grade 2

Withhold nivolumab/relatlimab; resume after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue nivolumab/relatlimab if no complete or partial response within 12 weeks of last nivolumab/relatlimab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 3 or 4

Permanently discontinue nivolumab/relatlimab.

Ocular disorders: Vogt-Koyanagi-Harada-like syndrome

May require systemic corticosteroids to reduce the risk of permanent vision loss.

Pulmonary toxicity: Pneumonitis

Grade 2

Withhold nivolumab/relatlimab; resume after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue nivolumab/relatlimab if no complete or partial response within 12 weeks of last nivolumab/relatlimab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 3 or 4

Permanently discontinue nivolumab/relatlimab.

Other adverse reactions

Infusion-related reactions

Grade 1 or 2

Interrupt or slow the rate of nivolumab/relatlimab infusion.

Grade 3 or 4

Permanently discontinue nivolumab/relatlimab.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Opdualag: Nivolumab 240 mg and relatlimab rmbw 80 mg per 20 mL (20 mL) [contains polysorbate 80]

Generic Equivalent Available: US

No

Administration: Adult

IV: Infuse over 30 minutes via an IV line containing a sterile, nonpyrogenic, low protein binding polyethersulfone, nylon, or polyvinylidene fluoride 0.2 to 1.2 micrometer inline filter. Flush IV line at the end of the infusion. Do not administer other medications through the same IV line. Monitor for signs/symptoms of infusion-related reactions.

Check label to ensure appropriate product is being administered; nivolumab/relatlimab and nivolumab are different products and are NOT interchangeable.

Administration: Pediatric

Note: Nivolumab/relatlimab and nivolumab are different products and are NOT interchangeable; check label to ensure appropriate product is being administered.

IV: Infuse over 30 minutes via an IV line containing a sterile, nonpyrogenic, low protein binding polyethersulfone, nylon, or polyvinylidene fluoride 0.2 to 1.2 micrometer in-line filter. Flush IV line at the end of the infusion. Do not administer other medications through the same IV line. Monitor for signs/symptoms of infusion-related reactions.

Use: Labeled Indications

Melanoma, unresectable or metastatic: Treatment of unresectable or metastatic melanoma in adult and pediatric patients ≥12 years of age.

Medication Safety Issues
Sound-alike/look-alike issues:

Nivolumab/relatlimab may be confused with ipilimumab, nivolumab, pembrolizumab, rituximab.

Opdualag may be confused with Opdivo.

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Other safety concerns:

Nivolumab/relatlimab (Opdualag) may be confused with nivolumab (Opdivo); these products are not interchangeable. Verify product prior to preparation and administration to prevent medication errors.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reaction incidence reported in adults. Also see nivolumab.

>10%:

Dermatologic: Pruritus (25%), skin rash (9% to 28%), vitiligo (˂15%)

Endocrine & metabolic: Decreased serum sodium (24%), hypothyroidism (17%)

Gastrointestinal: Decreased appetite (15%), diarrhea (≤24%; grade 2: ≤5%; grades 3/4: ≤2%), nausea (17%; grades 3/4: <1%)

Hematologic & oncologic: Lymphocytopenia (32%; grades 3/4: 3%)

Hepatic: Increased serum alanine aminotransferase (26%), increased serum alkaline phosphatase (19%), increased serum aspartate aminotransferase (30%)

Nervous system: Fatigue (39%), headache (18%)

Neuromuscular & skeletal: Musculoskeletal pain (45%)

Renal: Increased serum creatine (19%)

Respiratory: Cough (15%)

1% to 10%:

Cardiovascular: Acute myocardial infarction (1%), myocarditis (1% to 2%)

Endocrine & metabolic: Adrenocortical insufficiency (4%; severe: 1%), hyperthyroidism (6%), hypophysitis (3%), thyroiditis (3%)

Gastrointestinal: Colitis (≤7%; severe colitis: 1%)

Hematologic & oncologic: Severe anemia (1%)

Hepatic: Hepatitis (6%)

Neuromuscular & skeletal: Back pain (severe: 1%)

Renal: Nephritis (≤2%), renal insufficiency (≤2%)

Respiratory: Pneumonia (1%), pneumonitis (4%; severe: 1%)

Miscellaneous: Infusion related reaction (7%)

<1% (may include adverse reactions from other PD-1/PD-L1 blocking antibodies):

Cardiovascular: Pericarditis, vasculitis

Endocrine & metabolic: Diabetes mellitus, hypoparathyroidism

Gastrointestinal: Duodenitis, gastritis, increased serum amylase, increased serum lipase, pancreatitis

Hematologic & oncologic: Aplastic anemia, hemolytic anemia, hemophagocytic lymphohistiocytosis, immune thrombocytopenia, lymphadenitis (histiocytic necrotizing lymphadenitis [Kikuchi lymphadenitis]), sarcoidosis

Immunologic: Organ transplant rejection (solid)

Infection: Systemic inflammatory response syndrome

Nervous system: Demyelinating disease, encephalitis, Guillain-Barre syndrome, meningitis, myasthenia (myasthenic syndrome), myasthenia gravis (including exacerbation of myasthenia gravis), neuropathy (autoimmune), paresis

Neuromuscular & skeletal: Arthritis, myelitis, myositis, polymyalgia rheumatica, polymyositis, rhabdomyolysis

Frequency not defined:

Neuromuscular & skeletal: Arthralgia

Miscellaneous: Troponin increased in blood specimen (including increased troponin T)

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Warnings/Precautions

Concerns related to adverse effects:

• Adverse reactions (immune mediated): Nivolumab/relatlimab potentially breaks peripheral tolerance and induces immune-mediated adverse reactions. Severe and fatal immune-mediated adverse reactions may occur in any organ system or tissue. Reactions generally occur during treatment (may occur at any time after nivolumab/relatlimab initiation); reactions may also occur after nivolumab/relatlimab discontinuation. Early identification and management of immune-mediated adverse reactions are necessary to ensure safe use of nivolumab/relatlimab. If suspected immune-mediated reactions occur, initiate appropriate workup to exclude alternative causes (including infection). Medically manage immune-mediated adverse reactions promptly and refer for specialty consultation as appropriate.

• Cardiotoxicity: Nivolumab/relatlimab can cause immune-mediated myocarditis, which is defined as requiring the use of corticosteroids and the absence of another clear etiology. Grades 2 and 3 events were observed. An immune-mediated myocarditis diagnosis requires a high index of suspicion. Assess for potential myocarditis in patients with cardiac or cardiopulmonary symptoms. All patients experiencing immune-mediated myocarditis required systemic corticosteroids; myocarditis resolved in all cases. Pericarditis and vasculitis have also been reported.

• Dermatologic toxicity: Nivolumab/relatlimab can cause immune-mediated rash or dermatitis, defined as requiring the use of corticosteroids and the absence of another clear etiology. Grades 2 and 3 events have been reported. Exfoliative dermatitis, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms, has occurred with anti-PD-1/PD-L1 monoclonal antibodies. Immune-mediated dermatologic reactions were treated with systemic corticosteroids in most patients, and reactions resolved in over two-thirds of patients. In cases where nivolumab/relatlimab was withheld, most reinitiated treatment after symptom improvement, and immune-mediated dermatologic toxicity recurred in some patients.

• Endocrinopathies: Nivolumab/relatlimab is associated with immune-mediated endocrinopathies.

- Adrenal insufficiency: Nivolumab/relatlimab can cause primary and secondary adrenal insufficiency. Grades 2 and 3 adrenal insufficiency have been observed. The majority of patients received hormonal replacement therapy, and systemic corticosteroids were required in most cases. Adrenal insufficiency resolved in one-third of patients. In cases where nivolumab/relatlimab was withheld for adrenal insufficiency, some patients reinitiated treatment after symptom improvement.

- Diabetes mellitus: Type 1 diabetes mellitus was observed rarely. Insulin therapy may be required.

- Hypophysitis: Nivolumab/relatlimab can cause immune-mediated hypophysitis, which may present with acute mass effect symptoms (headache, photophobia, or visual field defects). Hypophysitis may lead to hypopituitarism. Cases of grades 2 and 3 hypophysitis were reported. All hypophysitis cases were managed with hormone replacement therapy and also required systemic corticosteroids. Hypophysitis resolved in one-fifth of cases. In cases where nivolumab/relatlimab was withheld for hypophysitis, it was not reinitiated after symptom improvement.

- Thyroid disorders: Nivolumab/relatlimab can cause immune-mediated thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Grade 2 hyperthyroidism has been observed. Systemic corticosteroids were required in some patients with hyperthyroidism, which resolved in a majority of patients. In the case where nivolumab/relatlimab was withheld for hyperthyroidism, it was reinitiated after symptom improvement without recurrence of hyperthyroidism. Hypothyroidism (including grade 2 events) has occurred with nivolumab/relatlimab; management did not require systemic corticosteroids. In cases where nivolumab/relatlimab was withheld for hypothyroidism, some reinitiated nivolumab/relatlimab after symptom improvement; hypothyroidism recurred in some patients. Hypothyroidism may follow hyperthyroidism. Thyroiditis was observed (including grade 2 cases) and may present with or without endocrinopathy. Systemic corticosteroids were required in some patients with thyroiditis, and thyroiditis resolved in most patients. In 1 case where nivolumab/relatlimab was withheld for thyroiditis, it was reinitiated without recurrence of thyroiditis.

• GI toxicity: Nivolumab/relatlimab can cause immune-mediated colitis (which is defined as requiring the use of systemic corticosteroids and the absence of another clear etiology; with diarrhea as a common symptom). Cases of grades 2 and 3 colitis were reported. Systemic corticosteroids were administered to all patients for immune-mediated colitis. Most patients with colitis experienced resolution. In cases where nivolumab/relatlimab was withheld for colitis, most reinitiated treatment after symptom improvement; colitis recurred in over two-thirds of patients. Cytomegalovirus infection/reactivation has been observed in patients with corticosteroid-refractory immune-mediated colitis. Pancreatitis (including increased serum amylase and lipase levels), gastritis, and duodenitis have also been reported.

• Hepatotoxicity: Nivolumab/relatlimab can cause immune-mediated hepatitis (which is defined as requiring the use of systemic corticosteroids and the absence of another clear etiology). Grades 2 to 4 events have been reported. Systemic corticosteroids were used in all patients experiencing immune-mediated hepatitis. Hepatitis resolved in over two-thirds of patients. In cases where nivolumab/relatlimab was withheld for hepatitis, some patients reinitiated treatment after symptom improvement; hepatitis recurred in 50% of these patients.

• Infusion-related reactions: Nivolumab/relatlimab can cause infusion-related reactions.

• Nephrotoxicity: Nivolumab/relatlimab can cause immune-mediated nephritis (which is defined as requiring the use of systemic corticosteroids and the absence of another clear etiology) and kidney dysfunction. Grades 2 and 3 events were observed. All patients with immune-mediated nephritis and kidney dysfunction required systemic corticosteroids, and a majority of patients experienced resolution. In the cases where nivolumab/relatlimab was withheld for nephritis and kidney dysfunction, 1 patient reinitiated treatment after symptom improvement without nephritis recurrence.

• Ocular toxicity: Uveitis, iritis, and other ocular inflammatory toxicities may occur with anti-PD-1/PD-L1 monoclonal antibodies (some cases may be associated with retinal detachment). Various grades of visual impairment (including blindness) can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome.

• Pulmonary toxicity: Nivolumab/relatlimab can cause immune-mediated pneumonitis, which may be fatal. Grades 2 and 3 events have been reported. All patients experiencing pneumonitis required management with systemic corticosteroids. Pneumonitis resolved in a majority of the affected patients. In cases where nivolumab/relatlimab was withheld for pneumonitis, all patients reinitiated nivolumab/relatlimab after symptom improvement and there were no recurrences of pneumonitis. In patients treated with other anti-PD-1/PD-L1 monoclonal antibodies, the incidence of pneumonitis was higher in patients with a history of prior thoracic radiation.

• Other immune-mediated toxicities: Other clinically relevant immune-mediated disorders have been observed rarely with nivolumab/relatlimab (or other anti-PD-1/PD-L1 monoclonal antibodies) and may be fatal, including meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy, myositis/polymyositis, rhabdomyolysis (and associated sequelae including kidney failure), arthritis, polymyalgia rheumatic, hypoparathyroidism, hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, and solid organ transplant rejection.

Disease-related concerns:

• Hematopoietic stem cell transplantation: Fatal and other serious complications may occur in patients who receive allogeneic hematopoietic stem cell transplant (HSCT) before or after treatment with an anti-PD-L1/PD-1 monoclonal antibody. Transplant-related complications included hyperacute graft-versus-host disease (GVHD), acute or chronic GVHD, hepatic veno-occlusive disease (also known as sinusoidal obstruction syndrome) after reduced-intensity conditioning, and steroid-requiring febrile syndrome (with no identified infectious etiology). These complications may occur despite intervening therapy between PD-L1/PD-1 blockade and HSCT. Manage early signs/symptoms of transplant-related complications promptly. Assess the risks/benefits of treatment with an anti-PD-L1/PD-1 monoclonal antibody prior to or after an allogenic HSCT.

• Myasthenia gravis: Checkpoint inhibitors may worsen or precipitate new myasthenia gravis (MG), especially within the first 16 weeks of treatment; use with caution. Patients with well-controlled MG may be considered for checkpoint inhibitor therapy if MG treatment is maintained (or reinitiated in patients whose MG is in remission), combination therapy (eg, anti–CTLA-4 with anti–PD-a/PD-L1 monoclonal antibodies) is avoided, and respiratory and bulbar function are closely followed. In patients who develop overt MG during checkpoint inhibitor therapy, early aggressive treatment with plasma exchange or IVIG in combination with high-dose corticosteroids may be required (AAN [Narayanaswami 2021]).

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Antibiotics: May diminish the therapeutic effect of Immune Checkpoint Inhibitors. Risk C: Monitor therapy

Corticosteroids (Systemic): May diminish the therapeutic effect of Immune Checkpoint Inhibitors. Management: Carefully consider the need for corticosteroids, at doses of a prednisone-equivalent of 10 mg or more per day, during the initiation of immune checkpoint inhibitor therapy. Use of corticosteroids to treat immune related adverse events is still recommended Risk D: Consider therapy modification

Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy

Inhibitors of the Proton Pump (PPIs and PCABs): May diminish the therapeutic effect of Immune Checkpoint Inhibitors. Risk C: Monitor therapy

Ketoconazole (Systemic): Immune Checkpoint Inhibitors may enhance the hepatotoxic effect of Ketoconazole (Systemic). Risk C: Monitor therapy

Reproductive Considerations

Verify pregnancy status prior to treatment initiation.

Patients who could become pregnant should use effective contraceptive measures during treatment and for at least 5 months after the last dose of nivolumab/relatlimab.

Pregnancy Considerations

Nivolumab/relatlimab are humanized monoclonal antibodies (IgG4). Human IgG crosses the placenta. Fetal exposure is dependent upon the IgG subclass, maternal serum concentrations, placental integrity, newborn birth weight, and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis and the highest during the third trimester (Clements 2020; Palmeira 2012; Pentsuk 2009).

Based on the mechanism of action and data from animal reproduction studies, in utero exposure to nivolumab/relatlimab may cause fetal harm.

Breastfeeding Considerations

It is not known if nivolumab/relatlimab are present in breast milk.

Nivolumab/relatlimab are humanized monoclonal antibodies (IgG4). Human IgG is present in breast milk; concentrations are dependent upon IgG subclass and postpartum age (Anderson 2021). Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during treatment and for at least 5 months after the last dose of nivolumab/relatlimab.

Monitoring Parameters

Monitor hepatic (ALT, AST, and total bilirubin; baseline and periodically during treatment) and renal function (serum creatinine; baseline and periodically during treatment), thyroid function (baseline and periodically during treatment); monitor blood glucose (for hyperglycemia). Verify pregnancy status prior to treatment initiation (in patients who could become pregnant). Monitor closely for signs/symptoms of immune-mediated adverse reactions, including adrenal insufficiency, hypophysitis, thyroid disorders, diabetes mellitus, diarrhea/colitis (consider initiating or repeating infectious workup in patients with corticosteroid-refractory immune-mediated colitis to exclude alternative causes), myocarditis (assess for potential myocarditis in patients with cardiac or cardiopulmonary symptoms), pneumonitis, rash/dermatologic toxicity, neurotoxicity, and ocular disorders. If suspected immune-mediated reactions occur, initiate appropriate workup to exclude alternative causes (including infection). If received/receiving hematopoietic stem cell transplant, monitor closely for early signs/symptoms of transplant-related complications. Monitor for signs/symptoms of infusion-related reactions.

The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

Mechanism of Action

Relatlimab is a human IgG4 monoclonal antibody that binds to the LAG-3 receptor (Tawbi 2022) and blocks interaction between LAG-3 and its ligands (including MHC II) to reduce LAG-3 pathway-mediated immune response inhibition; antagonism of this pathway promotes T cell proliferation and cytokine secretion. Nivolumab is a human IgG4 monoclonal antibody that binds to the PD-1 receptor and blocks interaction with its ligands PD-L1 and PD-L2 and reduces PD-1 pathway mediated inhibition of the immune response, including the anti-tumor immune response. Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors; therefore, signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. In animal tumor models, blocking PD-1 activity resulted in decreased tumor growth and blocking LAG-3 potentiated the antitumor effect of PD-1 blockade (inhibiting tumor growth and promoting tumor regression). Combining nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) results in increased T-cell activation compared to the activity of either antibody alone.

Pharmacokinetics

Distribution: Vdss: Nivolumab: 6.6 L; Relatlimab: 6.6 L.

Half-life elimination: Nivolumab: ~27 days; Relatlimab: ~26 days.

Excretion: Clearance (geometric mean at steady state): Nivolumab: 7.6 mL/hour; Relatlimab: 5.5 mL/hour.

Pricing: US

Solution (Opdualag Intravenous)

240-80 mg/20 mL (per mL): $821.66

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

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