5 WARNINGS AND PRECAUTIONS

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

OPDUALAG potentially breaks peripheral tolerance and induces immune-mediated adverse reactions (IMARs) [see Clinical Pharmacology (12.1)]. Important IMARs listed under Warnings and Precautions may not include all possible severe and fatal IMARs.

IMARs, which may be severe or fatal, can occur in any organ system or tissue. IMARs can occur at any time after starting treatment with a LAG-3 and PD-1/PD-L1 blocking antibodies. While IMARs usually manifest during treatment, IMARs can also manifest after discontinuation.

Early identification and management of IMARs are essential to ensure safe use. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying IMARs. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected IMARs, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDUALAG depending on severity [see Dosage and Administration (2.2)]. In general, if OPDUALAG requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose IMARs are not controlled with corticosteroid therapy.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDUALAG can cause immune-mediated pneumonitis, which may be fatal. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation.

Immune-mediated pneumonitis occurred in 3.7% (13/355) of patients receiving OPDUALAG, including Grade 3 (0.6%), and Grade 2 (2.3%) adverse reactions. Pneumonitis led to permanent discontinuation of OPDUALAG in 0.8% and withholding of OPDUALAG in 1.4% of patients.

Systemic corticosteroids were required in 100% (13/13) of patients with pneumonitis. Pneumonitis resolved in 85% of the 13 patients. Of the 5 patients in whom OPDUALAG was withheld for pneumonitis, 5 reinitiated OPDUALAG after symptom improvement; of these, none had recurrence of pneumonitis.

Immune-Mediated Colitis

OPDUALAG can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-mediated diarrhea or colitis occurred in 7% (24/355) of patients receiving OPDUALAG, including Grade 3 (1.1%) and Grade 2 (4.5%) adverse reactions. Colitis led to permanent discontinuation of OPDUALAG in 2% and withholding of OPDUALAG in 2.8% of patients.

Systemic corticosteroids were required in 100% (24/24) of patients with diarrhea or colitis. Colitis resolved in 83% of the 24 patients. Of the 10 patients in whom OPDUALAG was withheld for colitis, 9 reinitiated OPDUALAG after symptom improvement; of these, 67% had recurrence of colitis.

Immune-Mediated Hepatitis

OPDUALAG can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology.

Immune-mediated hepatitis occurred in 6% (20/355) of patients receiving OPDUALAG, including Grade 4 (0.6%), Grade 3 (3.4%), and Grade 2 (1.4%) adverse reactions. Hepatitis led to permanent discontinuation of OPDUALAG in 1.7% and withholding of OPDUALAG in 2.3% of patients.

Systemic corticosteroids were required in 100% (20/20) of patients with hepatitis. 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 (2.2)].

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.

Hypophysitis

OPDUALAG can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue OPDUALAG depending on severity [see Dosage and Administration (2.2)].

Hypophysitis occurred in 2.5% (9/355) of patients receiving OPDUALAG, including Grade 3 (0.3%) and Grade 2 (1.4%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDUALAG in 0.3% and withholding of OPDUALAG in 0.6% of patients.

All (9/9) of patients with hypophysitis received hormone replacement therapy. Systemic corticosteroids were required in 100% (9/9) of patients with hypophysitis. Hypophysitis resolved in 22% of the 9 patients. Of the 2 patients in whom OPDUALAG was withheld for hypophysitis, none reinitiated OPDUALAG after symptom improvement.

Thyroid Disorders

OPDUALAG can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement or medical management as clinically indicated. Withhold or permanently discontinue OPDUALAG depending on severity [see Dosage and Administration (2.2)].

Thyroiditis

Thyroiditis occurred in 2.8% (10/355) of patients receiving OPDUALAG, including Grade 2 (1.1%) adverse reactions. Thyroiditis did not lead to permanent discontinuation of OPDUALAG. Thyroiditis led withholding of OPDUALAG in 0.3% of patients.

Systemic corticosteroids were required in 20% (2/10) of patients with thyroiditis. Thyroiditis resolved in 90% of the 10 patients. For the 1 patient in whom OPDUALAG was withheld for thyroiditis, OPDUALAG was reinitiated after symptom improvement without recurrence of thyroiditis.

Hyperthyroidism

Hyperthyroidism occurred in 6% (22/355) of patients receiving OPDUALAG, including Grade 2 (1.4%) adverse reactions. Hyperthyroidism did not lead to permanent discontinuation of OPDUALAG. Hyperthyroidism led to withholding of OPDUALAG in 0.3% of patients.

Systemic corticosteroids were required in 23% (5/22) of patients. Hyperthyroidism resolved in 82% of the 22 patients. For the 1 patient in whom OPDUALAG was withheld for hyperthyroidism, OPDUALAG was reinitiated after symptom improvement without recurrence of hyperthyroidism.

Hypothyroidism

Hypothyroidism occurred in 17% (59/355) of patients receiving OPDUALAG, including Grade 2 (11%) adverse reactions. Hypothyroidism led to the permanent discontinuation of OPDUALAG in 0.3% and withholding of OPDUALAG in 2.5% of patients.

None of the patients with hypothyroidism required systemic corticosteroids. Hypothyroidism resolved in 12% of the 59 patients. Of the 9 patients in whom OPDUALAG was withheld for hypothyroidism, 6 reinitiated OPDUALAG after symptom improvement; of these, 33% had recurrence of hypothyroidism.

Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue OPDUALAG depending on severity [see Dosage and Administration (2.2)].

Diabetes occurred in 0.3% (1/355) of patients receiving OPDUALAG, a Grade 3 (0.3%) adverse reaction, and no cases of diabetic ketoacidosis. 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 (2.2)].

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. Nephritis and renal dysfunction resolved in 71% of the 7 patients. Of the 2 patients in whom OPDUALAG was withheld for nephritis or renal dysfunction, 1 reinitiated OPDUALAG after symptom improvement without recurrence of nephritis or renal dysfunction.

Immune-Mediated Dermatologic Adverse Reactions

OPDUALAG can cause immune-mediated rash or dermatitis, defined as requiring use of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, and Drug Rash with Eosinophilia and Systemic Symptoms has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue OPDUALAG depending on severity [see Dosage and Administration (2.2)].

Immune-mediated rash occurred in 9% (33/355) of patients receiving OPDUALAG, including Grade 3 (0.6%) and Grade 2 (3.4%) adverse reactions. Immune-mediated rash did not lead to permanent discontinuation of OPDUALAG. Immune-mediated rash led to withholding of OPDUALAG in 1.4% of patients.

Systemic corticosteroids were required in 88% (29/33) of patients with immune-mediated rash. Rash resolved in 70% of the 33 patients. Of the 5 patients in whom OPDUALAG was withheld for immune-mediated rash, 4 reinitiated OPDUALAG after symptom improvement; of these, 25% had recurrence of immune-mediated rash.

Immune-Mediated Myocarditis

OPDUALAG can cause immune-mediated myocarditis, which is defined as requiring use of steroids and no clear alternate etiology. The diagnosis of immune-mediated myocarditis requires a high index of suspicion. Patients with cardiac or cardio-pulmonary symptoms should be assessed for potential myocarditis. If myocarditis is suspected, withhold dose, promptly initiate high dose steroids (prednisone or methylprednisolone 1 to 2 mg/kg/day) and promptly arrange cardiology consultation with diagnostic workup. If clinically confirmed, permanently discontinue OPDUALAG for Grade 2-4 myocarditis [see Dosage and Administration (2.2)].

Myocarditis occurred in 1.7% (6/355) of patients receiving OPDUALAG, including Grade 3 (0.6%), and Grade 2 (1.1%) adverse reactions. Myocarditis led to permanent discontinuation of OPDUALAG in 1.7% of patients.

Systemic corticosteroids were required in 100% (6/6) of patients with myocarditis. Myocarditis resolved in 100% of the 6 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant IMARs occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDUALAG or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Cardiac/Vascular: Pericarditis, vasculitis.

Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.

Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other IMARs, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis.

Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae including renal failure), arthritis, polymyalgia rheumatica.

Endocrine: Hypoparathyroidism.

Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.

5.2 Infusion-Related Reactions

OPDUALAG can cause severe infusion-related reactions. Discontinue OPDUALAG in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion-related reactions [see Dosage and Administration (2.2)].

In patients who received OPDUALAG as a 60-minute intravenous infusion, infusion-related reactions occurred in 7% (23/355) of patients.

5.3 Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause) [see Adverse Reactions (6.1)]. These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 receptor blocking antibody prior to or after an allogeneic HSCT.

5.4 Embryo-Fetal Toxicity

Based on its mechanism of action and data from animal studies, OPDUALAG can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDUALAG for at least 5 months after the last dose of OPDUALAG [see Use in Specific Populations (8.1, 8.3)].