Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Traceability
In order to improve the traceability of biological medicinal products, the name of the administered product should be clearly recorded. It is recommended to record the batch number as well.

Immune-related adverse reactions
Immune-related adverse reactions can occur with nivolumab in combination with relatlimab which require appropriate management, including initiation of corticosteroids and treatment modifications (see section 4.2).

Immune-related adverse reactions affecting more than one body system can occur simultaneously.

Patients should be monitored continuously (at least up to 5 months after the last dose) as an adverse reaction with Opdualag may occur at any time during or after discontinuation of therapy.

For suspected immune-related adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, Opdualag should be withheld and corticosteroids administered. If immunosuppression with corticosteroids is used to treat an adverse reaction, a taper of at least 1 month duration should be initiated upon improvement. Rapid tapering may lead to worsening or recurrence of the adverse reaction. Non-corticosteroid immunosuppressive therapy should be added if there is worsening or no improvement despite corticosteroid use.

Opdualag should not be resumed while the patient is receiving immunosuppressive doses of corticosteroids or other immunosuppressive therapy. Prophylactic antibiotics may be used to prevent opportunistic infections in patients receiving immunosuppressive therapy.

Opdualag must be permanently discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening immune-related adverse reaction.

Immune-related pneumonitis
Severe pneumonitis or interstitial lung disease, including a fatal case, has been observed with nivolumab in combination with relatlimab (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis such as radiographic changes (e.g. focal ground glass opacities, patchy infiltrates), dyspnoea, and hypoxia. Infectious and disease-related aetiologies should be ruled out.

For Grade 3 or 4 pneumonitis, Opdualag must be permanently discontinued, and corticosteroids should be initiated at a dose of 2 to 4 mg/kg/day methylprednisolone equivalents.

For Grade 2 (symptomatic) pneumonitis, Opdualag should be withheld and corticosteroids initiated at a dose of 1 mg/kg/day methylprednisolone equivalents. Upon improvement, Opdualag may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 2 to 4 mg/kg/day methylprednisolone equivalents, and Opdualag must be permanently discontinued.

Immune-related colitis
Severe diarrhoea or colitis has been observed with nivolumab in combination with relatlimab (see section 4.8). Patients should be monitored for diarrhoea and additional symptoms of colitis, such as abdominal pain and mucus and/or blood in stool. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-related colitis. Infectious and other aetiologies of diarrhoea should be ruled out, therefore appropriate laboratory tests and additional examinations must be performed. If diagnosis of corticosteroid-refractory immune-related colitis is confirmed, addition of an alternative immunosuppressive agent to the corticosteroid therapy, or replacement of the corticosteroid therapy should be considered.

For Grade 4 diarrhoea or colitis, Opdualag must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

Opdualag should be withheld for Grade 3 diarrhoea or colitis, and corticosteroids initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents. Upon improvement, Opdualag may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, Opdualag must be permanently discontinued.

For Grade 2 diarrhoea or colitis, Opdualag should be withheld. Persistent diarrhoea or colitis should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, Opdualag may be resumed after corticosteroid taper, if needed. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents, and Opdualag must be permanently discontinued.

Immune-related hepatitis
Severe hepatitis has been observed with nivolumab in combination with relatlimab (see section 4.8).
Patients should be monitored for signs and symptoms of hepatitis such as transaminase and total bilirubin elevations. Infectious and disease-related aetiologies should be ruled out.

For AST or ALT increases to more than 5 times ULN regardless of baseline, total bilirubin increases to more than 3 times ULN, or concurrent AST or ALT increase to more than 3 times ULN and total bilirubin increase to more than 2 times ULN, Opdualag must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

For AST/ALT increases to more than 3 and up to 5 times ULN, or total bilirubin increases to more than 1.5 and up to 3 times ULN, Opdualag should be withheld. Persistent elevations in these laboratory values should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, Opdualag may be resumed after corticosteroid taper, if needed. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents, and Opdualag must be permanently discontinued.

Immune-related nephritis and renal dysfunction
Severe nephritis and renal dysfunction have been observed with nivolumab in combination with relatlimab (see section 4.8). Patients should be monitored for signs and symptoms of nephritis or renal dysfunction. Most patients present with asymptomatic increases in serum creatinine. Disease-related aetiologies should be ruled out.

For Grade 4 serum creatinine elevation, Opdualag must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

For Grade 2 or 3 serum creatinine elevation, Opdualag should be withheld, and corticosteroids should be initiated at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, Opdualag may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents, and Opdualag must be permanently discontinued.

Immune-related endocrinopathies
Severe endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency (including secondary adrenocortical insufficiency), hypophysitis (including hypopituitarism), and diabetes mellitus have been observed with nivolumab in combination with relatlimab. Cases of diabetic ketoacidosis have been observed with nivolumab monotherapy and could potentially occur with nivolumab in combination with relatlimab (see section 4.8).


Patients should be monitored for clinical signs and symptoms of endocrinopathies, and for hyperglycaemia and changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation). Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate aetiology has been identified, signs or symptoms of endocrinopathies should be considered immune-related.

Thyroid dysfunction
For symptomatic hypothyroidism, Opdualag should be withheld, and thyroid hormone replacement should be initiated as needed. For symptomatic hyperthyroidism, Opdualag should be withheld and antithyroid treatment should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the thyroid is suspected. Upon improvement, Opdualag may be resumed after corticosteroid taper, if needed.
Monitoring of thyroid function should continue to ensure appropriate hormone replacement is utilised.
Opdualag must be permanently discontinued for life-threatening (Grade 4) hyperthyroidism or hypothyroidism.

Adrenal insufficiency
Opdualag must be permanently discontinued for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. For symptomatic Grade 2 adrenal insufficiency, Opdualag should be withheld, and physiologic corticosteroid replacement should be initiated as needed. Monitoring of adrenal function and hormone levels should continue to ensure appropriate corticosteroid replacement is utilised.

Hypophysitis
Opdualag must be permanently discontinued for life-threatening (Grade 4) hypophysitis. For symptomatic Grade 2 or 3 hypophysitis, Opdualag should be withheld, and hormone replacement should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the pituitary gland is suspected. Upon improvement, Opdualag may be resumed after corticosteroid taper, if needed. Monitoring of pituitary function and hormone levels should continue to ensure appropriate hormone replacement is utilised.

Diabetes mellitus
For symptomatic diabetes, Opdualag should be withheld, and insulin replacement should be initiated as needed. Monitoring of blood sugar should continue to ensure appropriate insulin replacement is utilised. Opdualag must be permanently discontinued for life-threatening diabetes.

Immune-related skin adverse reactions
Severe rash has been observed with nivolumab in combination with relatlimab (see section 4.8).
Opdualag should be withheld for Grade 3 rash and discontinued for Grade 4 rash. Severe rash should be managed with high-dose corticosteroid at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

Rare cases of SJS and TEN, some of them with fatal outcome, have been observed with nivolumab monotherapy and could potentially occur with nivolumab in combination with relatlimab. If symptoms or signs of SJS or TEN are suspected, Opdualag should be withheld and the patient referred to a specialised unit for assessment and treatment. If the patient has confirmed SJS or TEN with the use of Opdualag, permanent discontinuation of treatment is recommended (see section 4.2).

Caution should be used when considering the use of Opdualag in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immune-stimulatory anticancer agents.



Immune-related myocarditis
Severe immune-related myocarditis has been observed with nivolumab in combination with relatlimab. The diagnosis of myocarditis requires a high index of suspicion. Patients with cardiac or cardio-pulmonary symptoms should be assessed for potential myocarditis. If myocarditis is suspected, prompt initiation of a high dose of steroids (prednisone 1 to 2 mg/kg/day or methylprednisolone 1 to 2 mg/kg/day) and prompt cardiology consultation with diagnostic workup according to current clinical guidelines should be initiated. Once a diagnosis of myocarditis is established, Opdualag should be withheld or permanently discontinued as described below.

For Grade 3 or 4 myocarditis, Opdualag must be permanently discontinued, and corticosteroids should be initiated at a dose of 2 to 4 mg/kg/day methylprednisolone equivalents (see section 4.2).

For Grade 2 myocarditis, Opdualag should be withheld and corticosteroids initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalent. Upon improvement, resumption of Opdualag may be considered after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 2 to 4 mg/kg/day methylprednisolone equivalents, and Opdualag must be permanently discontinued (see section 4.2).

Other immune-related adverse reactions
The following clinically significant immune-related adverse reactions have been rarely reported in patient treated with nivolumab in combination with relatlimab: uveitis, pancreatitis, Guillain-Barré syndrome, myositis/rhabdomyolysis, encephalitis, haemolytic anaemia, Vogt-Koyanagi-Harada syndrome (VKH).

The following additional clinically significant immune-related adverse reactions have been rarely reported with nivolumab monotherapy or nivolumab in combination with other approved agents: demyelination, autoimmune neuropathy (including facial and abducens nerve paresis), myasthenia gravis, myasthenic syndrome, aseptic meningitis, gastritis, sarcoidosis, duodenitis, hypoparathyroidism, and cystitis noninfective.

For suspected immune-related adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, Opdualag should be withheld and corticosteroids administered. Upon improvement, Opdualag may be resumed after corticosteroid taper. Opdualag must be permanently discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening immune-related adverse reaction.

Other important warnings and precautions, including class effects
Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with nivolumab in combination with relatlimab may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with nivolumab in combination with relatlimab versus the risk of possible organ rejection should be considered in these patients.

Haemophagocytic lymphohistiocytosis (HLH) has been observed with nivolumab as monotherapy, nivolumab in combination with relatlimab and nivolumab in combination with other agents with a fatal event reported with nivolumab in combination with relatlimab. Caution should be taken when administering nivolumab in combination with relatlimab. If HLH is confirmed, administration of nivolumab in combination with relatlimab should be discontinued and treatment for HLH initiated.

In patients treated with nivolumab before or after allogeneic Haematopoietic Stem Cell Transplantation (HSCT), rapid-onset and severe graft-versus-host disease (GVHD), some with fatal outcome, have been reported. Treatment with nivolumab in combination with relatlimab may increase the risk of severe GVHD and death in patients who have had prior allogeneic HSCT, mainly in those with prior history of GVHD. The benefit of treatment with nivolumab in combination with relatlimab versus the possible risk should be considered in these patients.


Infusion reactions
Severe infusion reactions have been reported in clinical studies of nivolumab in combination with relatlimab (see section 4.8). In case of a severe or life-threatening infusion reaction, Opdualag infusion must be discontinued and appropriate medical therapy administered. Patients with mild or moderate infusion reaction may receive Opdualag with close monitoring and preventative treatment according to local guidelines for prophylaxis of infusion reactions.

Patients excluded from pivotal advanced melanoma clinical study
Patients with active autoimmune disease, medical conditions requiring systemic treatment with moderate or high dose corticosteroids or immunosuppressive medicinal products, uveal melanoma, active or untreated brain, or leptomeningeal metastases, and those with a history of myocarditis, elevated troponin levels > 2 times ULN or ECOG performance status score ≥ 2, were excluded from the pivotal clinical study of nivolumab in combination with relatlimab. In the absence of data, nivolumab in combination with relatlimab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Effects on Driving

4.7   Effects on ability to drive and use machines
Opdualag has a minor influence on the ability to drive and use machines. Because of potential adverse reactions such as fatigue and dizziness (see section 4.8), patients should be advised to use caution when driving or operating machines until they are certain that Opdualag does not adversely affect them.