Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Bristol-Myers Squibb Pharma EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
When assessing the PD-L1 status of the tumour, it is important that a well-validated and robust methodology is used.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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 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.
The prescriber must discuss the risks of Opdualag therapy with the patient. The patient will be provided with the patient card and instructed to carry the card at all times.
Nivolumab and relatlimab are both human monoclonal antibodies and as such, no interaction studies have been conducted. As monoclonal antibodies are not metabolised by cytochrome P450 (CYP) enzymes or other active substances metabolising enzymes, inhibition or induction of these enzymes by co-administered medicinal products is not anticipated to affect the pharmacokinetics of relatlimab or nivolumab.
Nivolumab and relatlimab are not expected to affect the pharmacokinetics of other active substances that are metabolised by CYP enzymes given the lack of significant modulation of cytokines by nivolumab and relatlimab and therefore lack of effect on expression of cytochrome P450 enzyme.
The use of systemic corticosteroids and other immunosuppressants at baseline, before starting nivolumab in combination with relatlimab, should be avoided because of their potential interference with the pharmacodynamic activity. However, systemic corticosteroids and other immunosuppressants can be used after starting nivolumab in combination with relatlimab to treat immune-related adverse reactions.
Opdualag is not recommended in women of childbearing potential not using effective contraception unless the clinical benefit outweighs the potential risk. Effective contraception should be used for at least 5 months following the last dose of Opdualag.
There is a limited amount of data from the use of nivolumab in combination with relatlimab in pregnant women. Based on its mechanism of action and data from animal studies, nivolumab in combination with relatlimab can cause foetal harm when administered to a pregnant woman. Studies in animals receiving nivolumab have shown embryofoetal toxicity (see section 5.3). Human IgG4 is known to cross the placental barrier and nivolumab and relatlimab are an IgG4; therefore, nivolumab and relatlimab have the potential to be transmitted from the mother to the developing foetus. Opdualag is not recommended during pregnancy and in women of childbearing potential not using effective contraception unless the clinical benefit outweighs the potential risk.
It is unknown whether nivolumab and/or relatlimab are excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period. Afterwards, Opdualag could be used during breast-feeding if clinically needed.
Studies to evaluate the effect of nivolumab and/or relatlimab on fertility have not been performed. Thus, the effect of nivolumab and/or relatlimab on male and female fertility is unknown.
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.
Nivolumab in combination with relatlimab is associated with immune-related adverse reactions (see “Description of selected adverse reactions” below). The management guidelines for these adverse reactions are described in section 4.4.
The most common adverse reactions are fatigue (41%), musculoskeletal pain (32%), rash (29%), arthralgia (26%), diarrhoea (26%), pruritus (26%), headache (20%), nausea (19%), cough (16%), decreased appetite (16%), hypothyroidism (16%), abdominal pain (14%), vitiligo (13%), pyrexia (12%), constipation (11%), urinary tract infection (11%), dyspnoea (10%), and vomiting (10%).
The most common serious adverse reactions are adrenal insufficiency (1.4%), anaemia (1.4%), back pain (1.1%), colitis (1.1%), diarrhoea (1.1%), myocarditis (1.1%), pneumonia (1.1%), and urinary tract infection (1.1%). Incidences of Grade 3-5 adverse reactions in patients with advanced (unresectable or metastatic) melanoma were 43% for nivolumab in combination with relatlimab and 35% for nivolumab treated patients.
The safety of nivolumab in combination with relatlimab has been evaluated in 355 patients with advanced (unresectable or metastatic) melanoma (study CA224047). Adverse reactions reported in the dataset for patients treated with nivolumab in combination with relatlimab, with a median follow-up of 19.94 months, are presented in Table 2. The frequencies included above and in Table 2 are based on all-cause adverse event frequencies. These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Table 2. Adverse reactions in clinical studies:
| Infections and infestations | |
| Very common | urinary tract infection |
| Common | upper respiratory tract infection |
| Uncommon | folliculitis |
| Blood and lymphatic system disorders | |
| Very common | anaemiaa, lymphopaeniaa, neutropaeniaa, leucopaeniaa |
| Common | thrombocytopaeniaa, eosinophilia |
| Uncommon | haemolytic anaemia |
| Endocrine disorders | |
| Very common | hypothyroidism |
| Common | adrenal insufficiency, hypophysitis, hyperthyroidism, thyroiditis |
| Uncommon | hypopituitarism, hypogonadism |
| Metabolism and nutrition disorders | |
| Very common | decreased appetite |
| Common | diabetes mellitus, hypoglycaemiaa, weight decreased, hyperuricaemia, hypoalbuminaemia, dehydration |
| Psychiatric disorders | |
| Common | confusional state |
| Nervous system disorders | |
| Very common | headache |
| Common | peripheral neuropathy, dizziness, dysgeusia |
| Uncommon | encephalitis, Guillain-Barré syndrome, optic neuritis |
| Eye disorders | |
| Common | uveitis, visual impairment, dry eye, increased lacrimation |
| Uncommon | Vogt-Koyanagi-Harada disease, ocular hyperaemia |
| Cardiac disorders | |
| Common | myocarditis |
| Uncommon | pericardial effusion |
| Vascular disorders | |
| Common | phlebitis |
| Respiratory, thoracic and mediastinal disorders | |
| Very common | dyspnoea, cough |
| Common | pneumonitisb, nasal congestion |
| Uncommon | asthma |
| Gastrointestinal disorders | |
| Very common | diarrhoea, vomiting, nausea, abdominal pain, constipation |
| Common | colitis, pancreatitis, gastritis, dysphagia, stomatitis, dry mouth |
| Uncommon | oesophagitis |
| Hepatobiliary disorders | |
| Common | hepatitis |
| Uncommon | cholangitis |
| Skin and subcutaneous tissue disorders | |
| Very common | rash, vitiligo, pruritus |
| Common | alopecia, lichenoid keratosis, photosensitivity reaction, dry skin |
| Uncommon | pemphigoid, psoriasis, urticaria |
| Musculoskeletal and connective tissue disorders | |
| Very common | musculoskeletal pain, arthralgia |
| Common | arthritis, muscle spasms, muscular weakness |
| Uncommon | myositis, Sjogren’s Syndrome, polymyalgia rheumatica, rheumatoid arthritis, systemic lupus erythematosus |
| Renal and urinary disorders | |
| Common | renal failure, proteinuria |
| Uncommon | nephritis |
| Reproductive system and breast disorders | |
| Uncommon | azoospermia |
| General disorders and administration site conditions | |
| Very common | fatigue, pyrexia |
| Common | oedema, influenza-like illness, chills |
| Investigations | |
| Very common | increased ASTa, increased ALTa, hyponatraemiaa, increased creatininea, increased alkaline phosphatasea, hyperkalaemiaa, hypocalcaemiaa, hypomagnesaemiaa, hypercalcaemiaa, hypokalaemiaa |
| Common | increased bilirubina, hypernatraemiaa, hypermagnesaemiaa, troponin increased, gamma- glutamyl transferase increased, blood lactate dehydrogenase increased, lipase increased, amylase increased |
| Uncommon | c-reactive protein increased, red blood cell sedimentation rate increased |
| Injury, poisoning and procedural complications | |
| Common | infusion-related reaction |
a Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from baseline in laboratory measurements.
b Fatal case has been reported in the clinical study.
In patients treated with nivolumab in combination with relatlimab, pneumonitis, including interstitial lung disease and lung infiltration occurred in 5.1% of patients. Incidences of Grade ¾ events were 0.8%. Fatal events occurred in 0.28% of patients. Median time to onset was 28 weeks (range: 3.6-94.4). Resolution occurred in 83.3% patients with a median time to resolution of 12.0 weeks (range: 2.1-29.7+). Immune-related pneumonitis led to permanent discontinuation of nivolumab in combination with relatlimab in 1.7% of patients and required high dose corticosteroids (prednisone ≥40 mg per day or equivalent) in 55.6% of patients with immune-related pneumonitis.
In patients treated with nivolumab in combination with relatlimab, diarrhoea, colitis, or frequent bowel movements occurred in 15.8% of patients. Incidences of Grade ¾ events were 2.0%. Median time to onset was 14 weeks (range: 0.1-95.6). Resolution occurred in 92.7% patients with a median time to resolution of 3.9 weeks (range: 0.1-136.9+). Immune-related colitis led to permanent discontinuation of nivolumab in combination with relatlimab in 2.0% of patients and required high dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) in 33.9% of patients with immune-related colitis.
In patients treated with nivolumab in combination with relatlimab, liver function test abnormalities occurred in 13.2% of patients. Incidences of Grade ¾ events were 3.9%. Median time to onset was 11 weeks (range: 2.0-144.9). Resolution occurred in 78.7% patients with a median time to resolution of 6.1 weeks (range: 1.0-88.1+). Immune-related hepatitis led to permanent discontinuation of nivolumab in combination with relatlimab in 2.0% of patients and required high dose corticosteroids in 38.3% of patients with immune-related hepatitis.
In patients treated with nivolumab in combination with relatlimab, nephritis or renal dysfunction occurred in 4.5% of patients. Incidences of Grade ¾ events were 1.4%. Median time to onset was 21 weeks (range: 1.9-127.9). Resolution occurred in 81.3% patients with a median time to resolution of 8.1 weeks (range: 0.9-91.6+). Immune-related nephritis and renal dysfunction led to permanent discontinuation of nivolumab in combination with relatlimab in 1.1% of patients and required high dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) in 25.0% of patients with immune-related nephritis and renal dysfunction.
In patients treated with nivolumab in combination with relatlimab, endocrinopathies occurred in 26% of patients.
Thyroid disorders, including hypothyroidism or hyperthyroidism, occurred in 20.8% of patients. There were no incidences of Grade ¾ thyroid disorder. Adrenal insufficiency (including adrenocortical insufficiency acute) occurred in 4.8% of patients. Incidences of Grade ¾ events adrenal insufficiency occurred in 1.4%. There were no incidences of Grade ¾ hypopituitarism. Hypophysitis occurred in 1.1% of patients. Incidence of Grade ¾ hypophysitis were 0.3%. Diabetes mellitus (including Type 1 diabetes mellitus) occurred in 0.3% of patients. Incidences of Grade ¾ diabetes mellitus were in 0.3%.
Median time to onset of these endocrinopathies was 13 weeks (range: 1.0-73.0). Resolution occurred in 27.7% patients. Time to resolution ranged from 0.4 to 176.0+ weeks. Immune-related endocrinopathies led to permanent discontinuation of nivolumab in combination with relatlimab in 1.1% of patients and required high dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) in 7.4% of patients with immune-related endocrinopathies.
In patients treated with nivolumab in combination with relatlimab, rash, including pruritis and vitiligo occurred in 45.1% of patients. Incidences of Grade ¾ events were 1.4%. Median time to onset was 8 weeks (range: 0.1-116.4). Resolution occurred in 47.5% patients. Time to resolution ranged from 0.1-166.9+ weeks. Immune-related skin adverse reactions led to permanent discontinuation of nivolumab in combination with relatlimab in 0.3% of patients and required high dose corticosteroids (prednisone ≥40 mg per day or equivalent) in 3.8% of patients with immune-related skin adverse reactions.
In patients treated with nivolumab in combination with relatlimab, myocarditis occurred in 1.4% of patients. Incidences of Grade ¾ events were 0.6%. Median time to onset was 4.14 weeks (range: 2.1-6.3). Resolution occurred in 100% of patients with a median time to resolution of 3 weeks (1.9-14.0). Myocarditis led to permanent discontinuation of nivolumab in combination with relatlimab in 1.4% of patients and required high dose corticosteroids (prednisone ≥40 mg per day or equivalent) in 100% of patients with immune-related myocarditis.
In patients treated with nivolumab in combination with relatlimab, hypersensitivity/infusion reactions occurred in 6.8% of patients. All incidents were Grade 1/2.
In patients treated with nivolumab in combination with relatlimab, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 3.6% for anaemia, 5.2% for lymphopaenia, 0.3% for neutropaenia, 0.6% for increased alkaline phosphatase, 2.9% for increased AST, 3.5% for increased ALT, 0.3% for increased total bilirubin, 0.9% for increased creatinine, 1.5% for hyponatraemia, 1.8% for hyperkalaemia, 0.3% for hypokalaemia, 0.9% for hypercalcaemia, 0.6% for hypocalcaemia, 0.9% for hypermagnesaemia, and 0.6% for hypomagnesaemia.
In study CA224047, out of the evaluable patients for anti-drug antibodies, the incidence of treatment-emergent anti-relatlimab antibodies and neutralizing antibodies against relatlimab in the Opdualag group were 5.6% (17/301) and 0.3% (1/301), respectively. The incidence of treatment-emergent anti-nivolumab antibodies and neutralizing antibodies against nivolumab in the Opdualag group were 4.0% (12/299) and 0.3% (1/299), respectively, which were similar to that observed in the nivolumab group 6.7% (19/283) and 0.4% (1/283), respectively. There was no evidence of an altered PK, efficacy, or safety profile with anti-nivolumab or anti-relatlimab antibody development.
Overall, no differences in safety were reported between elderly (≥ 65 years) and younger patients (see section 5.1).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. Opdualag should not be infused concomitantly in the same intravenous line with other medicinal products.
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