OPDUALAG 240mg / 80mg concentrate for solution for infusion medication leaflet

Opdualag 240 mg/80 mg concentrate for solution for infusion

Each mL of concentrate for solution for infusion contains 12 mg of nivolumab and 4 mg of relatlimab.

One vial of 20 mL contains 240 mg of nivolumab and 80 mg of relatlimab.

Nivolumab and relatlimab are human immunoglobulin G4 (IgG4) monoclonal antibodies produced in

Chinese Hamster Ovary cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear to opalescent, colourless to slightly yellow liquid that is essentially free of particles.

The solution has a pH of approximately 5.8 and an osmolality of approximately 310 mOsm/kg.

Opdualag is indicated for the first-line treatment of advanced (unresectable or metastatic) melanoma inadults and adolescents 12 years of age and older with tumour cell PD-L1 expression < 1%.

Treatment must be initiated and supervised by physicians experienced in the treatment of cancer.

Patients treated with Opdualag must be given the patient card and be informed about the risks of

Opdualag (see also package leaflet).

Patients should be selected for treatment with Opdualag based on the tumour expression of PD-L1confirmed by a validated test (see sections 4.4 and 5.1).

The recommended dose for adults and adolescents 12 years of age and older is 480 mg nivolumab and160 mg relatlimab every 4 weeks administered as an intravenous infusion over 30 minutes. This doseis established for adolescent patients weighing at least 30 kg (see section 5.2).

Treatment with Opdualag should be continued as long as clinical benefit is observed or until treatmentis no longer tolerated by the patient. Dose escalation or reduction is not recommended. Dosing delayor discontinuation may be required based on individual safety and tolerability. Guidelines forpermanent discontinuation or withholding of doses are described in Table 1. Detailed guidelines forthe management of immune-related adverse reactions are described in section 4.4.

Table 1: Recommended treatment modifications for Opdualag

Immune-related Severity Treatment modificationadverse reaction

Grade 2 pneumonitis Withhold dose(s) until symptoms resolve,

Immune-related radiographic abnormalities improve, andpneumonitis management with corticosteroids is complete

Grade 3 or 4 pneumonitis Permanently discontinue treatment

Grade 2 or 3 diarrhoea or colitis Withhold dose(s) until symptoms resolve and

Immune-related management with corticosteroids, if needed, iscolitis complete

Grade 4 diarrhoea or colitis Permanently discontinue treatment

Aspartate aminotransferase (AST)or alanine aminotransferase (ALT)increases to more than 3 and up to5 times upper limit of normal Withhold dose(s) until laboratory values return(ULN) to baseline and management withor corticosteroids, if needed, is complete

Total bilirubin increases to morethan 1.5 and up to 3 times ULN

Immune-related AST or ALT increases to morehepatitis than 5 times ULN regardless ofbaseline.or

Total bilirubin increases to morethan 3 times ULN Permanently discontinue treatmentor

Concurrent AST or ALT increaseto more than 3 times ULN andtotal bilirubin increase to morethan 2 times ULN

Immune-related Grade 2 or 3 creatinine elevation Withhold dose(s) until creatinine returns tonephritis and renal baseline and management with corticosteroidsdysfunction is complete

Grade 4 creatinine elevation Permanently discontinue treatment

Symptomatic Grade 2 or 3 Withhold dose(s) until symptoms resolve andhypothyroidism, hyperthyroidism, management with corticosteroids (if needed forhypophysitis symptoms of acute inflammation) is complete.

Grade 2 adrenal insufficiency Treatment should be continued in the presence

Immune-related Grade 3 diabetes of hormone replacement therapya as long as noendocrinopathies symptoms are present

Grade 4 hypothyroidism

Grade 4 hyperthyroidism

Grade 4 hypophysitis Permanently discontinue treatment

Grade 3 or 4 adrenal insufficiency

Grade 4 diabetes

Grade 3 rash Withhold dose(s) until symptoms resolve andmanagement with corticosteroids is complete

Immune-related skin Suspected Stevens-Johnson Withhold dose(s)adverse reactions syndrome (SJS) or toxic epidermalnecrolysis (TEN)

Grade 4 rash Permanently discontinue treatment (see

Confirmed SJS/TEN section 4.4)

Immune-related Severity Treatment modificationadverse reaction

Immune-related Grade 2 myocarditis Withhold dose(s) until symptoms resolve andmyocarditis management with corticosteroids is completeb

Grade 3 or 4 myocarditis Permanently discontinue treatment

Grade 3 (first occurrence) Withhold dose(s)

Grade 4 or recurrent Grade 3;

Other immune- persistent Grade 2 or 3 despiterelated adverse treatment modification; inability toreactions reduce corticosteroid dose Permanently discontinue treatmentto 10 mg prednisone or equivalentper day

Grade 2 Myocarditis-Myositis-

Myocarditis- Myasthenia Gravis Overlap Withhold dose(s) until symptoms resolve andb

Myositis-Myasthenia Syndrome management with corticosteroids is complete

Gravis Overlap Grade 3 or 4 Myocarditis-

Syndromec Myositis-Myasthenia Gravis Permanently discontinue treatment

Overlap Syndrome

Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for

Adverse Events Version 5.0 (NCI-CTCAE v5).a Recommendation for the use of hormone replacement therapy is provided in section 4.4.b The safety of re-initiating Opdualag in patients previously experiencing immune-related myocarditis isnot known.c Presenting as an overlap of either two or all three conditions. The most severe CTCAE grade from theindividual events should be considered to assess the recommended treatment modification for Opdualag.

The safety and efficacy of Opdualag in children below 12 years of age have not been established. Nodata are available (see section 5.2).

No dose adjustment is required for elderly patients (≥ 65 years) (see section 5.2).

No dose adjustment is required in patients with mild or moderate renal impairment (see section 5.2).

Data from patients with severe renal impairment are too limited to draw conclusions on thispopulation.

No dose adjustment is required in patients with mild or moderate hepatic impairment (see section 5.2).

Data from patients with severe hepatic impairment are too limited to draw conclusions on thispopulation.

Opdualag is for intravenous use only. It is to be administered as an intravenous infusion over a periodof 30 minutes.

Opdualag must not be administered as an intravenous push or bolus injection.

Opdualag can be used without dilution, or may be diluted with sodium chloride 9 mg/mL (0.9%)solution for injection or glucose 50 mg/mL (5%) solution for injection (see section 6.6).

For instructions on the preparation and handling of the medicinal product before administration, seesection 6.6.

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 numberof the administered product should be clearly recorded.

When assessing the PD-L1 status of the tumour, it is important that a well-validated and robustmethodology is used.

Immune-related adverse reactions can occur with nivolumab in combination with relatlimab whichrequire 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 adversereaction 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 confirmaetiology or exclude other causes. Based on the severity of the adverse reaction, Opdualag should bewithheld and corticosteroids administered. If immunosuppression with corticosteroids is used to treatan adverse reaction, a taper of at least 1 month duration should be initiated upon improvement. Rapidtapering may lead to worsening or recurrence of the adverse reaction. Non-corticosteroidimmunosuppressive therapy should be added if there is worsening or no improvement despitecorticosteroid use.

In patients with pre-existing autoimmune disease (AID), data from observational studies suggest thatthe risk of immune-mediated adverse reactions following immune-checkpoint inhibitor therapy maybe increased as compared with the risk in patients without pre-existing AID. In addition, flares of theunderlying AID were frequent, but the majority were mild and manageable. However, data specific tothe combination of nivolumab and relatlimab are scarce.

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

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

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

For Grade 3 or 4 pneumonitis, Opdualag must be permanently discontinued, and corticosteroidsshould 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 ata dose of 1 mg/kg/day methylprednisolone equivalents. Upon improvement, Opdualag may beresumed after corticosteroid taper. If worsening or no improvement occurs despite initiation ofcorticosteroids, corticosteroid dose should be increased to 2 to 4 mg/kg/day methylprednisoloneequivalents, and Opdualag must be permanently discontinued.

Severe diarrhoea or colitis has been observed with nivolumab in combination with relatlimab (seesection 4.8). Patients should be monitored for diarrhoea and additional symptoms of colitis, such asabdominal pain and mucus and/or blood in stool. Cytomegalovirus (CMV) infection/reactivation hasbeen reported in patients with corticosteroid-refractory immune-related colitis. Infectious and otheraetiologies of diarrhoea should be ruled out, therefore appropriate laboratory tests and additionalexaminations must be performed. If diagnosis of corticosteroid-refractory immune-related colitis isconfirmed, addition of an alternative immunosuppressive agent to the corticosteroid therapy, orreplacement of the corticosteroid therapy should be considered.

For Grade 4 diarrhoea or colitis, Opdualag must be permanently discontinued, and corticosteroidsshould 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 doseof 1 to 2 mg/kg/day methylprednisolone equivalents. Upon improvement, Opdualag may be resumedafter 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 bemanaged with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Uponimprovement, Opdualag may be resumed after corticosteroid taper, if needed. If worsening or noimprovement occurs despite initiation of corticosteroids, corticosteroid dose should be increasedto 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 totalbilirubin 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 increasesto more than 3 times ULN, or concurrent AST or ALT increase to more than 3 times ULN and totalbilirubin increase to more than 2 times ULN, Opdualag must be permanently discontinued, andcorticosteroids 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 morethan 1.5 and up to 3 times ULN, Opdualag should be withheld. Persistent elevations in theselaboratory values should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/daymethylprednisolone equivalents. Upon improvement, Opdualag may be resumed after corticosteroidtaper, 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 withrelatlimab (see section 4.8). Patients should be monitored for signs and symptoms of nephritis or renaldysfunction. Most patients present with asymptomatic increases in serum creatinine. Disease-relatedaetiologies should be ruled out.

For Grade 4 serum creatinine elevation, Opdualag must be permanently discontinued, andcorticosteroids 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 shouldbe 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 despiteinitiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/daymethylprednisolone equivalents, and Opdualag must be permanently discontinued.

Severe endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency (includingsecondary adrenocortical insufficiency), hypophysitis (including hypopituitarism), and diabetesmellitus have been observed with nivolumab in combination with relatlimab. Cases of diabeticketoacidosis have been observed with nivolumab monotherapy and could potentially occur withnivolumab in combination with relatlimab (see section 4.8).

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

For symptomatic hypothyroidism, Opdualag should be withheld, and thyroid hormone replacementshould be initiated as needed. For symptomatic hyperthyroidism, Opdualag should be withheld andantithyroid treatment should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/daymethylprednisolone equivalents should also be considered if acute inflammation of the thyroid issuspected. 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 orhypothyroidism.

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

Hypophysitis

Opdualag must be permanently discontinued for life-threatening (Grade 4) hypophysitis. Forsymptomatic Grade 2 or 3 hypophysitis, Opdualag should be withheld, and hormone replacementshould be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisoloneequivalents should also be considered if acute inflammation of the pituitary gland is suspected. Uponimprovement, Opdualag may be resumed after corticosteroid taper, if needed. Monitoring of pituitaryfunction 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 initiatedas needed. Monitoring of blood sugar should continue to ensure appropriate insulin replacement isutilised. 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 shouldbe managed with high-dose corticosteroid at a dose of 1 to 2 mg/kg/day methylprednisoloneequivalents.

Rare cases of SJS and TEN, some of them with fatal outcome, have been observed with nivolumabmonotherapy and could potentially occur with nivolumab in combination with relatlimab. If symptomsor signs of SJS or TEN are suspected, Opdualag should be withheld and the patient referred to aspecialised 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 previouslyexperienced a severe or life-threatening skin adverse reaction on prior treatment with otherimmune-stimulatory anticancer agents.

Severe immune-related myocarditis has been observed with nivolumab in combination withrelatlimab. The diagnosis of myocarditis requires a high index of suspicion. Patients with cardiac orcardio-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 methylprednisolone1 to 2 mg/kg/day) and prompt cardiology consultation with diagnostic workup according to currentclinical guidelines should be initiated. Once a diagnosis of myocarditis is established, Opdualagshould be withheld or permanently discontinued as described below.

For Grade 3 or 4 myocarditis, Opdualag must be permanently discontinued, and corticosteroids shouldbe 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 doseof 1 to 2 mg/kg/day methylprednisolone equivalent. Upon improvement, resumption of Opdualag maybe considered after corticosteroid taper. If worsening or no improvement occurs despite initiation ofcorticosteroids, corticosteroid dose should be increased to 2 to 4 mg/kg/day methylprednisoloneequivalents, and Opdualag must be permanently discontinued (see section 4.2).

The following clinically significant immune-related adverse reactions have been reported in patientstreated with nivolumab in combination with relatlimab: uveitis, pancreatitis, gastritis, Guillain-Barrésyndrome, myositis/rhabdomyolysis, myasthenia gravis, Myocarditis-Myositis-Myasthenia Gravis

Overlap Syndrome, encephalitis, haemolytic anaemia, Vogt-Koyanagi-Harada syndrome (VKH).

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

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

Cases of Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome (presenting as an overlap ofeither two or all three conditions), some with fatal outcome, have been reported with nivolumab incombination with relatlimab. Early recognition and aggressive management are essential to addressassociated morbidity and risk of mortality.

For Grade 3 or 4 Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome, Opdualag must bepermanently discontinued (see section 4.2). Corticosteroids should be initiated as clinically indicated.

For Grade 2 Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome, Opdualag should bewithheld and corticosteroids initiated as clinically indicated (see section 4.2). Upon improvement,resumption of Opdualag may be considered after corticosteroid taper. If worsening or no improvementoccurs despite initiation of corticosteroids, corticosteroid dose should be adjusted as clinicallyindicated, and Opdualag must be permanently discontinued.

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 ofrejection in solid organ transplant recipients. The benefit of treatment with nivolumab in combinationwith 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 afatal event reported with nivolumab in combination with relatlimab. Caution should be taken whenadministering nivolumab in combination with relatlimab. If HLH is confirmed, administration ofnivolumab 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 fataloutcome, have been reported. Treatment with nivolumab in combination with relatlimab may increasethe risk of severe GVHD and death in patients who have had prior allogeneic HSCT, mainly in thosewith prior history of GVHD. The benefit of treatment with nivolumab in combination with relatlimabversus the possible risk should be considered in these patients.

Infusion reactions

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

Patients excluded from pivotal advanced melanoma clinical study

Patients with active autoimmune disease, medical conditions requiring systemic treatment withmoderate 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 fromthe 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 aftercareful 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 beprovided 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 studieshave 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 byco-administered medicinal products is not anticipated to affect the pharmacokinetics of relatlimab ornivolumab.

Nivolumab and relatlimab are not expected to affect the pharmacokinetics of other active substancesthat are metabolised by CYP enzymes given the lack of significant modulation of cytokines bynivolumab and relatlimab and therefore lack of effect on expression of cytochrome P450 enzyme.

Systemic immunosuppression

The use of systemic corticosteroids and other immunosuppressants at baseline, before startingnivolumab in combination with relatlimab, should be avoided because of their potential interferencewith the pharmacodynamic activity. However, systemic corticosteroids and other immunosuppressantscan be used after starting nivolumab in combination with relatlimab to treat immune-related adversereactions.

Opdualag is not recommended in women of childbearing potential not using effective contraceptionunless the clinical benefit outweighs the potential risk. Effective contraception should be used for atleast 5 months following the last dose of Opdualag.

There is a limited amount of data from the use of nivolumab in combination with relatlimab inpregnant women. Based on its mechanism of action and data from animal studies, nivolumab incombination with relatlimab can cause foetal harm when administered to a pregnant woman. Studiesin animals receiving nivolumab have shown embryofoetal toxicity (see section 5.3). Human IgG4 isknown to cross the placental barrier and nivolumab and relatlimab are an IgG4; therefore, nivolumaband relatlimab have the potential to be transmitted from the mother to the developing foetus. Opdualagis not recommended during pregnancy and in women of childbearing potential not using effectivecontraception unless the clinical benefit outweighs the potential risk.

It is unknown whether nivolumab and/or relatlimab are excreted in human milk. Human IgGs areknown to be excreted in breast milk during the first few days after birth, which is decreasing to lowconcentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded duringthis 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 adversereactions such as fatigue and dizziness (see section 4.8), patients should be advised to use cautionwhen driving or operating machines until they are certain that Opdualag does not adversely affectthem.

Nivolumab in combination with relatlimab is associated with immune-related adverse reactions (see“Description of selected adverse reactions” below). The management guidelines for these adversereactions 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%), backpain (1.1%), colitis (1.1%), diarrhoea (1.1%), myocarditis (1.1%), pneumonia (1.1%), and urinary tractinfection (1.1%). Incidences of Grade 3-5 adverse reactions in patients with advanced (unresectable ormetastatic) melanoma were 43% for nivolumab in combination with relatlimab and 35% fornivolumab treated patients.

The safety of nivolumab in combination with relatlimab has been evaluated in 355 patients withadvanced (unresectable or metastatic) melanoma (study CA224047). Adverse reactions reported in thedataset for patients treated with nivolumab in combination with relatlimab, with a median follow-up of19.94 months, are presented in Table 2. The frequencies included above and in Table 2 are based onall-cause adverse event frequencies. These reactions are presented by system organ class and byfrequency. 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) and notknown (cannot be estimated from the available data). Within each frequency grouping, adversereactions are presented in the order of decreasing seriousness.

Table 2: Adverse reactions in clinical studies

Very common urinary tract infection

Common upper respiratory tract infection

Uncommon folliculitis

Very common anaemiaa, lymphopaeniaa, neutropaeniaa, leucopaeniaa

Common thrombocytopaeniaa, eosinophilia

Uncommon haemolytic anaemia

Very common hypothyroidism

Common adrenal insufficiency, hypophysitis, hyperthyroidism, thyroiditis

Uncommon hypopituitarism, hypogonadism

Very common decreased appetite

Common diabetes mellitus, hypoglycaemiaa, weight decreased, hyperuricaemia, hypoalbuminaemia,dehydration

Common confusional state

Very common headache

Common peripheral neuropathy, dizziness, dysgeusia

Uncommon encephalitis, Guillain-Barré syndrome, optic neuritis, myasthenia gravis, Myocarditis-

Myositis-Myasthenia Gravis Overlap Syndromec

Common uveitis, visual impairment, dry eye, increased lacrimation

Uncommon Vogt-Koyanagi-Harada disease, ocular hyperaemia

Common myocarditis

Uncommon pericardial effusion

Common phlebitis

Very common dyspnoea, cough

Common pneumonitisb, nasal congestion

Uncommon asthma, pleural effusion

Very common diarrhoea, vomiting, nausea, abdominal pain, constipation

Common colitis, pancreatitis, gastritis, dysphagia, stomatitis, dry mouth

Uncommon oesophagitis

Rare pancreatic exocrine insufficiency

Not known coeliac disease

Common hepatitis

Uncommon cholangitis

Very common rash, vitiligo, pruritus

Common alopecia, lichenoid keratosis, photosensitivity reaction, dry skin

Uncommon pemphigoid, psoriasis, urticaria

Very common musculoskeletal pain, arthralgia

Common arthritis, muscle spasms, muscular weakness

Uncommon myositis, Sjogren’s Syndrome, polymyalgia rheumatica, rheumatoid arthritis, systemic lupuserythematosus

Common renal failure, proteinuria

Uncommon nephritis

Uncommon azoospermia

Very common fatigue, pyrexia

Common oedema, influenza-like illness, chills

Rare serositis

Very common increased ASTa, increased ALTa, hyponatraemiaa, increased creatininea, increased alkalinephosphatasea, 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

Common infusion-related reactiona Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening frombaseline in laboratory measurements.

b Fatal case has been reported in the clinical study.c Cases of Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome (presenting as an overlap of eithertwo or all three conditions), some with fatal outcome, have been reported with nivolumab in combinationwith relatlimab (see section 4.4).

In patients treated with nivolumab in combination with relatlimab, pneumonitis, including interstitiallung disease and lung infiltration occurred in 5.1% of patients. Incidences of Grade 3/4 events were0.8%. 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 of12.0 weeks (range: 2.1-29.7+). Immune-related pneumonitis led to permanent discontinuation ofnivolumab 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 bowelmovements occurred in 15.8% of patients. Incidences of Grade 3/4 events were 2.0%. Median time toonset was 14 weeks (range: 0.1-95.6). Resolution occurred in 92.7% patients with a median time toresolution of 3.9 weeks (range: 0.1-136.9+). Immune-related colitis led to permanent discontinuationof nivolumab in combination with relatlimab in 2.0% of patients and required high dosecorticosteroids (prednisone ≥ 40 mg per day or equivalent) in 33.9% of patients with immune-relatedcolitis.

In patients treated with nivolumab in combination with relatlimab, liver function test abnormalitiesoccurred in 13.2% of patients. Incidences of Grade 3/4 events were 3.9%. Median time to onset was11 weeks (range: 2.0-144.9). Resolution occurred in 78.7% patients with a median time to resolutionof 6.1 weeks (range: 1.0-88.1+). Immune-related hepatitis led to permanent discontinuation ofnivolumab in combination with relatlimab in 2.0% of patients and required high dose corticosteroidsin 38.3% of patients with immune-related hepatitis.

In patients treated with nivolumab in combination with relatlimab, nephritis or renal dysfunctionoccurred in 4.5% of patients. Incidences of Grade 3/4 events were 1.4%. Median time to onset was21 weeks (range: 1.9-127.9). Resolution occurred in 81.3% patients with a median time to resolutionof 8.1 weeks (range: 0.9-91.6+). Immune-related nephritis and renal dysfunction led to permanentdiscontinuation of nivolumab in combination with relatlimab in 1.1% of patients and required highdose corticosteroids (prednisone ≥ 40 mg per day or equivalent) in 25.0% of patients withimmune-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. Therewere no incidences of Grade 3/4 thyroid disorder. Adrenal insufficiency (including adrenocorticalinsufficiency acute) occurred in 4.8% of patients. Incidences of Grade 3/4 events adrenal insufficiencyoccurred in 1.4%. There were no incidences of Grade 3/4 hypopituitarism. Hypophysitis occurred in1.1% of patients. Incidence of Grade 3/4 hypophysitis were 0.3%. Diabetes mellitus (including Type 1diabetes mellitus) occurred in 0.3% of patients. Incidences of Grade 3/4 diabetes mellitus were in0.3%.

Median time to onset of these endocrinopathies was 13 weeks (range: 1.0-73.0). Resolution occurredin 27.7% patients. Time to resolution ranged from 0.4 to 176.0+ weeks. Immune-relatedendocrinopathies led to permanent discontinuation of nivolumab in combination with relatlimab in1.1% of patients and required high dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) in7.4% of patients with immune-related endocrinopathies.

In patients treated with nivolumab in combination with relatlimab, rash, including pruritis and vitiligooccurred in 45.1% of patients. Incidences of Grade 3/4 events were 1.4%. Median time to onset was8 weeks (range: 0.1-116.4). Resolution occurred in 47.5% patients. Time to resolution rangedfrom 0.1-166.9+ weeks. Immune-related skin adverse reactions led to permanent discontinuation ofnivolumab 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 adversereactions.

In patients treated with nivolumab in combination with relatlimab, myocarditis occurred in 1.4% ofpatients. Incidences of Grade 3/4 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 relatlimabin 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 reactionsoccurred in 6.8% of patients. All incidents were Grade 1/2.

In patients treated with nivolumab in combination with relatlimab, the proportion of patients whoexperienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 3.6% foranaemia, pct. 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% forincreased 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% forhypomagnesaemia.

In study CA224047, out of the evaluable patients for anti-drug antibodies, the incidence oftreatment-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 oftreatment-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 thatobserved in the nivolumab group 6.7% (19/283) and 0.4% (1/283), respectively. There was noevidence of an altered PK, efficacy, or safety profile with anti-nivolumab or anti-relatlimab antibodydevelopment.

Overall, no differences in safety were reported between elderly (≥ 65 years) and younger patients (seesection 5.1).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions,and appropriate symptomatic treatment instituted immediately.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01FY02.

Opdualag is a fixed-dose combination (FDC) of nivolumab, a programmed death-1 inhibitor(anti-PD-1) and relatlimab, a lymphocyte-activation gene-3 inhibitor (anti-LAG-3).

Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cellproliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumours, andsignalling through this pathway can contribute to inhibition of active T cell immune surveillance oftumours. Nivolumab is a human IgG4 monoclonal antibody that binds to the PD-1 receptor, blocksinteraction with its ligands PD-L1 and PD-L2 and reduces PD-1 pathway-mediated inhibition of theimmune response, including the anti-tumour immune response. In syngeneic mouse tumour models,blocking PD-1 activity resulted in decreased tumour growth.

Relatlimab is a human IgG4 monoclonal antibody that binds to the LAG-3 receptor, blocks itsinteraction with ligands, including MHC II, and reduces LAG-3 pathway-mediated inhibition of theimmune response. Antagonism of this pathway promotes T cell proliferation and cytokine secretion.

The combination of nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) results in increased T-cellactivation compared to the activity of either antibody alone. In murine syngeneic tumour models,

LAG-3 blockade potentiates the anti-tumour activity of PD-1 blockage, inhibiting tumour growth andpromoting tumour regression.

Randomised phase 2/3 study of nivolumab in combination with relatlimab vs. nivolumab in patientswith previously untreated metastatic or unresectable melanoma (CA224047)

The safety and efficacy of nivolumab in combination with relatlimab for the treatment of patients withpreviously untreated metastatic or unresectable melanoma were evaluated in a phase 2/3, randomised,double-blinded study (CA224047). The study included patients with ECOG performance statusscore 0 or 1, and histologically confirmed stage III (unresectable) or stage IV melanoma per American

Joint Committee on Cancer (AJCC) version 8. Patients were allowed to have received prior adjuvantor neoadjuvant melanoma therapy (anti-PD-1, anti-CTLA-4, or BRAF-MEK therapy was allowed aslong as there was at least 6 months between the last dose of therapy and date of recurrence; interferontherapy was allowed as long as the last dose was at least 6 weeks prior to randomisation). Patients withactive autoimmune disease, a history of myocarditis, elevated troponin levels > 2 times ULN, or

ECOG performance status score ≥ 2, medical conditions requiring systemic treatment with moderateor high dose corticosteroids or immunosuppressive medicinal products, uveal melanoma, and active oruntreated brain or leptomeningeal metastases were excluded from the study (see section 4.4).

A total of 714 patients were randomised to receive either nivolumab in combination with relatlimab(n = 355), or nivolumab (n = 359). Patients in the combination arm received 480 mgnivolumab/160 mg relatlimab over 60 minutes every 4 weeks. Patients in the nivolumab arm receivednivolumab 480 mg every 4 weeks. Randomisation was stratified by tumour PD-L1 (≥ 1% vs. < 1)using PD-L1 IHC 28-8 pharmDx test, and LAG-3 expression (≥ 1% vs. < 1) as determined by ananalytically validated LAG-3 IHC assay, BRAF V600 mutation status, and M stage per the AJCCversion 8 staging system (M0/M1any[0] vs. M1any[1]). Patients were treated until disease progressionor unacceptable toxicity. Tumour assessments, according to the Response Evaluation Criteria in Solid

Tumours (RECIST), version 1.1, were conducted 12 weeks after randomisation and continuedevery 8 weeks up to 52 weeks and then every 12 weeks until disease progression or treatmentdiscontinuation, whichever occurred later. The primary efficacy outcome measure wasprogression-free survival determined by Blinded Independent Central Review (BICR). The secondaryefficacy outcome measures were overall survival (OS), and overall response rate (ORR) by BICR. Thehierarchical statistical testing order was PFS followed by OS and then ORR. The primary andsecondary outcome measures were evaluated in the intention to treat (ITT) population. No formaltesting of ORR was conducted since the formal comparison of OS was not statistically significant.

Baseline characteristics in the ITT population were balanced between the two groups. The median agewas 63 years (range: 20-94) with 47% ≥ 65 years of age and 19% ≥ 75 years of age. The majority ofpatients were white (97%) and male (58%). Baseline ECOG performance status was 0 (67%) or1 (33%). The majority of the patients had AJCC Stage IV disease (92%); 38.9% had M1c, 2.4% had

M1d disease, 8.7% had prior systemic therapies, 36% had a baseline LDH level greater than ULN atstudy entry. Thirty nine percent of patients had BRAF mutation-positive melanoma, 75% had

LAG-3 ≥ 1% and 41% of patients had PD-L1 ≥ 1% tumour cell membrane expression. Among patientswith quantifiable tumour PD-L1 expression, the distribution of patients was balanced across the twotreatment groups. The demographics and baseline disease characteristics in patients with PD-L1expression < 1% were generally balanced between the treatment arms.

At primary analysis in the ITT population, with median follow-up of 13.21 months(range: 0-33.1 months), a statistically significant improvement in PFS was observed with a median

PFS of 10.12 months in the nivolumab in combination with relatlimab group as compared with4.63 months in the nivolumab group (HR = 0.75, 95% CI: 0.62, 0.92; p = 0.0055). At the time of thepre-specified final OS analysis in the ITT population, with median follow up of 19.3 months, OS wasnot statistically significant (HR = 0.80, 95% CI: 0.64, 1.01).

Pre-specified subgroup analysis by PD-L1 expression < 1%

The key efficacy results for the subgroup of patients with tumour PD-L1 expression < 1% from anexploratory analysis with median follow-up of 17.78 months (range: 0.26-40.64 months) aresummarised in Table 3.

Table 3: Efficacy results in patients with PD-L1 < 1% tumour cell expression (CA224047)nivolumab + relatlimab nivolumab(n = 209) (n = 212)

Progression-free survival

Hazard ratio (95% CI)a 0.68 (0.53, 0.86)

Median in months 6.7 3.0(95% CI) (4.7, 12.0) (2.8, 4.5)

Rate (95% CI) at 12 months 42.3 26.9(35.1, 49.4) (20.9, 33.3)

Overall survivalb

Hazard ratio (95% CI)a 0.78 (0.59, 1.04)

Median in months NR 27.0(95% CI) (27.4, NR) (17.1, NR)

Rate (95% CI) at 12 months 73.9 67.4(67.4, 79.4) (60.6, 73.3)

Rate (95% CI) at 24 months 59.6 53.1(52.2, 66.2) (45.8, 59.9)

Overall response rate (%) 36.4 24.1(95% CI) (29.8, 43.3) (18.5, 30.4)

Complete response rate (%) 25 (12.0) 20 (9.4)

Partial response rate (%) 51 (24.4) 31 (14.6)

Stable disease rate (%) 41 (19.6) 31 (14.6)a Hazard ratio based on unstratified Cox proportional hazards model.b OS results are not yet mature.

Median extent of follow-up: 17.78 months.

NR = not reached.

The Kaplan-Meier curves for PFS and OS in patients with tumour cell PD-L1 expression < 1% arepresented in Figures 1 and 2, respectively.

Figure 1: Kaplan-Meier curves of PFS in patients with PD-L1 < 1% tumour cell expression(CA224047)

Progression-free survival per BICR (months)

Number of subjects at risk

Nivolumab/relatlimab209 122 99 80 65 53 44 36 33 30 27 9 2 0

Nivolumab212 98 71 57 41 34 27 24 22 20 14 8 2 0

- ------- Nivolumab/relatlimab (events: 124/209), median (95% CI): 6.67 months (4.67, 11.99)

- - -- - - Nivolumab (events: 155/212), median (95% CI): 2.96 months (2.79, 4.50)

Probability of progression-free survival per BICR

Figure 2: Kaplan-Meier curves of OS in patients with PD-L1 < 1% tumour cell expression(CA224047)

Overall survival (months)

Number of subjects at risk

Nivolumab/relatlimab209 195 177 164 147 128 114 98 85 83 80 68 29 6 0

Nivolumab212 189 168 155 132 106 94 82 72 68 63 56 27 6 0

- ------- Nivolumab/relatlimab (events: 89/209), median (95% CI): N.A. (27.43, N.A.)

- - -- - - Nivolumab (events: 104/212), median (95% CI): 27.04 months (17.12, N.A.)

The pharmacokinetics (PK) of relatlimab following the administration of nivolumab in combinationwith relatlimab was characterised in patients with various cancers who received relatlimab doses of20 to 800 mg every 2 weeks and 160 to 1440 mg every 4 weeks either as a monotherapy or incombination with nivolumab doses of 80 or 240 mg every 2 weeks or 480 mg every 4 weeks.

Steady-state concentrations of relatlimab were reached by 16 weeks with an every 4-week regimenand the systemic accumulation was 1.9-fold. The average concentration (Cavg) of relatlimab after thefirst dose increased dose proportionally at doses ≥ 160 mg every 4 weeks.

Table 4: Geometric mean (CV%) of nivolumab and relatlimab steady-state exposuresfollowing 480 mg nivolumab and 160 mg relatlimab fixed-dose combination every4 weeks

Cmax (μg/mL) Cmin (μg/mL) Cavg (μg/mL)

Relatlimab 62.2 (30.1) 15.3 (64.3) 28.8 (44.8)

Nivolumab 187 (32.9) 59.7 (58.6) 94.4 (43.3)

Based on population PK analyses, the nivolumab and relatlimab FDC infusion duration of 30 min and60 min were predicted to produce similar (< 1% different) exposures of nivolumab and relatlimab.

In CA224047, the nivolumab geometric mean Cmin at steady state in the nivolumab in combinationwith relatlimab arm was similar to the nivolumab arm with a geometric mean ratio of0.931 (95% CI: 0.855-1.013).

Probability of overall survival

The geometric mean value (CV%) for nivolumab volume of distribution at steady state is6.65 L (19.2%) and relatlimab is 6.65 L (19.8%).

Nivolumab and relatlimab are therapeutic mAb IgG4 that are expected to be catabolised into smallpeptides, amino acids, and small carbohydrates by lysosome or receptor-mediated endocytosis.

Nivolumab clearance is 21.1% lower [geometric mean (CV%), 7.57 mL/h (40.1%)] at steady statethan that after the first dose [9.59 mL/h (40.3%)] and the terminal half-life (t1/2) is 26.5 days (36.4%).

Relatlimab clearance is 9.7% lower [geometric mean (CV%), 5.48 mL/h (41.3%)] at steady state thanthat after the first dose [6.06 mL/h (38.9%)]. Following administration of relatlimab 160 mg andnivolumab 480 mg administered every 4 weeks, the geometric mean (CV%) effective half-life (t1/2)of relatlimab is 26.2 days (37%).

A population PK analysis suggested that the following factors had no clinically important effect on theclearance of nivolumab and relatlimab: age (range: 17 to 92 years), sex, [male (1056) andfemale (657)], or race [Caucasian (1655), African American (167) and Asian (41)]. The body weight(range: 37 to 170 kg) was a significant covariate on the nivolumab and relatlimab PK, however, thereis no clinically relevant impact based on exposure-response analysis.

Limited data suggest that nivolumab clearance and volume of distribution in adolescent subjects withsolid tumours were 36% and 16% lower, respectively, than those of adult reference patients. It isunknown if the same holds for melanoma patients and if relatlimab clearance and volume ofdistribution are also lower in adolescents than adults. However, based on population PK simulations,the exposure of nivolumab and relatlimab in adolescents weighing at least 30 kg are expected to resultin similar safety and efficacy to that of adults of the same weight, at the same recommended dose.

The effect of renal impairment on the clearance of nivolumab and relatlimab was evaluated by apopulation PK analysis in patients with mild or moderate renal impairment compared to patients withnormal renal function. No clinically important differences in the clearance of nivolumab or relatlimabwere found between patients with renal impairment and patients with normal renal function.

The effect of hepatic impairment on the clearance of nivolumab and relatlimab was evaluated bypopulation PK analysis in patients with mild hepatic impairment (total bilirubin [TB] less than orequal to upper limit of normal [ULN] and AST greater than ULN or TB greater than 1 to 1.5 times

ULN and any AST) or moderate hepatic impairment (TB greater than 1.5 to 3 times ULN and any

AST) compared to patients with normal hepatic function. No clinically important differences in theclearance of nivolumab or relatlimab were found between patients with hepatic impairment andpatients with normal hepatic function.

The observed low incidence rate of treatment emergent anti-nivolumab antibody and treatmentemergent anti-relatlimab antibody had no effects on PK of nivolumab and relatlimab.

Nivolumab in combination with relatlimab

No animal studies were conducted with nivolumab in combination with relatlimab to evaluatepotential carcinogenicity, genotoxicity or reproductive and developmental toxicity.

In a 1-month study in monkeys dosed with nivolumab and relatlimab, inflammation within the centralnervous system (choroid plexus, vasculature, meninges, spinal cord) and the reproductive tract(epididymis, seminal vesicles and testes) was observed. Although safety margins were not establishedfor these effects with the combination, they occurred at doses that suppose exposure levelssignificantly higher (13 folds for nivolumab and 97 folds for relatlimab) than those reached in patients.

Relatlimab

There are no available animal data on effect of relatlimab on pregnancy and reproduction. In aembryo-foetal toxicity study in mice using murine anti-LAG-3 antibodies, no maternal ordevelopmental effects were observed. The effects of relatlimab on prenatal and postnatal developmenthave not been evaluated; however, based on the mechanism of action, blockade of LAG-3 withrelatlimab can have a similar negative effect as nivolumab on pregnancy. There were no fertilitystudies performed with relatlimab.

Nivolumab

Blockade of the PD-1/PD-L1 pathway has been shown in murine models of pregnancy to disrupttolerance to the foetus and to increase foetal loss. The effects of nivolumab on prenatal and postnataldevelopment were evaluated in monkeys that received nivolumab twice weekly from the onset oforganogenesis in the first trimester through delivery, at exposure levels either 8 or 35 times higherthan those observed at the clinical dose of 3 mg/kg of nivolumab (based on AUC). There was adose-dependent increase in foetal losses and increased neonatal mortality beginning in the thirdtrimester.

The remaining offspring of nivolumab-treated females survived to scheduled termination, with notreatment-related clinical signs, alterations to normal development, organ-weight effects, or gross andmicroscopic pathology changes. Results for growth indices, as well as teratogenic, neurobehavioral,immunological, and clinical pathology parameters throughout the 6-month postnatal period werecomparable to the control group. However, based on their mechanism of action, foetal exposure tonivolumab, and, similarly, relatlimab, may increase the risk of developing immune-related disorders oraltering the normal immune response and immune-related disorders have been reported in PD-1 and

PD-1/LAG-3 knockout mice. Fertility studies have not been performed with nivolumab.

Histidine

Histidine hydrochloride monohydrate

Sucrose

Pentetic acid (diethylenetriaminepentaacetic acid)

Polysorbate 80 (E433)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts. Opdualag should not be infused concomitantly in the same intravenous line with othermedicinal products.

Unopened vial3 years

Chemical and physical in-use stability from the time of preparation has been demonstrated as follows(times are inclusive of the administration period):

Chemical and physical in-use stability

Infusion preparation Storage at 2 °C to 8 °C Storage at room temperatureprotected from light (≤ 25 °C) and room light

Undiluted or diluted with sodiumchloride 9 mg/mL (0.9%) solution for 30 days 24 hours (of total 30 days storage)injection

Diluted with 50 mg/mL (5%) glucosesolution for injection 7 days 24 hours (of total 7 days storage)

From a microbiological point of view, the prepared solution for infusion, regardless of the diluent,should be used immediately. If not used immediately, in-use storage times and conditions prior to useare the responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C,unless preparation has taken place in controlled and validated aseptic conditions (see section 6.6).

Store in a refrigerator (2 °C-8 °C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

The unopened vials can be stored at controlled room temperature (up to 25 °C) for up to 72 hours.

For storage conditions after preparation of the infusion, see section 6.3.

Pack of one 25 mL vial (Type I glass), with a stopper (coated butyl rubber) and a yellow flip-offaluminium seal. Each vial is filled with 21.3 mL of solution, which includes an overfill of 1.3 mL.

Opdualag is supplied as a single-dose vial and does not contain any preservatives. Preparation shouldbe performed by trained personnel in accordance with good practices rules, especially with respect toasepsis.

Opdualag can be used for intravenous administration either: without dilution, after transfer to an infusion container using an appropriate sterile syringe; or after diluting according to the following instructions:

 the final infusion concentration should range between 3 mg/mL of nivolumab and1 mg/mL of relatlimab to 12 mg/mL of nivolumab and 4 mg/mL of relatlimab the total volume of infusion must not exceed 160 mL. For patients weighing less than40 kg, the total volume of infusion should not exceed 4 mL per kilogram of patientweight.

Opdualag concentrate may be diluted with either: sodium chloride 9 mg/mL (0.9%) solution for injection; or 50 mg/mL (5%) glucose solution for injection.

Preparing the infusion Inspect the Opdualag concentrate for particulate matter or discolouration. Do not shake the vial.

Opdualag is a clear to opalescent, colourless to slightly yellow solution. Discard the vial if thesolution is cloudy, discoloured, or contains extraneous particulate matter.

 Withdraw the required volume of Opdualag concentrate using an appropriate sterile syringe andtransfer the concentrate into a sterile, intravenous container (ethylvinyl acetate (EVA),polyvinyl chloride [PVC], or polyolefin).

 If applicable, dilute Opdualag solution with the required volume of sodiumchloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) glucose solution forinjection. For ease of preparation, the concentrate can also be transferred directly into apre-filled bag containing the appropriate volume of sodium chloride 9 mg/mL (0.9%) solutionfor injection or 50 mg/mL (5%) glucose solution for injection.

 Gently mix the infusion by manual rotation. Do not shake.

Opdualag infusion must not be administered as an intravenous push or bolus injection.

Administer the Opdualag infusion intravenously over a period of 30 minutes.

Use of an infusion set and an in-line or add-on, sterile, non-pyrogenic, low protein binding filter (poresize of 0.2 μm to 1.2 μm) is recommended.

Opdualag infusion is compatible with EVA, PVC and polyolefin containers, PVC infusion sets andin-line filters with polyethersulfone (PES), nylon, and polyvinylidene fluoride (PVDF) membraneswith pore sizes of 0.2 μm to 1.2 μm.

Do not co-administer other medicinal products through the same infusion line.

After administration of the Opdualag dose, flush the line with sodium chloride 9 mg/mL (0.9%)solution for injection or 50 mg/mL (5%) glucose solution for injection.

Do not store any unused portion of the infusion solution for reuse. Any unused medicinal product orwaste material should be disposed of in accordance with local requirements.

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

EU/1/22/1679/001

Date of first authorisation: 15 September 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.