Opdivo

Treatment must be initiated and supervised by physicians experienced in the treatment of cancer. 5 PD-L1 testing If specified in the indication, patient selection for treatment with OPDIVO based on the tumour expression of PD-L1 should be assessed by a CE-marked in vitro IVD medical device test.

1). MSI/MMR testing If specified in the indication, patient selection for treatment with OPDIVO based on MSI-H/dMMR tumour status should be assessed by a CE-marked IVD with the corresponding intended purpose. 1). 2), as presented in Table 1.

1. **For adjuvant therapy, the maximum treatment duration with OPDIVO is 12 months. If melanoma, RCC, OC, GEJC or MIUC (adjuvant treatment) patients need to be switched from the 240 mg every 2 weeks schedule to the 480 mg every 4 weeks schedule, the first 480 mg dose should be administered two weeks after the last 240 mg dose.

Conversely, if patients need to be switched from the 480 mg every 4 weeks schedule to the 240 mg every 2 weeks schedule, the first 240 mg dose should be administered four weeks after the last 480 mg dose. 2) Combination phase, for 4 dosing cycles Monotherapy phase Nivolumab Adults and adolescents 12 years of age and older: (regardless of weight) 1 mg/kg every 3 weeks over 30 minutes Adults and adolescents (12 years of age and older and weighing at least 50 kg): 240 mg every 2 weeks over 30 minutes or 480 mg every 4 weeks over 60 minutes The first dose should be administered: • 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 240 mg every 2 weeks; or • 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 480 mg every 4 weeks Adolescents (12 years of age and older and weighing less than 50 kg): 3 mg/kg every 2 weeks over 30 minutes or 6 mg/kg every 4 weeks over 60 minutes The first dose should be administered: • 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 3 mg/kg every 2 weeks; or • 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 6 mg/kg every 4 weeks Ipilimumab Adults and adolescents 12 years of age and older (regardless of weight): 3 mg/kg every 3 weeks over 30 minutes - Malignant pleural mesothelioma (MPM) Table 3: Recommended doses and infusion times for intravenous administration of nivolumab in combination with ipilimumab for MPM Combination therapy* Nivolumab 360 mg every 3 weeks over 30 minutes Ipilimumab 1 mg/kg every 6 weeks over 30 minutes *Treatment is continued for up to 24 months in patients without disease progression.

3 to 28 months, the most frequent adverse reactions (≥ 10%) were fatigue (44%), musculoskeletal pain (28%), diarrhoea (26%), rash (24%), cough (22%), nausea (22%), pruritus (19%), decreased appetite (17%), arthralgia (17%), constipation (16%), dyspnoea (16%), abdominal pain (15%), upper respiratory tract infection (15%), pyrexia (13%), headache (13%), anaemia (13%) and vomiting (12%).

The majority of adverse reactions were mild to moderate (Grade 1 or 2). 3% fatal adverse reactions attributed to study drug. With a minimum of 63 months follow-up in NSCLC, no new safety signals were identified. 26 Tabulated summary of adverse reactions Adverse reactions reported in the pooled dataset for patients treated with nivolumab monotherapy (n = 4646) are presented in Table 18.

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); not known (cannot be estimated from available post-marketing data).

Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 18:

Adverse reactions with nivolumab monotherapy Nivolumab monotherapy Infections and infestations Very common upper respiratory tract infection Common pneumoniaa, bronchitis Rare aseptic meningitis Neoplasms benign, malignant and unspecified (including cysts and polyps) Rare histiocytic necrotising lymphadenitis (Kikuchi lymphadenitis) Blood and lymphatic system disorders Very common lymphopeniab, anaemiab,i, leucopoeniab, neutropeniaa,b, thrombocytopeniab Uncommon eosinophilia Not known haemophagocytic lymphohistiocytosis Immune system disorders Common infusion related reaction (including cytokine release syndrome), hypersensitivity (including anaphylactic reaction) Uncommon sarcoidosis Not known solid organ transplant rejectionf Endocrine disorders Common hypothyroidism, hyperthyroidism, thyroiditis Uncommon adrenal insufficiencyj, hypopituitarism, hypophysitis, diabetes mellitus Rare diabetic ketoacidosis, hypoparathyroidism Metabolism and nutrition disorders Very common decreased appetite, hyperglycaemiab Common dehydration, weight decreased, hypoglycaemiab Uncommon metabolic acidosis Not known tumour lysis syndromeg Nervous system disorders Very common headache Common peripheral neuropathy, dizziness Uncommon polyneuropathy, autoimmune neuropathy (including facial and abducens nerve paresis) Rare Guillain-Barré syndrome, demyelination, myasthenic syndrome, encephalitisa,k, optic neuritis Not known myelitis (including transverse myelitis) Eye disorders Common blurred vision, dry eye Uncommon uveitis Not known Vogt-Koyanagi-Harada syndromef Cardiac disorders Common tachycardia, atrial fibrillation Uncommon myocarditisa, pericardial disordersh, arrhythmia (including ventricular arrhythmia) 27 Nivolumab monotherapy Vascular disorders Common hypertension Rare vasculitis Respiratory, thoracic and mediastinal disorders Very common dyspnoeaa, cough Common pneumonitisa, pleural effusion Uncommon lung infiltration Gastrointestinal disorders Very common diarrhoea, vomiting, nausea, abdominal pain, constipation Common colitisa, stomatitis, dry mouth Uncommon pancreatitis, gastritis Rare duodenal ulcer, pancreatic exocrine insufficiency, coeliac disease Hepatobiliary disorders Uncommon hepatitis, cholestasis Skin and subcutaneous tissue disorders Very common rashc, pruritus Common vitiligo, dry skin, erythema, alopecia Uncommon psoriasis, rosacea, erythema multiforme, urticaria Rare toxic epidermal necrolysisa, d, Stevens-Johnson syndromea Not known lichen sclerosusg, other lichen disorders Musculoskeletal and connective tissue disorders Very common musculoskeletal paine, arthralgia Common arthritis Uncommon polymyalgia rheumatica Rare Sjögren's syndrome, myopathy, myositis (including polymyositis)a, rhabdomyolysisa,d Renal and urinary disorders Common renal failure (including acute kidney injury)a Rare tubulointerstitial nephritis, cystitis noninfective General disorders and administration site conditions Very common fatigue, pyrexia Common pain, chest pain, oedemal Investigationsb Very common increased AST, hyponatraemia, hypoalbuminaemia, increased alkaline phosphatase, increased creatinine, increased ALT, increased lipase, hyperkalaemia, increased amylase, hypocalcaemia, hypomagnesaemia, hypokalaemia, hypercalcaemia Common increased total bilirubin, hypernatraemia, hypermagnesaemia Adverse reaction frequencies presented in Table 18 may not be fully attributable to nivolumab alone but may contain contributions from the underlying disease.

4. When nivolumab is administered in combination with other therapeutic agents, refer to the SmPC of these other combination therapeutic agents regarding dosing.

Table 17:

Recommended treatment modifications for OPDIVO or OPDIVO in combination Immune-related adverse reaction Severity Treatment modification Immune-related pneumonitis Grade 2 pneumonitis Withhold dose(s) until symptoms resolve, radiographic abnormalities improve, and management with corticosteroids is complete Grade 3 or 4 pneumonitis Permanently discontinue treatment 12 Immune-related adverse reaction Severity Treatment modification Immune-related colitis Grade 2 diarrhoea or colitis Withhold dose(s) until symptoms resolve and management with corticosteroids, if needed, is complete Grade 3 diarrhoea or colitis - OPDIVO monotherapy Withhold dose(s) until symptoms resolve and management with corticosteroids is complete - OPDIVO+ipilimumaba Permanently discontinue treatment Grade 4 diarrhoea or colitis Permanently discontinue treatment Immune-related hepatitis without HCC NOTE: for RCC patients treated with OPDIVO in combination with cabozantinib with liver enzyme elevations, see dosing guidelines following this table.

Grade 2 elevation in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin Withhold dose(s) until laboratory values return to baseline and management with corticosteroids, if needed, is complete Grade 3 or 4 elevation in AST, ALT, or total bilirubin Permanently discontinue treatment Immune-related hepatitis with HCC If AST/ALT is within normal limits at baseline and increases to > 3 and ≤ 10 times ULN or Baseline AST/ALT is > 1 and ≤ 3 times ULN and increases to > 5 and ≤ 10 times ULN or Baseline AST/ALT is > 3 and ≤ 5 times ULN and increases to > 8 and ≤ 10 times ULN.

Withhold dose(s) until laboratory values return to baseline and management with corticosteroids, if needed, is complete AST/ALT increases to > 10 times ULN or Total bilirubin increases to > 3 times ULN Permanently discontinue treatment Immune-related nephritis and renal dysfunction Grade 2 or 3 creatinine elevation Withhold dose(s) until creatinine returns to baseline and management with corticosteroids is complete Grade 4 creatinine elevation Permanently discontinue treatment 13 Immune-related adverse reaction Severity Treatment modification Immune-related endocrinopathies Symptomatic Grade 2 or 3 hypothyroidism, hyperthyroidism, hypophysitis, Grade 2 adrenal insufficiency Grade 3 diabetes Withhold dose(s) until symptoms resolve and management with corticosteroids (if needed for symptoms of acute inflammation) is complete.

1.