Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Assessment of PD-L1 status

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

When nivolumab is administered in combination, refer to the SmPC of the other combination therapy agents prior to initiation of treatment. Immune-related adverse reactions have occurred at higher frequencies when nivolumab was administered in combination with ipilimumab compared with nivolumab as monotherapy. Immune-related adverse reactions have occurred at similar frequencies when OPDIVO was administered in combination with cabozantinib relative to nivolumab monotherapy. Therefore, the guidance below for immune-related adverse reactions applies to the OPDIVO component of the combination, except where specifically noted. Most immune-related adverse reactions improved or resolved with 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.

Cardiac and pulmonary adverse reactions including pulmonary embolism have also been reported with combination therapy. Patients should be monitored for cardiac and pulmonary adverse reactions continuously, as well as for clinical signs, symptoms, and laboratory abnormalities indicative of electrolyte disturbances and dehydration prior to and periodically during treatment. Nivolumab in combination with ipilimumab should be discontinued for life-threatening or recurrent severe cardiac and pulmonary adverse reactions (see section 4.2).

Patients should be monitored continuously (at least up to 5 months after the last dose) as an adverse reaction with nivolumab or nivolumab in combination with ipilimumab 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, nivolumab or nivolumab in combination with ipilimumab 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.

Nivolumab or nivolumab in combination with ipilimumab should not be resumed while the patient is receiving immunosuppressive doses of corticosteroids or other immunosuppressive therapy. Prophylactic antibiotics should be used to prevent opportunistic infections in patients receiving immunosuppressive therapy.

Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening immune-related adverse reaction.

Immune-related pneumonitis

Severe pneumonitis or interstitial lung disease, including fatal cases, has been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (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 filtrates), dyspnoea, and hypoxia. Infectious and disease-related aetiologies should be ruled out.

For Grade 3 or 4 pneumonitis, nivolumab or nivolumab in combination with ipilimumab 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, nivolumab or nivolumab in combination with ipilimumab should be withheld and corticosteroids initiated at a dose of 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab 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 nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.

Immune-related colitis

Severe diarrhoea or colitis has been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8). Patients should be monitored for diarrhoea and additional symptoms of colitis, such as abdominal pain and mucus 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, nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

Nivolumab monotherapy 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, nivolumab monotherapy may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, nivolumab monotherapy must be permanently discontinued. Grade 3 diarrhoea or colitis observed with nivolumab in combination with ipilimumab requires permanent discontinuation of treatment and initiation of corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

For Grade 2 diarrhoea or colitis, nivolumab or nivolumab in combination with ipilimumab 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, nivolumab or nivolumab in combination with ipilimumab 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 nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.

Immune-related hepatitis

Severe hepatitis has been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (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 Grade 3 or 4 transaminase or total bilirubin elevation, nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

For Grade 2 transaminase or total bilirubin elevation, nivolumab or nivolumab in combination with ipilimumab 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, nivolumab or nivolumab in combination with ipilimumab 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 nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.

Immune-related nephritis and renal dysfunction

Severe nephritis and renal dysfunction have been observed with monotherapy treatment or nivolumab in combination with ipilimumab (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, nivolumab or nivolumab in combination with ipilimumab 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, nivolumab or nivolumab in combination with ipilimumab should be withheld, and corticosteroids should be initiated at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab 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 nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.

Immune-related endocrinopathies

Severe endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency (including secondary adrenocortical insufficiency), hypophysitis (including hypopituitarism), diabetes mellitus, and diabetic ketoacidosis have been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (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.

For symptomatic hypothyroidism, nivolumab or nivolumab in combination with ipilimumab should be withheld, and thyroid hormone replacement should be initiated as needed. For symptomatic hyperthyroidism, nivolumab or nivolumab in combination with ipilimumab should be withheld and antithyroid medication 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, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper, if needed. Monitoring of thyroid function should continue to ensure appropriate hormone replacement is utilised. Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for life-threatening hyperthyroidism or hypothyroidism.

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

For symptomatic Grade 2 or 3 hypophysitis, nivolumab or nivolumab in combination with ipilimumab 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, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper, if needed. Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for life-threatening (Grade 4) hypophysitis. Monitoring of pituitary function and hormone levels should continue to ensure appropriate hormone replacement is utilised.

For symptomatic diabetes, nivolumab or nivolumab in combination with ipilimumab should be withheld, and insulin replacement should be initiated as needed. Monitoring of blood sugar should continue to ensure appropriate insulin replacement is utilised. Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for life-threatening diabetes.

Immune-related skin adverse reactions

Severe rash has been observed with nivolumab in combination with ipilimumab and, less commonly, with nivolumab as monotherapy (see section 4.8). Nivolumab or nivolumab in combination with ipilimumab 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. If symptoms or signs of SJS or TEN appear, treatment with nivolumab or nivolumab in combination with ipilimumab should be discontinued and the patient referred to a specialised unit for assessment and treatment. If the patient has developed SJS or TEN with the use of nivolumab or nivolumab in combination with ipilimumab, permanent discontinuation of treatment is recommended (see section 4.2).

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

Other immune-related adverse reactions

The following immune-related adverse reactions were reported in less than 1% of patients treated with nivolumab monotherapy or nivolumab in combination with ipilimumab in clinical trials across doses and tumour types: pancreatitis, uveitis, demyelination, autoimmune neuropathy (including facial and abducens nerve paresis), Guillain-Barré syndrome, myasthenia gravis, myasthenic syndrome, aseptic meningitis, encephalitis, gastritis, sarcoidosis, duodenitis, myositis, myocarditis, rhabdomyolysis, and myelitis. Cases of Vogt-Koyanagi-Harada syndrome, hypoparathyroidism, and cystitis noninfective have been reported post-marketing (see sections 4.2 and 4.8).

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, nivolumab or nivolumab in combination with ipilimumab should be withheld and corticosteroids administered. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper. Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening immune-related adverse reaction.

Cases of myotoxicity (myositis, myocarditis, and rhabdomyolysis), some with fatal outcome, have been reported with nivolumab or nivolumab in combination with ipilimumab. If a patient develops signs and symptoms of myotoxicity, close monitoring should be implemented, and the patient referred to a specialist for assessment and treatment without delay. Based on the severity of myotoxicity, nivolumab or nivolumab in combination with ipilimumab should be withheld or discontinued (see section 4.2), and appropriate treatment instituted.

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, nivolumab or nivolumab in combination with ipilimumab should be withheld or permanently discontinued (see section 4.2).

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with nivolumab may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with nivolumab versus the risk of possible organ rejection should be considered in these patients.

Haemophagocytic lymphohistiocytosis (HLH) has been observed with nivolumab as monotherapy and nivolumab in combination with ipilimumab. Caution should be taken when nivolumab is administered as monotherapy or in combination with ipilimumab. If HLH is confirmed, administration of nivolumab or nivolumab in combination with ipilimumab should be discontinued and treatment for HLH initiated.

Infusion reactions

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

Disease-specific precautions

Advanced melanoma

Patients with a baseline performance score ≥2, active brain metastases or leptomeningeal metastases, autoimmune disease, and patients who had been receiving systemic immunosuppressants prior to study entry were excluded from the pivotal clinical trials of nivolumab or nivolumab in combination with ipilimumab (see sections 4.5 and 5.1). Patients with ocular/uveal melanoma were excluded from pivotal clinical trials of melanoma. In addition, CA209037 excluded patients who have had a Grade 4 adverse reaction that was related to anti-CTLA-4 therapy (see section 5.1). Patients with baseline performance score of 2, treated leptomeningeal metastases, ocular/uveal melanoma, autoimmune disease and patients who have had a Grade 3-4 adverse reaction that was related to prior anti-CTLA-4 therapy were included in study CA209172 (see section 5.1). In the absence of data for patients who had been receiving systemic immunosuppressants prior to study entry, and for patients with active brain or leptomeningeal metastases, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Relative to nivolumab monotherapy, an increase in PFS for the combination of nivolumab with ipilimumab is established only in patients with low tumour PD-L1 expression. The improvement in OS was similar between nivolumab in combination with ipilimumab and nivolumab monotherapy in patients with high tumour PD-L1 expression (PD-L1 ≥ 1%). Before initiating treatment with the combination, physicians are advised to carefully evaluate the individual patient and tumour characteristics, taking into consideration the observed benefits and the toxicity of the combination relative to nivolumab monotherapy (see sections 4.8 and 5.1).

Use of nivolumab in melanoma patients with rapidly progressing disease:

Physicians should consider the delayed onset of nivolumab effect before initiating treatment in patients with rapidly progressing disease (see section 5.1).

Adjuvant treatment of melanoma

There are no data on adjuvant treatment in patients with melanoma with the following risk factors (see sections 4.5 and 5.1):

• patients with prior autoimmune disease, and any condition requiring systemic treatment with either corticosteroids (≥10 mg daily prednisone or equivalent) or other immunosuppressive medications,
• patients with prior therapy for melanoma (except patients with surgery, adjuvant radiotherapy after neurosurgical resection for lesions of the central nervous system, and prior adjuvant interferon completed ≥6 months prior to randomisation),
• patients treated with prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways),
• subjects under the age of 18 years.

In the absence of data, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Non-small cell lung cancer

First-line treatment of NSCLC:

Patients with active autoimmune disease, symptomatic interstitial lung disease, medical conditions requiring systemic immunosuppression, active (untreated) brain metastasis, who received prior systemic treatment for advanced disease, or who had sensitising EGFR mutations or ALK translocations were excluded from the pivotal trial in first-line treatment of NSCLC (see sections 4.5 and 5.1). Limited data are available in elderly patients (≥75 years) (see section 5.1). In these patients, nivolumab in combination with ipilimumab and chemotherapy should be used with caution after careful consideration of the potential benefit/risk on an individual basis.

Treatment of NSCLC after prior chemotherapy:

Patients with a baseline performance score ≥2, active brain metastases or autoimmune disease, symptomatic interstitial lung disease, and patients who had been receiving systemic immunosuppressants prior to study entry were excluded from the pivotal clinical trials of NSCLC (see sections 4.5 and 5.1). Patients with baseline performance score of 2 were included in study CA209171 (see section 5.1). In the absence of data for patients with autoimmune disease, symptomatic interstitial lung disease, active brain metastases and patients who had been receiving systemic immunosuppressants prior to study entry, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Physicians should consider the delayed onset of nivolumab effect before initiating treatment in patients with poorer prognostic features and/or aggressive disease. In non-squamous NSCLC, a higher number of deaths within 3 months was observed in nivolumab compared to docetaxel. Factors associated with early deaths were poorer prognostic factors and/or more aggressive disease combined with low or no tumour PD-L1 expression (see section 5.1).

Neoadjuvant treatment of NSCLC:

Patients with a baseline performance score ≥2, active autoimmune disease, symptomatic interstitial lung disease, medical conditions requiring systemic immunosuppression, unresectable or metastatic disease, who received prior anti-cancer treatment for resectable disease, or who had known EGFR mutations or ALK translocations were excluded from the pivotal trial in neoadjuvant treatment of resectable NSCLC (see section 5.1). In the absence of data, nivolumab in combination with chemotherapy should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Malignant pleural mesothelioma

Patients with primitive peritoneal, pericardial, testis, or tunica vaginalis mesothelioma, interstitial lung disease, active autoimmune disease, medical conditions requiring systemic immunosuppression, and brain metastasis (unless surgically resected or treated with stereotaxic radiotherapy and no evolution within 3 months prior to inclusion in the study) were excluded from the pivotal trial in first-line treatment of MPM (see sections 4.5 and 5.1). In the absence of data, nivolumab in combination with ipilimumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Renal cell carcinoma

Nivolumab or nivolumab in combination with ipilimumab:

Patients with any history of concurrent brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the clinical trials of nivolumab or nivolumab in combination with ipilimumab (see sections 4.5 and 5.1). In the absence of data, nivolumab or nivolumab in combination with ipilimumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Nivolumab in combination with cabozantinib:

Patients with any active brain metastases, autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the clinical trials of nivolumab in combination with cabozantinib (see sections 4.5 and 5.1). In the absence of data, nivolumab in combination with cabozantinib should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

When nivolumab is given with cabozantinib, higher frequencies of Grades 3 and 4 ALT and AST elevations have been reported relative to nivolumab monotherapy in patients with advanced RCC (see section 4.8). Liver enzymes should be monitored before initiation of and periodically throughout treatment. Medical management guidelines for both medicines should be followed (see section 4.2 and refer to the SmPC for cabozantinib).

Classical Hodgkin lymphoma

Patients with active autoimmune disease and symptomatic interstitial lung disease were excluded from clinical trials of cHL (see section 5.1). In the absence of data, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Complications of allogeneic haematopoietic stem cell transplant (HSCT) in classical Hodgkin lymphoma:

Cases of acute graft-versus-host disease (GVHD) and transplant related mortality (TRM) have been observed from the follow-up of patients with cHL undergoing allogeneic HSCT after previous exposure to nivolumab. Careful consideration to the potential benefits of HSCT and the possible increased risk of transplant related complications should be made case-by-case (see section 4.8).

In patients treated with nivolumab after allogeneic HSCT, rapid-onset and severe GVHD, some with fatal outcome, have been reported in the post-marketing setting. Treatment with nivolumab 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 versus the possible risk should be considered in these patients (see section 4.8).

Head and neck cancer

Patients with a baseline performance score ≥2, active brain or leptomeningeal metastases, active autoimmune disease, medical conditions requiring systemic immunosuppression, or carcinoma of the nasopharynx or salivary gland as the primary tumour sites were excluded from the SCCHN clinical trial (see sections 4.5 and 5.1). In the absence of data, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Physicians should consider the delayed onset of nivolumab effect before initiating treatment in patients with poorer prognostic features and/or aggressive disease. In head and neck cancer, a higher number of deaths within 3 months was observed in nivolumab compared to docetaxel. Factors associated with early deaths were ECOG performance status, fast progressive disease on prior platinum therapy and high tumour burden.

Urothelial carcinoma

Treatment of advanced urothelial carcinoma:

Patients with a baseline performance score ≥2, active brain metastases or leptomeningeal metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the clinical trials of urothelial carcinoma (see sections 4.5 and 5.1). In the absence of data, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Adjuvant treatment of urothelial carcinoma:

Patients with a baseline performance score of ≥2 (except patients with a baseline performance score of 2 who have not received cisplatin based neoadjuvant chemotherapy and are considered ineligible for cisplatin adjuvant chemotherapy), evidence of disease after surgery, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the clinical trial of adjuvant treatment of urothelial carcinoma (see sections 4.5 and 5.1). In the absence of data, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

dMMR or MSI-H colorectal cancer

Patients with a baseline performance score ≥2, active brain metastases or leptomeningeal metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the clinical trial in dMMR or MSI-H metastatic CRC (see sections 4.5 and 5.1). In the absence of data, nivolumab in combination with ipilimumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Oesophageal squamous cell carcinoma

First-line treatment of OSCC:

Patients with a baseline performance score ≥2, any history of concurrent brain metastases, active autoimmune disease, medical conditions requiring systemic immunosuppression, or at high risk of bleeding or fistula due to apparent invasion of tumour to organs adjacent to the oesophageal tumour were excluded from the clinical trial in OSCC (see sections 4.5 and 5.1). In the absence of data, nivolumab in combination with ipilimumab or chemotherapy should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

In the first-line OSCC trial, a higher number of deaths within 4 months was observed with nivolumab in combination with ipilimumab compared to chemotherapy. Physicians should consider the delayed onset of effect of nivolumab in combination with ipilimumab before initiating treatment in patients with poorer prognostic features and/or aggressive disease (see section 5.1).

Treatment of OSCC after prior first-line chemotherapy:

The majority of clinical data available in oesophageal squamous cell carcinoma are in patients of Asian origin (see section 5.1).

Patients with a baseline performance score ≥2, brain metastases that were symptomatic or required treatment, apparent tumour invasion in organs located adjacent to the oesophagus (e.g. the aorta or respiratory tract), active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the clinical study in OSCC (see sections 4.5 and 5.1). In the absence of data, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Physicians should consider the delayed onset of nivolumab effect before initiating treatment in patients with OSCC. A higher number of deaths within 2.5 months after randomisation was observed with nivolumab compared to chemotherapy. No specific factor(s) associated with early deaths could be identified (see section 5.1).

Adjuvant treatment of oesophageal or gastro-oesophageal junction cancer

Patients with a baseline performance score ≥2, who did not receive concurrent chemoradiotherapy (CRT) prior to surgery, with stage IV resectable disease, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the clinical study in oesophageal and gastro-oesophageal junction cancer (see sections 4.5 and 5.1). In the absence of data, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Gastric, gastro-oesophageal junction or oesophageal adenocarcinoma

Patients who had baseline ECOG performance score ≥2, untreated central nervous system metastases, active, known, or suspected autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the clinical study in gastric, GEJ or oesophageal adenocarcinoma (see sections 4.5 and 5.1). In the absence of data, nivolumab in combination with chemotherapy should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Study CA209649 excluded patients with known HER2-positive status. Patients with undetermined status were allowed in the study and represented 40.3% of patients (see section 5.1).

Patients on controlled sodium diet

Each mL of this medicinal product contains 0.1 mmol (or 2.5 mg) sodium. This medicinal product contains 10 mg sodium per 4 mL vial, 25 mg sodium per 10 mL vial, 30 mg sodium per 12 mL vial or 60 mg sodium per 24 mL vial, which is equivalent to 0.5%, 1.25%, 1.5% or 3% respectively, of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Patient alert card

All prescribers of OPDIVO must be familiar with the physician information and management guidelines. The prescriber must discuss the risks of OPDIVO therapy with the patient. The patient will be provided with the patient alert card with each prescription.

Nivolumab is a human monoclonal antibody, as such pharmacokinetic interaction studies have not been conducted. As monoclonal antibodies are not metabolised by cytochrome P450 (CYP) enzymes or other drug metabolising enzymes, inhibition or induction of these enzymes by co-administered medicinal products is not anticipated to affect the pharmacokinetics of nivolumab.

Other forms of interaction

Systemic immunosuppression

The use of systemic corticosteroids and other immunosuppressants at baseline, before starting nivolumab, should be avoided because of their potential interference with the pharmacodynamic activity. However, systemic corticosteroids and other immunosuppressants can be used after starting nivolumab to treat immune-related adverse reactions. The preliminary results show that systemic immunosuppression after starting nivolumab treatment does not appear to preclude the response on nivolumab.

Pregnancy

There are no data on the use of nivolumab in pregnant women. Studies in animals have shown embryofoetal toxicity (see section 5.3). Human IgG4 is known to cross the placental barrier and nivolumab is an IgG4; therefore, nivolumab has the potential to be transmitted from the mother to the developing foetus. Nivolumab is not recommended during pregnancy and 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 nivolumab.

Breast-feeding

It is unknown whether nivolumab is secreted in human milk. Because many medicinal products, including antibodies, can be secreted in human milk, a risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from nivolumab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Studies to evaluate the effect of nivolumab on fertility have not been performed. Thus, the effect of nivolumab on male and female fertility is unknown.

Nivolumab or nivolumab in combination with ipilimumab may have a minor influence on the ability to drive and use machines. Because of potential adverse reactions such as fatigue (see section 4.8), patients should be advised to use caution when driving or operating machinery until they are certain that nivolumab does not adversely affect them.

Nivolumab as monotherapy (see section 4.2)

Summary of the safety profile

In the pooled dataset of nivolumab as monotherapy across tumour types (n=4646) with minimum follow-up ranging from 2.3 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). The incidence of Grade 3-5 adverse reactions was 44%, with 0.3% fatal adverse reactions attributed to study drug. With a minimum of 63 months follow-up in NSCLC, no new safety signals were identified.

Tabulated summary of adverse reactions

Adverse reactions reported in the pooled dataset for patients treated with nivolumab monotherapy (n=4646) are presented in Table 6. 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 6. Adverse reactions with nivolumab monotherapy:

Adverse reaction frequencies presented in Table 6 may not be fully attributable to nivolumab alone but may contain contributions from the underlying disease.
^a Fatal cases have been reported in completed or ongoing clinical studies.
^b Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from baseline in laboratory measurements. See “Description of selected adverse reactions; laboratory abnormalities” below.
^c Rash is a composite term which includes rash maculopapular, rash erythematous, rash pruritic, rash follicular, rash macular, rash morbilliform, rash papular, rash pustular, rash vesicular, exfoliative rash, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, dermatitis exfoliative, dermatitis psoriasiform, drug eruption and pemphigoid.
^d Reported also in studies outside the pooled dataset. The frequency is based on the program-wide exposure.
^e Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, myalgia intercostal, neck pain, pain in extremity, and spinal pain.
^f Post-marketing event (also see section 4.4).
^g Reported in clinical studies and in the post-marketing setting.
^h Pericardial disorders is a composite term which includes pericarditis, pericardial effusion, cardiac tamponade, and Dressler’s syndrome.
ⁱ Anaemia is a composite term which includes, among other causes, haemolytic anaemia and autoimmune anaemia, haemoglobin decreased, iron deficiency anaemia and red blood cell count decreased.
^j Includes adrenal insufficiency, adrenocortical insufficiency acute, and secondary adrenocortical insufficiency.
^k Includes encephalitis and limbic encephalitis.
^l Oedema is a composite term which includes generalised oedema, oedema peripheral, peripheral swelling and swelling.

Nivolumab in combination with other therapeutic agents (see section 4.2)

Summary of the safety profile

When nivolumab is administered in combination, refer to the SmPC for the other therapeutic agents for additional information on the safety profile, prior to initiation of treatment.

Nivolumab in combination with ipilimumab (with or without chemotherapy)

In the pooled dataset of nivolumab administered in combination with ipilimumab (with or without chemotherapy) across tumour types (n = 2094) with minimum follow-up ranging from 6 to 47 months, the most frequent adverse reactions (≥10%) were fatigue (50%), rash (38%), diarrhoea (37%), nausea (31%), pruritus (29%), musculoskeletal pain (28%), pyrexia (25%), cough (24%), decreased appetite (23%), vomiting (20%), dyspnoea (19%), constipation (19%), arthralgia (19%), abdominal pain (18%), hypothyroidism (16%), headache (16%), upper respiratory tract infection (15%), oedema (13%), and dizziness (11%). The incidence of Grade 3-5 adverse reactions was 67% for nivolumab in combination with ipilimumab (with or without chemotherapy), with 0.7% fatal adverse reactions attributed to study drug. Among patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg, fatigue (62%), rash (57%), diarrhoea (52%), nausea (42%), pruritus (40%), pyrexia (36%), and headache (26%) were reported at an incidence rate ≥10% higher than the rates reported in the pooled dataset of nivolumab in combination with ipilimumab (with or without chemotherapy) incidence rate. Among patients treated with nivolumab 360 mg in combination with ipilimumab 1 mg/kg and chemotherapy, anaemia (32%) and neutropaenia (15%) were reported at an incidence rate ≥10% higher than the rates reported in the pooled dataset of nivolumab in combination with ipilimumab (with or without chemotherapy) incidence rate.

Nivolumab in combination with chemotherapy

In the pooled dataset of nivolumab 240 mg every 2 weeks or 360 mg every 3 weeks in combination with chemotherapy across tumour types (n=1572), with a minimum follow-up ranging from 7.4 to 20 months for gastric, GEJ or oesophageal adenocarcinoma, OSCC, or urothelial carcinoma, or following 3 cycles of treatment for resectable NSCLC, the most frequent adverse reactions (≥10%) were nausea (51%), fatigue (41%), peripheral neuropathy (34%), decreased appetite (32%), constipation (31%), diarrhoea (30%), vomiting (26%), stomatitis (19%), abdominal pain (19%), rash (19%), musculoskeletal pain (18%), pyrexia (17%), oedema (including peripheral oedema) (13%), cough (12%), pruritus (11%), and hypoalbuminaemia (10%). Incidences of Grade 3-5 adverse reactions were 72% for nivolumab in combination with chemotherapy, with 1.3% fatal adverse reactions attributed to nivolumab in combination with chemotherapy. Median duration of therapy was 6.44 months (95% CI: 5.95, 6.80) for nivolumab in combination with chemotherapy, 4.34 months (95% CI: 4.04, 4.70) for chemotherapy for gastric, GEJ or oesophageal adenocarcinoma, or OSCC and 7.39 months (95% CI: 7.06, 8.38) for urothelial carcinoma. For resectable NSCLC, ninetythree percent (93%) of patients received 3 cycles of nivolumab in combination with chemotherapy.

Nivolumab in combination with cabozantinib

In the dataset of nivolumab 240 mg every 2 weeks in combination with cabozantinib 40 mg once daily in RCC (n=320), with a minimum follow -up of 16.0 months, the most frequent adverse reactions (≥10%) were diarrhoea (64.7%), fatigue (51.3%), -palmar plantar erythrodysaesthesia syndrome (40.0%), stomatitis (38.8%), musculoskeletal pain (37.5%), hypertension (37.2%), rash (36.3%), hypothyroidism (35.6%), decreased appetite (30.3%), nausea (28.8%), abdominal pain (25.0%), dysgeusia (23.8%), upper respiratory tract infection (20.6%), cough (20.6%), pruritus (20.6%), arthralgia (19.4%), vomiting (18.4%), dysphonia (17.8%), headache (16.3%), dyspepsia (15.9%), dizziness (14.1%), constipation (14.1%), pyrexia (14.1%), oedema (13.4%), muscle spasm (12.2%), dyspnoea (11.6%), proteinuria (10.9%) and hyperthyroidism (10.0%). The incidence of Grade 3-5 adverse reactions was 78%, with 0.3% fatal adverse reactions attributed to study drug.

Tabulated summary of adverse reactions

Adverse reactions reported in the pooled dataset for patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy) (n=2094), nivolumab in combination with chemotherapy (n=1572), and nivolumab in combination with cabozantinib (n=320) are presented in Table 7. 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), 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 7. Adverse reactions with nivolumab in combination with other therapeutic agents:

Adverse reaction frequencies presented in Table 7 may not be fully attributable to nivolumab alone or in combination with other therapeutic agents, but may contain contributions from the underlying disease or from medicinal product used in combination.
^a Fatal cases have been reported in completed or ongoing clinical studies.
^b Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from baseline in laboratory measurements. See “Description of selected adverse reactions; laboratory abnormalities” below.
^c Rash is a composite term which includes maculopapular rash, rash erythematous, rash pruritic, rash follicular, rash macular, rash morbilliform, rash papular, rash pustular, rash papulosquamous, rash vesicular, rash generalised, exfoliative rash, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, dermatitis exfoliative, dermatitis psoriasiform, drug eruption, nodular rash, and pemphigoid.
^d Reported also in studies outside the pooled dataset. The frequency is based on the program-wide exposure.
^e Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, myalgia intercostal, neck pain, pain in extremity, and spinal pain.
^f Post-marketing event (also see section 4.4).
^g Reported in clinical studies and in the post-marketing setting.
^h Pericardial disorders is a composite term which includes pericarditis, pericardial effusion, cardiac tamponade, and Dressler’s syndrome.
ⁱ Anaemia is a composite term which includes, among other causes, haemolytic anaemia and autoimmune anaemia, haemoglobin decreased, iron deficiency anaemia and red blood cell count decreased.
^j Thrombosis is a composite term which includes portal vein thrombosis, pulmonary vein thrombosis, pulmonary thrombosis, aortic thrombosis, arterial thrombosis, deep vein thrombosis, pelvic vein thrombosis, vena cava thrombosis, venous thrombosis, limb venous thrombosis.

Description of selected adverse reactions

Nivolumab or nivolumab in combination with other therapeutic agents is associated with immune-related adverse reactions. With appropriate medical therapy, immune-related adverse reactions resolved in most cases. Permanent discontinuation of treatment generally was required in a greater proportion of patients receiving nivolumab in combination with other agents than in those receiving nivolumab monotherapy. Table 8 presents the percentage of patients with immune-related adverse reactions who were permanently discontinued from treatment by dosing regimen. Additionally, for patients who experienced an event, Table 8 presents the percentage of patients who required high-dose corticosteroids (at least 40 mg daily prednisone equivalents) by dosing regimen. The management guidelines for these adverse reactions are described in section 4.4.

Table 8. Immune-related adverse reactions leading to permanent discontinuation or requiring high-dose corticosteroids by dosing regimen (nivolumab monotherapy, nivolumab in combination with ipilimumab (with or without chemotherapy), nivolumab in combination with chemotherapy, or nivolumab in combination with cabozantinib):

^a at least 40 mg daily prednisone equivalents
^b frequency is based on the number of patients who experienced the immune-related adverse reaction

Immune-related pneumonitis

In patients treated with nivolumab monotherapy, the incidence of pneumonitis, including interstitial lung disease and lung infiltration, was 3.3% (155/4646). The majority of cases were Grade 1 or 2 in severity reported in 0.9% (42/4646) and 1.7% (77/4646) of patients respectively. Grade 3 and 4 cases were reported in 0.7% (33/4646) and <0.1% (1/4646) of patients respectively. Six patients (0.1%) had a fatal outcome. Median time to onset was 15.1 weeks (range: 0.7-85.1). Resolution occurred in 107 patients (69.0%) with a median time to resolution of 6.7 weeks (range: 0.1+ - 109.1+); + denotes a censored observation.

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy), the incidence of pneumonitis including interstitial lung disease, was 6.9% (145/2094). Grade 2, Grade 3, and Grade 4 cases were reported in 3.5% (73/2094), 1.1% (24/2094), and 0.4% (8/2094) of patients, respectively. Four patients (0.2%) had a fatal outcome. Median time to onset was 2.7 months (range: 0.1-56.8). Resolution occurred in 119 patients (82.1%) with a median time to resolution of 6.1 weeks (range: 0.3 – 149.3+).

In patients treated with nivolumab in combination with chemotherapy, the incidence of pneumonitis including interstitial lung disease was 4.3% (67/1572). Grade 2, Grade 3, and Grade 4 cases were reported in 2.1% (33/1572), 0.9% (14/1572), and 0.2% (3/1572), of patients, respectively. Two patients (0.1%) had a fatal outcome. Median time to onset was 25 weeks (range: 1.6-96.9). Resolution occurred in 48 patients (71.6%) with a median time to resolution of 10.4 weeks (range: 0.3+ - 121.3+).

In patients treated with nivolumab in combination with cabozantinib, the incidence of pneumonitis including interstitial lung disease was 5.6% (18/320). Grade 2 and Grade 3 cases were reported in 1.9% (6/320) and 1.6% (5/320) of patients, respectively. Median time to onset was 26.9 weeks (range: 12.3-74.3 weeks). Resolution occurred in 14 patients (77.8%) with a median time to resolution of 7.5 weeks (range: 2.1-60.7+ weeks).

Immune-related colitis

In patients treated with nivolumab monotherapy, the incidence of diarrhoea, colitis, or frequent bowel movements was 15.4% (716/4646). The majority of cases were Grade 1 or 2 in severity reported in 9.9% (462/4646) and 4.0% (186/4646) of patients respectively. Grade 3 and 4 cases were reported in 1.4% (67/4646) and <0.1% (1/4646) of patients respectively. Median time to onset was 8.3 weeks (range: 0.1-115.6). Resolution occurred in 639 patients (90.3%) with a median time to resolution of 2.9 weeks (range: 0.1-124.4+).

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy), the incidence of diarrhoea or colitis was 27.7% (580/2094). Grade 2, Grade 3, and Grade 4 cases were reported in 8.8% (184/2094), 6.8% (142/2094), and 0.1% (3/2094), of patients, respectively. One patient (<0.1%) had a fatal outcome. Median time to onset was 1.4 months (range: 0.0-48.9). Resolution occurred in 577 patients (90.8%) with a median time to resolution of 2.7 weeks (range: 0.1-159.4+). Among patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg, the incidence of diarrhoea or colitis was 46.7%, including Grade 2 (13.6%), Grade 3 (15.8%), and Grade 4 (0.4%).

In patients treated with nivolumab in combination with chemotherapy, the incidence of diarrhoea or colitis was 24.0% (377/1572). Grade 2, Grade 3, and Grade 4 cases were reported in 7.3% (115/1572), 3.2% (51/1572), and 0.4% (6/1572) of patients, respectively. One patient (<0.1%) had a fatal outcome. Median time to onset was 4.4 weeks (range: 0.1-93.6). Resolution occurred in 329 patients (87.7%) with a median time to resolution of 1.6 weeks (range: 0.1 – 212.3+).

In patients treated with nivolumab in combination with cabozantinib, the incidence of diarrhoea, colitis, frequent bowel movements or enteritis was 59.1% (189/320). Grade 2 and Grade 3 cases were reported in 25.6% (82/320) and 6.3% (20/320) of patients, respectively. Grade 4 were reported in 0.6% (2/320). Median time to onset was 12.9 weeks (range: 0.3-110.9 weeks). Resolution occurred in 143 patients (76.1%) with a median time to resolution of 12.9 weeks (range: 0.1-139.7+ weeks).

Immune-related hepatitis

In patients treated with nivolumab monotherapy, the incidence of liver function test abnormalities was 8.0% (371/4646). The majority of cases were Grade 1 or 2 in severity reported in 4.3% (200/4646) and 1.8% (82/4646) of patients respectively. Grade 3 and 4 cases were reported in 1.6% (74/4646) and 0.3% (15/4646) of patients, respectively. Median time to onset was 10.6 weeks (range: 0.1-132.0). Resolution occurred in 298 patients (81.4%) with a median time to resolution of 6.1 weeks (range: 0.1-126.4+).

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy), the incidence of liver function test abnormalities was 19.2% (402/2094). Grade 2, Grade 3, and Grade 4 cases were reported in 4.2% (88/2094), 7.8% (163/2094), and 1.2% (25/2094) of patients, respectively. Median time to onset was 1.9 months (range: 0.0-36.6). Resolution occurred in 351 patients (87.8%) with a median time to resolution of 5.3 weeks (range: 0.1-175.9+). Among patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg, the incidence of liver function test abnormalities was 30.1% including Grade 2 (6.9%), Grade 3 (15.8%), and Grade 4 (1.8%).

In patients treated with nivolumab in combination with chemotherapy, the incidence of liver function test abnormalities was 18.6% (293/1572). Grade 2, Grade 3 and Grade 4 cases were reported in 5.6% (88/1572), 2.9% (45/1572) and <0.1% (1/1572) of patients, respectively. Median time to onset was 7.7 weeks (range: 0.1-99.0). Resolution occurred in 231 patients (79.9%) with a median time to resolution of 7.4 weeks (range: 0.4-240.0+).

In patients treated with nivolumab in combination with cabozantinib, the incidence of liver function test abnormalities was 41.6% (133/320). Grade 2, Grade 3, and Grade 4 cases were reported in 14.7% (47/320), 10.3% (33/320), and 0.6% (2/320) of patients, respectively. Median time to onset was 8.3 weeks (range: 0.1-107.9 weeks). Resolution occurred in 101 patients (75.9%) with a median time to resolution of 9.6 weeks (range: 0.1-89.3+ weeks).

Immune-related nephritis and renal dysfunction

In patients treated with nivolumab monotherapy, the incidence of nephritis or renal dysfunction was 2.6% (121/4646). The majority of cases were Grade 1 or 2 in severity reported in 1.5% (69/4646) and 0.7% (32/4646) of patients respectively. Grade 3 and 4 cases were reported in 0.4% (18/4646) and <0.1% (2/4646) of patients, respectively. Median time to onset was 12.1 weeks (range: 0.1-79.1). Resolution occurred in 80 patients (69.0%) with a median time to resolution of 8.0 weeks (range: 0.3-79.1+).

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy), the incidence of nephritis or renal dysfunction was 6.1% (128/2094). Grade 2, Grade 3, and Grade 4 cases were reported in 2.3% (49/2094), 1.0% (20/2094), and 0.5% (10/2094) of patients, respectively. Two patients (<0.1%) had a fatal outcome. Median time to onset was 2.5 months (range: 0.0-34.8). Resolution occurred in 97 patients (75.8%) with a median time to resolution of 6.3 weeks (range: 0.1-172.1+).

In patients treated with nivolumab in combination with chemotherapy, the incidence of nephritis or renal dysfunction was 10.8% (170/1572). Grade 2, Grade 3, and Grade 4 cases were reported in 4.1% (64/1572), 1.5% (24/1572), and 0.1% (2/1572) of patients, respectively. Two patients (0.1%) had a fatal outcome. Median time to onset was 6.9 weeks (range: 0.1-60.7). Resolution occurred in 111 patients (65.3%) with a median time to resolution of 11.6 weeks (range: 0.1-226.0+).

In patients treated with nivolumab in combination with cabozantinib, the incidence of nephritis, immune mediated nephritis, renal failure, acute kidney injury, blood creatinine increased or blood urea increased was 10.0% (32/320). Grade 2 and Grade 3 cases were reported in 3.4% (11/320), and 1.3% (4/320) of patients, respectively. Median time to onset was 14.2 weeks (range: 2.1-87.1 weeks). Resolution occurred in 18 patients (58.1%) with a median time to resolution of 10.1 weeks (range: 0.6-90.9+ weeks).

Immune-related endocrinopathies

In patients treated with nivolumab monotherapy, the incidence of thyroid disorders, including hypothyroidism or hyperthyroidism, was 13.0% (603/4646). The majority of cases were Grade 1 or 2 in severity reported in 6.6% (305/4646) and 6.2% (290/4646) of patients, respectively. Grade 3 thyroid disorders were reported in 0.2% (8/4646) of patients. Hypophysitis (3 Grade 1, 7 Grade 2, 9 Grade 3, and 1 Grade 4), hypopituitarism (6 Grade 2 and 1 Grade 3), adrenal insufficiency (including secondary adrenocortical insufficiency, adrenocortical insufficiency acute and blood corticotrophin decreased) (2 Grade 1, 23 Grade 2, and 11 Grade 3), diabetes mellitus (including Type 1 diabetes mellitus, and diabetic ketoacidosis) (1 Grade 1, 3 Grade 2 and 8 Grade 3 and 2 Grade 4), were reported. Median time to onset of these endocrinopathies was 11.1 weeks (range: 0.1-126.7). Resolution occurred in 323 patients (48.7%). Median time to resolution was 48.6 weeks (range: 0.4-204.4+).

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy), the incidence of thyroid disorders was 22.9% (479/2094). Grade 2 and Grade 3 thyroid disorders were reported in 12.5% (261/2094) and 1.0% (21/2094) of patients, respectively. Grade 2 and Grade 3 hypophysitis (including lymphocytic hypophysitis) occurred in 2.0% (42/2094) and 1.6% (33/2094) of patients, respectively. Grade 2 and Grade 3 hypopituitarism occurred in 0.8% ((16/2094)) and 0.5% ((11/2094)) of patients, respectively. Grade 2, Grade 3, and Grade 4 adrenal insufficiency (including secondary adrenocortical insufficiency) occurred in 2.3% (49/2094), 1.5% (32/2094) and 0.2% (4/2094) of patients, respectively. Grade 1, Grade 2, Grade 3, and Grade 4 diabetes mellitus occurred in 0.1% (1/2094), 0.2% (4/2094), <0.1% (1/2094), and 0.1 (3/2094) of patients, respectively, and Grade 4 diabetic ketoacidosis was reported in < 0.1% (2/2094) of patients. Median time to onset of these endocrinopathies was 2.1 months (range: 0.0-28.1). Resolution occurred in 201 patients (40.7%). Time to resolution ranged from 0.3 to 257.1+ weeks.

In patients treated with nivolumab in combination with chemotherapy, the incidence of thyroid disorders was 12.7% (199/1572). Grade 2 thyroid disorder was reported in 6.2% (97/1572) patients. Grade 3 hypophysitis occurred in 0.1% (2/1572) of patients. Grade 2 and Grade 3 hypopituitarism occurred in 0.2% (3/1572) and 0.3% (4/1572) of patients, respectively. Grade 2, Grade 3 and Grade 4 adrenal insufficiency occurred in 0.6% (9/1572), 0.2% (3/1572) and <0.1% (1/1572) of patients, respectively. One patient (<0.1%) had a fatal outcome due to adrenal insufficiency. Diabetes mellitus including Type 1 diabetes mellitus, fulminant Type 1 diabetes mellitus and diabetic ketoacidosis (3 Grade 2, 2 Grade 3 and 1 Grade 4) were reported. Median time to onset of these endocrinopathies was 14.7 weeks (range: 1.1-124.3). Resolution occurred in 81 patients (37.2%). Time to resolution ranged from 0.4 to 233.6+ weeks.

In patients treated with nivolumab in combination with cabozantinib, the incidence of thyroid disorders was 43.1% (138/320). Grade 2 and Grade 3 thyroid disorders were reported in 23.1% (74/320) and 0.9% (3/320) of patients, respectively. Hypophysitis occurred in 0.6% (2/320) of patients, all Grade 2. Adrenal insufficiency (including secondary adrenocortical insufficiency) occurred in 4.7% (15/320) of patients. Grade 2 and Grade 3 adrenal insufficiency cases were reported in 2.2% (7/320) and 1.9% (6/320) of patients, respectively. Median time to onset of these endocrinopathies was 12.3 weeks (range: 2.0-89.7 weeks). Resolution occurred in 50 patients (35.2%). Time to resolution ranged from 0.9 to 132.0+ weeks.

Immune-related skin adverse reactions

In patients treated with nivolumab monotherapy, the incidence of rash was 30.0% (1396/4646). The majority of cases were Grade 1 in severity reported in 22.8% (1060/4646) of patients. Grade 2 and Grade 3 cases were reported in 5.9% (274/4646) and 1.3% (62/4646) of patients respectively. Median time to onset was 6.7 weeks (range: 0.1-121.1). Resolution occurred in 896 patients (64.6%) with a median time to resolution of 20.1 weeks (0.1-192.7+).

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy), the incidence of rash was 46.2% (968/2094). Grade 2, Grade 3, and Grade 4 cases were reported in 14.1% (296/2094), 4.6% (97/2094), and <0.1% (2/2094) of patients, respectively. Median time to onset was 0.7 months (range: 0.0-33.8). Resolution occurred in 671 patients (69.6%) with a median time to resolution of 11.1 weeks (range: 0.1-268.7+). Among patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg, the incidence of rash was 65.2%, including Grade 2 (20.3%) and Grade 3 (7.8%).

In patients treated with nivolumab in combination with chemotherapy, the incidence of rash was 25.6% (402/1572). Grade 2 and Grade 3 cases were reported in 6.2% (97/1572), and 2.5% (39/1572) of patients, respectively. Median time to onset was 7.0 weeks (range: 0.1-97.4). Resolution occurred in 273 patients (68.1%) with a median time to resolution of 12.3 weeks (range: 0.1-258.7+).

In patients treated with nivolumab in combination with cabozantinib, the incidence of rash was 62.8% (201/320). Grade 2 and Grade 3 cases were reported in 23.1% (74/320) and 10.6% (34/320) of patients, respectively. Median time to onset was 6.14 weeks (range: 0.1-104.4 weeks). Resolution occurred in 137 patients (68.2%) with a median time to resolution of 18.1 weeks (range: 0.1-130.6+ weeks).

Rare cases of SJS and TEN some of them with fatal outcome have been observed (see sections 4.2 and 4.4).

Infusion reactions

In patients treated with nivolumab monotherapy, the incidence of hypersensitivity/infusion reactions was 4.0% (188/4646), including 9 Grade 3 and 3 Grade 4 cases.

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy), the incidence of hypersensitivity/infusion reactions was 4.9% (103/2094). Grade 1, Grade 2, Grade 3, and Grade 4 cases were reported in 2.1% (44/2094), 2.5% (53/2094), 0.2% (5/2094), and <0.1% (1/2094) of patients, respectively. Among patients with MPM treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg, the incidence of hypersensitivity/infusion reactions was 12%.

In patients treated with nivolumab in combination with chemotherapy, the incidence of hypersensitivity/infusion reactions was 8.5% (134/1572). Grade 2, Grade 3, and Grade 4 cases were reported in 4.8% (76/1572), 1.1% (18/1572) and 0.2% (3/1572) of patients, respectively.

In patients treated with nivolumab in combination with cabozantinib, the incidence of hypersensitivity/infusion reactions was 2.5% (8/320). All 8 patients were Grade 1 or 2 in severity. Grade 2 cases were reported in 0.3% (1/320) of patients.

Complications of allogeneic HSCT in classical Hodgkin lymphoma

Rapid onset of GVHD has been reported with nivolumab use before and after allogeneic HSCT (see section 4.4).

In 62 evaluated patients from two cHL studies who underwent allogeneic HSCT after discontinuing nivolumab monotherapy, Grade 3 or 4 acute GVHD was reported in 17/62 patients (27.4%).

Hyperacute GVHD, defined as acute GVHD occurring within 14 days after stem cell infusion, was reported in four patients (6%). A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in six patients (12%) within the first 6 weeks post-transplantation. Steroids were used in four patients and three patients responded to steroids. Hepatic veno-occlusive disease occurred in two patients, one of whom died of GVHD and multi-organ failure. Nineteen of 62 patients (30.6%) died from complications of allogeneic HSCT after nivolumab. The 62 patients had a median follow-up from subsequent allogeneic HSCT of 38.5 months (range: 0-68 months).

Elevated liver enzymes when nivolumab is combined with cabozantinib in RCC

In a clinical study of previously untreated patients with RCC receiving nivolumab in combination with cabozantinib, a higher incidence of Grades 3 and 4 ALT increased (10.1%) and AST increased (8.2%) were observed relative to nivolumab monotherapy in patients with advanced RCC. In patients with Grade ≥2 increased ALT or AST (n=85): median time to onset was 10.1 weeks (range: 2.0 to 106.6 weeks), 26% received corticosteroids for median duration of 1.4 weeks (range: 0.9 to 75.3 weeks), and resolution to Grades 0-1 occurred in 91% with median time to resolution of 2.3 weeks (range: 0.4 to 108.1+ weeks). Among the 45 patients with Grade ≥2 increased ALT or AST who were rechallenged with either nivolumab (n=10) or cabozantinib (n=10) administered as a single agent or with both (n=25), recurrence of Grade ≥ 2 increased ALT or AST was observed in 3 patients receiving OPDIVO, 4 patients receiving cabozantinib, and 8 patients receiving both OPDIVO and cabozantinib.

Laboratory abnormalities

In patients treated with nivolumab monotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 3.4% for anaemia (all Grade 3), 0.7% for thrombocytopaenia, 0.7% for leucopoenia, 8.7% for lymphopaenia, 0.9% for neutropaenia, 1.7% for increased alkaline phosphatase, 2.6% for increased AST, 2.3% for increased ALT, 0.8% for increased total bilirubin, 0.7% for increased creatinine, 2.0% for hyperglycaemia, 0.7% for hypoglycaemia, 3.8% for increased amylase, 6.9% for increased lipase, 4.7% for hyponatraemia, 1.6% for hyperkalaemia, 1.3% for hypokalaemia, 1.1% for hypercalcaemia, 0.6% for hypermagnesaemia, 0.4% for hypomagnesaemia, 0.6% for hypocalcaemia, 0.6% for hypoalbuminaemia, and <0.1% for hypernatraemia.

In patients treated with nivolumab in combination with ipilimumab(with or without chemotherapy), the proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 4.9% for anaemia, 1.5% for thrombocytopaenia, 2.3% for leucopoenia, 7.3% for lymphopaenia, 3.4% for neutropaenia, 2.9% for increased alkaline phosphatase, 7.3% for increased AST, 8.4% for increased ALT, 1.2% for increased total bilirubin, 1.6% for increased creatinine, 5.8% for hyperglycaemia, 0.9% for hypoglycaemia, 8.4% for increased amylase, 16.7% for increased lipase, 0.8% for hypocalcaemia, 0.2% for hypernatraemia, 1.0% for hypercalcaemia, 1.9% for hyperkalaemia, 0.5% for hypermagnesaemia, 3.4% for hypokalaemia, and 9.8% for hyponatraemia.

Among patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg, a higher proportion of patients experienced a worsening from baseline to Grade 3 or 4 increased ALT (15.3%).

In patients treated with nivolumab in combination with chemotherapy, the proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 15.8% for anaemia, 6.9% for thrombocytopaenia, 12.2% leukopaenia, 14.6% for lymphopaenia, 27.6% neutropaenia, 2.4% for increased alkaline phosphatase, 3.4% for increased AST, 2.6% for increased ALT, 2.0% for increased bilirubin, 1.4% for increased creatinine, 4.5% for increased amylase, 5.2% for increased lipase, 0.5% for hypernatraemia, 8.8% for hyponatraemia, 1.9% for hyperkalaemia, 5.6% for hypokalaemia, 0.8% for hypercalcaemia, 1.9% for hypocalcaemia, 1.5% for hypermagnesaemia, 2.9% for hypomagnesaemia, 3.5% for hyperglycaemia, and 0.7% for hypoglycaemia.

In patients treated with nivolumab in combination with cabozantinib, the proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 3.5% for anaemia (all Grade 3), 0.3% for thrombocytopaenia, 0.3% for leucopoenia, 7.5% for lymphopaenia, 3.5% for neutropaenia, 3.2% for increased alkaline phosphatase, 8.2% for increased AST, 10.1% for increased ALT, 1.3% for increased total bilirubin, 1.3% for increased creatinine, 11.9% for increased amylase, 15.6% for increased lipase, 3.5% for hyperglycaemia, 0.8% for hypoglycaemia, 2.2% for hypocalcaemia, 0.3% for hypercalcaemia, 5.4% for hyperkalaemia, 4.2% for hypermagnesaemia, 1.9% for hypomagnesaemia 3.2% for hypokalaemia, 12.3% for hyponatraemia, and 21.2% for hypophosphataemia.

Immunogenicity

Of the 3529 patients who were treated with nivolumab monotherapy 3 mg/kg or 240 mg every 2 weeks and evaluable for the presence of anti-product-antibodies, 328 patients (9.3%) tested positive for treatment-emergent anti-product-antibodies with 21 patients (0.6%) testing positive for neutralising antibodies.

Co-administration with chemotherapy did not affect nivolumab immunogenicity. Of the patients who were treated with nivolumab 240 mg every 2 weeks or 360 mg every 3 weeks in combination with chemotherapy and evaluable for the presence of anti-product-antibodies, 7.5% tested positive for treatment emergent anti-product-antibodies with 0.5% tested positive for neutralising antibodies.

Of the patients who were treated with nivolumab in combination with ipilimumab and evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 26.0% with nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks, 24.9% with nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks, and 37.8% with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks. The incidence of neutralising antibodies against nivolumab was 0.8% with nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks, 1.5% with nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks, and 4.6% with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks. Of patients evaluable for the presence of anti-ipilimumab antibodies, the incidence of anti-ipilimumab antibodies ranged from 6.3 to 13.7% and neutralising antibodies against ipilimumab ranged from 0 to 0.4%.

Of the patients who were treated with nivolumab in combination with ipilimumab and chemotherapy and evaluable for the presence of anti-nivolumab antibodies or neutralising antibodies against nivolumab, the incidence of anti-nivolumab antibodies was 33.8% and the incidence of neutralising antibodies was 2.6%. Of the patients who were treated with nivolumab in combination with ipilimumab and chemotherapy and evaluable for the presence of anti-ipilimumab antibodies or neutralising antibodies against ipilimumab, the incidence of anti-ipilimumab antibodies was 7.5%, and the neutralising antibodies was 1.6%.

Although the clearance of nivolumab was increased by 20% when anti-nivolumab-antibodies were present, there was no evidence of loss of efficacy or altered toxicity profile in the presence of nivolumab antibodies based on the pharmacokinetic and exposure-response analyses for both monotherapy and combination.

Paediatric population

The safety of nivolumab as monotherapy (3 mg/kg every 2 weeks) and in combination with ipilimumab (nivolumab 1 mg/kg or 3 mg/kg in combination with ipilimumab 1 mg/kg every 3 weeks for the first 4 doses, followed by nivolumab 3 mg/kg as monotherapy every 2 weeks) was evaluated in 97 paediatric patients aged ≥1 year to <18 years (including 53 patients 12 to <18 years) with recurrent or refractory solid or haematological tumours, including advanced melanoma, in clinical study CA209070. The safety profile in paediatric patients was generally similar to that seen in adults treated with nivolumab as monotherapy or in combination with ipilimumab. No new safety signals were observed. Long-term safety data is unavailable on the use of nivolumab in adolescents 12 years of age and older.

The most common adverse reactions (reported in at least 20% of paediatric patients) treated with nivolumab monotherapy were fatigue (35.9%) and decreased appetite (21.9%). The majority of adverse reactions reported for nivolumab monotherapy were Grade 1 or 2 in severity. Twenty-one patients (33%) had one or more Grades 3 to 4 adverse reactions.

The most common adverse reactions (reported in at least 20% of paediatric patients) treated with nivolumab in combination with ipilimumab were fatigue (33.3%) and rash maculo-papular (21.2%). The majority of adverse reactions reported for nivolumab in combination with ipilimumab were Grade 1 or 2 in severity. Ten patients (30%) had one or more Grades 3 to 4 adverse reactions.

No new safety signals were observed in clinical study CA209908 of 151 paediatric patients with high-grade primary central nervous system (CNS) malignancies (see section 5.1), relative to data available in adult studies across indications.

Elderly

No overall differences in safety were reported between elderly (≥65 years) and younger patients (<65 years). Data from SCCHN, adjuvant melanoma, and adjuvant OC or GEJC patients 75 years of age or older are too limited to draw conclusions on this population (see section 5.1). Data from dMMR or MSI-H CRC patients 75 years of age or older are limited (see section 5.1). Data from cHL patients 65 years of age or older are too limited to draw conclusions on this population (see section 5.1). In MPM patients, there was a higher rate of serious adverse reactions and discontinuation rate due to adverse reactions in patients 75 years of age or older (68% and 35%, respectively) relative to all patients who received nivolumab in combination with ipilimumab (54% and 28%, respectively). For patients treated with nivolumab in combination with cabozantinib, data from RCC patients 75 years of age or older are too limited to draw conclusions on this population (see section 5.1).

Hepatic or renal impairment

In the non-squamous NSCLC study (CA209057), the safety profile in patients with baseline renal or hepatic impairment was comparable to that in the overall population. These results should be interpreted with caution due to the small sample size within the subgroups.

Reporting of suspected adverse reactions

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. OPDIVO should not be infused concomitantly in the same intravenous line with other medicinal products.