Opdivo · 4.1 Therapeutic indications · 2

HOS-097439 · has-adverse-reaction-information · PDF-Seite 163

Nivolumab as monotherapy (see section 4.2) Summary of the safety profile In the pooled dataset of nivolumab as monotherapy administered intravenously 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. The safety of nivolumab administered subcutaneously was similar to the known safety profile of the intravenous formulation of nivolumab, with an additional adverse reaction of injection site reaction (7% in the subcutaneous nivolumab arm (n = 247) vs 0% in the intravenous nivolumab arm (n = 245)). Tabulated summary of adverse reactions Adverse reactions reported in the pooled dataset for patients treated with nivolumab monotherapy (n = 4646) are presented in Table 12. 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); 163 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 12: 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 haemopha

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HOS-097433 · has-adverse-reaction-information · PDF-Seite 26

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 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

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HOS-097435 · has-contraindication-information · PDF-Seite 153

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-097429 · has-contraindication-information · PDF-Seite 15

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-097434 · has-indication-information · PDF-Seite 144

Melanoma OPDIVO as monotherapy is indicated for the adjuvant treatment of adults with Stage IIB or IIC melanoma, or melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection (see section 5.1). OPDIVO as monotherapy or in combination with ipilimumab is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults (see section 4.2). Relative to nivolumab monotherapy, an increase in progression-free survival (PFS) and overall survival (OS) for the combination of nivolumab with ipilimumab is established only in patients with low tumour PD-L1 expression (see sections 4.4 and 5.1). Non-small cell lung cancer (NSCLC) OPDIVO in combination with platinum-based chemotherapy is indicated for the neoadjuvant treatment of resectable non-small cell lung cancer at high risk of recurrence in adult patients whose tumours have PD-L1 expression ≥ 1% (see section 5.1 for selection criteria). OPDIVO, in combination with platinum-based chemotherapy as neoadjuvant treatment, followed by OPDIVO as monotherapy as adjuvant treatment, is indicated for the treatment of resectable non-small 144 cell lung cancer at high risk of recurrence in adult patients whose tumours have PD-L1 expression ≥ 1% (see section 5.1 for selection criteria). OPDIVO as monotherapy is indicated for the treatment of locally advanced or metastatic non-small cell lung cancer after prior chemotherapy in adults. Renal cell carcinoma (RCC) OPDIVO in combination with ipilimumab is indicated for the first-line treatment of adult patients with intermediate/poor-risk advanced renal cell carcinoma (see sections 4.2 and 5.1). OPDIVO in combination with cabozantinib is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (see section 5.1). OPDIVO as monotherapy is indicated for the treatment of advanced renal cell carcinoma after prior therapy in adults. Squamous cell cancer of the head and neck (SCCHN) OPDIVO as monotherapy is indicated for the treatment of recurrent or metastatic squamous cell cancer of the head and neck in adults progressing on or after platinum-based therapy (see section 5.1). Urothelial carcinoma (UC) OPDIVO as monotherapy is indicated for the adjuvant treatment of adults with muscle invasive urothelial carcinoma (MIUC) with tumour cell PD-L1 expression ≥ 1%, who are at high risk of recurrence after undergoing radical resecti

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HOS-097428 · has-indication-information · PDF-Seite 2

Melanoma OPDIVO as monotherapy is indicated for the adjuvant treatment of adults and adolescents 12 years of age and older with Stage IIB or IIC melanoma, or melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection (see section 5.1). OPDIVO as monotherapy or in combination with ipilimumab is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults and adolescents 12 years of age and older. Relative to nivolumab monotherapy, an increase in progression-free survival (PFS) and overall survival (OS) for the combination of nivolumab with ipilimumab is established only in patients with low tumour PD-L1 expression (see sections 4.4 and 5.1). 2 Non-small cell lung cancer (NSCLC) OPDIVO in combination with platinum-based chemotherapy is indicated for the neoadjuvant treatment of resectable non-small cell lung cancer at high risk of recurrence in adult patients whose tumours have PD-L1 expression ≥ 1% (see section 5.1 for selection criteria). OPDIVO in combination with platinum-based chemotherapy as neoadjuvant treatment, followed by OPDIVO as monotherapy as adjuvant treatment, is indicated for the treatment of resectable non-small cell lung cancer at high risk of recurrence in adult patients whose tumours have PD-L1 expression ≥ 1% (see section 5.1 for selection criteria). OPDIVO in combination with ipilimumab and 2 cycles of platinum-based chemotherapy is indicated for the first-line treatment of metastatic non-small cell lung cancer in adults whose tumours have no sensitising EGFR mutation or ALK translocation. OPDIVO as monotherapy is indicated for the treatment of locally advanced or metastatic non-small cell lung cancer after prior chemotherapy in adults. Malignant pleural mesothelioma (MPM) OPDIVO in combination with ipilimumab is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma. Renal cell carcinoma (RCC) OPDIVO in combination with ipilimumab is indicated for the first-line treatment of adult patients with intermediate/poor-risk advanced renal cell carcinoma (see section 5.1). OPDIVO in combination with cabozantinib is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (see section 5.1). OPDIVO as monotherapy is indicated for the treatment of advanced renal cell carcinoma after prior therapy in adults. Classical Hodgki

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HOS-097431 · has-interaction-information · PDF-Seite 25

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.

HOS-097437 · has-interaction-information · PDF-Seite 162

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 162 immunosuppression after starting nivolumab treatment does not appear to preclude the response on nivolumab.

HOS-097432 · has-pregnancy-information · PDF-Seite 25

Pregnancy There are no data from 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. 25

HOS-097438 · has-pregnancy-information · PDF-Seite 163

Pregnancy There are no data from 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.

HOS-097436 · has-warning-information · PDF-Seite 153

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. 153 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. Assessment of MSI/MMR status When assessing the MSI-H and dMMR 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

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HOS-097430 · has-warning-information · PDF-Seite 15

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. Assessment of MSI/MMR status When assessing the MSI-H and dMMR 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, in combination with brentuximab vedotin or in combination with AVD 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). 15 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, nivol

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