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.

Severe hepatitis has been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab. 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.

Severe pneumonitis or interstitial lung disease, including fatal cases, has been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab. 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.

Severe endocrinopathies, including hypophysitis (including hypopituitarism) have been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab.

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 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.

Severe endocrinopathies, including hypothyroidism, hyperthyroidism have been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab.

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.

Severe endocrinopathies, including adrenal insufficiency (including secondary adrenocortical insufficiency) have been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab.

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 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.

Severe nephritis and renal dysfunction have been observed with monotherapy treatment or nivolumab in combination with ipilimumab. 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.

Severe diarrhoea or colitis has been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab. Patients should be monitored for diarrhoea and additional symptoms of colitis, such as abdominal pain and mucus or blood in stool. Infectious and disease-related aetiologies should be ruled out.

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.

Severe endocrinopathies, including diabetes mellitus, and diabetic ketoacidosis have been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab.

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 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.

There are no data on the use of nivolumab in pregnant women. Studies in animals have shown embryofoetal toxicity. 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.

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.

Based on its pharmacodynamic properties, nivolumab is unlikely to affect the ability to drive and use machines. Because of potential adverse reactions such as fatigue, 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

Summary of the safety profile

In the pooled dataset of nivolumab 3 mg/kg as monotherapy across tumour types (n=2,578) with minimum follow-up ranging from 2.3 to 28 months, the most frequent adverse reactions (≥10%) were fatigue (30%), rash (17%), pruritus (13%), diarrhoea (13%), and nausea (12%). The majority of adverse reactions were mild to moderate (Grade 1 or 2). With a minimum of 24 months follow-up in NSCLC, no new safety signals were identified.

Adjuvant treatment of melanoma

In the dataset of nivolumab 3 mg/kg as monotherapy for the adjuvant treatment of melanoma (n=452), the most frequent adverse reactions (≥10%) were fatigue (46%), rash (29%), diarrhoea (24%), pruritus (23%), nausea (15%), arthralgia (13%), musculoskeletal pain (11%), and hypothyroidism (11%). The majority of adverse reactions were mild to moderate (Grade 1 or 2).

Summary of adverse reactions

Adverse reactions reported in the pooled dataset for patients treated with nivolumab monotherapy (n=2,578) are presented below. 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.

Adverse reactions with nivolumab monotherapy:

Infections and infestations

Common: upper respiratory tract infection

Uncommon: pneumonia^a, bronchitis

Not known: aseptic meningitis^h

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Rare: histiocytic necrotising lymphadenitis (Kikuchi lymphadenitis)

Blood and lymphatic system disorders

Very common: neutropaenia^a,b

Uncommon: eosinophilia

Immune system disorders

Common: infusion related reaction^c, hypersensitivity^c

Rare: anaphylactic reaction^c

Not known: solid organ transplant rejection^h, sarcoidosis^h

Endocrine disorders

Common: hypothyroidism, hyperthyroidism

Uncommon: adrenal insufficiency, hypopituitarism, hypophysitis, thyroiditis, diabetes mellitus

Rare: diabetic ketoacidosis

Metabolism and nutrition disorders

Common: decreased appetite

Uncommon: dehydration, metabolic acidosis

Not known: tumour lysis syndromeⁱ

Hepatobiliary disorders

Uncommon: hepatitis^c

Rare: cholestasis

Nervous system disorders

Common: peripheral neuropathy, headache, dizziness

Uncommon: polyneuropathy, autoimmune neuropathy (including facial and abducens nerve paresis)

Rare: Guillain-Barré syndrome, demyelination, myasthenic syndrome, encephalitis^a,c

Eye disorders

Uncommon: uveitis, blurred vision, dry eye

Not known: Vogt-Koyanagi-Harada syndrome^h

Cardiac disorders

Uncommon: tachycardia, pericardial disorders^j

Rare: arrhythmia (including ventricular arrhythmia)^d, atrial fibrillation, myocarditis^a,f

Vascular disorders

Common: hypertension

Uncommon: vasculitis

Respiratory, thoracic and mediastinal disorders

Common: pneumonitis^a,c, dyspnoea^a, cough

Uncommon: pleural effusion

Rare: lung infiltration

Gastrointestinal disorders

Very common: diarrhoea, nausea

Common: colitis^a, stomatitis, vomiting, abdominal pain, constipation, dry mouth

Uncommon: pancreatitis, gastritis

Rare: duodenal ulcer

Skin and subcutaneous tissue disorders

Very common: rash^e, pruritus

Common: vitiligo, dry skin, erythema, alopecia

Uncommon: erythema multiforme, psoriasis, rosacea, urticaria

Rare: toxic epidermal necrolysis^a,f, Stevens-Johnson syndrome^a,f

Musculoskeletal and connective tissue disorders

Common: musculoskeletal pain^g, arthralgia

Uncommon: polymyalgia rheumatica, arthritis

Rare: Sjogren’s syndrome, myopathy, myositis (including polymyositis)^a,f, rhabdomyolysis^a,f

Renal and urinary disorders

Uncommon: tubulointerstitial nephritis, renal failure (including acute kidney injury)^a,c

General disorders and administration site conditions

Very common: fatigue

Common: pyrexia, oedema (including peripheral oedema)

Uncommon: pain, chest pain

Investigations^b

Very common: increased AST, increased ALT, increased alkaline phosphatase, increased lipase, increased amylase, hypocalcaemia, increased creatinine, hyperglycaemia^c, lymphopaenia, leucopoenia, thrombocytopaenia, anaemia^k, hypercalcaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia, hyponatraemia

Common: increased total bilirubin, hypoglycaemia, hypermagnesaemia, hypernatraemia, weight decreased

^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 Life-threatening cases have been reported in completed or ongoing clinical studies.
^d The frequency of adverse events in the cardiac disorders system organ class regardless of causality was higher in the nivolumab group than in the chemotherapy group in post-CTLA4/BRAF inhibitor metastatic melanoma population. Incidence rates per 100 person-years of exposure were 9.3 vs. 0; serious cardiac events were reported by 4.9% patients in the nivolumab group vs. 0 in the investigator ́s choice group. The frequency of cardiac adverse events was lower in the nivolumab group than in the dacarbazine group in the metastatic melanoma without prior treatment population. All were considered not related to nivolumab by investigators except arrhythmia (atrial fibrillation, tachycardia and ventricular arrhythmia).
^e 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 and pemphigoid.
^f Reported also in studies outside the pooled dataset. The frequency is based on the program-wide exposure.
^g Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.
^h Post-marketing event.
ⁱ Reported in clinical studies and in the post-marketing setting.
^j Pericardial disorders is a composite term which includes pericarditis, pericardial effusion, cardiac tamponade, and Dressler’s syndrome.
^k Anaemia is a composite term which includes, among other causes, haemolytic anaemia and autoimmune anaemia.

The overall safety profile of nivolumab 3 mg/kg for the adjuvant treatment of melanoma (n=452) was consistent with that established across tumour types for nivolumab monotherapy.

Nivolumab in combination with ipilimumab

Summary of the safety profile

When nivolumab is administered in combination with ipilimumab, refer to the Summary of Product Characteristics for ipilimumab prior to initiation of treatment. For additional information on the safety profile of ipilimumab monotherapy, please refer to the ipilimumab SmPC.

Melanoma

In the pooled dataset of nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma (n=448) with minimum follow-up ranging from 6 to 28 months, the most frequent adverse reactions (≥10%) were rash (52%), fatigue (46%), diarrhoea (43%), pruritus (36%), nausea (26%), pyrexia (19%), decreased appetite (16%), hypothyroidism (16%), colitis (15%), vomiting (14%), arthralgia (13%), abdominal pain (13%), headache (11%), and dyspnoea (10%). The majority of adverse reactions were mild to moderate (Grade 1 or 2).

Among the patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in CA209067, 154/313 (49%) had the first onset of Grade 3 or 4 adverse reactions during the initial combination phase. Among the 147 patients in this group who continued treatment in the single-agent phase, 47 (32%) experienced at least one Grade 3 or 4 adverse reaction during the single-agent phase.

RCC

In the dataset of nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC (n=547), with a minimum follow-up of 17.5 months, the most frequent adverse reactions (≥10%) were fatigue (48%), rash (34%), pruritus (28%), diarrhoea (27%), nausea (20%), hypothyroidism (16%), musculoskeletal pain (15%), arthralgia (14%), decreased appetite (14%), pyrexia (14%), vomiting (11%), hyperthyroidism (11%). The majority of adverse reactions were mild to moderate (Grade 1 or 2).

Among the patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in CA209214, 169/547 (31%) had the first onset of Grade 3 or 4 adverse reactions during the initial combination phase. Among the 382 patients in this group who continued treatment in the single-agent phase, 144 (38%) experienced at least one Grade 3 or 4 adverse reaction during the single-agent phase.

Summary of adverse reactions

Adverse reactions reported in the pooled dataset for patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg (n=448) and for patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg (n=547) are presented below. 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.

Adverse reactions with nivolumab in combination with ipilimumab:

Infections and infestations

Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:

Common: pneumonia, upper respiratory tract infection

Uncommon: bronchitis

Not known: aseptic meningitis^h

Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:

Common: pneumonia, upper respiratory tract infection, conjunctivitis

Uncommon: bronchitis, aseptic meningitis

Blood and lymphatic system disorders

Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:

Common: eosinophilia

Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:

Uncommon: eosinophilia

Immune system disorders

Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:

Common: infusion related reaction, hypersensitivity

Uncommon: sarcoidosis

Not known: solid organ transplant rejection^h

Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:

Common: infusion related reaction, hypersensitivity

Endocrine disorders

Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:

Very common: hypothyroidism

Common: adrenal insufficiency, hypopituitarism, hypophysitis, hyperthyroidism, thyroiditis

Uncommon: diabetic ketoacidosis^c, diabetes mellitus^c

Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:

Very common: hypothyroidism, hyperthyroidism

Common: adrenal insufficiency^c, hypophysitis^c, thyroiditis, diabetes mellitus^c

Uncommon: diabetic ketoacidosis^c, hypopituitarism

Metabolism and nutrition disorders

Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:

Very common: decreased appetite

Common: dehydration

Not known: tumour lysis syndromeⁱ

Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:

Very common: decreased appetite

Common: dehydration

Uncommon: metabolic acidosis

Hepatobiliary disorders

Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:

Common: hepatitis^c

Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:

Common: hepatitis^c

Nervous system disorders

Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:

Very common: headache

Common: peripheral neuropathy, dizziness

Uncommon: Guillain-Barré syndrome, polyneuropathy, neuritis, peroneal nerve palsy, autoimmune neuropathy (including facial and abducens nerve paresis), encephalitis^c

Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:

Common: headache, peripheral neuropathy, dizziness

Uncommon: polyneuropathy, autoimmune neuropathy (including facial and abducens nerve paresis), myasthenia gravis^c

Eye disorders

Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:

Common: uveitis, blurred vision

Not known: Vogt-Koyanagi-Harada syndrome^h

Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:

Common: blurred vision

Uncommon: uveitis

Cardiac disorders

Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:

Common: tachycardia

Uncommon: arrhythmia (including ventricular arrhythmia)^a,d, atrial fibrillation, myocarditis^a,f

Not known: pericardial disorders^j

Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:

Common: tachycardia

Uncommon: arrhythmia (including ventricular arrhythmia), myocarditis^c

Vascular disorders

Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:

Common: hypertension

Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:

Common: hypertension

Respiratory, thoracic and mediastinal disorders

Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:

Very common: dyspnoea

Common: pneumonitis^a,c, pulmonary embolism^a, cough

Uncommon: pleural effusion

Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:

Common: pneumonitis, dyspnoea, pleural effusion, cough

Gastrointestinal disorders

Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:

Very common: colitis^a, diarrhoea, vomiting, nausea, abdominal pain

Common: stomatitis, pancreatitis, constipation, dry mouth

Uncommon: intestinal perforation^a, gastritis, duodenitis

Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:

Very common: diarrhoea, vomiting, nausea

Common: colitis, stomatitis, pancreatitis, abdominal pain, constipation, dry mouth

Uncommon: gastritis

Skin and subcutaneous tissue disorders

Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:

Very common: rash^e, pruritus

Common: vitiligo, dry skin, erythema, alopecia, urticaria

Uncommon: psoriasis

Σπάνιες: toxic epidermal necrolysis^a,f, StevensJohnson syndrome^f

Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:

Very common: rash^e, pruritus

Common: dry skin, erythema, urticaria

Uncommon: Stevens-Johnson syndrome, vitiligo, erythema multiforme, alopecia, psoriasis

Musculoskeletal and connective tissue disorders

Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:

Very common: arthralgia

Common: musculoskeletal pain^g

Uncommon: spondyloarthropathy, Sjogren’s syndrome, arthritis, myopathy, myositis (including polymyositis)^a,e, rhabdomyolysis^a,f

Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:

Very common: musculoskeletal pain^g, arthralgia

Common: arthritis, muscle spasms, muscular weakness

Uncommon: polymyalgia rheumatica, myositis (including polymyositis), rhabdomyolysis

Renal and urinary disorders

Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:

Common: renal failure (including acute kidney injury)^a,c

Uncommon: tubulointerstitial nephritis

Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:

Common: renal failure (including acute kidney injury)^c

Uncommon: tubulointerstitial nephritis

General disorders and administration site conditions

Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:

Very common: fatigue, pyrexia

Common: oedema (including peripheral oedema), pain

Uncommon: chest pain

Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:

Very common: fatigue, pyrexia

Common: oedema (including peripheral oedema), pain, chest pain, chills

Investigations^b

Nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg*:

Very common: increased AST, increased ALT, increased total bilirubin, increased alkaline phosphatase, increased lipase, increased amylase, increased creatinine, hyperglycaemia^c, hypoglycaemia, lymphopaenia, leucopoenia, neutropaenia, thrombocytopaenia, anaemia^k, hypocalcaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia, hyponatraemia

Common: hypercalcaemia, hypermagnesaemia, hypernatraemia, weight decreased

Nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg**:

Very common: increased AST, increased ALT, increased total bilirubin, increased alkaline phosphatase, increased lipase, increased amylase, increased creatinine, hyperglycaemia^c, hypoglycaemia, lymphopaenia, leucopoenia, neutropaenia^c, thrombocytopaenia, anaemia^k, hypercalcaemia, hypocalcaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia, hyponatraemia

Common: hypermagnesaemia, hypernatraemia, weight decreased

* nivolumab in combination with ipilimumab for the first 4 doses then followed by nivolumab monotherapy in melanoma.
** nivolumab in combination with ipilimumab for the first 4 doses then followed by nivolumab monotherapy in RCC.
^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 Life-threatening cases have been reported in completed or ongoing clinical studies.
^d The frequency of adverse events in the cardiac disorders system organ class regardless of causality was higher in the nivolumab group than in the chemotherapy group in post-CTLA4/BRAF inhibitor metastatic melanoma population. Incidence rates per 100 person-years of exposure were 9.3 vs. 0; serious cardiac events were reported by 4.9% patients in the nivolumab group vs. 0 in the investigator´s choice group. The frequency of cardiac adverse events was lower in the nivolumab group than in the dacarbazine group in the metastatic melanoma without prior treatment population. All were considered not related to nivolumab by investigators except arrhythmia (atrial fibrillation, tachycardia and ventricular arrhythmia).
^e 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 and pemphigoid.
^f Reported also in studies outside the pooled dataset. The frequency is based on the program-wide exposure.
^g Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.
^h Post-marketing event.
ⁱ Reported in clinical studies and in the post-marketing setting.
^j Pericardial disorders is a composite term which includes pericarditis, pericardial effusion, cardiac tamponade, and Dressler’s syndrome.
^k Anaemia is a composite term which includes, among other causes, haemolytic anaemia and autoimmune anaemia.

Description of selected adverse reactions

Nivolumab or nivolumab in combination with ipilimumab is associated with immune-related adverse reactions. With appropriate medical therapy, immune-related adverse reactions resolved in most cases. Permanent discontinuation of treatment was required in a greater proportion of patients receiving nivolumab in combination with ipilimumab than in those receiving nivolumab monotherapy. Table 1 presents the percentage for immune-related adverse reactions who were permanently discontinued from treatment by dosing regimen. Additionally, for patients who experienced an event, Table 1 presents the percentage of patients who required high-dose corticosteroids (at least 40 mg daily prednisone equivalents) by dosing regimen.

Table 1. Immune-related adverse reactions leading to permanent discontinuation or requiring high-dose corticosteroids by dosing regimen:

^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 3.4% (87/2578). The majority of cases were Grade 1 or 2 in severity reported in 0.8% (21/2578) and 1.7% (44/2578) of patients respectively. Grade 3 and 4 cases were reported in 0.7% (19/2578) and <0.1% (1/2578) of patients respectively. Grade 5 cases were reported in <0.1% (2/2578) of patients in these studies. Median time to onset was 3.6 months (range: 0.2-19.6). Resolution occurred in 63 patients (72.4%) with a median time to resolution of 6.1 weeks (range: 0.1+ - 96.7+); + denotes a censored observation.

In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of pneumonitis including interstitial lung disease, was 7.8% (35/448). Grade 2, Grade 3, and Grade 4 cases were reported in 4.7% (21/448), 1.1% (5/448), and 0.2% (1/448) of patients, respectively. One of the Grade 3 pneumonitis cases worsened over 11 days with a fatal outcome. Median time to onset was 2.6 months (range: 0.7-12.6). Resolution occurred in 33 patients (94.3%) with a median time to resolution of 6.1 weeks (range: 0.3-35.1).

In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of pneumonitis including interstitial lung disease was 6.2% (34/547). Grade 2 and Grade 3 cases were reported in 3.1% (17/547) and 1.1% (6/547), of patients, respectively. No Grade 4 or 5 cases were reported in this study. Median time to onset was 2.6 months (range: 0.25-20.6). Resolution occurred in 31 patients (91.2%) with a median time to resolution of 6.1 weeks (range: 0.7 – 85.9+).

Immune-related colitis

In patients treated with nivolumab monotherapy, the incidence of diarrhoea, colitis, or frequent bowel movements was 13.1% (339/2578). The majority of cases were Grade 1 or 2 in severity reported in 8.5% (220/2578) and 3.0% (78/2578) of patients respectively. Grade 3 cases were reported in 1.6% (41/2578) of patients. No Grade 4 or 5 cases were reported in these studies. Median time to onset was 1.8 months (range: 0.0-26.6). Resolution occurred in 296 patients (88.1%) with a median time to resolution of 2.1 weeks (range: 0.1 – 124.4+).

In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of diarrhoea or colitis was 46.7% (209/448). Grade 2, Grade 3, and Grade 4 cases were reported in 13.6% (61/448), 15.8% (71/448), and 0.4% (2/448) of patients, respectively. No Grade 5 cases were reported. Median time to onset was 1.2 months (range: 0.0-22.6). Resolution occurred in 186 patients (89.4%) with a median time to resolution of 3.0 weeks (range: 0.1 – 159.4+).

In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of diarrhoea or colitis was 28.2% (154/547). Grade 2 and Grade 3 cases were reported in 10.4% (57/547) and 4.9% (27/547) of patients, respectively. No Grade 4 or 5 cases were reported. Median time to onset was 1.2 months (range: 0.0-24.7). Resolution occurred in 140 patients (91.5%) with a median time to resolution of 2.4 weeks (range: 0.1 – 103.1+).

Immune-related hepatitis

In patients treated with nivolumab monotherapy, the incidence of liver function test abnormalities was 6.7% (173/2578). The majority of cases were Grade 1 or 2 in severity reported in 3.5% (91/2578) and 1.2% (32/2578) of patients respectively. Grade 3 and 4 cases were reported in 1.6% (41/2578) and 0.3% (9/2578) of patients, respectively. No Grade 5 cases were reported in these studies. Median time to onset was 2.1 months (range: 0.0-27.6). Resolution occurred in 132 patients (76.7%) with a median time to resolution of 5.9 weeks (range: 0.1 – 82.6+).

In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of liver function test abnormalities was 29.5% (132/448). Grade 2, Grade 3, and Grade 4 cases were reported in 6.7% (30/448), 15.4% (69/448), and 1.8% (8/448) of patients, respectively. No Grade 5 cases were reported. Median time to onset was 1.5 months (range: 0.0-30.1). Resolution occurred in 124 patients (93.9%) with a median time to resolution of 5.1 weeks (range: 0.1-106.9).

In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of liver function test abnormalities was 18.5% (101/547). Grade 2, Grade 3, and Grade 4 cases were reported in 4.8% (26/547), 6.6% (36/547), and 1.6% (9/547) of patients, respectively. No Grade 5 cases were reported. Median time to onset was 2.0 months (range: 0.4-26.8). Resolution occurred in 86 patients (85.1%) with a median time to resolution of 6.1 weeks (range: 0.1+ - 82.9+).

Immune-related nephritis and renal dysfunction

In patients treated with nivolumab monotherapy, the incidence of nephritis or renal dysfunction was 2.8% (71/2578). The majority of cases were Grade 1 or 2 in severity reported in 1.6% (41/2578) and 0.7% (18/2578) of patients respectively. Grade 3 and 4 cases were reported in 0.4% (11/2578) and <0.1% (1/2578) of patients, respectively. No Grade 5 nephritis or renal dysfunction was reported in these studies. Median time to onset was 2.3 months (range: 0.0-18.2). Resolution occurred in 42 patients (61.8%) with a median time to resolution of 12.1 weeks (range: 0.3 – 79.1+).

In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of nephritis or renal dysfunction was 5.1% (23/448). Grade 2, Grade 3, and Grade 4 cases were reported in 1.6% (7/448), 0.9% (4/448), and 0.7% (3/448) of patients, respectively. No Grade 5 cases were reported. Median time to onset was 2.6 months (range: 0.5-21.8). Resolution occurred in 21 patients (91.3%) with a median time to resolution of 2.1 weeks (range: 0.1 – 125.1+).

In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of nephritis or renal dysfunction was 8.8% (48/547). Grade 2, Grade 3, and Grade 4 cases were reported in 4.4% (24/547), 0.7% (4/547), and 0.5% (3/547) of patients, respectively. No Grade 5 cases were reported. Median time to onset was 2.1 months (range: 0.0-16.1). Resolution occurred in 37 patients (77.1%) with a median time to resolution of 13.2 weeks (range: 0.1+ - 106.0+).

Immune-related endocrinopathies

In patients treated with nivolumab monotherapy, the incidence of thyroid disorders, including hypothyroidism or hyperthyroidism, was 9.6% (248/2578). The majority of cases were Grade 1 or 2 in severity reported in 4.2% (107/2578) and 5.4% (139/2578) of patients, respectively. Grade 3 thyroid disorders were reported in <0.1% (2/2578) of patients. Hypophysitis (1 Grade 1, 2 Grade 2, 5 Grade 3, and 1 Grade 4), hypopituitarism (4 Grade 2 and 1 Grade 3), adrenal insufficiency (including secondary adrenocortical insufficiency) (1 Grade 1, 9 Grade 2, and 5 Grade 3), diabetes mellitus (including Type 1 diabetes mellitus) (3 Grade 2 and 1 Grade 3), and diabetic ketoacidosis (2 Grade 3) were reported. No Grade 5 cases were reported in these studies. Median time to onset of these endocrinopathies was 2.8 months (range: 0.3-29.1). Resolution occurred in 117 patients (42.9%). Time to resolution ranged from 0.4 to 144.1+ weeks.

In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of thyroid disorders was 25.2% (113/448). Grade 2 and Grade 3 thyroid disorders were reported in 14.5% (65/448) and 1.3% (6/448) of patients, respectively. Grade 2 and Grade 3 hypophysitis (including lymphocytic hypophysitis) occurred in 5.8% (26/448) and 2.0% (9/448) of patients, respectively. Grade 2 and Grade 3 hypopituitarism occurred in 0.4% (2/448) and 0.7% (3/448) of patients, respectively. Grade 2, Grade 3, and Grade 4 adrenal insufficiency (including secondary adrenocortical insufficiency) occurred in 1.6% (7/448), 1.3% (6/448) and 0.2% (1/448) of patients, respectively. Grade 1, Grade 2, Grade 3, and Grade 4 diabetes mellitus and Grade 4 diabetic ketoacidosis were each reported in 0.2% (1/448) of patients. No Grade 5 endocrinopathy was reported. Median time to onset of these endocrinopathies was 1.9 months (range: 0.0-28.1). Resolution occurred in 64 patients (45.4%). Time to resolution ranged from 0.4 to 155.4+ weeks.

In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of thyroid disorders was 27.2% (149/547). Grade 2 and Grade 3 thyroid disorders were reported in 15.7% (86/547) and 1.3% (7/547) of patients, respectively. Hypophysitis occurred in 4.0% (22/547) of patients. Grade 2, Grade 3, and Grade 4 cases were reported in 0.5% (3/547), 2.4% (13/547), and 0.4% (2/547) of patients, respectively. Grade 2 hypopituitarism occurred in 0.4% (2/547) of patients. Grade 2, Grade 3, and Grade 4 adrenal insufficiency (including secondary adrenocortical insufficiency) occurred in 2.9% (16/547), 2.2% (12/547) and 0.4% (2/547) of patients, respectively. Diabetes mellitus including Type 1 diabetes mellitus (3 Grade 2, 2 Grade 3, and 3 Grade 4), and diabetic ketoacidosis (1 Grade 4) were reported. No Grade 5 endocrinopathy was reported. Median time to onset of these endocrinopathies was 1.9 months (range: 0.0-22.3). Resolution occurred in 76 patients (42.7%). Time to resolution ranged from 0.4 to 130.3+ weeks.

Immune-related skin adverse reactions

In patients treated with nivolumab monotherapy, the incidence of rash was 26.4% (680/2578). The majority of cases were Grade 1 in severity reported in 20.1% (518/2578) of patients. Grade 2 and Grade 3 cases were reported in 5.1% (131/2578) and 1.2% (31/2578) of patients respectively. No Grade 4 or 5 cases were reported in these studies. Median time to onset was 1.4 months (range: 0.0-27.9). Resolution occurred in 428 patients (63.8%) with a median time to resolution of 17.1 weeks (0.1 – 150.0+).

In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the incidence of rash was 65.0% (291/448). Grade 2 and Grade 3 cases were reported in 20.3% (91/448) and 7.6% (34/448) of patients, respectively. No Grade 4 or 5 cases were reported. Median time to onset was 0.5 months (range: 0.0-19.4). Resolution occurred in 191 patients (65.9%) with a median time to resolution of 11.4 weeks (range: 0.1 – 150.1+).

In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the incidence of rash was 48.8% (267/547). Grade 2 and Grade 3 cases were reported in 13.7% (75/547) and 3.7% (20/547) of patients, respectively. No Grade 4 or 5 cases were reported. Median time to onset was 0.9 months (range: 0.0-17.9). Resolution occurred in 192 patients (72.2%) with a median time to resolution of 11.6 weeks (range: 0.1 – 126.7+).

Rare cases of SJS and TEN some of them with fatal outcome have been observed.

Infusion reactions

In patients treated with nivolumab monotherapy, the incidence of hypersensitivity/infusion reactions was 4.7% (121/2578), including 6 Grade 3 and 2 Grade 4 cases.

In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg, the incidence of hypersensitivity/infusion reactions was 3.8% (17/448); all were Grade 1 or 2 in severity. Grade 2 cases were reported in 2.2% (10/448) of patients. No Grade 3-5 cases were reported.

In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg//kg, the incidence of hypersensitivity/infusion reactions was 4.0% (22/547); all were Grade 1 or 2 in severity. Grade 2 cases were reported in 2.4% (13/547) of patients. No Grade 3-5 cases were reported.

Complications of allogeneic HSCT in classical Hodgkin Lymphoma

Rapid onset of GVHD has been reported with nivolumab use before and after allogeneic HSCT. In 49 evaluated patients from two cHL studies who underwent allogeneic HSCT after discontinuing nivolumab monotherapy, Grade 3 or 4 acute GVHD was reported in 13/49 patients (26.5%). Hyperacute GVHD, defined as acute GVHD occurring within 14 days after stem cell infusion, was reported in three 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, with three patients responding to steroids. Hepatic veno-occlusive disease occurred in one patient, who died of GVHD and multi-organ failure. Nine of 49 patients (18.4%) died from complications of allogeneic HSCT after nivolumab. The 49 patients had a median follow-up from subsequent allogeneic HSCT of 5.6 months (range: 0-19 months).

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: 5.2% for anaemia (all Grade 3), 1.0% for thrombocytopaenia, 1.0% for leucopoenia, 10.0% for lymphopaenia, 1.1% for neutropaenia, 2.1% for increased alkaline phosphatase, 2.7% for increased AST, 2.2% for increased ALT, 1.2% for increased total bilirubin, 0.9% for increased creatinine, 3.8% for hyperglycaemia, 1.0% for hypoglycaemia, 3.5% for increased amylase, 7.9% for increased lipase, 6.4% for hyponatraemia, 1.8% for hyperkalaemia, 1.5% for hypokalaemia, 1.2% for hypercalcaemia, 0.7% for hypermagnesaemia, 0.5% for hypomagnesaemia, 0.7% for hypocalcaemia, and 0.1% for hypernatraemia.

In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 2.8% for anaemia (all Grade 3), 1.2% for thrombocytopaenia, 0.5% for leucopoenia, 6.7% for lymphopaenia, 0.7% for neutropaenia, 4.3% for increased alkaline phosphatase, 12.4% for increased AST, 15.3% for increased ALT, 1.2% for increased total bilirubin, 2.4% for increased creatinine, 5.3% for hyperglycaemia, 8.7% for increased amylase, 19.5% for increased lipase, 1.2% for hypocalcaemia, 0.2% each for hypernatraemia and hypercalcaemia, 0.5% for hyperkalemia, 0.3% for hypermagnesaemia, 4.8% for hypokalaemia, and 9.5% for hyponatraemia.

In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 3.0% for anaemia (all Grade 3), 0.7% for thrombocytopaenia, 0.6% for leucopoenia, 5.1% for lymphopaenia, 1.1% for neutropaenia, 2.0% for increased alkaline phosphatase, 4.8% for increased AST, 6.5% for increased ALT, 1.1% for increased total bilirubin, 2.1% for increased creatinine, 7.2% for hyperglycaemia, 1.8% for hypoglycemia, 12.2% for increased amylase, 20.1% for increased lipase, 0.4% for hypocalcaemia, 1.3% for hypercalcaemia, 2.4% for hyperkalemia, 1.1% for hypermagnesaemia, 0.4% for hypomagnesaemia 1.9% for hypokalaemia, and 9.9% for hyponatraemia.

Immunogenicity

Of the 2022 patients who were treated with nivolumab monotherapy 3 mg/kg every 2 weeks and evaluable for the presence of anti-product-antibodies, 231 patients (11.4%) tested positive for treatment-emergent anti-product-antibodies with fifteen patients (0.7%) testing 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 and 37.8% with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks. The incidence of neutralising antibodies against nivolumab was 0.5% with nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 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 8.4% and neutralising antibodies against ipilimumab ranged from 0 to 0.3%.

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.

Elderly

No overall differences in safety were reported between elderly (≥65 years) and younger patients (<65 years). Data from SCCHN and adjuvant melanoma patients 75 years of age or older are too limited to draw conclusions on this population. Data from cHL patients 65 years of age or older are too limited to draw conclusions on this population.

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.