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.

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

Data from patients with moderate or severe hepatic impairment are too limited to draw conclusions on these populations. OPDIVO must be administered with caution in patients with moderate (total bilirubin >1.5 × to 3 × the upper limit of normal [ULN] and any AST) or severe (total bilirubin >3 × ULN and any AST) hepatic impairment.

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.

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, 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 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 1. 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 1. Adverse reactions with nivolumab monotherapy:

Adverse reaction frequencies presented in Table 1 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.
^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

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 2. 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 2. Adverse reactions with nivolumab in combination with other therapeutic agents:

Adverse reaction frequencies presented in Table 2 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.
^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 3 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 3 presents the percentage of patients who required high-dose corticosteroids (at least 40 mg daily prednisone equivalents) by dosing regimen.

Table 3. 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.

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.

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 nivolumab, 4 patients receiving cabozantinib, and 8 patients receiving both nivolumab 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, 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. Data from dMMR or MSI-H CRC patients 75 years of age or older are limited. Data from cHL patients 65 years of age or older are too limited to draw conclusions on this population. 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.

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.