nivolumab: prescribing information – dosing, contraindications, interactions, side effects

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).

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 Hodgkin lymphoma (cHL)

OPDIVO in combination with doxorubicin, vinblastine and dacarbazine (AVD) is indicated for adults and adolescents 12 years of age and older with previously untreated Stage III or IV classical Hodgkin lymphoma.

OPDIVO in combination with brentuximab vedotin is indicated for the treatment of children 5 years of age and older, adolescents and adults up to 30 years of age with relapsed or refractory classical Hodgkin lymphoma after one prior line of therapy (see section 5.1).

OPDIVO as monotherapy is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma after autologous stem cell transplant (ASCT) and treatment with brentuximab vedotin.

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 resection of MIUC (see section 5.1).

OPDIVO in combination with cisplatin and gemcitabine is indicated for the first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma.

OPDIVO as monotherapy is indicated for the treatment of locally advanced unresectable or metastatic urothelial carcinoma in adults after failure of prior platinum-containing therapy.

Mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer (CRC)

OPDIVO in combination with ipilimumab is indicated for the treatment of adult patients with mismatch repair deficient or microsatellite instability-high colorectal cancer in the following settings:
- first-line treatment of unresectable or metastatic colorectal cancer;
- treatment of metastatic colorectal cancer after prior fluoropyrimidine-based combination chemotherapy (see section 5.1).

Oesophageal squamous cell carcinoma (OSCC)

OPDIVO in combination with ipilimumab is indicated for the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma with tumour cell PD-L1 expression ≥ 1%.

OPDIVO in combination with fluoropyrimidine- and platinum-based combination chemotherapy is indicated for the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma with tumour cell PD-L1 expression ≥ 1%.

OPDIVO as monotherapy is indicated for the treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma after prior fluoropyrimidine- and platinum-based combination chemotherapy.

Adjuvant treatment of oesophageal or gastro-oesophageal junction cancer (OC or GEJC)

OPDIVO as monotherapy is indicated for the adjuvant treatment of adult patients with oesophageal or gastro-oesophageal junction cancer who have residual pathologic disease following prior neoadjuvant chemoradiotherapy (see section 5.1).

Gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinoma

OPDIVO in combination with fluoropyrimidine- and platinum-based combination chemotherapy is indicated for the first-line treatment of adult patients with HER2-negative advanced or metastatic gastric, gastro-oesophageal junction or oesophageal adenocarcinoma whose tumours express PD-L1 with a combined positive score (CPS) ≥ 5.

Hepatocellular carcinoma (HCC)

OPDIVO in combination with ipilimumab is indicated for the first-line treatment of adult patients with unresectable or advanced hepatocellular carcinoma.

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

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 resection of MIUC (see section 5.1).

OPDIVO in combination with cisplatin and gemcitabine is indicated for the first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma (see sections 4.2 and 5.1).

OPDIVO as monotherapy is indicated for the treatment of locally advanced unresectable or metastatic urothelial carcinoma in adults after failure of prior platinum-containing therapy.

Mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer (CRC)

OPDIVO in combination with ipilimumab is indicated for the treatment of adult patients with mismatch repair deficient or microsatellite instability-high colorectal cancer in the following settings:
- first-line treatment of unresectable or metastatic colorectal cancer (see sections 4.2 and 5.1);
- treatment of metastatic colorectal cancer after prior fluoropyrimidine-based combination chemotherapy (see sections 4.2 and 5.1).

Oesophageal squamous cell carcinoma (OSCC)

OPDIVO in combination with fluoropyrimidine- and platinum-based combination chemotherapy is indicated for the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma with tumour cell PD-L1 expression ≥ 1%.

OPDIVO as monotherapy is indicated for the treatment of adult patients with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma after prior fluoropyrimidine- and platinum-based combination chemotherapy.

Adjuvant treatment of oesophageal or gastro-oesophageal junction cancer (OC or GEJC)

OPDIVO as monotherapy is indicated for the adjuvant treatment of adult patients with oesophageal or gastro-oesophageal junction cancer who have residual pathologic disease following prior neoadjuvant chemoradiotherapy (see section 5.1).

Gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinoma

OPDIVO in combination with fluoropyrimidine- and platinum-based combination chemotherapy is indicated for the first-line treatment of adult patients with HER2-negative advanced or metastatic gastric, gastro-oesophageal junction or oesophageal adenocarcinoma whose tumours express PD-L1 with a combined positive score (CPS) ≥ 5.

Hepatocellular carcinoma (HCC)

OPDIVO in combination with ipilimumab is indicated for the first-line treatment of adult patients with unresectable or advanced hepatocellular carcinoma.

Treatment must be initiated and supervised by physicians experienced in the treatment of cancer.

PD-L1 testing

If specified in the indication, patient selection for treatment with OPDIVO based on the tumour expression of PD-L1 should be assessed by a CE-marked in vitro IVD medical device test. If the CE- marked IVD is not available, an alternative validated test should be used (see sections 4.1, 4.4, and 5.1).

MSI/MMR testing

If specified in the indication, patient selection for treatment with OPDIVO based on MSI-H/dMMR tumour status should be assessed by a CE-marked IVD with the corresponding intended purpose. If the CE-marked IVD is not available, an alternative validated test should be used (see sections 4.1, 4.4, and 5.1).

Posology

OPDIVO as monotherapy
The recommended dose of OPDIVO is either nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks depending on the indication and population (see sections 5.1 and 5.2), as presented in Table 1.

Table 1:
Recommended dose and infusion time for intravenous administration of nivolumab monotherapy Indication* Recommended dose and infusion time Melanoma (advanced or adjuvant** treatment)

Adults and adolescents (12 years of age and older and weighing at least 50 kg):
240 mg every 2 weeks over 30 minutes or
480 mg every 4 weeks over 60 minutes or over 30 minutes
(adjuvant melanoma, see section 5.1)
Adolescents (12 years of age and older and weighing less than
50 kg):
3 mg/kg every 2 weeks over 30 minutes or
6 mg/kg every 4 weeks over 60 minutes
Renal cell carcinoma
Muscle invasive urothelial carcinoma (MIUC) (adjuvant** treatment)
240 mg every 2 weeks over 30 minutes or
480 mg every 4 weeks over 60 minutes
Oesophageal or gastro-oesophageal junction cancer (adjuvant** treatment)
240 mg every 2 weeks over 30 minutes or
480 mg every 4 weeks over 30 minutes for the first 16 weeks, followed by 480 mg every 4 weeks over 30 minutes Non-small cell lung cancer Relapsed or refractory classical Hodgkin lymphoma Squamous cell cancer of the head and neck Urothelial carcinoma Oesophageal squamous cell carcinoma 240 mg every 2 weeks over 30 minutes *As per monotherapy indication in section 4.1.
**For adjuvant therapy, the maximum treatment duration with OPDIVO is 12 months.

If melanoma, RCC, OC, GEJC or MIUC (adjuvant treatment) patients need to be switched from the 240 mg every 2 weeks schedule to the 480 mg every 4 weeks schedule, the first 480 mg dose should be administered two weeks after the last 240 mg dose. Conversely, if patients need to be switched from the 480 mg every 4 weeks schedule to the 240 mg every 2 weeks schedule, the first 240 mg dose should be administered four weeks after the last 480 mg dose.

OPDIVO in combination with ipilimumab

Melanoma

Table 2:
Recommended doses and infusion times for intravenous administration of nivolumab in combination with ipilimumab followed by nivolumab monotherapy for melanoma (see sections 5.1 and 5.2)

Combination phase, for
4 dosing cycles
Monotherapy phase
Nivolumab
Adults and adolescents
12 years of age and older:
(regardless of weight)
1 mg/kg every 3 weeks over
30 minutes
Adults and adolescents (12 years of age and older and weighing at least 50 kg):
240 mg every 2 weeks over 30 minutes or
480 mg every 4 weeks over 60 minutes

The first dose should be administered:
- 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 240 mg every 2 weeks; or
- 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 480 mg every 4 weeks

Adolescents (12 years of age and older and weighing less than 50 kg):
3 mg/kg every 2 weeks over 30 minutes or
6 mg/kg every 4 weeks over 60 minutes

The first dose should be administered:
- 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 3 mg/kg every 2 weeks; or
- 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 6 mg/kg every 4 weeks Ipilimumab Adults and adolescents 12 years of age and older (regardless of weight):
3 mg/kg every 3 weeks over
30 minutes

Malignant pleural mesothelioma (MPM)

Table 3:
Recommended doses and infusion times for intravenous administration of nivolumab in combination with ipilimumab for MPM

Combination therapy*
Nivolumab
360 mg every 3 weeks over 30 minutes
Ipilimumab
1 mg/kg every 6 weeks over 30 minutes
*Treatment is continued for up to 24 months in patients without disease progression.

Renal cell carcinoma (RCC)

Table 4:
Recommended doses and infusion times for intravenous administration of nivolumab in combination with ipilimumab followed by nivolumab monotherapy for RCC

Combination phase, for
4 dosing cycles
Monotherapy phase
Nivolumab
3 mg/kg every 3 weeks over
30 minutes
240 mg every 2 weeks over 30 minutes or
480 mg every 4 weeks over 60 minutes

The first dose should be administered:
- 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 240 mg every 2 weeks; or
- 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 480 mg every 4 weeks.
Ipilimumab
1 mg/kg every 3 weeks over
30 minutes

dMMR or MSI-H colorectal cancer (CRC)

Table 5:
Recommended doses and infusion times for intravenous administration of nivolumab in combination with ipilimumab followed by nivolumab monotherapy for dMMR or MSI-H CRC

Combination phase, for up to 4 dosing cycles
Monotherapy phase
Nivolumab
First-line treatment
240 mg every 3 weeks over 30 minutes
240 mg every 2 weeks over 30 minutes or
480 mg every 4 weeks over 30 minutes

The first dose should be administered
3 weeks after the last dose of the combination of nivolumab and ipilimumab.

Treatment with nivolumab is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Treatment after prior fluoropyrimidine-based combination chemotherapy
3 mg/kg every 3 weeks over 30 minutes
240 mg every 2 weeks over 30 minutes

The first dose of nivolumab should be administered 3 weeks after the last dose of the combination of nivolumab and ipilimumab.
Ipilimumab
1 mg/kg every 3 weeks over 30 minutes

Oesophageal squamous cell carcinoma (OSCC)

Table 6:
Recommended doses and infusion times for intravenous administration of nivolumab in combination with ipilimumab for OSCC

Combination therapy*
Nivolumab
3 mg/kg every 2 weeks over 30 minutes or
360 mg every 3 weeks over 30 minutes
Ipilimumab
1 mg/kg every 6 weeks over 30 minutes
*Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Hepatocellular carcinoma (HCC)

Table 7:
Recommended doses and infusion times for intravenous administration of nivolumab in combination with ipilimumab followed by nivolumab monotherapy for HCC (see sections 5.1 and 5.2)

Combination phase, for up to 4 dosing cycles
Monotherapy phase*
Nivolumab
1 mg/kg every 3 weeks over
30 minutes
240 mg every 2 weeks over 30 minutes or
480 mg every 4 weeks over 30 minutes

The first dose should be administered 3 weeks after the last dose of the combination of nivolumab and ipilimumab.
Ipilimumab
3 mg/kg every 3 weeks over
30 minutes
- *Treatment with nivolumab is recommended until disease progression, unacceptable toxicity, or up to 24 months.

OPDIVO in combination with cabozantinib

Renal cell carcinoma (RCC)

Table 8:
Recommended doses and infusion times for intravenous administration of nivolumab in combination with oral administration of cabozantinib for RCC

Combination therapy*
Nivolumab
240 mg every 2 weeks over 30 minutes or
480 mg every 4 weeks over 60 minutes
Cabozantinib
40 mg once daily, orally
*For OPDIVO in combination with cabozantinib, OPDIVO should be continued until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. Cabozantinib should be continued until disease progression or unacceptable toxicity. Refer to the Summary of Product Characteristics (SmPC) for cabozantinib.

OPDIVO in combination with ipilimumab and chemotherapy

Non-small cell lung cancer (NSCLC)

Table 9:
Recommended doses and infusion times for intravenous administration of nivolumab in combination with ipilimumab and platinum-based chemotherapy followed by nivolumab in combination with ipilimumab for NSCLC

Combination phase for
2 cycles of platinum-based chemotherapy
Combination phase of nivolumab plus ipilimumab*
Nivolumab
360 mg every 3 weeks over
30 minutes
360 mg every 3 weeks over 30 minutes

Combination phase for
2 cycles of platinum-based chemotherapy
Combination phase of nivolumab plus ipilimumab*
Ipilimumab
1 mg/kg every 6 weeks over
30 minutes
1 mg/kg every 6 weeks over 30 minutes
Platinum-based chemotherapy
Every 3 weeks
- *Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

OPDIVO in combination with chemotherapy

Neoadjuvant treatment of NSCLC

Table 10:
Recommended doses and infusion times for intravenous administration of nivolumab in combination with platinum-based chemotherapy for neoadjuvant treatment of NSCLC (see section 5.1)

Combination therapy for 3 cycles
Nivolumab
360 mg every 3 weeks over 30 minutes
Platinum-based chemotherapy
Every 3 weeks

Neoadjuvant and adjuvant treatment of NSCLC

Table 11:
Recommended doses and infusion times for intravenous administration of nivolumab in combination with platinum-based chemotherapy for neoadjuvant treatment followed by nivolumab monotherapy for adjuvant treatment of NSCLC

Combination phase
Neoadjuvant phase for 4 cycles
Monotherapy phase*
Adjuvant phase
Nivolumab
360 mg every 3 weeks over 30 minutes
480 mg every 4 weeks over 30 minutes
Platinum-based chemotherapy
Every 3 weeks
- *Treatment is recommended until disease progression or recurrence, unacceptable toxicity, or up to 13 cycles (see section 5.1).

Oesophageal squamous cell carcinoma (OSCC)

Table 12:
Recommended doses and infusion times for intravenous administration of nivolumab in combination with fluoropyrimidine- and platinum-based chemotherapy for OSCC (see section 5.1)*

Combination therapy
Nivolumab
240 mg every 2 weeks over 30 minutes or
480 mg every 4 weeks over 30 minutes
Fluoropyrimidine- and platinum- based chemotherapy
Every 4 weeks
*Treatment with nivolumab is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinoma

Table 13:
Recommended doses and infusion times for intravenous administration of nivolumab in combination with fluoropyrimidine- and platinum-based chemotherapy for gastric, GEJ or oesophageal adenocarcinoma (see section 5.1)*

Combination therapy
Nivolumab
360 mg every 3 weeks over 30 minutes or
240 mg every 2 weeks over 30 minutes
Fluoropyrimidine- and platinum- based chemotherapy
Every 2 weeks or every 3 weeks, depending on the regimen
*Treatment with nivolumab is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial carcinoma (UC)

Table 14:
Recommended doses and infusion times for intravenous administration of nivolumab in combination with cisplatin and gemcitabine followed by nivolumab monotherapy for UC (see section 5.1)

Combination phase, up to
6 cycles
Monotherapy phase*
Nivolumab
360 mg every 3 weeks over
30 minutes
240 mg every 2 weeks over 30 minutes or
480 mg every 4 weeks over 30 minutes
Cisplatin and gemcitabine
Every 3 weeks
- *Treatment with nivolumab is recommended until disease progression, unacceptable toxicity, or up to 24 months from first dose, whichever comes first.

Previously untreated Stage III or IV classical Hodgkin lymphoma (cHL)

Table 15:
Recommended doses and infusion times for intravenous administration of nivolumab in combination with AVD chemotherapy for previously untreated cHL (see section 5.1)

Combination phase for 6 dosing cycles*
Nivolumab
Adults and adolescents (12 years of age and older weighing at least
80 kg)
240 mg every 2 weeks over 30 minutes
Nivolumab
Adolescents (12 years of age and older weighing less than 80 kg)
3 mg/kg every 2 weeks over 30 minutes
Doxorubicin, vinblastine and dacarbazine (AVD)

Every 2 weeks
*One dosing cycle of nivolumab in combination with AVD is 28 days

OPDIVO in combination with brentuximab vedotin

Relapsed or refractory cHL

Table 16:
Recommended doses and infusion times for intravenous administration of nivolumab in combination with brentuximab vedotin for relapsed or refractory cHL

Combination therapy*
Nivolumab
3 mg/kg every 3 weeks over 30 minutes
For Cycle 1 only, nivolumab should be administered on Day 8 of the cycle. For
Cycles 2-6, nivolumab should be administered 30 minutes after completion of brentuximab vedotin administration, on the same day.
Brentuximab
Vedotin
1.8 mg/kg up to a maximum of 180 mg, every 3 weeks over 30 minutes
For Cycles 1-6, brentuximab vedotin should be administered on Day 1 of the Cycle.
*Treatment is risk-based, response-adapted. For information on risk stratification see section 5.1. Patients should have tumour assessment after every 2 cycles and discontinue treatment in case of progressive disease at any point of assessment:
- low risk of relapse: up to 6 cycles of the combination and proceed to consolidation therapy, if achieving complete response
- standard risk of relapse: up to 4 cycles of the combination and proceed to consolidation therapy, if achieving complete response.
In case of sub-optimal response to 4 cycles of the combination treatment, patients should receive intensification therapy prior to proceeding to consolidation therapy once complete response is achieved (see section 5.1).

Duration of treatment
Treatment with OPDIVO, either as a monotherapy or in combination with ipilimumab or other therapeutic agents, should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient (and up to maximum duration of therapy if specified for an indication).

Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. It is recommended to continue treatment with nivolumab or nivolumab in combination with ipilimumab for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.

Dose escalation or reduction is not recommended for OPDIVO as monotherapy or in combination with other therapeutic agents. Dosing delay or discontinuation may be required based on individual safety and tolerability. Guidelines for permanent discontinuation or withholding of doses are described in Table 17. Detailed guidelines for the management of immune-related adverse reactions are described in section 4.4. When nivolumab is administered in combination with other therapeutic agents, refer to the SmPC of these other combination therapeutic agents regarding dosing.

Table 17:
Recommended treatment modifications for OPDIVO or OPDIVO in combination
Immune-related adverse reaction
Severity
Treatment modification
Immune-related pneumonitis
Grade 2 pneumonitis
Withhold dose(s) until symptoms resolve, radiographic abnormalities improve, and management with corticosteroids is complete

Grade 3 or 4 pneumonitis
Permanently discontinue treatment

Immune-related adverse reaction
Severity
Treatment modification
Immune-related colitis
Grade 2 diarrhoea or colitis
Withhold dose(s) until symptoms resolve and management with corticosteroids, if needed, is complete

Grade 3 diarrhoea or colitis
- OPDIVO monotherapy

Withhold dose(s) until symptoms resolve and management with corticosteroids is complete

- OPDIVO+ipilimumaba
Permanently discontinue treatment

Grade 4 diarrhoea or colitis
Permanently discontinue treatment
Immune-related hepatitis without HCC

NOTE: for RCC patients treated with OPDIVO in combination with cabozantinib with liver enzyme elevations, see dosing guidelines following this table.
Grade 2 elevation in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin Withhold dose(s) until laboratory values return to baseline and management with corticosteroids, if needed, is complete

Grade 3 or 4 elevation in AST, ALT, or total bilirubin
Permanently discontinue treatment

Immune-related hepatitis with HCC
If AST/ALT is within normal limits at baseline and increases to > 3 and ≤ 10 times ULN or Baseline AST/ALT is > 1 and ≤ 3 times ULN and increases to > 5 and ≤ 10 times ULN or Baseline AST/ALT is > 3 and ≤ 5 times ULN and increases to > 8 and ≤ 10 times ULN.

Withhold dose(s) until laboratory values return to baseline and management with corticosteroids, if needed, is complete AST/ALT increases to > 10 times ULN or Total bilirubin increases to > 3 times ULN Permanently discontinue treatment Immune-related nephritis and renal dysfunction Grade 2 or 3 creatinine elevation Withhold dose(s) until creatinine returns to baseline and management with corticosteroids is complete

Grade 4 creatinine elevation
Permanently discontinue treatment

Immune-related adverse reaction
Severity
Treatment modification
Immune-related endocrinopathies
Symptomatic Grade 2 or 3 hypothyroidism, hyperthyroidism, hypophysitis,
Grade 2 adrenal insufficiency
Grade 3 diabetes
Withhold dose(s) until symptoms resolve and management with corticosteroids (if needed for symptoms of acute inflammation) is complete. Treatment should be continued in the presence of hormone replacement therapyb as long as no symptoms are present Grade 4 hypothyroidism Grade 4 hyperthyroidism Grade 4 hypophysitis Grade 3 or 4 adrenal insufficiency Grade 4 diabetes Permanently discontinue treatment Immune-related skin adverse reactions Grade 3 rash Withhold dose(s) until symptoms resolve and management with corticosteroids is complete

Grade 4 rash
Permanently discontinue treatment

Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN)
Permanently discontinue treatment (see section 4.4)
Immune-related myocarditis
Grade 2 myocarditis
Withhold dose(s) until symptoms resolve and management with corticosteroids is completec

Grade 3 or 4 myocarditis
Permanently discontinue treatment
Other immune-related adverse reactions
Grade 3 (first occurrence)
Withhold dose(s)

Grade 4 or recurrent Grade 3; persistent
Grade 2 or 3 despite treatment modification;
inability to reduce corticosteroid dose to 10 mg prednisone or equivalent per day Permanently discontinue treatment Myocarditis-Myositis- Myasthenia Gravis Overlap Syndromed Grade 2 Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome Withhold dose(s) until symptoms resolve and management with corticosteroids is complete Grade 3 or 4 Myocarditis-Myositis- Myasthenia Gravis Overlap Syndrome Permanently discontinue treatment Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4).
a
During administration of the second phase of treatment (nivolumab monotherapy) following combination treatment, permanently discontinue treatment if Grade 3 diarrhoea or colitis occurs.
b
Recommendation for the use of hormone replacement therapy is provided in section 4.4.
c
The safety of re-initiating nivolumab or nivolumab in combination with ipilimumab therapy in patients previously experiencing immune-related myocarditis is not known.
d
Presenting as an overlap of either two or all three conditions. The most severe CTCAE grade from the individual events should be considered to assess the recommended treatment modification.

OPDIVO as monotherapy or in combination with other therapeutic agents should be permanently discontinued for:
- Grade 4 or recurrent Grade 3 adverse reactions;
- Persistent Grade 2 or 3 adverse reactions despite management.

Patients treated with OPDIVO must be given the patient card and be informed about the risks of OPDIVO (see also package leaflet).

When OPDIVO is administered in combination with ipilimumab, if either agent is withheld, the other agent should also be withheld. If dosing is resumed after a delay, either the combination treatment or OPDIVO monotherapy could be resumed based on the evaluation of the individual patient.

When OPDIVO is administered in combination with chemotherapy, refer to the SmPC of the other combination therapy agents regarding dosing. If any agents are withheld, the other agents may be continued. If dosing is resumed after a delay, either the combination treatment, OPDIVO monotherapy or chemotherapy alone could be resumed based on the evaluation of the individual patient.

OPDIVO in combination with cabozantinib in RCC
When OPDIVO is used in combination with cabozantinib, the above treatment modifications in Table 17 also apply to the OPDIVO component. In addition, for liver enzyme elevations, in patients with RCC being treated with OPDIVO in combination with cabozantinib:
- If ALT or AST > 3 times ULN but ≤ 10 times ULN without concurrent total bilirubin ≥ 2 times ULN, both OPDIVO and cabozantinib should be withheld until these adverse reactions recover to Grades 0-1. Corticosteroid therapy may be considered. Rechallenge with a single medicine or rechallenge with both medicines after recovery may be considered. If rechallenging with cabozantinib, refer to cabozantinib SmPC.
- If ALT or AST > 10 times ULN or > 3 times ULN with concurrent total bilirubin ≥ 2 times ULN, both OPDIVO and cabozantinib should be permanently discontinued and corticosteroid therapy may be considered.

Special populations

Elderly
No dose adjustment is required for elderly patients (≥ 65 years) (see section 5.2).

Renal impairment
Based on the population pharmacokinetic (PK) results, no dose adjustment is required in patients with mild or moderate renal impairment (see section 5.2). Data from patients with severe renal impairment are too limited to draw conclusions on this population.

Hepatic impairment
Based on the population PK results, no dose adjustment is required in patients with mild or moderate hepatic impairment (see section 5.2). Data from patients with severe hepatic impairment are too limited to draw conclusions on this population. OPDIVO must be administered with caution in patients with severe (total bilirubin > 3 × ULN and any AST) hepatic impairment.

Paediatric population

The safety and efficacy of OPDIVO in children below 18 years of age have not been established except in adolescents 12 years of age and older with melanoma or previously untreated cHL, and paediatric patients 5 years of age and older with relapsed or refractory cHL. Currently available data of OPDIVO as monotherapy, in combination with ipilimumab, in combination with brentuximab vedotin or in combination with AVD are described in sections 4.2, 4.8, 5.1 and 5.2.

Method of administration

OPDIVO is for intravenous use only. It is to be administered as an intravenous infusion over a period of 30 or 60 minutes depending on the dose (see Tables 1 to 16). The infusion must be administered through a sterile, non-pyrogenic, low protein binding in-line filter with a pore size of 0.2-1.2 μm.

OPDIVO must not be administered as an intravenous push or bolus injection.

The total dose of OPDIVO required can be infused directly as a 10 mg/mL solution or can be diluted with sodium chloride 9 mg/mL (0.9%) solution for injection or glucose 50 mg/mL (5%) solution for injection (see section 6.6).

When administered in combination with ipilimumab and/or chemotherapy, OPDIVO should be given first followed by ipilimumab (if applicable) and then by chemotherapy on the same day, except for administration in combination with AVD in patients with previously untreated cHL. When administered in combination with AVD, doxorubicin, vinblastine and dacarbazine should be given first, followed by OPDIVO on the same day. When administered in combination with brentuximab vedotin, for Cycle 1, brentuximab vedotin should be given on Day 1 and OPDIVO on Day 8. For Cycle 2-6, OPDIVO should be given at least 30 minutes after the completion of brentuximab vedotin infusion on the same day. Use separate infusion bags and filters for each infusion.

For instructions on the preparation and handling of the medicinal product before administration, see section 6.6.

Treatment must be initiated and supervised by physicians experienced in the treatment of cancer.

Patients currently receiving intravenous nivolumab monotherapy, or in combination with chemotherapy or cabozantinib, may transition to OPDIVO solution for injection.

PD-L1 testing
If specified in the indication, patient selection for treatment with OPDIVO based on the tumour expression of PD-L1 should be assessed by a CE-marked in vitro IVD medical device test. If the CE- marked IVD is not available, an alternative validated test should be used (see sections 4.1, 4.4, and 5.1).

MSI/MMR testing
If specified in the indication, patient selection for treatment with OPDIVO based on MSI-H/dMMR tumour status should be assessed by a CE-marked IVD with the corresponding intended purpose. If the CE-marked IVD is not available, an alternative validated test should be used (see sections 4.1, 4.4, and 5.1).

Posology

OPDIVO as monotherapy
The recommended dose of OPDIVO solution for injection is either nivolumab 600 mg every 2 weeks or 1200 mg every 4 weeks (see section 5.1).

If patients need to be switched from the 600 mg every 2 weeks schedule to the 1200 mg every 4 weeks schedule, the first 1200 mg dose should be administered two weeks after the last 600 mg dose.
Conversely, if patients need to be switched from the 1200 mg every 4 weeks schedule to the 600 mg every 2 weeks schedule, the first 600 mg dose should be administered four weeks after the last 1200 mg dose.

OPDIVO in combination with ipilimumab

Melanoma

Table 1:
Recommended doses and infusion times for OPDIVO solution for infusion in combination with ipilimumab followed by OPDIVO solution for injection monotherapy for melanoma (see section 5.1)

Combination phase
OPDIVO solution for infusion, intravenously
(IV) and ipilimumab, for
4 dosing cycles
Monotherapy phase
OPDIVO solution for injection, subcutaneously (SC)

Nivolumab
1 mg/kg every 3 weeks over
30 minutes
600 mg every 2 weeks or 1200 mg every 4 weeks

The first dose should be administered:
- 3 weeks after the last dose of the combination of IV nivolumab and ipilimumab if using 600 mg every 2 weeks; or
- 6 weeks after the last dose of the combination of IV nivolumab and ipilimumab if using 1200 mg every 4 weeks.
Ipilimumab
3 mg/kg every 3 weeks over
30 minutes

Renal cell carcinoma (RCC)

Table 2:
Recommended doses and infusion times for OPDIVO solution for infusion in combination with ipilimumab followed by OPDIVO solution for injection monotherapy for RCC

Combination phase
OPDIVO solution for infusion, intravenously
(IV) and ipilimumab, for
4 dosing cycles
Monotherapy phase
OPDIVO solution for injection, subcutaneously (SC)
Nivolumab
3 mg/kg every 3 weeks over
30 minutes
600 mg every 2 weeks or 1200 mg every 4 weeks

The first dose should be administered:
- 3 weeks after the last dose of the combination of IV nivolumab and ipilimumab if using 600 mg every 2 weeks; or
- 6 weeks after the last dose of the combination of IV nivolumab and ipilimumab if using 1200 mg every 4 weeks.
Ipilimumab
1 mg/kg every 3 weeks over
30 minutes

dMMR or MSI-H colorectal cancer (CRC)

Table 3:
Recommended doses and infusion times for OPDIVO solution for infusion in combination with ipilimumab followed by OPDIVO solution for injection monotherapy for dMMR or MSI-H CRC

Combination phase,
OPDIVO solution for infusion, intravenously
(IV), and ipilimumab for up to 4 dosing cycles
Monotherapy phase
OPDIVO solution for injection, subcutaneously (SC)
Nivolumab
First-line treatment
240 mg every 3 weeks over 30 minutes
600 mg every 2 weeks or 1200 mg every
4 weeks

The first dose should be administered
3 weeks after the last dose of the combination of IV nivolumab and ipilimumab.

Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Treatment after prior first-line fluoropyrimidine-based combination chemotherapy 3 mg/kg every 3 weeks over 30 minutes 600 mg every 2 weeks or 1200 mg every 4 weeks

The first dose should be administered
3 weeks after the last dose of the combination of IV nivolumab and ipilimumab.
Ipilimumab
1 mg/kg every 3 weeks over 30 minutes

Hepatocellular carcinoma (HCC)

Table 4:
Recommended doses and infusion times for OPDIVO solution for infusion in combination with ipilimumab followed by OPDIVO solution for injection monotherapy for the treatment of HCC (see sections 5.1 and 5.2)

Combination phase
OPDIVO solution for infusion, intravenously
(IV) and ipilimumab for up to 4 dosing cycles
Monotherapy phase*
OPDIVO solution for injection, subcutaneously (SC)
Nivolumab
1 mg/kg every 3 weeks over
30 minutes
600 mg every 2 weeks or 1200 mg every 4 weeks

The first dose should be administered 3 weeks after the last dose of the combination of IV nivolumab and ipilimumab.
Ipilimumab
3 mg/kg every 3 weeks over
30 minutes
- *Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months.

OPDIVO in combination with cabozantinib

Renal cell carcinoma (RCC)

Table 5:
Recommended doses for OPDIVO solution for injection in combination with cabozantinib for the treatment of RCC

Combination therapy*
Nivolumab
600 mg every 2 weeks or 1200 mg of every 4 weeks
Cabozantinib
40 mg every day, orally
*For OPDIVO in combination with cabozantinib, OPDIVO should be continued until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. Cabozantinib should be continued until disease progression or unacceptable toxicity. Refer to the Summary of Product Characteristics (SmPC) for cabozantinib.

OPDIVO in combination with chemotherapy

Oesophageal squamous cell carcinoma (OSCC)

Table 6:
Recommended doses for administration of OPDIVO solution for injection in combination with fluoropyrimidine- and platinum-based chemotherapy for the treatment of OSCC (see section 5.1)*

Combination therapy
Nivolumab
600 mg every 2 weeks or 1200 mg every 4 weeks
Fluoropyrimidine- and platinum- based chemotherapy
Every 4 weeks
*Treatment with nivolumab is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinoma

Table 7:
Recommended doses for administration of OPDIVO solution for injection in combination with fluoropyrimidine- and platinum-based chemotherapy for the treatment of gastric, GEJ or oesophageal adenocarcinoma (see section 5.1)*

Combination therapy
Nivolumab
600 mg every 2 weeks or 900 mg every 3 weeks
Fluoropyrimidine- and platinum- based chemotherapy
Every 2 weeks or every 3 weeks, depending on the nivolumab regimen
*Treatment with nivolumab is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial carcinoma (UC)

Table 8:
Recommended doses for OPDIVO solution for injection in combination with cisplatin and gemcitabine followed by OPDIVO monotherapy for UC (see section 5.1)

Combination phase for up to 6 dosing cycles
Monotherapy phase*
Nivolumab
900 mg every 3 weeks
600 mg every 2 weeks or 1200 mg every 4 weeks
Cisplatin and gemcitabine
Every 3 weeks
- *Treatment with nivolumab is recommended until disease progression, unacceptable toxicity, or up to 24 months from first dose, whichever comes first.

Neoadjuvant treatment of NSCLC

Table 9:
Recommended doses for OPDIVO solution for injection in combination with platinum-based chemotherapy for neoadjuvant treatment of NSCLC (see section 5.1)

Combination therapy for 3 cycles
Nivolumab
900 mg every 3 weeks
Platinum-based chemotherapy
Every 3 weeks

Neoadjuvant and adjuvant treatment of non-small cell lung cancer (NSCLC)

Table 10
Recommended doses for OPDIVO solution for injection in combination with platinum-based chemotherapy for neoadjuvant treatment followed by OPDIVO monotherapy for adjuvant treatment of NSCLC

Combination phase
(neoadjuvant treatment) for 4 cycles
Monotherapy phase*
(adjuvant treatment)

Nivolumab
900 mg every 3 weeks
1200 mg every 4 weeks
Platinum-based chemotherapy
Every 3 weeks
- *Treatment is recommended until disease progression or recurrence, unacceptable toxicity, or up to 13 cycles (see section 5.1).

Duration of treatment
Treatment with OPDIVO, either as a monotherapy or in combination with other therapeutic agents, should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient (and up to maximum duration of therapy if specified for an indication).

For adjuvant therapy, the maximum treatment duration with OPDIVO is 12 months.

Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. It is recommended to continue treatment with nivolumab or nivolumab in combination with ipilimumab for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.

Dose escalation or reduction is not recommended for OPDIVO as monotherapy or in combination with other therapeutic agents. Dosing delay or discontinuation may be required based on individual safety and tolerability. Guidelines for permanent discontinuation or withholding of doses are described in Table 10. Detailed guidelines for the management of immune-related adverse reactions are described in section 4.4. When nivolumab is administered in combination with other therapeutic agents, refer to the SmPC of these other combination therapeutic agents regarding dosing.

Table 11:
Recommended treatment modifications for OPDIVO or OPDIVO in combination
Immune-related adverse reaction
Severity
Treatment modification
Immune-related pneumonitis
Grade 2 pneumonitis
Withhold dose(s) until symptoms resolve, radiographic abnormalities improve, and management with corticosteroids is complete

Grade 3 or 4 pneumonitis
Permanently discontinue treatment

Immune-related adverse reaction
Severity
Treatment modification
Immune-related colitis
Grade 2 diarrhoea or colitis
Withhold dose(s) until symptoms resolve and management with corticosteroids, if needed, is complete

Grade 3 diarrhoea or colitis
OPDIVO monotherapy

Withhold dose(s) until symptoms resolve and management with corticosteroids is complete

OPDIVO+ipilimumaba
Permanently discontinue treatment

Grade 4 diarrhoea or colitis
Permanently discontinue treatment
Immune-related hepatitis

NOTE: for RCC patients treated with OPDIVO in combination with cabozantinib with liver enzyme elevations, see dosing guidelines following this table.
Grade 2 elevation in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin Withhold dose(s) until laboratory values return to baseline and management with corticosteroids, if needed, is complete

Grade 3 or 4 elevation in AST, ALT, or total bilirubin
Permanently discontinue treatment

Immune-related nephritis and renal dysfunction
Grade 2 or 3 creatinine elevation
Withhold dose(s) until creatinine returns to baseline and management with corticosteroids is complete

Grade 4 creatinine elevation
Permanently discontinue treatment
Immune-related endocrinopathies
Symptomatic Grade 2 or 3 hypothyroidism, hyperthyroidism, hypophysitis,
Grade 2 adrenal insufficiency
Grade 3 diabetes
Withhold dose(s) until symptoms resolve and management with corticosteroids (if needed for symptoms of acute inflammation) is complete.
Treatment should be continued in the presence of hormone replacement therapyb as long as no symptoms are present Grade 4 hypothyroidism Grade 4 hyperthyroidism Grade 4 hypophysitis Grade 3 or 4 adrenal insufficiency Grade 4 diabetes Permanently discontinue treatment Immune-related skin adverse reactions Grade 3 rash Withhold dose(s) until symptoms resolve and management with corticosteroids is complete

Grade 4 rash
Permanently discontinue treatment

Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN)
Permanently discontinue treatment (see section 4.4)
Immune-related myocarditis
Grade 2 myocarditis
Withhold dose(s) until symptoms resolve and management with corticosteroids is completec

Grade 3 or 4 myocarditis
Permanently discontinue treatment

Immune-related adverse reaction
Severity
Treatment modification
Other immune-related adverse reactions
Grade 3 (first occurrence)
Withhold dose(s)

Grade 4 or recurrent Grade 3; persistent
Grade 2 or 3 despite treatment modification; inability to reduce corticosteroid dose to 10 mg prednisone or equivalent per day Permanently discontinue treatment Myocarditis-Myositis- Myasthenia Gravis Overlap Syndromed Grade 2 Myocarditis-Myositis- Myasthenia Gravis Overlap Syndrome Withhold dose(s) until symptoms resolve and management with corticosteroids is complete Grade 3 or 4 Myocarditis-Myositis- Myasthenia Gravis Overlap Syndrome Permanently discontinue treatment Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4).
a
During administration of the second phase of treatment (nivolumab monotherapy) following combination treatment, permanently discontinue treatment if Grade 3 diarrhoea or colitis occurs.
b
Recommendation for the use of hormone replacement therapy is provided in section 4.4.
c
The safety of re-initiating nivolumab or nivolumab in combination with ipilimumab therapy in patients previously experiencing immune-related myocarditis is not known.
d
Presenting as an overlap of either two or all three conditions. The most severe CTCAE grade from the individual events should be considered to assess the recommended treatment modification.

OPDIVO as monotherapy or in combination with other therapeutic agents should be permanently discontinued for:
- Grade 4 or recurrent Grade 3 adverse reactions;
- Persistent Grade 2 or 3 adverse reactions despite management.

Patients treated with OPDIVO must be given the patient card and be informed about the risks of OPDIVO (see also package leaflet).

When OPDIVO is administered intravenously in combination with ipilimumab, if either agent is withheld, the other agent should also be withheld. If dosing is resumed after a delay, either the intravenous combination treatment or OPDIVO monotherapy administered intravenously or subcutaneously could be resumed based on the evaluation of the individual patient.

When OPDIVO is administered in combination with chemotherapy, refer to the SmPC of the other combination therapy agents regarding dosing. If any agents are withheld, the other agents may be continued. If dosing is resumed after a delay, either the combination treatment, OPDIVO monotherapy or chemotherapy alone could be resumed based on the evaluation of the individual patient.

OPDIVO in combination with cabozantinib in RCC
When OPDIVO is used in combination with cabozantinib, the above treatment modifications in Table 10 also apply to the OPDIVO component. In addition, for liver enzyme elevations, in patients with RCC being treated with OPDIVO in combination with cabozantinib:
- If ALT or AST > 3 times ULN but ≤ 10 times ULN without concurrent total bilirubin ≥ 2 times ULN, both OPDIVO and cabozantinib should be withheld until these adverse reactions recover to Grades 0-1. Corticosteroid therapy may be considered. Rechallenge with a single medicine or rechallenge with both medicines after recovery may be considered. If rechallenging with cabozantinib, refer to cabozantinib SmPC.
- If ALT or AST > 10 times ULN or > 3 times ULN with concurrent total bilirubin ≥ 2 times ULN, both OPDIVO and cabozantinib should be permanently discontinued and corticosteroid therapy may be considered.

Special populations

Elderly
No dose adjustment is required for elderly patients (≥ 65 years).

Renal impairment
Based on the population pharmacokinetic (PK) results for intravenous nivolumab, no dose adjustment is required in patients with mild or moderate renal impairment (see section 5.2). Data from patients with severe renal impairment are too limited to draw conclusions on this population.

Hepatic impairment
Based on the population PK results for intravenous nivolumab, no dose adjustment is required in patients with mild or moderate hepatic impairment (see section 5.2). Data from patients with severe hepatic impairment are too limited to draw conclusions on this populations. OPDIVO must be administered with caution in patients with severe (total bilirubin > 3 × ULN and any AST) hepatic impairment.

Paediatric population

The safety and efficacy of OPDIVO solution for injection in children below 18 years of age have not been established.

Method of administration

OPDIVO solution for injection is for subcutaneous use.
It is important to check the vial labels to ensure that the appropriate formulation (intravenous or subcutaneous formulation) and dose is being administered to the patient as prescribed.

OPDIVO solution for injection is not intended for intravenous administration and must be given by subcutaneous injection only using the doses specified. More than one vial of OPDIVO solution for injection may be needed to give the total dose for the patient. For instructions on use and handling of the OPDIVO solution for injection before administration, see section 6.6.

Administer the full contents of the syringe of OPDIVO solution for injection into the subcutaneous tissue of the abdomen or thigh over a period of 3 to 5 minutes. The dose should not be split between two syringes or between two sites of administration. Alternate injection sites for successive injections.
Do not inject into areas where the skin is tender, red, or bruised, or areas where there are scars or moles. If the administration of OPDIVO solution for injection is interrupted, it can be resumed at the same site, or at an alternate site.

During the treatment course with OPDIVO solution for injection, other medicinal products for subcutaneous administration should preferably be injected at different sites.

OPDIVO solution for infusion (intravenous formulation)
The Summary of Product Characteristics (SmPC) of OPDIVO concentrate for solution for infusion should be referred to for information on dosing instructions and method of administration.

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

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 hypothyroidism, hyperthyroidism, thyroiditis Uncommon adrenal insufficiencyj, hypopituitarism, hypophysitis, diabetes mellitus Rare diabetic ketoacidosis, hypoparathyroidism

Nivolumab monotherapy
Metabolism and nutrition disorders
Very common decreased appetite, hyperglycaemiab
Common dehydration, weight decreased, hypoglycaemiab
Uncommon metabolic acidosis
Not known tumour lysis syndromeg
Nervous system disorders
Very common headache
Common peripheral neuropathy, dizziness
Uncommon polyneuropathy, autoimmune neuropathy (including facial and abducens nerve paresis), Myocarditis-Myositis-Myasthenia Gravis Overlap Syndromem Rare Guillain-Barré syndrome, demyelination, myasthenic syndrome, encephalitisa,k, optic neuritis Not known myelitis (including transverse myelitis) Eye disorders Common blurred vision, dry eye Uncommon uveitis Not known Vogt-Koyanagi-Harada syndromef Cardiac disorders Common tachycardia, atrial fibrillation Uncommon myocarditisa, pericardial disordersh, arrhythmia (including ventricular arrhythmia) Vascular disorders Common hypertension Rare vasculitis Respiratory, thoracic and mediastinal disorders Very common dyspnoeaa, cough Common pneumonitisa, pleural effusion Uncommon lung infiltration Gastrointestinal disorders Very common diarrhoea, vomiting, nausea, abdominal pain, constipation Common colitisa, stomatitis, dry mouth Uncommon pancreatitis, gastritis Rare duodenal ulcer, pancreatic exocrine insufficiency, coeliac disease Hepatobiliary disorders Uncommon hepatitis, cholestasis Skin and subcutaneous tissue disorders Very common rashc, pruritus Common vitiligo, dry skin, erythema, alopecia Uncommon psoriasis, rosacea, erythema multiforme, urticaria Rare toxic epidermal necrolysisa, d, Stevens-Johnson syndromea Not known lichen sclerosusg, other lichen disorders Musculoskeletal and connective tissue disorders Very common musculoskeletal paine, arthralgia Common arthritis Uncommon polymyalgia rheumatica Rare Sjögren's syndrome, myopathy, myositis (including polymyositis)a, rhabdomyolysisa,d

Nivolumab monotherapy
Renal and urinary disorders
Common renal failure (including acute kidney injury)a
Rare tubulointerstitial nephritis, cystitis noninfective
General disorders and administration site conditions
Very common fatigue, pyrexia
Common pain, chest pain, oedemal
Investigationsb
Very common increased AST, hyponatraemia, hypoalbuminaemia, increased alkaline phosphatase, increased creatinine, increased ALT, increased lipase, hyperkalaemia, increased amylase, hypocalcaemia, hypomagnesaemia, hypokalaemia, hypercalcaemia Common increased total bilirubin, hypernatraemia, hypermagnesaemia Adverse reaction frequencies presented in Table 18 may not be fully attributable to nivolumab alone but may contain contributions from the underlying disease.
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 programme-wide exposure.
e
Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, myalgia intercostal, neck pain, pain in extremity, and spinal pain.
f
Post-marketing event (also see section 4.4).
g
Reported in clinical studies and in the post-marketing setting.
h
Pericardial disorders is a composite term which includes pericarditis, pericardial effusion, cardiac tamponade, and Dressler’s syndrome.
i
Anaemia is a composite term which includes, among other causes, haemolytic anaemia and autoimmune anaemia, haemoglobin decreased, iron deficiency anaemia and red blood cell count decreased.
j
Includes adrenal insufficiency, adrenocortical insufficiency acute, and secondary adrenocortical insufficiency.
k
Includes encephalitis and limbic encephalitis.
l
Oedema is a composite term which includes generalised oedema, oedema peripheral, peripheral swelling and swelling.
m
Cases of Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome (presenting as an overlap of either two or all three conditions), some with fatal outcome, have been reported with nivolumab and nivolumab in combination with other therapeutic agents (see section 4.4).

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

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

Nivolumab in combination with ipilimumab (with or without chemotherapy)
In the pooled dataset of nivolumab administered in combination with ipilimumab (with or without chemotherapy) across tumour types (n = 2626) with minimum follow-up ranging from 6 to 47 months, the most frequent adverse reactions (≥ 10%) were fatigue (47%), diarrhoea (35%), rash (37%), nausea (27%), pruritus (29%), musculoskeletal pain (26%), pyrexia (23%), decreased appetite (22%), cough (21%), abdominal pain (18%), vomiting (18%), constipation (18%), arthralgia (18%), dyspnoea (17%), hypothyroidism (16%), headache (15%), upper respiratory tract infection (13%), oedema (13%), and dizziness (10%). The incidence of Grade 3-5 adverse reactions was 66% for nivolumab in combination with ipilimumab (with or without chemotherapy), with 1.0% fatal adverse reactions attributed to study drug. Among patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg for melanoma, 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 for NSCLC, anaemia (32%) and neutropenia (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 = 1800), with a minimum follow-up ranging from 7.4 to 23.6 months, or following 3 cycles of treatment for resectable NSCLC, the most frequent adverse reactions (≥ 10%) were nausea (48%), fatigue (40%), peripheral neuropathy (33%), decreased appetite (31%), constipation (31%), diarrhoea (28%), vomiting (24%), rash (19%), abdominal pain (18%), stomatitis (18%), musculoskeletal pain (18%), pyrexia (16%), cough (13%), oedema (including peripheral oedema) (12%), and pruritus (11%). Incidences of Grade 3-5 adverse reactions were 69% for nivolumab in combination with chemotherapy, with 1.2% fatal adverse reactions attributed to nivolumab in combination with chemotherapy. Median duration of therapy was 6.14 months (95% CI: 5.78, 6.60) for nivolumab in combination with chemotherapy. For resectable NSCLC, ninety-three percent (93%) of patients received 3 cycles of nivolumab in combination with chemotherapy.

Nivolumab in combination with AVD chemotherapy
In the dataset for nivolumab 240 mg or 3 mg/kg every 2 weeks in combination with AVD chemotherapy as first line treatment of cHL (n = 490) with a minimum follow-up of 30.4 months, the most frequent adverse reactions (≥ 10%) were nausea (70.4%), neutropenia (61%), fatigue (59.0%), anaemia (52%), constipation (49.2%), leucopenia (45.1%), musculoskeletal pain (42.7%), transaminase increased (41.2%), peripheral neuropathy (41%), vomiting (33.5%), stomatitis (30.6%), hyperglycaemia (29.8%), diarrhoea (27.6%), lymphopenia (25.9%), cough (25.7%), rash (24.7%), headache (23.9%), alopecia (22.7%), abdominal pain (21.8%), dyspnoea (21.6%), pyrexia (21.6%), dyspepsia (20.4%), hypoalbuminaemia (18%), blood alkaline phosphatase increased (17.6%), pruritus (17.6%), hypertension (16.3%), decreased appetite (16.3%), pain (15.7%), hypocalcaemia (13.3%), thrombocytopenia (12%), hyponatraemia (12%), dizziness (12%), hypokalaemia (11%), tachycardia (10.8%), chest pain (10.8%), and dysgeusia (10%). The incidence of Grade 3-5 adverse reactions was 71.2%, with 0.6% fatal adverse reactions attributed to nivolumab in combination with AVD.

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.

Nivolumab in combination with brentuximab vedotin
In the dataset of nivolumab 3 mg/kg every 3 weeks in combination with brentuximab vedotin 1.8 mg/kg every 3 weeks in all treated patients with relapse or refractory cHL (n = 72), with a minimum follow-up of 40.7 months, the most frequent adverse reactions (≥ 10%) were nausea (50.0%), rash (29.2%), pyrexia (26.4%), headache (25.0%), diarrhoea (25.0%), musculoskeletal pain (25.0%), abdominal pain (22.2%), hypersensitivity (20.8%), infusion related reaction (18.1%), vomiting (18.1%), fatigue (18.1%), transaminases increased (13.9%), and constipation (11.1%). The incidence of Grade 3-5 adverse reactions was 36.1%. No fatal drug related adverse reactions were reported.

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 = 2626), nivolumab in combination with

chemotherapy (n = 1800), and nivolumab in combination with cabozantinib (n = 320) are presented in Table 19. 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 19:
Adverse reactions with nivolumab in combination with other therapeutic agents

Combination with ipilimumab (with or without chemotherapy)
Combination with chemotherapy
Combination with cabozantinib
Infections and infestations
Very common upper respiratory tract infection

upper respiratory tract infection
Common pneumonia, bronchitis, conjunctivitis upper respiratory tract infection, pneumoniaa pneumonia Rare aseptic meningitis

Blood and lymphatic system disorders
Very common anaemiab,j, thrombocytopeniab, leucopoeniab, lymphopeniab, neutropeniab neutropeniab, anaemiab,j, leucopoeniab, lymphopeniab, thrombocytopeniab anaemiab, thrombocytopeniab, leucopoeniab, lymphopeniab, neutropeniab Common eosinophilia febrile neutropaeniaa eosinophilia Uncommon febrile neutropaenia eosinophilia

Not known haemophagocytic lymphohistiocytosis

Immune system disorders
Common infusion related reaction
(including cytokine release syndrome), hypersensitivity hypersensitivity, infusion related reaction (including cytokine release syndrome) hypersensitivity (including anaphylactic reaction) Uncommon

infusion related hypersensitivity reaction
Rare sarcoidosis

Not known solid organ transplant rejectiong

Endocrine disorders
Very common hypothyroidism

hypothyroidism, hyperthyroidism
Common hyperthyroidism, thyroiditis, adrenal insufficiency, hypophysitis, hypopituitarism, diabetes mellitus hypothyroidism, hyperthyroidism, diabetes mellitus adrenal insufficiency Uncommon diabetic ketoacidosis adrenal insufficiency, thyroiditis, hypopituitarism, hypophysitis hypophysitis, thyroiditis Rare hypoparathyroidism

Combination with ipilimumab (with or without chemotherapy)
Combination with chemotherapy
Combination with cabozantinib
Metabolism and nutrition disorders
Very common decreased appetite, hyperglycaemiab, hypoglycaemiab decreased appetite, hyperglycaemiab, hypoglycaemiab decreased appetite, hypoglycaemiab, hyperglycaemiab, weight decreased Common dehydration, hypoalbuminaemia, hypophosphataemia, weight decreased hypoalbuminaemia, hypophosphataemia dehydration Uncommon metabolic acidosis

Rare

tumour lysis syndrome

Not known tumour lysis syndromeh

Nervous system disorders
Very common headache peripheral neuropathy dysgeusia, dizziness, headache
Common dizziness, peripheral neuropathy paraesthesia, dizziness, headache peripheral neuropathy Uncommon polyneuropathy, peroneal nerve palsy, autoimmune neuropathy (including facial and abducens nerve paresis), encephalitis, myasthenia gravis, Myocarditis-Myositis- Myasthenia Gravis Overlap Syndromel Guillain-Barré syndrome encephalitis autoimmune, Guillain-Barré syndrome, myasthenic syndrome Rare Guillain-Barré syndrome, neuritis, myelitis (including transverse myelitis), optic neuritis encephalitis, Myocarditis-Myositis- Myasthenia Gravis Overlap Syndromel

Not known

myelitis (including transverse myelitis), optic neuritis
Myocarditis-Myositis-
Myasthenia Gravis Overlap
Syndromel
Ear and labyrinth disorders
Common

tinnitus
Eye disorders
Common blurred vision, dry eye dry eye, blurred vision dry eye, blurred vision
Uncommon uveitis, episcleritis uveitis uveitis
Rare
Vogt-Koyanagi-Harada syndrome

Cardiac disorders
Common tachycardia, atrial fibrillation tachycardia, atrial fibrillation atrial fibrillation, tachycardia Uncommon myocarditisa, arrhythmia (including ventricular arrhythmia)a, bradycardia myocarditis myocarditis Not known pericardial disordersi

Vascular disorders
Very common

hypertension
Common hypertension thrombosisa, k, hypertension, vasculitis thrombosisk

Combination with ipilimumab (with or without chemotherapy)
Combination with chemotherapy
Combination with cabozantinib
Respiratory, thoracic and mediastinal disorders
Very common cough, dyspnoea cough dysphonia, dyspnoea, cough
Common pneumonitisa, pulmonary embolisma, pleural effusion pneumonitisa, dyspnoea pneumonitis, pulmonary embolism, pleural effusion, epistaxis Gastrointestinal disorders Very common diarrhoea, vomiting, nausea, abdominal pain, constipation diarrhoeaa, stomatitis, vomiting, nausea, abdominal pain, constipation diarrhoea, vomiting, nausea, constipation, stomatitis, abdominal pain, dyspepsia Common colitisa, pancreatitis, stomatitis, gastritis, dry mouth colitis, dry mouth colitis, gastritis, oral pain, dry mouth, haemorrhoids Uncommon duodenitis pancreatitis pancreatitis, small intestine perforationa, glossodynia Rare intestinal perforationa, pancreatic exocrine insufficiency, coeliac disease

Not known

pancreatic exocrine insufficiency, coeliac disease pancreatic exocrine insufficiency, coeliac disease Hepatobiliary disorders Common hepatitis

hepatitis
Uncommon

hepatitis

Skin and subcutaneous tissue disorders
Very common rashc, pruritus rashc, pruritus palmar-plantar erythrodysaesthesia syndrome, rashc, pruritus Common alopecia, vitiligo, urticaria, dry skin, erythema palmar-plantar erythrodysaesthesia syndrome, skin hyperpigmentation, alopecia, dry skin, erythema alopecia, dry skin, erythema, hair colour change Uncommon Stevens-Johnson syndrome, erythema multiforme, psoriasis, other lichen disordersd

psoriasis, urticaria
Rare toxic epidermal necrolysisa,e, lichen sclerosus

Not known

lichen sclerosus, other lichen disorders

Combination with ipilimumab (with or without chemotherapy)
Combination with chemotherapy
Combination with cabozantinib
Musculoskeletal and connective tissue disorders
Very common musculoskeletal painf, arthralgia musculoskeletal painf musculoskeletal painf, arthralgia, muscle spasm Common muscle spasms, muscular weakness, arthritis arthralgia, muscular weakness arthritis Uncommon polymyalgia rheumatica, myopathy, myositis (including polymyositis)a

myopathy, osteonecrosis of the jaw, fistula
Rare spondyloarthropathy,
Sjögren's syndrome, rhabdomyolysisa

Renal and urinary disorders
Very common

proteinuria
Common renal failure (including acute kidney injury)a renal failurea renal failure, acute kidney injury Uncommon tubulointerstitial nephritis, nephritis cystitis noninfective, nephritis nephritis Rare cystitis noninfective

cystitis noninfectiveh
General disorders and administration site conditions
Very common fatigue, pyrexia, oedema
(including peripheral oedema) fatigue, pyrexia, oedema
(including peripheral oedema) fatigue, pyrexia, oedema
Common chest pain, pain, chills malaise pain, chest pain
Investigations
Very common increased alkaline phosphataseb, increased
ASTb, increased ALTb, increased total bilirubinb, increased creatinineb, increased amylaseb, increased lipaseb, hyponatraemiab, hyperkalaemiab, hypokalaemiab, hypercalcaemiab, hypocalcaemiab, hypomagnesaemiab hypocalcaemiab, increased AST b, increased ALT b, hyponatraemiab, increased amylaseb, hypomagnesaemiab, increased alkaline phosphataseb, hypokalaemiab, increased creatinineb, increased lipaseb, hyperkalaemiab, increased total bilirubinb increased alkaline phosphataseb, increased ALTb, increased ASTb, increased total bilirubinb, increased creatinineb, increased amylaseb, increased lipaseb, hypokalaemiab, hypomagnesaemiab, hyponatraemiab, hypocalcaemiab, hypercalcaemiab, hypophosphataemiab, hyperkalaemiab, hypermagnesaemiab, hypernatraemiab Common hypernatraemiab, hypermagnesaemiab, increased thyroid stimulating hormone, increased gamma- glutamyltransferase hypernatraemiab, hypercalcaemiab, hypermagnesaemiab blood cholesterol increased, hypertriglyceridaemia Adverse reaction frequencies presented in Table 19 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
Lichen disorders is a composite term which includes lichen keratosis and lichen planus.
e
Reported also in studies outside the pooled dataset. The frequency is based on the programme-wide exposure.
f
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.
g
Post-marketing event (also see section 4.4).
h
Reported in clinical studies and in the post-marketing setting.
i
Pericardial disorders is a composite term which includes pericarditis, pericardial effusion, cardiac tamponade, and Dressler’s syndrome.
j
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.
k
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.
l
Cases of Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome (presenting as an overlap of either two or all three conditions), some with fatal outcome, have been reported with nivolumab and nivolumab in combination with other therapeutic agents (see section 4.4).

Adverse reactions reported for patients treated with nivolumab in combination with brentuximab vedotin (n = 72) and nivolumab in combination with AVD (n = 490) are presented in Table 20. 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).

Table 20:
Adverse reactions with nivolumab in combination with other therapeutic agents

Combination with brentuximab vedotin
Combination with AVD
Infections and infestations
Very common upper respiratory tract infection

Common

upper respiratory tract infection, pneumonia
Blood and lymphatic system disorders
Very common

neutropeniaa, anaemia, leucopeniab, lymphopeniac, thrombocytopenia
Common neutropenia, anaemia, lymphopenia, febrile neutropenia, leucopenia, thrombocytopenia febrile neutropenia, eosinophilia Immune system disorders Very common hypersensitivityd, infusion related reaction

Common

infusion related reaction, hypersensitivityd
Uncommon

sarcoidosis
Endocrine disorders
Common hyperthyroidism, hypothyroidism hypothyroidism, hyperthyroidism
Uncommon

thyroiditis, adrenal insufficiency, hypoparathyroidism
Metabolism and nutrition disorders
Very common decreased appetite, hyperglycaemia, hypokalaemia, hypernatraemia hyperglycaemia, hypoalbuminaemia, decreased appetite, hypocalcaemia, hyponatraemia, hypokalaemia Common

hypoglycaemia, dehydration, hypophosphataemia, hyperkalaemia, hypercalcaemia, hypomagnesaemia, hypernatraemia, hypermagnesaemia Uncommon

tumour lysis syndrome, diabetes mellitus

Combination with brentuximab vedotin
Combination with AVD
Nervous system disorders
Very common headache peripheral neuropathy, headache, dizziness, dysgeusia
Common peripheral neuropathy, dizziness

Uncommon

encephalitis
Cardiac disorders
Very common

tachycardia
Common

pericardial effusion
Uncommon

atrial fibrillation, pericarditis
Eye disorders
Common

blurred vision, dry eye
Uncommon

uveitis
Vascular disorders
Very common

hypertension
Common thrombosis thrombosis
Respiratory, thoracic and mediastinal disorders
Very common cough cough, dyspnoea
Common pneumonitis, dyspnoea pneumonitis, pleural effusion
Gastrointestinal disorders
Very common diarrhoea, vomiting, nausea, abdominal pain, constipation nausea, constipation, vomiting, stomatitis, diarrhoea, abdominal pain, dyspepsia Common stomatitis dry mouth, gastritis, colitis Uncommon

pancreatitis
Hepatobiliary disorders
Uncommon

immune-mediated hepatitis
Skin and subcutaneous tissue disorders
Very common rashe rashe, alopecia, pruritus
Common alopecia, pruritus, dry skin, erythema, urticaria dry skin, skin hyperpigmentation Uncommon

palmar-plantar erythrodysaesthesia syndrome
Musculoskeletal and connective tissue disorders
Very common musculoskeletal painf musculoskeletal painf
Common

muscular spasms, muscular weakness
Uncommon

arthritis, myositis
Renal and urinary disorders
Common renal failure

Uncommon

renal failure
General disorders and administration site conditions
Very common pyrexia, fatigue fatigue, pyrexia, pain, chest pain
Common oedema oedema, chills

Combination with brentuximab vedotin
Combination with AVD
Investigations
Very common transaminases increasedg transaminases increasedg, blood alkaline phosphatase increased Common increased total bilirubin, increased amylase, increased lipase increased blood creatinine, weight decreased, increased blood bilirubin Uncommon

increased gamma-glutamyltransferase, increased lipase, increased amylase
Adverse reaction frequencies presented in Table 20 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
Neutropenia includes neutropenia and neutrophil count decreased.
b
Leucopenia includes leucopenia and white blood cell count decreased.
c
Lymphopenia includes lymphopenia and lymphocyte count decreased.
d
Hypersensitivity is a composite term which includes anaphylactic reaction.
e
Rash is a composite term which includes rash maculopapular, rash erythematous, rash pruritic, rash papular, dermatitis acneiform and dermatitis allergic.
f
Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, myalgia, neck pain, pain in extremity, spinal pain, arthralgia and jaw pain.
g
Transaminases increased is a composite term which includes alanine aminotransferase increased and aspartate aminotransferase increased.

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 21 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 21 presents the percentage of patients who required high-dose corticosteroids (at least 40 mg daily prednisone equivalents) by dosing regimen.
The management guidelines for these adverse reactions are described in section 4.4.

Table 21:
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)

Nivolumab monotherapy
%
Nivolumab in combination with ipilimumab (with or without chemotherapy)
%
Nivolumab in combination with chemotherapy
%
Nivolumab in combination with cabozantinib
%
Immune-related adverse reaction leading to permanent discontinuation
Pneumonitis

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);

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 haemophagocytic lymphohistiocytosis Immune system disorders Common infusion related reaction (including cytokine release syndrome), hypersensitivity (including anaphylactic reaction) Uncommon sarcoidosis Not known solid organ transplant rejectionf Endocrine disorders Common hypothyroidism, hyperthyroidism, thyroiditis Uncommon adrenal insufficiencyj, hypopituitarism, hypophysitis, diabetes mellitus Rare diabetic ketoacidosis, hypoparathyroidism Metabolism and nutrition disorders Very common decreased appetite, hyperglycaemiab Common dehydration, weight decreased, hypoglycaemiab Uncommon metabolic acidosis Not known tumour lysis syndromeg Nervous system disorders Very common headache Common peripheral neuropathy, dizziness Uncommon polyneuropathy, autoimmune neuropathy (including facial and abducens nerve paresis), Myocarditis-Myositis-Myasthenia Gravis Overlap Syndromen Rare Guillain-Barré syndrome, demyelination, myasthenic syndrome, encephalitisa,k, optic neuritis Not known myelitis (including transverse myelitis) Eye disorders Common blurred vision, dry eye Uncommon uveitis Not known Vogt-Koyanagi-Harada syndromef Cardiac disorders Common tachycardia, atrial fibrillation Uncommon myocarditisa, pericardial disordersh, arrhythmia (including ventricular arrhythmia) Vascular disorders Common hypertension Rare vasculitis

Nivolumab monotherapy
Respiratory, thoracic and mediastinal disorders
Very common dyspnoeaa, cough
Common pneumonitisa, pleural effusion
Uncommon lung infiltration
Gastrointestinal disorders
Very common diarrhoea, vomiting, nausea, abdominal pain, constipation
Common colitisa, stomatitis, dry mouth
Uncommon pancreatitis, gastritis
Rare duodenal ulcer, pancreatic exocrine insufficiency, coeliac disease
Hepatobiliary disorders
Uncommon hepatitis, cholestasis
Skin and subcutaneous tissue disorders
Very common rashc, pruritus
Common vitiligo, dry skin, erythema, alopecia
Uncommon psoriasis, rosacea, erythema multiforme, urticaria
Rare toxic epidermal necrolysisa, d, Stevens-Johnson syndromea
Not known lichen sclerosusg, other lichen disorders
Musculoskeletal and connective tissue disorders
Very common musculoskeletal paine, arthralgia
Common arthritis
Uncommon polymyalgia rheumatica
Rare
Sjögren's syndrome, myopathy, myositis (including polymyositis)a, rhabdomyolysisa,d Renal and urinary disorders Common renal failure (including acute kidney injury)a Rare tubulointerstitial nephritis, cystitis noninfective General disorders and administration site conditions Very common fatigue, pyrexia Common pain, chest pain, oedemal, injection site reactionm Investigationsb Very common increased AST, hyponatraemia, hypoalbuminaemia, increased alkaline phosphatase, increased creatinine, increased ALT, increased lipase, hyperkalaemia, increased amylase, hypocalcaemia, hypomagnesaemia, hypokalaemia, hypercalcaemia Common increased total bilirubin, hypernatraemia, hypermagnesaemia Adverse reaction frequencies presented in Table 12 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 programme-wide exposure.
e
Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, myalgia intercostal, neck pain, pain in extremity, and spinal pain.
f
Post-marketing event (also see section 4.4).
g
Reported in clinical studies and in the post-marketing setting.
h
Pericardial disorders is a composite term which includes pericarditis, pericardial effusion, cardiac tamponade, and Dressler’s syndrome.
i
Anaemia is a composite term which includes, among other causes, haemolytic anaemia and autoimmune anaemia, haemoglobin decreased, iron deficiency anaemia and red blood cell count decreased.
j
Includes adrenal insufficiency, adrenocortical insufficiency acute, and secondary adrenocortical insufficiency.
k
Includes encephalitis and limbic encephalitis.

l
Oedema is a composite term which includes generalised oedema, oedema peripheral, peripheral swelling and swelling.
m
Reported in a study outside of the pooled dataset (subcutaneous injection related). The frequency is based on exposure to OPDIVO solution for injection in CA20967T and includes injection site erythema, application site pain, injection site oedema, injection site pain, application site erythema, application site rash, injection site discolouration, injection site inflammation, and injection site pruritus.
n
Cases of Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome (presenting as an overlap of either two or all three conditions), some with fatal outcome, have been reported with nivolumab and nivolumab in combination with other therapeutic agents (see section 4.4).

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

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

Nivolumab in combination with ipilimumab (with or without chemotherapy)
In the pooled dataset of nivolumab administered in combination with ipilimumab (with or without chemotherapy) across tumour types (n = 2626) with minimum follow-up ranging from 6 to 47 months, the most frequent adverse reactions (≥ 10%) were fatigue (47%), diarrhoea (35%), rash (37%), nausea (27%), pruritus (29%), musculoskeletal pain (26%), pyrexia (23%), decreased appetite (22%), cough (21%), abdominal pain (18%), vomiting (18%), constipation (18%), arthralgia (18%), dyspnoea (17%), hypothyroidism (16%), headache (15%), upper respiratory tract infection (13%), oedema (13%), and dizziness (10%). The incidence of Grade 3-5 adverse reactions was 66% for nivolumab in combination with ipilimumab (with or without chemotherapy), with 1.0% fatal adverse reactions attributed to study drug. Among patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg for melanoma, 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 for NSCLC, anaemia (32%) and neutropenia (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 = 1800), with a minimum follow-up ranging from 7.4 to 23.6 months, or following 3 cycles of treatment for resectable NSCLC, the most frequent adverse reactions (≥ 10%) were nausea (48%), fatigue (40%), peripheral neuropathy (33%), decreased appetite (31%), constipation (31%), diarrhoea (28%), vomiting (24%), rash (19%), abdominal pain (18%), stomatitis (18%), musculoskeletal pain (18%), pyrexia (16%), cough (13%), oedema (including peripheral oedema) (12%), and pruritus (11%). Incidences of Grade 3-5 adverse reactions were 69% for nivolumab in combination with chemotherapy, with 1.2% fatal adverse reactions attributed to nivolumab in combination with chemotherapy. Median duration of therapy was 6.14 months (95% CI: 5.78, 6.60) for nivolumab in combination with chemotherapy. For resectable NSCLC, ninety-three percent (93%) of patients received 3 cycles of nivolumab in combination with chemotherapy.

Nivolumab in combination with cabozantinib

In the dataset of nivolumab intravenous formulation 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 = 2626), nivolumab in combination with chemotherapy (n = 1800), and nivolumab in combination with cabozantinib (n = 320) are presented in Table 13. 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 13:
Adverse reactions with nivolumab in combination with other therapeutic agents

Combination with ipilimumab (with or without chemotherapy)
Combination with chemotherapy
Combination with cabozantinib
Infections and infestations
Very common upper respiratory tract infection

upper respiratory tract infection
Common pneumonia, bronchitis, conjunctivitis upper respiratory tract infection, pneumoniaa pneumonia Rare aseptic meningitis

Blood and lymphatic system disorders
Very common anaemiab,j, thrombocytopeniab, leucopoeniab, lymphopeniab, neutropeniab neutropeniab, anaemiab,j, leucopoeniab, lymphopeniab, thrombocytopeniab anaemiab, thrombocytopeniab, leucopoeniab, lymphopeniab, neutropeniab Common eosinophilia febrile neutropaeniaa eosinophilia Uncommon febrile neutropaenia eosinophilia

Not known haemophagocytic lymphohistiocytosis

Immune system disorders
Common infusion related reaction
(including cytokine release syndrome), hypersensitivity hypersensitivity, infusion related reaction (including cytokine release syndrome) hypersensitivity (including anaphylactic reaction) Uncommon

infusion related hypersensitivity reaction
Rare sarcoidosis

Not known solid organ transplant rejectiong

Combination with ipilimumab (with or without chemotherapy)
Combination with chemotherapy
Combination with cabozantinib
Endocrine disorders
Very common hypothyroidism

hypothyroidism, hyperthyroidism
Common hyperthyroidism, thyroiditis, adrenal insufficiency, hypophysitis, hypopituitarism, diabetes mellitus hypothyroidism, hyperthyroidism, diabetes mellitus adrenal insufficiency Uncommon diabetic ketoacidosis adrenal insufficiency, thyroiditis, hypopituitarism, hypophysitis hypophysitis, thyroiditis Rare hypoparathyroidism

Metabolism and nutrition disorders
Very common decreased appetite, hyperglycaemiab, hypoglycaemiab decreased appetite, hyperglycaemiab, hypoglycaemiab decreased appetite, hypoglycaemiab, hyperglycaemiab, weight decreased Common dehydration, hypoalbuminaemia, hypophosphataemia, weight decreased hypoalbuminaemia, hypophosphataemia, dehydration Uncommon metabolic acidosis

Rare

tumour lysis syndrome

Not known tumour lysis syndromeh

Nervous system disorders
Very common headache peripheral neuropathy dysgeusia, dizziness, headache
Common dizziness, peripheral neuropathy paraesthesia, dizziness, headache peripheral neuropathy Uncommon polyneuropathy, peroneal nerve palsy, autoimmune neuropathy (including facial and abducens nerve paresis), encephalitis, myasthenia gravis, Myocarditis-Myositis- Myasthenia Gravis Overlap Syndromel Guillain-Barré syndrome encephalitis autoimmune, Guillain-Barré syndrome, myasthenic syndrome Rare Guillain-Barré syndrome, neuritis, myelitis (including transverse myelitis), optic neuritis encephalitis, Myocarditis-Myositis- Myasthenia Gravis Overlap Syndromel

Not known

myelitis (including transverse myelitis), optic neuritis
Myocarditis-Myositis-
Myasthenia Gravis Overlap
Syndromel
Ear and labyrinth disorders
Common

tinnitus

Combination with ipilimumab (with or without chemotherapy)
Combination with chemotherapy
Combination with cabozantinib
Eye disorders
Common blurred vision, dry eye dry eye, blurred vision dry eye, blurred vision
Uncommon uveitis, episcleritis uveitis uveitis
Rare
Vogt-Koyanagi-Harada syndrome

Cardiac disorders
Common tachycardia, atrial fibrillation tachycardia, atrial fibrillation atrial fibrillation, tachycardia Uncommon myocarditisa, arrhythmia (including ventricular arrhythmia)a, bradycardia myocarditis myocarditis Not known pericardial disordersi

Vascular disorders
Very common

hypertension
Common hypertension thrombosisa, k, hypertension, vasculitis thrombosisk
Respiratory, thoracic and mediastinal disorders
Very common cough, dyspnoea cough dysphonia, dyspnoea, cough
Common pneumonitisa, pulmonary embolisma, pleural effusion pneumonitisa, dyspnoea pneumonitis, pulmonary embolism, pleural effusion, epistaxis Gastrointestinal disorders Very common diarrhoea, vomiting, nausea, abdominal pain, constipation diarrhoeaa, stomatitis, vomiting, nausea, abdominal pain, constipation diarrhoea, vomiting, nausea, constipation, stomatitis, abdominal pain, dyspepsia Common colitisa, pancreatitis, stomatitis, gastritis, dry mouth colitis, dry mouth colitis, gastritis, oral pain, dry mouth, haemorrhoids Uncommon duodenitis pancreatitis pancreatitis, small intestine perforationa, glossodynia Rare intestinal perforationa, pancreatic exocrine insufficiency, coeliac disease

Not known

pancreatic exocrine insufficiency, coeliac disease pancreatic exocrine insufficiency, coeliac disease Hepatobiliary disorders Common hepatitis

hepatitis
Uncommon

hepatitis

Combination with ipilimumab (with or without chemotherapy)
Combination with chemotherapy
Combination with cabozantinib
Skin and subcutaneous tissue disorders
Very common rashc, pruritus rashc, pruritus palmar-plantar erythrodysaesthesia syndrome, rashc, pruritus Common alopecia, vitiligo, urticaria, dry skin, erythema palmar-plantar erythrodysaesthesia syndrome, skin hyperpigmentation, alopecia, dry skin, erythema alopecia, dry skin, erythema, hair colour change Uncommon Stevens-Johnson syndrome, erythema multiforme, psoriasis, other lichen disordersd

psoriasis, urticaria
Rare toxic epidermal necrolysisa,e, lichen sclerosus

Not known

lichen sclerosus, other lichen disorders
Musculoskeletal and connective tissue disorders
Very common musculoskeletal painf, arthralgia musculoskeletal painf musculoskeletal painf, arthralgia, muscle spasm Common muscle spasms, muscular weakness, arthritis arthralgia, muscular weakness arthritis Uncommon polymyalgia rheumatica, myopathy, myositis (including polymyositis)a

myopathy, osteonecrosis of the jaw, fistula
Rare spondyloarthropathy,
Sjögren's syndrome, rhabdomyolysisa

Renal and urinary disorders
Very common

proteinuria
Common renal failure (including acute kidney injury)a renal failurea renal failure, acute kidney injury Uncommon tubulointerstitial nephritis, nephritis cystitis noninfective, nephritis nephritis Rare cystitis noninfective

cystitis noninfectiveh
General disorders and administration site conditions
Very common fatigue, pyrexia, oedema
(including peripheral oedema) fatigue, pyrexia, oedema
(including peripheral oedema) fatigue, pyrexia, oedema
Common chest pain, pain, chills malaise pain, chest pain

Combination with ipilimumab (with or without chemotherapy)
Combination with chemotherapy
Combination with cabozantinib
Investigations
Very common increased alkaline phosphataseb, increased
ASTb, increased ALTb, increased total bilirubinb, increased creatinineb, increased amylaseb, increased lipaseb, hyponatraemiab, hyperkalaemiab, hypokalaemiab, hypercalcaemiab, hypocalcaemiab, hypomagnesaemiab hypocalcaemiab, increased AST b, increased ALT b, hyponatraemiab, increased amylaseb, hypomagnesaemiab, increased alkaline phosphataseb, hypokalaemiab, increased creatinineb, increased lipaseb, hyperkalaemiab, increased total bilirubinb increased alkaline phosphataseb, increased ALTb, increased ASTb, increased total bilirubinb, increased creatinineb, increased amylaseb, increased lipaseb, hypokalaemiab, hypomagnesaemiab, hyponatraemiab, hypocalcaemiab, hypercalcaemiab, hypophosphataemiab, hyperkalaemiab, hypermagnesaemiab, hypernatraemiab Common hypernatraemiab, hypermagnesaemiab, increased thyroid stimulating hormone, increased gamma- glutamyltransferase hypernatraemiab, hypercalcaemiab, hypermagnesaemiab blood cholesterol increased, hypertriglyceridaemia Adverse reaction frequencies presented in Table 13 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
Lichen disorders is a composite term which includes lichen keratosis and lichen planus.
e
Reported also in studies outside the pooled dataset. The frequency is based on the programme-wide exposure.
f
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.
g
Post-marketing event (also see section 4.4).
h
Reported in clinical studies and in the post-marketing setting.
i
Pericardial disorders is a composite term which includes pericarditis, pericardial effusion, cardiac tamponade, and Dressler’s syndrome.
j
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.
k
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.
l
Cases of Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome (presenting as an overlap of either two or all three conditions), some with fatal outcome, have been reported with nivolumab and nivolumab in combination with other therapeutic agents (see section 4.4).

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 14 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 14 presents the percentage of patients who required high-dose corticosteroids (at least 40 mg daily prednisone equivalents) by dosing regimen.
The management guidelines for these adverse reactions are described in section 4.4.

Table 14:
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)

Nivolumab monotherapy
%
Nivolumab in combination with ipilimumab (with or without chemotherapy)
%
Nivolumab in combination with chemotherapy
%
Nivolumab in combination with cabozantinib
%
Immune-related adverse reaction leading to permanent discontinuation
Pneumonitis

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).

Patients should be monitored continuously (at least up to 5 months after the last dose) as an adverse reaction with nivolumab or nivolumab in combination with ipilimumab may occur at any time during or after discontinuation of therapy.

For suspected immune-related adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, nivolumab or nivolumab in combination with ipilimumab should be withheld and corticosteroids administered. If immunosuppression with corticosteroids is used to treat an adverse reaction, a taper of at least 1 month duration should be initiated upon improvement. Rapid tapering may lead to worsening or recurrence of the adverse reaction. Non-corticosteroid immunosuppressive therapy should be added if there is worsening or no improvement despite corticosteroid use.

In patients with pre-existing autoimmune disease (AID), data from observational studies suggest that the risk of immune-mediated adverse reactions following immune-checkpoint inhibitor therapy may be increased as compared with the risk in patients without pre-existing AID. In addition, flares of the underlying AID were frequent, but the majority were mild and manageable.

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

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

Immune-related pneumonitis
Severe pneumonitis or interstitial lung disease, including fatal cases, has been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis such as radiographic changes (e.g., focal ground glass opacities, patchy filtrates), dyspnoea, and hypoxia. Infectious and disease-related aetiologies should be ruled out.

For Grade 3 or 4 pneumonitis, nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 2 to 4 mg/kg/day methylprednisolone equivalents.

For Grade 2 (symptomatic) pneumonitis, nivolumab or nivolumab in combination with ipilimumab should be withheld and corticosteroids initiated at a dose of 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 2 to 4 mg/kg/day methylprednisolone equivalents and nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.

Immune-related colitis
Severe diarrhoea or colitis has been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8). Patients should be monitored for diarrhoea and additional symptoms of colitis, such as abdominal pain and mucus or blood in stool. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-related colitis. Infectious and other aetiologies of diarrhoea should be ruled out, therefore appropriate laboratory tests and additional examinations must be performed. If diagnosis of corticosteroid-refractory immune-related colitis is confirmed, addition of an alternative immunosuppressive agent to the corticosteroid therapy, or replacement of the corticosteroid therapy, should be considered.

For Grade 4 diarrhoea or colitis, nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

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

For Grade 2 diarrhoea or colitis, nivolumab or nivolumab in combination with ipilimumab should be withheld. Persistent diarrhoea or colitis should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper, if needed. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents and nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.

Immune-related hepatitis
Severe hepatitis has been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8). Patients should be monitored for signs and symptoms of hepatitis such as transaminase and total bilirubin elevations. Infectious and disease-related aetiologies should be ruled out.

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

For Grade 2 transaminase or total bilirubin elevation, nivolumab or nivolumab in combination with ipilimumab should be withheld. Persistent elevations in these laboratory values should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper, if needed. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents and nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.

Immune-related nephritis and renal dysfunction
Severe nephritis and renal dysfunction have been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8). Patients should be monitored for signs and symptoms of nephritis or renal dysfunction. Most patients present with asymptomatic increases in serum creatinine. Disease-related aetiologies should be ruled out.

For Grade 4 serum creatinine elevation, nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

For Grade 2 or 3 serum creatinine elevation, nivolumab or nivolumab in combination with ipilimumab should be withheld, and corticosteroids should be initiated at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents, and nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.

Immune-related endocrinopathies
Severe endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency (including secondary adrenocortical insufficiency), hypophysitis (including hypopituitarism), diabetes mellitus, and diabetic ketoacidosis have been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8).

Patients should be monitored for clinical signs and symptoms of endocrinopathies and for hyperglycaemia and changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation). Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate aetiology has been identified, signs or symptoms of endocrinopathies should be considered immune-related.

For symptomatic hypothyroidism, nivolumab or nivolumab in combination with ipilimumab should be withheld, and thyroid hormone replacement should be initiated as needed. For symptomatic hyperthyroidism, nivolumab or nivolumab in combination with ipilimumab should be withheld and antithyroid medication should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the thyroid is suspected. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper, if needed. Monitoring of thyroid function should continue to ensure appropriate hormone replacement is utilised. Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for life-threatening hyperthyroidism or hypothyroidism.

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

For symptomatic Grade 2 or 3 hypophysitis, nivolumab or nivolumab in combination with ipilimumab should be withheld, and hormone replacement should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the pituitary gland is suspected. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper, if needed. Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for life-threatening (Grade 4) hypophysitis. Monitoring of pituitary function and hormone levels should continue to ensure appropriate hormone replacement is utilised.

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

Immune-related skin adverse reactions
Severe rash has been observed with nivolumab in combination with ipilimumab and, less commonly, with nivolumab as monotherapy (see section 4.8). Nivolumab or nivolumab in combination with ipilimumab should be withheld for Grade 3 rash and discontinued for Grade 4 rash. Severe rash should be managed with high-dose corticosteroid at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

Rare cases of SJS and TEN some of them with fatal outcome have been observed. If symptoms or signs of SJS or TEN appear, treatment with nivolumab or nivolumab in combination with ipilimumab should be discontinued and the patient referred to a specialised unit for assessment and treatment. If the patient has developed SJS or TEN with the use of nivolumab or nivolumab in combination with ipilimumab, permanent discontinuation of treatment is recommended (see section 4.2).

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

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

For suspected immune-related adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, nivolumab or nivolumab in combination with ipilimumab should be withheld and corticosteroids administered.
Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper. Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening immune-related adverse reaction.

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

The diagnosis of myocarditis requires a high index of suspicion. Patients with cardiac or cardio-pulmonary symptoms should be assessed for potential myocarditis. If myocarditis is suspected, prompt initiation of a high dose of steroids (prednisone 1 to 2 mg/kg/day or methylprednisolone 1 to 2 mg/kg/day) and prompt cardiology consultation with diagnostic workup according to current clinical guidelines should be initiated. Once a diagnosis of myocarditis is established, nivolumab or nivolumab in combination with ipilimumab should be withheld or permanently discontinued (see section 4.2).

Cases of Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome (presenting as an overlap of either two or all three conditions), some with fatal outcome, have been reported with nivolumab and nivolumab in combination with other therapeutic agents. Early recognition and aggressive management are essential to address associated morbidity and risk of mortality.

For Grade 3 or 4 Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome, nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued (see section 4.2).
Corticosteroids should be initiated as clinically indicated.

For Grade 2 Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome, nivolumab or nivolumab in combination with ipilimumab should be withheld and corticosteroids initiated as clinically indicated (see section 4.2). Upon improvement, resumption of nivolumab may be considered after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be adjusted as clinically indicated, and nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with nivolumab may increase the risk of rejection in solid organ transplant

recipients. The benefit of treatment with nivolumab versus the risk of possible organ rejection should be considered in these patients.

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

Infusion reactions

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

Disease-specific precautions

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

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

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

Adjuvant treatment of melanoma
There are no data on adjuvant treatment in patients with melanoma with the following risk factors (see sections 4.5 and 5.1):
- patients with prior autoimmune disease, and any condition requiring systemic treatment with either corticosteroids (≥ 10 mg daily prednisone or equivalent) or other immunosuppressive medications,
- patients with prior therapy for melanoma (except patients with surgery, adjuvant radiotherapy after neurosurgical resection for lesions of the central nervous system, and prior adjuvant interferon completed ≥ 6 months prior to randomisation),

- patients treated with prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways),
- subjects under the age of 18 years.
In the absence of data, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

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

Treatment of NSCLC after prior chemotherapy
Patients with a baseline performance score ≥ 2, active brain metastases or autoimmune disease, symptomatic interstitial lung disease, and patients who had been receiving systemic immunosuppressants prior to study entry were excluded from the pivotal clinical trials of NSCLC (see sections 4.5 and 5.1). Patients with baseline performance score of 2 were included in study CA209171 (see section 5.1). In the absence of data for patients with autoimmune disease, symptomatic interstitial lung disease, active brain metastases and patients who had been receiving systemic immunosuppressants prior to study entry, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.
Physicians should consider the delayed onset of nivolumab effect before initiating treatment in patients with poorer prognostic features and/or aggressive disease. In non-squamous NSCLC, a higher number of deaths within 3 months was observed in nivolumab compared to docetaxel. Factors associated with early deaths were poorer prognostic factors and/or more aggressive disease combined with low or no tumour PD-L1 expression (see section 5.1).

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

Neoadjuvant and adjuvant treatment of non-small cell lung cancer
Patients with a baseline performance score ≥ 2, Grade 2 or greater peripheral neuropathy, active autoimmune disease, symptomatic interstitial lung disease, medical conditions requiring systemic immunosuppression, unresectable or metastatic disease, who received prior anti-cancer treatment for resectable disease, who had EGFR mutations or known ALK translocations, or who had brain metastasis, were excluded from the pivotal trial in neoadjuvant and adjuvant treatment of NSCLC (see sections 4.5 and 5.1). In the absence of data, nivolumab in combination with chemotherapy should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Malignant pleural mesothelioma
Patients with primitive peritoneal, pericardial, testis, or tunica vaginalis mesothelioma, interstitial lung disease, active autoimmune disease, medical conditions requiring systemic immunosuppression, and brain metastasis (unless surgically resected or treated with stereotaxic radiotherapy and no evolution within 3 months prior to inclusion in the study) were excluded from the pivotal trial in first-line treatment of MPM (see sections 4.5 and 5.1). In the absence of data, nivolumab in combination with

ipilimumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

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

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

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

Classical Hodgkin lymphoma
Nivolumab monotherapy

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

Nivolumab in combination with AVD chemotherapy
Patients with active autoimmune disease requiring systemic treatment in the past 2 years, patients with > Grade 2 peripheral neuropathy, CNS lymphoma, and patients with active interstitial pneumonitis or interstitial lung disease were excluded from the clinical trial of nivolumab in combination with AVD chemotherapy. In the absence of data, nivolumab in combination with AVD chemotherapy should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

When nivolumab is administered in combination with AVD in patients with classical Hodgkin lymphoma, higher frequencies of Grades 3 and 4 neutropenia have been reported. Complete blood counts should be performed prior to each cycle and as clinically indicated. Patients at increased risk for febrile neutropenia, including older adults, should be monitored closely, and prophylaxis with granulocyte colony-stimulating factor (G-CSF) should be considered according to local clinical guidelines.

Nivolumab in combination with brentuximab vedotin
Patients with active autoimmune disease, with nodular lymphocyte predominant HL, and who had prior exposure to anti-PD1, anti-PDL1, anti-PD-L2, anti-CD137 or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways were excluded from the clinical trial of nivolumab in combination with brentuximab vedotin in the treatment of cHL (see section 5.1).

Complications of allogeneic haematopoietic stem cell transplant (HSCT) in classical Hodgkin lymphoma Cases of acute graft-versus-host disease (GVHD) and transplant-related mortality (TRM) have been observed from the follow-up of patients with cHL undergoing allogeneic HSCT after previous

exposure to nivolumab. Careful consideration to the potential benefits of HSCT and the possible increased risk of transplant related complications should be made case-by-case (see section 4.8).

In patients treated with nivolumab after allogeneic HSCT, rapid-onset and severe GVHD, some with fatal outcome, have been reported in the post-marketing setting. Treatment with nivolumab may increase the risk of severe GVHD and death in patients who have had prior allogeneic HSCT, mainly in those with prior history of GVHD. The benefit of treatment with nivolumab versus the possible risk should be considered in these patients (see section 4.8).

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

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

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

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

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

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

In the first-line OSCC trial, a higher number of deaths within 4 months was observed with nivolumab in combination with ipilimumab compared to chemotherapy. Physicians should consider the delayed

onset of effect of nivolumab in combination with ipilimumab before initiating treatment in patients with poorer prognostic features and/or aggressive disease (see section 5.1).

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

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

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

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

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

Hepatocellular carcinoma
Patients who had baseline ECOG performance score ≥ 2, prior liver transplant, Child-Pugh C liver disease, a history of concurrent brain metastases, a history of hepatic encephalopathy (within 12 months of randomisation), clinically significant ascites, infection with HIV, or active co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) or HBV and hepatitis D virus (HDV), active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the clinical study in HCC (see sections 4.5 and 5.1). Limited data are available in HCC patients with Child-Pugh B. In the absence of data, nivolumab in combination with ipilimumab followed by nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

In HCC, a higher number of deaths within 6 months was observed with nivolumab in combination with ipilimumab compared to lenvatinib or sorafenib. A higher risk of death may be associated with poor prognostic features. Physicians should consider this risk before initiating treatment with nivolumab in combination with ipilimumab in patients with poor prognostic features.

Patients on controlled sodium diet
Each mL of this medicinal product contains 0.1 mmol (or 2.5 mg) sodium. This medicinal product contains 10 mg sodium per 4 mL vial, 25 mg sodium per 10 mL vial, 30 mg sodium per 12 mL vial or 60 mg sodium per 24 mL vial, which is equivalent to 0.5%, 1.25%, 1.5% or 3% respectively, of the

WHO recommended maximum daily intake of 2 g sodium for an adult. Sodium intake could vary in case sodium chloride is used for the dilution steps.

OPDIVO contains polysorbate 80 (E433)
This medicinal product contains 0.94 mg of polysorbate 80 in each 4 mL vial; 2.14 mg of polysorbate 80 in each 10 mL vial; 2.6 mg of polysorbate 80 in each 12 mL vial; and 5.0 mg of polysorbate 80 in each 24 mL vial. Polysorbates may cause allergic reactions.

Patient card

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

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 relative to nivolumab monotherapy. Therefore, the guidance below for immune-related adverse reactions applies to the OPDIVO component of the combination, except where specifically noted. Most immune-related adverse reactions improved or resolved with appropriate management, including initiation of corticosteroids and treatment modifications (see section 4.2).

Immune-related adverse reactions affecting more than one body system can occur simultaneously.

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

Patients should be monitored continuously (at least up to 5 months after the last dose) as an adverse reaction with nivolumab or nivolumab in combination with ipilimumab may occur at any time during or after discontinuation of therapy.

For suspected immune-related adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, nivolumab or nivolumab in combination with ipilimumab should be withheld and corticosteroids administered. If immunosuppression with corticosteroids is used to treat an adverse reaction, a taper of at least 1 month duration should be initiated upon improvement. Rapid tapering may lead to worsening or recurrence of the adverse reaction. Non-corticosteroid immunosuppressive therapy should be added if there is worsening or no improvement despite corticosteroid use.

In patients with pre-existing autoimmune disease (AID), data from observational studies suggest that the risk of immune-mediated adverse reactions following immune-checkpoint inhibitor therapy may be increased as compared with the risk in patients without pre-existing AID. In addition, flares of the underlying AID were frequent, but the majority were mild and manageable.

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

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

Immune-related pneumonitis
Severe pneumonitis or interstitial lung disease, including fatal cases, has been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8). Patients

should be monitored for signs and symptoms of pneumonitis such as radiographic changes (e.g., focal ground glass opacities, patchy filtrates), dyspnoea, and hypoxia. Infectious and disease-related aetiologies should be ruled out.

For Grade 3 or 4 pneumonitis, nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 2 to 4 mg/kg/day methylprednisolone equivalents.

For Grade 2 (symptomatic) pneumonitis, nivolumab or nivolumab in combination with ipilimumab should be withheld and corticosteroids initiated at a dose of 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 2 to 4 mg/kg/day methylprednisolone equivalents and nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.

Immune-related colitis
Severe diarrhoea or colitis has been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8). Patients should be monitored for diarrhoea and additional symptoms of colitis, such as abdominal pain and mucus or blood in stool. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-related colitis. Infectious and other aetiologies of diarrhoea should be ruled out, therefore appropriate laboratory tests and additional examinations must be performed. If diagnosis of corticosteroid-refractory immune-related colitis is confirmed addition of an alternative immunosuppressive agent to the corticosteroid therapy, or replacement of the corticosteroid therapy, should be considered.

For Grade 4 diarrhoea or colitis, nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

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

For Grade 2 diarrhoea or colitis, nivolumab or nivolumab in combination with ipilimumab should be withheld. Persistent diarrhoea or colitis should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper, if needed. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents and nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.

Immune-related hepatitis
Severe hepatitis has been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8). Patients should be monitored for signs and symptoms of hepatitis such as transaminase and total bilirubin elevations. Infectious and disease-related aetiologies should be ruled out.

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

For Grade 2 transaminase or total bilirubin elevation, nivolumab or nivolumab in combination with ipilimumab should be withheld. Persistent elevations in these laboratory values should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper, if needed. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents and nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.

Immune-related nephritis and renal dysfunction
Severe nephritis and renal dysfunction have been observed with monotherapy treatment or nivolumab in combination with ipilimumab (see section 4.8). Patients should be monitored for signs and symptoms of nephritis or renal dysfunction. Most patients present with asymptomatic increases in serum creatinine. Disease-related aetiologies should be ruled out.

For Grade 4 serum creatinine elevation, nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

For Grade 2 or 3 serum creatinine elevation, nivolumab or nivolumab in combination with ipilimumab should be withheld, and corticosteroids should be initiated at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents, and nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.

Immune-related endocrinopathies
Severe endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency (including secondary adrenocortical insufficiency), hypophysitis (including hypopituitarism), diabetes mellitus, and diabetic ketoacidosis have been observed with nivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8).

Patients should be monitored for clinical signs and symptoms of endocrinopathies and for hyperglycaemia and changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation). Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate aetiology has been identified, signs or symptoms of endocrinopathies should be considered immune-related.

For symptomatic hypothyroidism, nivolumab or nivolumab in combination with ipilimumab should be withheld, and thyroid hormone replacement should be initiated as needed. For symptomatic hyperthyroidism, nivolumab or nivolumab in combination with ipilimumab should be withheld and antithyroid medication should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the thyroid is suspected. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper, if needed. Monitoring of thyroid function should continue to ensure appropriate hormone replacement is utilised. Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for life-threatening hyperthyroidism or hypothyroidism.

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

For symptomatic Grade 2 or 3 hypophysitis, nivolumab or nivolumab in combination with ipilimumab should be withheld, and hormone replacement should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the pituitary gland is suspected. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper, if needed. Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for life-threatening (Grade 4) hypophysitis. Monitoring of pituitary function and hormone levels should continue to ensure appropriate hormone replacement is utilised.

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

Immune-related skin adverse reactions
Severe rash has been observed with nivolumab in combination with ipilimumab and, less commonly, with nivolumab as monotherapy (see section 4.8). Nivolumab or nivolumab in combination with ipilimumab should be withheld for Grade 3 rash and discontinued for Grade 4 rash. Severe rash should be managed with high-dose corticosteroid at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

Rare cases of SJS and TEN some of them with fatal outcome have been observed. If symptoms or signs of SJS or TEN appear, treatment with nivolumab or nivolumab in combination with ipilimumab should be discontinued and the patient referred to a specialised unit for assessment and treatment. If the patient has developed SJS or TEN with the use of nivolumab or nivolumab in combination with ipilimumab, permanent discontinuation of treatment is recommended (see section 4.2).

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

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

For suspected immune-related adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, nivolumab or nivolumab in combination with ipilimumab should be withheld and corticosteroids administered.
Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after corticosteroid taper. Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening immune-related adverse reaction.

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

The diagnosis of myocarditis requires a high index of suspicion. Patients with cardiac or cardio-pulmonary symptoms should be assessed for potential myocarditis. If myocarditis is suspected, prompt initiation of a high dose of steroids (prednisone 1 to 2 mg/kg/day or methylprednisolone 1 to 2 mg/kg/day) and prompt cardiology consultation with diagnostic workup according to current clinical guidelines should be initiated. Once a diagnosis of myocarditis is established, nivolumab or nivolumab in combination with ipilimumab should be withheld or permanently discontinued (see section 4.2).

Cases of Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome (presenting as an overlap of either two or all three conditions), some with fatal outcome, have been reported with nivolumab and nivolumab in combination with other therapeutic agents. Early recognition and aggressive management are essential to address associated morbidity and risk of mortality.

For Grade 3 or 4 Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome, nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued (see section 4.2).
Corticosteroids should be initiated as clinically indicated.

For Grade 2 Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome, nivolumab or nivolumab in combination with ipilimumab should be withheld and corticosteroids initiated as clinically indicated (see section 4.2). Upon improvement, resumption of nivolumab may be considered after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be adjusted as clinically indicated, and nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued.

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

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

Cases of acute graft-versus-host disease (GVHD) and transplant related mortality (TRM) have been observed from the follow-up of patients with classical Hodgkin lymphoma undergoing allogeneic haematopoietic stem cell transplant (HSCT) after previous exposure to intravenous nivolumab. Careful consideration to the potential benefits of HSCT and the possible increased risk of transplant related complications should be made case-by-case. In patients treated with intravenous nivolumab after allogeneic HSCT, rapid-onset and severe GVHD, some with fatal outcome, have been reported in the post-marketing setting. Treatment with nivolumab may increase the risk of severe GVHD and death in patients who have had prior allogeneic HSCT, mainly in those with prior history of GVHD. The benefit of treatment with nivolumab versus the possible risk should be considered in these patients.

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

Disease-specific precautions

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

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

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

Adjuvant treatment of melanoma
There are no data on adjuvant treatment in patients with melanoma with the following risk factors (see sections 4.5 and 5.1):
- patients with prior autoimmune disease, and any condition requiring systemic treatment with either corticosteroids (≥ 10 mg daily prednisone or equivalent) or other immunosuppressive medications,
- patients with prior therapy for melanoma (except patients with surgery, adjuvant radiotherapy after neurosurgical resection for lesions of the central nervous system, and prior adjuvant interferon completed ≥ 6 months prior to randomisation),
- patients treated with prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways),
- subjects under the age of 18 years.

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

Non-small cell lung cancer (NSCLC)

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

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

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

Neoadjuvant and adjuvant treatment of NSCLC
Patients with a baseline performance score ≥ 2, Grade 2 or greater peripheral neuropathy, active autoimmune disease, symptomatic interstitial lung disease, medical conditions requiring systemic immunosuppression, unresectable or metastatic disease, who received prior anti-cancer treatment for resectable disease, who had EGFR mutations or known ALK translocations, or who had brain metastasis, were excluded from the pivotal trial in neoadjuvant and adjuvant treatment of NSCLC (see sections 4.5 and 5.1). In the absence of data, nivolumab in combination with chemotherapy should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Renal cell carcinoma (RCC)

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

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

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

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

Physicians should consider the delayed onset of nivolumab effect before initiating treatment in patients with poorer prognostic features and/or aggressive disease. In head and neck cancer, a higher number of deaths within 3 months was observed in nivolumab compared to docetaxel. Factors

associated with early deaths were ECOG performance status, fast progressive disease on prior platinum therapy and high tumour burden.

Urothelial carcinoma

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

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

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

Oesophageal squamous cell carcinoma (OSCC)

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

Treatment of OSCC after prior first-line chemotherapy
The majority of clinical data available in oesophageal squamous cell carcinoma are in patients of Asian origin (see section 5.1).

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

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

Adjuvant treatment of oesophageal or gastro-oesophageal junction cancer
Patients with a baseline performance score ≥ 2, who did not receive concurrent chemoradiotherapy (CRT) prior to surgery, with stage IV resectable disease, active autoimmune disease, or medical

conditions requiring systemic immunosuppression were excluded from the clinical study in oesophageal and gastro-oesophageal junction cancer (see sections 4.5 and 5.1). In the absence of data, nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

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

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

Hepatocellular carcinoma (HCC)
Patients who had baseline ECOG performance score ≥ 2, prior liver transplant, Child-Pugh C liver disease, a history of concurrent brain metastases, a history of hepatic encephalopathy (within 12 months of randomisation), clinically significant ascites, infection with HIV, or active co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) or HBV and hepatitis D virus (HDV), active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the clinical study in HCC (see sections 4.5 and 5.1). Limited data are available in HCC patients with Child-Pugh B. In the absence of data, nivolumab in combination with ipilimumab followed by nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

In HCC, a higher number of deaths within 6 months was observed with nivolumab in combination with ipilimumab compared to lenvatinib or sorafenib. A higher risk of death may be associated with poor prognostic features. Physicians should consider this risk before initiating treatment with nivolumab in combination with ipilimumab in patients with poor prognostic features.

OPDIVO contains polysorbate 80 (E433)
This medicinal product contains 1.25 mg of polysorbate 80 in each 2.5 mL vial and 2.5 mg of polysorbate 80 in each 5 mL vial which is equivalent to 5 mg/10 mL. Polysorbates may cause allergic reactions.

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

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

Other forms of interaction

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

Pregnancy

There are no data 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.

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

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

No cases of overdose have been reported in clinical trials. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted immediately.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drug conjugates, PD-1/PDL-1 (Programmed cell death protein 1/ death ligand 1) inhibitors. ATC code:
L01FF01.

Mechanism of action

Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb), which binds to the programmed death-1 (PD-1) receptor and blocks its interaction with PD-L1 and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity that has been shown to be involved in the control of T-cell immune responses. Engagement of PD-1 with the ligands PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be expressed by tumours or other cells in the tumour microenvironment, results in inhibition of T-cell proliferation and cytokine secretion. Nivolumab potentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2 ligands. In syngeneic mouse models, blocking PD-1 activity resulted in decreased tumour growth.

Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition results in improved anti-tumour responses in metastatic melanoma. In murine syngeneic tumour models, dual blockade of PD-1 and CTLA-4 resulted in synergistic anti-tumour activity.

Clinical efficacy and safety

Based on modelling of dose/exposure efficacy and safety relationships, there are no clinically significant differences in efficacy and safety between a nivolumab dose of 240 mg every 2 weeks or 3 mg/kg every 2 weeks. Additionally, based on these relationships, there were no clinically significant differences between a nivolumab dose of 480 mg every 4 weeks or 3 mg/kg every 2 weeks in adjuvant treatment of melanoma, advanced melanoma and advanced RCC.

Melanoma

Adjuvant treatment of melanoma

Randomised phase 3 study of nivolumab vs. placebo (CA20976K)
The safety and efficacy of nivolumab 480 mg monotherapy for the treatment of patients with completely resected melanoma were evaluated in a phase 3, randomised, double-blind study (CA20976K). The study included patients with an ECOG performance status score of 0 or 1 who had Stage IIB or IIC American Joint Committee on Cancer (AJCC), 8th edition, histologically confirmed melanoma that had been completely surgically resected. Enrolment required complete resection of the primary melanoma with negative margins and a negative sentinel lymph node biopsy within 12 weeks prior to randomisation. Patients were enrolled regardless of their tumour PD-L1 status. The study excluded patients with ocular/uveal or mucosal melanoma, active autoimmune disease, any condition requiring systemic treatment with either corticosteroids (≥ 10 mg daily prednisone or equivalent) or other immunosuppressive medications, as well as patients with prior therapy for melanoma except surgery.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drug conjugates, PD-1/PDL-1 (Programmed cell death protein 1/ death ligand 1) inhibitors. ATC code:
L01FF01.

OPDIVO solution for injection contains the active substance nivolumab, which provides the therapeutic effect of this medicinal product, and recombinant human hyaluronidase (rHuPH20), an enzyme used to increase the dispersion and absorption of co-formulated substances when administered subcutaneously.

Mechanism of action

Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb), which binds to the programmed death-1 (PD-1) receptor and blocks its interaction with PD-L1 and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity that has been shown to be involved in the control of T-cell immune responses. Engagement of PD-1 with the ligands PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be expressed by tumours or other cells in the tumour microenvironment, results in inhibition of T-cell proliferation and cytokine secretion. Nivolumab potentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2 ligands. In syngeneic mouse models, blocking PD-1 activity resulted in decreased tumour growth.

Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition results in improved anti-tumour responses in metastatic melanoma. In murine syngeneic tumour models, dual blockade of PD-1 and CTLA-4 resulted in synergistic anti-tumour activity.

Clinical efficacy and safety

Subcutaneous formulation
Results from a simulation-based pharmacokinetic bridging analyses showed that across all solid tumour types evaluated, subcutaneous nivolumab dosing regimens (600 mg every 2 weeks and 1200 mg every 4 weeks) produced exposures that were noninferior (geometric mean ratio > 1) to those for the approved intravenous nivolumab dosing regimens (240 mg every 2 weeks and 480 mg every 4 weeks). Geometric mean exposures were also below those for intravenous nivolumab 10 mg/kg Q2W, a regimen shown to be safe in clinical studies.

The subcutaneous nivolumab clinical safety profile was comparable to intravenous nivolumab.

Melanoma

Adjuvant treatment of melanoma

Intravenous formulation

Randomised phase 3 study of nivolumab vs. placebo (CA20976K)

Nivolumab monotherapy

The pharmacokinetics (PK) of nivolumab is linear in the dose range of 0.1 to 10 mg/kg. The geometric mean clearance (CL), terminal half-life, and average exposure at steady state at 3 mg/kg every 2 weeks of nivolumab were 7.9 mL/h, 25.0 days, and 86.6 μg/mL, respectively, based on a population PK analysis.

Nivolumab CL in cHL patients was approximately 32% lower relative to NSCLC. Nivolumab baseline CL in adjuvant melanoma patients was approximately 40% lower and steady state CL approximately 20% lower relative to advanced melanoma. With available safety data, these decreases in CL were not clinically meaningful.

The metabolic pathway of nivolumab has not been characterised. Nivolumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

Nivolumab in combination with ipilimumab

When nivolumab 1 mg/kg was administered in combination with ipilimumab 3 mg/kg, the CL of nivolumab was increased by 29% and the CL of ipilimumab was increased by 9%, which was not considered clinically relevant. When nivolumab 3 mg/kg was administered in combination with ipilimumab 1 mg/kg, the CL of nivolumab was increased by 1% and the CL of ipilimumab was decreased by 1.5%, which were not considered clinically relevant.

When administered in combination with ipilimumab, the CL of nivolumab increased by 20% in the presence of anti-nivolumab antibodies and the CL of ipilimumab increased by 5.7% in the presence of anti-ipilimumab antibodies. These changes were not considered clinically relevant.

Nivolumab in combination with ipilimumab and chemotherapy

When nivolumab 360 mg every 3 weeks was administered in combination with ipilimumab 1 mg/kg every 6 weeks and with 2 cycles of chemotherapy, the CL of nivolumab decreased approximately 10% and the CL of ipilimumab increased approximately 22%, which were not considered clinically relevant.

Special populations

Nivolumab solution for injection pharmacokinetics (PK) were assessed using a population PK approach. The PK was studied at a dose of 1200 mg administered as multiple doses every 4 weeks.

Nivolumab time-averaged serum concentration over 28 days (Cavgd28) showed non-inferiority of subcutaneous nivolumab (77.4 mcg/mL) to intravenous nivolumab (36.9 mcg/mL), with a geometric mean ratio of 2.098 (90% CI: 2.001, 2.200). Nivolumab minimum serum concentration at steady state Probability of overall survival

(Cminss) showed non-inferiority of subcutaneous nivolumab (122.2 mcg/mL) to intravenous nivolumab (68.9 mcg/mL), with a geometric mean ratio of 1.774 (90% CI: 1.633, 1.927).

Absorption

The mean absorption rate constant (Ka) and bioavailability (F) of nivolumab solution for injection are 0.0123 hr-1 (or 0.295 Day-1) and 78.8%, respectively. Peak concentrations occurred by around 6 days.

Distribution

The geometric mean (CV%) volume of distribution at steady state (Vss) is 6.32 L (21.3%).

Elimination

Nivolumab solution for injection human clearance (CL) decreases over time, with a mean maximal reduction from baseline values (CV%) of 24.6% (15.8%) resulting in a geometric mean (CV%) steady-state clearance (CLss) of 7.18 mL/h (52.3%) in patients with RCC; the decrease in CLss is not considered clinically relevant.

The geometric mean (CV%) elimination half-life (t1/2) is 26.5 days (32.1%).

Special populations

The following factors had no clinically important effect on the bioavailability of nivolumab solution for injection: sex and performance status. The following factors had no clinically important effect on the clearance of nivolumab solution for injection: body weight (35 to 153 kg), sex, eGFR (24 to 124 mL/min/1.73 m2), or performance status.

Renal impairment