4.1. Therapeutic indications

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 (tumours ≥ 4 cm or node positive) non-small cell lung cancer in adults (see section 5.1).

OPDIVO, in combination with platinum-based chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgical resection, is indicated for the treatment of adults with resectable (tumours ≥4 cm or node positive) non-small cell lung cancer and no known EGFR mutations or ALK rearrangements (see section 5.1).

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 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.

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 completely resected 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 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 completely resected 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.

4.2. Posology and method of administration

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 confirmed by a validated test (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 and 5.2)

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 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 priorfluoropyrimidine‑based combination chemotherapy

3 mg/kg every 3 weeks over 30 minutes

600 mg every 2 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 in patients without disease progression.

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 up to 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 11. 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 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

- OPDIVO+ipilimumaba

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

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

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

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.

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 11 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 (subcutaneous formulation)

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.

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. 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.

For instructions on use and handling of the OPDIVO solution for injection before administration, see section 6.6.

OPDIVO solution for infusion (intravenous formulation)

The SmPC of OPDIVO concentrate for solution for infusion should be referred to for information on dosing instructions and method of administration.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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 anticancer agents.

Other immune‑related adverse reactions

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

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

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

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

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

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

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 platinum-based 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 platinum-based chemotherapy as neoadjuvant therapy followed by nivolumab as adjuvant therapy 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, stage IV resectable disease, autoimmune disease, any condition requiring systemic treatment with either corticosteroids ( > 10 mg daily prednisone or equivalent) or other immunosuppressive medications 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 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.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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

lymphopaeniab, anaemiab,i, leucopoeniab, neutropaeniaa,b, thrombocytopaeniab

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)

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, erythema multiforme, urticaria

Rare

rosacea, 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

Sjogren'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 program-wide exposure.

e Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, myalgia intercostal, neck pain, pain in extremity, and spinal pain.

f Post-marketing event (also see section 4.4).

g Reported in clinical studies and in the post-marketing setting.

h Pericardial disorders is a composite term which includes pericarditis, pericardial effusion, cardiac tamponade, and Dressler's syndrome.

i Anaemia is a composite term which includes, among other causes, haemolytic anaemia and autoimmune anaemia, haemoglobin decreased, iron deficiency anaemia and red blood cell count decreased.

j Includes adrenal insufficiency, adrenocortical insufficiency acute, and secondary adrenocortical insufficiency.

k Includes encephalitis and limbic encephalitis.

l Oedema is a composite term which includes generalised oedema, oedema peripheral, peripheral swelling and swelling.

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.

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 1.00% 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 neutropaenia (15%) were reported at an incidence rate ≥ 10% higher than the rates reported in the pooled dataset of nivolumab in combination with ipilimumab (with or without chemotherapy) incidence rate.

Nivolumab in combination with chemotherapy

In the pooled dataset of nivolumab 240 mg every 2 weeks or 360 mg every 3 weeks in combination with chemotherapy across tumour types (n = 1800), with a minimum follow‑up ranging from 7.4 to 23.6 months, following 3 or 4 cycles of neoadjuvant 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%), stomatitis (18%), abdominal pain (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, 93% of patients received 3 cycles of nivolumab and 84% of patients received 4 cycles of nivolumab.

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, thrombocytopaeniab, leucopoeniab, lymphopaeniab, neutropaeniab

neutropaeniab, anaemiab,j, leucopoeniab, lymphopaeniab, thrombocytopaeniab

anaemiab, thrombocytopaeniab, leucopoeniab, lymphopaeniab, neutropaeniab

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 (including anaphylactic reaction), 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

hypopituitarism, thyroiditis, adrenal insufficiency, 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

headache, paraesthesia, dizziness

peripheral neuropathy

Uncommon

polyneuropathy, peroneal nerve palsy, autoimmune neuropathy (including facial and abducens nerve paresis), encephalitis, myasthenia gravis

Guillain Barré syndrome

encephalitis autoimmune, Guillain-Barré syndrome, myasthenic syndrome

Rare

Guillain‑Barré syndrome, neuritis, myelitis (including transverse myelitis), optic neuritis

encephalitis

Not known

myelitis (including transverse myelitis), optic neuritis

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

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

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, Sjogren'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

hypocalcaemiab, increased ASTb, increased ALTb, 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 program‑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.

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

1.4

2.1

2.0

2.5

Colitis

1.2

6

1.8

2.5

Hepatitis

1.1

5

0.7

4.1

Nephritis and renal dysfunction

0.3

1.1

3.1

0.6

Endocrinopathies

0.5

2.2

0.6

1.3

Skin

0.8

1.0

0.9

2.2

Hypersensitivity/Infusion reaction

0.1

0.3

1.7

0

Immune‑related adverse reaction requiring high‑dose corticosteroidsa,b

Pneumonitis

65

59

59

56

Colitis

14

32

9

8

Hepatitis

21

39

7

23

Nephritis and renal dysfunction

22

27

9

9

Endocrinopathies

5

18

4.3

4.2

Skin

3.3

8

6

8

Hypersensitivity/Infusion reaction

18

18

22

0

a at least 40 mg daily prednisone equivalents

b frequency is based on the number of patients who experienced the immune‑related adverse reaction

Immune‑related pneumonitis

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

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy), the incidence of pneumonitis including interstitial lung disease, was 6.0% (157/2626). Grade 2, Grade 3, and Grade 4 cases were reported in 3.0% (78/2626), 1.0% (27/2626), and 0.3% (8/2626) of patients, respectively. Four patients (0.2%) had a fatal outcome. Median time to onset was 2.7 months (range: 0.1‑56.8). Resolution occurred in 129 patients (82.2%) with a median time to resolution of 6.1 weeks (range: 0.1+‑149.3+).

In patients treated with nivolumab in combination with chemotherapy, the incidence of pneumonitis including interstitial lung disease was 4.4% (80/1800). Grade 2, Grade 3, and Grade 4 cases were reported in 2.2% (40/1800), 0.9% (17/1800), and 0.2% (3/1800), of patients, respectively. Three patients (0.2%) had a fatal outcome. Median time to onset was 24.6 weeks (range: 0.6‑96.9). Resolution occurred in 58 patients (72.5%) with a median time to resolution of 10.4 weeks (range: 0.3+‑171.4+).

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

Immune‑related colitis

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

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy), the incidence of diarrhoea or colitis was 26.0% (682/2626). Grade 2, Grade 3, and Grade 4 cases were reported in 8.1% (212/2626), 6.4% (167/2626), and 0.2% (4/2626), of patients, respectively. Two patients (<0.1%) had a fatal outcome. Median time to onset was 1.4 months (range: 0.0‑48.9). Resolution occurred in 618 patients (91%) with a median time to resolution of 2.9 weeks (range: 0.1‑170.0+). Among patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg for melanoma, the incidence of diarrhoea or colitis was 46.7%, including Grade 2 (13.6%), Grade 3 (15.8%), and Grade 4 (0.4%).

In patients treated with nivolumab in combination with chemotherapy, the incidence of diarrhoea or colitis was 22.5% (405/1800). Grade 2, Grade 3, and Grade 4 cases were reported in 7.2% (130/1800), 3.1% (56/1800), and 0.3% (6/1800) of patients, respectively. One patient (< 0.1%) had a fatal outcome. Median time to onset was 4.4 weeks (range: 0.1‑93.6). Resolution occurred in 357 patients (88.6%) with a median time to resolution of 1.6 weeks (range: 0.1‑212.3+).

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

Immune‑related hepatitis

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

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy), the incidence of liver function test abnormalities was 21.2% (556/2626). Grade 2, Grade 3, and Grade 4 cases were reported in 5.0% (132/2626), 8.3% (218/2626), and 1.3% (34/2626) of patients, respectively. Seven patients (0.3%) had a fatal outcome. Median time to onset was 1.5 months (range: 0.0‑36.6). Resolution occurred in 482 patients (87.0%) with a median time to resolution of 5.9 weeks (range: 0.1‑175.9+). Among patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg for melanoma, the incidence of liver function test abnormalities was 30.1% including Grade 2 (6.9%), Grade 3 (15.8%), and Grade 4 (1.8%). Among patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg for HCC, the incidence of liver function test abnormalities was 34.3% including Grade 2 (8.4%), Grade 3 (14.2%), and Grade 4 (2.7%).

In patients treated with nivolumab in combination with chemotherapy, the incidence of liver function test abnormalities was 18% (322/1800). Grade 2, Grade 3 and Grade 4 cases were reported in 5.1% (92/1800), 2.6% (47/1800) and < 0.1% (1/1800) of patients, respectively. Median time to onset was 7.0 weeks (range: 0.1‑99.0). Resolution occurred in 258 patients (81.1%) with a median time to resolution of 7.4 weeks (range: 0.4‑240.0+).

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

Immune‑related nephritis and renal dysfunction

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

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy), the incidence of nephritis or renal dysfunction was 5.4% (141/2626). Grade 2, Grade 3, and Grade 4 cases were reported in 2.0% (52/2626), 0.8% (21/2626), and 0.4% (11/2626) of patients, respectively. Two patients (< 0.1%) had a fatal outcome. Median time to onset was 2.6 months (range: 0.0‑34.8). Resolution occurred in 110 patients (78.0%) with a median time to resolution of 5.9 weeks (range: 0.1‑172.1+).

In patients treated with nivolumab in combination with chemotherapy, the incidence of nephritis or renal dysfunction was 10.9% (196/1800). Grade 2, Grade 3, and Grade 4 cases were reported in 3.7% (66/1800), 1.4% (25/1800), and 0.2% (3/1800) of patients, respectively. Two patients (0.1%) had a fatal outcome. Median time to onset was 6.7 weeks (range: 0.1‑60.7). Resolution occurred in 133 patients (67.9%) with a median time to resolution of 9.1 weeks (range: 0.1‑226.0+).

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

Immune‑related endocrinopathies

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

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy), the incidence of thyroid disorders was 23.2% (608/2626). Grade 2 and Grade 3 thyroid disorders were reported in 12.7% (333/2626) and 1.0% (27/2626) of patients, respectively. Grade 2 and Grade 3 hypophysitis (including lymphocytic hypophysitis) occurred in 1.9% (49/2626) and 1.5% (40/2626) of patients, respectively. Grade 2 and Grade 3 hypopituitarism occurred in 0.6% (16/2626) and 0.5% (13/2626) of patients, respectively. Grade 2, Grade 3, and Grade 4 adrenal insufficiency (including secondary adrenocortical insufficiency, adrenocortical insufficiency acute, blood corticotrophin decreased and immune-mediated adrenal insufficiency) occurred in 2.7% (72/2626), 1.6% (43/2626) and 0.2% (4/2626) of patients, respectively. Grade 1, Grade 2, Grade 3, and Grade 4 diabetes mellitus (including Type 1 diabetes mellitus, and diabetic ketoacidosis) occurred in < 0.1% (1/2626), 0.3% (8/2626), < 0.3% (7/2626), and 0.2% (6/2626) of patients, respectively. Median time to onset of these endocrinopathies was 2.1 months (range: 0.0‑28.1). Resolution occurred in 297 patients (40.0%). Time to resolution ranged from 0.3 to 257.1+ weeks.

In patients treated with nivolumab in combination with chemotherapy, the incidence of thyroid disorders was 12.8% (230/1800). Grade 2 and Grade 3 thyroid disorders were reported in 6.3% (114/1800) and 0.1% (2/1800) of patients, respectively. Grade 3 hypophysitis occurred in 0.1% (2/1800) of patients. Grade 2 and Grade 3 hypopituitarism occurred in 0.2% (4/1800) and 0.2% (4/1800) of patients, respectively. Grade 2, Grade 3 and Grade 4 adrenal insufficiency occurred in 0.6% (11/1800), 0.2% (3/1800) and <0.1% (1/1800) of patients, respectively. One patient (< 0.1%) had a fatal outcome due to adrenal insufficiency. Diabetes mellitus including Type 1 diabetes mellitus and fulminant Type 1 diabetes mellitus (4 Grade 2, 2 Grade 3, and 1 Grade 4), and diabetic ketoacidosis (1 Grade 2 and 1 Grade 4) were reported. Median time to onset of these endocrinopathies was 15.3 weeks (range: 1.1‑124.3). Resolution occurred in 101 patients (40.1%). Time to resolution ranged from 0.3+ to 233.6+ weeks.

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

Immune‑related skin adverse reactions

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

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy), the incidence of rash was 46.1% (1210/2626). Grade 2, Grade 3, and Grade 4 cases were reported in 14.3% (375/2626), 4.6% (120/2626), and 0.1% (3/2626) of patients, respectively. Median time to onset was 0.7 months (range: 0.0‑33.8). Resolution occurred in 843 patients (70%) with a median time to resolution of 12.1 weeks (range: 0.1‑268.7+). Among patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg for melanoma, the incidence of rash was 65.2%, including Grade 2 (20.3%) and Grade 3 (7.8%).

In patients treated with nivolumab in combination with chemotherapy, the incidence of rash was 25.4% (457/1800). Grade 2 and Grade 3 cases were reported in 6.2% (111/1800), and 2.3% (42/1800) of patients, respectively. Median time to onset was 6.4 weeks (range: 0.1‑97.4). Resolution occurred in 320 patients (70.2%) with a median time to resolution of 12.1 weeks (range: 0.1‑258.7+).

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

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

Infusion reactions (intravenous formulation)

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

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy), the incidence of hypersensitivity/infusion reactions was 4.5% (118/2626). Grade 1, Grade 2, Grade 3, and Grade 4 cases were reported in 1.9% (49/2626), 2.4% (62/2626), 0.2% (6/2626), and < 0.1% (1/2626) of patients, respectively. Among patients with Malignant pleural mesothelioma treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg, the incidence of hypersensitivity/infusion reactions was 12%.

In patients treated with nivolumab in combination with chemotherapy, the incidence of hypersensitivity/infusion reactions was 8.2% (148/1800). Grade 2, Grade 3, and Grade 4 cases were reported in 4.6% (83/1800), 1.1% (20/1800) and 0.2% (3/1800) of patients, respectively.

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

Elevated liver enzymes when nivolumab is combined with cabozantinib in RCC

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

Laboratory abnormalities

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

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy), the proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 4.8% for anaemia, 1.8% for thrombocytopaenia, 2.2% for leucopoenia, 6.9% for lymphopaenia, 3.3% for neutropaenia, 2.7% for increased alkaline phosphatase, 9.8% for increased AST, 9.3% for increased ALT, 2.3% for increased total bilirubin, 1.8% for increased creatinine, 1.4% for hypoalbuminaemia , 7.1% for hyperglycaemia, 0.7% for hypoglycaemia, 7.8% for increased amylase, 16.3% for increased lipase, 0.8% for hypocalcaemia, 0.2% for hypernatraemia, 0.8% for hypercalcaemia, 2.0% for hyperkalaemia, 0.8% for hypermagnesaemia, 0.4% for hypomagnesaemia, 3.0% for hypokalaemia, and 8.7% for hyponatraemia.

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

In patients treated with nivolumab in combination with chemotherapy, the proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 14.7% for anaemia, 6.2% for thrombocytopaenia, 11.7% leukopaenia, 13.6% for lymphopaenia, 26.3% neutropaenia, 2.0% for increased alkaline phosphatase, 3.3% for increased AST, 2.6% for increased ALT, 1.9% for increased bilirubin, 1.3% for increased creatinine, 4.5% for increased amylase, 5.2% for increased lipase, 0.4% for hypernatraemia, 8.1% for hyponatraemia, 1.8% for hyperkalaemia, 5.1% for hypokalaemia, 0.7% for hypercalcaemia, 1.8% for hypocalcaemia, 2.9% for hypomagnesaemia, 1.5% for hypermagnesaemia, 3.7% for hyperglycaemia, and 0.6% for hypoglycaemia.

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

Immunogenicity

Subcutaneous formulation

Of the 202 patients who were treated with nivolumab solution for injection and evaluable for the presence of anti-nivolumab antibodies, approximately 23% (46/202) tested positive for treatment-emergent anti-nivolumab antibodies by an electrochemiluminescent (ECL) assay and 1% (2/202) had neutralizing antibodies against nivolumab. The incidence of treatment-emergent anti-recombinant human hyaluronidase PH20 (anti-rHuPH20) antibodies in patients treated with nivolumab solution for injection was 8.8% (19/215).

Intravenous formulation

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

Co‑administration with chemotherapy did not affect nivolumab immunogenicity. Of the 1407 patients who were treated with nivolumab 240 mg every 2 weeks or 360 mg every 3 weeks in combination with chemotherapy and evaluable for the presence of anti‑product‑antibodies, 7.2% tested positive for treatment emergent anti‑product‑antibodies with 0.5% tested positive for neutralising antibodies.

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

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

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

Elderly

No overall differences in safety were reported between elderly (≥ 65 years) and younger patients (< 65 years). Data from SCCHN, adjuvant melanoma, and adjuvant OC or GEJC patients 75 years of age or older are too limited to draw conclusions on this population (see section 5.1). Data from dMMR or MSI‑H CRC patients 75 years of age or older are limited (see section 5.1). In HCC patients there were higher rates of serious adverse reactions and discontinuation due to adverse reactions in patients aged 75 years or older (67% and 35%, respectively) relative to all patients who received nivolumab with ipilimumab (53% and 27%, respectively).

For patients treated with nivolumab in combination with cabozantinib, data from RCC patients 75 years of age or older are too limited to draw conclusions on this population (see section 5.1).

Hepatic or renal impairment

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

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.