4.1. Therapeutic indications

Melanoma

YERVOY as monotherapy or in combination with nivolumab is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults, and adolescents 12 years of age and older (see section 4.4).

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).

Renal cell carcinoma (RCC)

YERVOY in combination with nivolumab is indicated for the first-line treatment of adult patients with intermediate/poor-risk advanced renal cell carcinoma (see section 5.1).

Non-small cell lung cancer (NSCLC)

YERVOY in combination with nivolumab and 2 cycles of platinum-based chemotherapy is indicated for the first-line treatment of metastatic non-small cell lung cancer in adults whose tumours have no sensitising EGFR mutation or ALK translocation.

Malignant pleural mesothelioma (MPM)

YERVOY in combination with nivolumab is indicated for the first‑line treatment of adult patients with unresectable malignant pleural mesothelioma.

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

YERVOY in combination with nivolumab 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)

YERVOY in combination with nivolumab 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%.

Hepatocellular carcinoma (HCC)

YERVOY in combination with nivolumab 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 specialist physicians experienced in the treatment of cancer.

PD-L1 testing

If specified in the indication, patient selection for treatment with YERVOY 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 YERVOY 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

YERVOY as monotherapy

Melanoma

Adults and adolescents 12 years of age and older

The recommended induction regimen of YERVOY is 3 mg/kg administered intravenously over a 30‑minute period every 3 weeks for a total of 4 doses. Patients should receive the entire induction regimen (4 doses) as tolerated, regardless of the appearance of new lesions or growth of existing lesions. Assessments of tumour response should be conducted only after completion of induction therapy.

YERVOY in combination with nivolumab

Melanoma

In adults and adolescents 12 years of age and older and weighing at least 50 kg, the recommended dose is 3 mg/kg ipilimumab in combination with 1 mg/kg nivolumab administered intravenously every 3 weeks for the first 4 doses. This is then followed by a second phase in which nivolumab monotherapy is administered intravenously at either 240 mg every 2 weeks or at 480 mg every 4 weeks (see sections 5.1 and 5.2), as presented in Table 1. For the monotherapy phase, the first dose of nivolumab should be administered:

▪ 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 240 mg every 2 weeks; or

▪ 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 480 mg every 4 weeks.

In adolescents 12 years of age and older and weighing less than 50 kg, the recommended dose is 3 mg/kg ipilimumab in combination with 1 mg/kg nivolumab administered intravenously every 3 weeks for the first 4 doses. This is then followed by a second phase in which nivolumab monotherapy is administered intravenously at either 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks (see sections 5.1 and 5.2), as presented in Table 1. For the monotherapy phase, the first dose of nivolumab should be administered:

▪ 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 3 mg/kg every 2 weeks; or

▪ 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 6 mg/kg every 4 weeks.

Table 1: Recommended doses and infusion times for intravenous administration of ipilimumab in combination with nivolumab

Combination phase, every 3 weeks for 4 dosing cycles

Monotherapy phase

Nivolumab

Adults and adolescents 12 years of age and older:

1 mg/kg over 30 minutes

Adults and adolescents (12 years of age and older weighing at least 50 kg):

240 mg every 2 weeks over 30 minutes or

480 mg every 4 weeks over 60 minutes

Adolescents (12 years of age and older and weighing less than 50 kg):

3 mg/kg every 2 weeks over 30 minutes or

6 mg/kg every 4 weeks over 60 minutes

Ipilimumab

Adults and adolescents 12 years of age and older:

3 mg/kg over 30 minutes

-

Renal cell carcinoma

The recommended dose is 1 mg/kg ipilimumab in combination with 3 mg/kg nivolumab administered intravenously every 3 weeks for the first 4 doses. This is then followed by a second phase in which nivolumab monotherapy is administered intravenously at either 240 mg every 2 weeks or at 480 mg every 4 weeks, as presented in Table 2. For the monotherapy phase, the first dose of nivolumab should be administered;

▪ 3 weeks after the last dose of the combination of ipilimumab and nivolumab if using 240 mg every 2 weeks; or

▪ 6 weeks after the last dose of the combination of ipilimumab and nivolumab if using 480 mg every 4 weeks.

Table 2: Recommended doses and infusion times for intravenous administration of ipilimumab in combination with nivolumab for RCC

Combination phase, every 3 weeks for 4 dosing cycles

Monotherapy phase

Nivolumab

3 mg/kg over 30 minutes

240 mg every 2 weeks over 30 minutes or

480 mg every 4 weeks over 60 minutes

Ipilimumab

1 mg/kg over 30 minutes

-

dMMR or MSI H colorectal cancer

The recommended dose for first-line treatment of dMMR or MSI-H CRC is 1 mg/kg ipilimumab in combination with 240 mg of nivolumab administered intravenously every 3 weeks for a maximum of 4 doses, followed by nivolumab monotherapy administered intravenously at either 240 mg every 2 weeks or at 480 mg every 4 weeks, as presented in Table 3. For the monotherapy phase, the first dose of nivolumab should be administered 3 weeks after the last dose of the combination of nivolumab and ipilimumab. Treatment with nivolumab is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

The recommended dose in patients who received prior fluoropyrimidine-based combination chemotherapy for dMMR or MSI-H CRC is 1 mg/kg ipilimumab in combination with 3 mg/kg nivolumab administered intravenously every 3 weeks for the first 4 doses, followed by nivolumab monotherapy administered intravenously 240 mg every 2 weeks, as presented in Table 3. For the monotherapy phase, the first dose of nivolumab should be administered 3 weeks after the last dose of the combination of ipilimumab and nivolumab.

Table 3: Recommended doses and infusion times for intravenous administration of ipilimumab in combination with nivolumab for dMMR or MSI-H CRC

Combination phase, every 3 weeks for 4 dosing cycles

Monotherapy phase

Nivolumab

First-line

240 mg over 30 minutes

240 mg every 2 weeks over 30 minutes or

480 mg every 4 weeks over 30 minutes

After prior fluoropyrimidine‑based combination chemotherapy

3 mg/kg over 30 minutes

240 mg every 2 weeks over 30 minutes

Ipilimumab

1 mg/kg over 30 minutes

-

Malignant pleural mesothelioma

The recommended dose is 1 mg/kg ipilimumab administered intravenously over 30 minutes every 6 weeks in combination with 360 mg nivolumab administered intravenously over 30 minutes every 3 weeks. Treatment is continued for up to 24 months in patients without disease progression.

Oesophageal squamous cell carcinoma

The recommended dose is 1 mg/kg ipilimumab administered intravenously over 30 minutes every 6 weeks in combination with either 3 mg/kg nivolumab every 2 weeks or 360 mg nivolumab every 3 weeks administered intravenously over 30 minutes. Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Hepatocellular carcinoma

The recommended dose is 3 mg/kg ipilimumab in combination with 1 mg/kg nivolumab administered intravenously every 3 weeks for up to 4 doses. This is then followed by a second phase in which nivolumab monotherapy is administered intravenously at either 240 mg every 2 weeks or at 480 mg every 4 weeks (see sections 5.1 and 5.2), as presented in Table 4. Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months. For the monotherapy phase, the first dose of nivolumab should be administered:

▪ 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 240 mg every 2 weeks or 480 mg every 4 weeks.

Table 4: Recommended doses and infusion times for intravenous administration of ipilimumab in combination with nivolumab for HCC

Combination phase, every 3 weeks for 4 dosing cycles

Monotherapy phase

Nivolumab

1 mg/kg over 30 minutes

240 mg every 2 weeks over 30 minutes or

480 mg every 4 weeks over 30 minutes

Ipilimumab

3 mg/kg over 30 minutes

-

YERVOY in combination with nivolumab and chemotherapy

Non-small cell lung cancer

The recommended dose is 1 mg/kg ipilimumab administered intravenously over 30 minutes every 6 weeks in combination with 360 mg nivolumab administered intravenously over 30 minutes every 3 weeks, and platinum-based chemotherapy administered every 3 weeks. After completion of 2 cycles of chemotherapy, treatment is continued with 1 mg/kg ipilimumab every 6 weeks in combination with 360 mg nivolumab administered intravenously every 3 weeks. Treatment is recommended until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Duration of treatment

Treatment with YERVOY in combination with nivolumab, should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient. (and up to maximum duration of therapy if specified for an indication).

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

Liver function tests (LFTs) and thyroid function tests should be evaluated at baseline and before each dose of YERVOY. In addition, any signs or symptoms of immune‑related adverse reactions, including diarrhoea and colitis, must be assessed during treatment with YERVOY (see Tables 5A, 5B, and section 4.4).

Children younger than 12 years of age

The safety and efficacy of ipilimumab in children younger than 12 years of age has not been established.

Permanent discontinuation of treatment or withholding of doses

Management of immune‑related adverse reactions may require withholding of a dose or permanent discontinuation of YERVOY therapy and institution of systemic high-dose corticosteroid. In some cases, addition of other immunosuppressive therapy may be considered (see section 4.4).

Dose escalation or reduction is not recommended. Dosing delay or discontinuation may be required based on individual safety and tolerability.

Guidelines for permanent discontinuation or withholding of doses are described in Tables 5A and 5B for YERVOY as monotherapy, and in Table 5C for YERVOY in combination with nivolumab or administration of the second phase of treatment (nivolumab monotherapy) following combination treatment. Detailed guidelines for the management of immune-related adverse reactions are described in section 4.4.

Table 5A When to permanently discontinue YERVOY as monotherapy

Permanently discontinue YERVOY in patients with the following adverse reactions. Management of these adverse reactions may also require systemic high‑dose corticosteroid therapy if demonstrated or suspected to be immune‑related (see section 4.4 for detailed management guidelines).

Adverse reactions

NCI‑CTCAE v4 Gradea

Gastrointestinal:

Severe symptoms (abdominal pain, severe diarrhoea or significant change in the number of stools, blood in stool, gastrointestinal haemorrhage, gastrointestinal perforation)

▪ Grade 3 or 4 diarrhoea or colitis

Hepatic:

Severe elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin or symptoms of hepatotoxicity

▪ Grade 3 or 4 elevation in AST, ALT, or total bilirubin

Skin:

Life threatening skin rash (including Stevens‑Johnson syndrome or toxic epidermal necrolysis) or severe widespread pruritus interfering with activities of daily living or requiring medical intervention

▪ Grade 4 rash or Grade 3 pruritus

Neurologic:

New onset or worsening severe motor or sensory neuropathy

▪ Grade 3 or 4 motor or sensory neuropathy

Other organ systemsb:

(e.g. nephritis, pneumonitis, pancreatitis, non‑infectious myocarditis, diabetes)

▪ ≥ Grade 3 immune‑related reactionsc

▪ ≥ Grade 2 for immune‑related eye disorders NOT responding to topical immunosuppressive therapy

▪ Grade 4 diabetes

a Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI‑CTCAE v4).

b Any other adverse reactions that are demonstrated or suspected to be immune‑related should be graded according to CTCAE. Decision whether to discontinue YERVOY should be based on severity.

c Patients with severe (Grade 3 or 4) endocrinopathy controlled with hormone replacement therapy may remain on therapy.

Table 5B When to withhold dose of YERVOY as monotherapy

Withhold YERVOY dosea in patients with the following immune-related adverse reactions. See section 4.4 for detailed management guidelines.

Adverse reactions

Action

Gastrointestinal:

Moderate diarrhoea or colitis that either is not controlled with medical management or that persists (5‑7 days) or recurs

1. Withhold dose until an adverse reaction resolves to Grade 1 or Grade 0 (or returns to baseline).

2. If resolution occurs, resume therapy.d

3. If resolution has not occurred, continue to withhold doses until resolution then resume treatment.d

4. Discontinue YERVOY if resolution to Grade 1 or Grade 0 or return to baseline does not occur.

Hepatic:

Grade 2 elevation in AST, ALT, or total bilirubin

Skin:

Moderate to severe (Grade 3)b skin rash or (Grade 2) widespread/intense pruritus regardless of etiology

Endocrine:

Severe adverse reactions in the endocrine glands, such as hypophysitis and thyroiditis that are not adequately controlled with hormone replacement therapy or high‑dose immunosuppressive therapy

Grade 3 diabetes

Neurological:

Moderate (Grade 2)b unexplained motor neuropathy, muscle weakness, or sensory neuropathy (lasting more than 4 days)

Other moderate adverse reactionsc

a No dose reduction of YERVOY is recommended.

b Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI‑CTCAE v4).

c Any other organ system adverse reactions that are considered immune‑related should be graded according to CTCAE. Decision whether to withhold a dose should be based on severity.

d Until administration of all 4 doses or 16 weeks from first dose, whichever occurs earlier.

Table 5C: Recommended treatment modifications for YERVOY in combination with nivolumab or administration of the second phase of treatment (nivolumab monotherapy) following combination treatment

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 or 4 diarrhoea or colitis

Permanently discontinue treatment

Immune-related hepatitis without HCC

Grade 2 elevation in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin

Withhold dose(s) until laboratory values return to baseline and management with corticosteroids, if needed, is complete

Grade 3 or 4 elevation in AST, ALT, or total bilirubin

Permanently discontinue treatment

Immune-related hepatitis with HCC

If AST/ALT is within normal limits at baseline and increases to > 3 and ≤ 10 times ULN

or

Baseline AST/ALT is > 1 and ≤ 3 times ULN and increases to > 5 and ≤ 10 times ULN

or

Baseline AST/ALT is > 3 and ≤ 5 times ULN and increases to > 8 and ≤ 10 times ULN

Withhold dose(s) until laboratory values return to baseline and management with corticosteroids, if needed, is complete

AST/ALT increases to > 10 times ULN

or

Total bilirubin increases to > 3 times ULN

Permanently discontinue treatment

Immune-related nephritis and renal dysfunction

Grade 2 or 3 creatinine elevation

Withhold dose(s) until creatinine returns to baseline and management with corticosteroids is complete

Grade 4 creatinine elevation

Permanently discontinue treatment

Immune-related 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 therapya 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 completeb

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 Recommendation for the use of hormone replacement therapy is provided in section 4.4.

b The safety of re‑initiating ipilimumab in combination with nivolumab therapy in patients previously experiencing immune-related myocarditis is not known.

YERVOY in combination with nivolumab should be permanently discontinued for:

• Grade 4 or recurrent Grade 3 adverse reactions;

• Persistent Grade 2 or 3 adverse reactions despite management.

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

Special populations

Paediatric population

The safety and efficacy of YERVOY as monotherapy in children younger than 12 years of age have not been established. Very limited data are available. YERVOY should not be used in children younger than 12 years of age.

The safety and efficacy of YERVOY in combination with nivolumab in children younger than 18 years of age have not been established, except in adolescents 12 years of age and older with melanoma. Currently available data are described in sections 4.2, 4.8, 5.1 and 5.2.

Elderly

No overall differences in safety or efficacy were reported between elderly (≥ 65 years) and younger patients (< 65 years). Data from first-line RCC patients 75 years of age or older are too limited to draw conclusions on this population (see section 5.1). No specific dose adjustment is necessary in this population (see section 5.1).

Renal impairment

The safety and efficacy of YERVOY have not been studied in patients with renal impairment. Based on population pharmacokinetic results, no specific dose adjustment is necessary in patients with mild to moderate renal dysfunction (see section 5.2).

Hepatic impairment

The safety and efficacy of YERVOY have not been studied in patients with hepatic impairment. Based on the population pharmacokinetic results, no specific dose adjustment is necessary in patients with mild hepatic impairment (see section 5.2). YERVOY must be administered with caution in patients with transaminase levels ≥ 5 x ULN or bilirubin levels > 3 x ULN at baseline (see section 5.1).

Method of administration

YERVOY is for intravenous use. The recommended infusion period is 30 minutes.

YERVOY can be used for intravenous administration without dilution or may be diluted in sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution for injection to concentrations between 1 and 4 mg/ml.

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

When administered in combination with nivolumab or in combination with nivolumab and chemotherapy, nivolumab should be given first followed by YERVOY and then by chemotherapy (if applicable) on the same day. Use separate infusion bags and filters for each infusion.

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

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.

Ipilimumab in combination with nivolumab

When ipilimumab is administered in combination, refer to the Summary of Product Characteristics of the other combination therapy components prior to initiation of treatment. For additional information on warnings and precautions associated with nivolumab treatment, please refer to the nivolumab SmPC. 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 have occurred at higher frequencies when nivolumab was administered in combination with ipilimumab compared with nivolumab as monotherapy.

Cardiac and pulmonary adverse events 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. Ipilimumab in combination with nivolumab 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 ipilimumab in combination with nivolumab may occur at any time during or after discontinuation of therapy.

Immune-related reactions

Ipilimumab is associated with inflammatory adverse reactions resulting from increased or excessive immune activity (immune-related adverse reactions), likely to be related to its mechanism of action. Immune-related adverse reactions, which can be severe or life-threatening, may involve the gastrointestinal, liver, skin, nervous, endocrine, or other organ systems. While most immune-related adverse reactions occurred during the induction period, onset months after the last dose of ipilimumab has also been reported. Unless an alternate etiology has been identified, diarrhoea, increased stool frequency, bloody stool, LFT elevations, rash and endocrinopathy must be considered inflammatory and ipilimumab‑related. Early diagnosis and appropriate management are essential to minimise life‑threatening complications.

Systemic high-dose corticosteroid with or without additional immunosuppressive therapy may be required for management of severe immune-related adverse reactions.

Ipilimumab specific management guidelines for immune-related adverse reactions are described below for use as monotherapy and in combination with nivolumab.

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, ipilimumab, or ipilimumab in combination with nivolumab should be withheld and corticosteroids administered. If immunosuppression with corticosteroids is used to treat an adverse reaction that occurs as a consequence of combination therapy, 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.

Ipilimumab in combination with nivolumab 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.

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

Immune‑related gastrointestinal reactions

Ipilimumab as monotherapy

Ipilimumab is associated with serious immune‑related gastrointestinal reactions. Fatalities due to gastrointestinal perforation have been reported in clinical trials (see section 4.8).

In patients who received ipilimumab 3 mg/kg monotherapy in a Phase 3 study of advanced (unresectable or metastatic) melanoma (MDX010‑20, see section 5.1), the median time to onset of severe or fatal (Grade 3‑5) immune‑related gastrointestinal reactions was 8 weeks (range 5 to 13 weeks) from the start of treatment. With protocol‑specified management guidelines, resolution (defined as improvement to mild [Grade 1] or less or to the severity at baseline) occurred in most cases (90%), with a median time from onset to resolution of 4 weeks (range 0.6 to 22 weeks).

Patients must be monitored for gastrointestinal signs and symptoms that may be indicative of immune‑related colitis or gastrointestinal perforation. Clinical presentation may include diarrhoea, increased frequency of bowel movements, abdominal pain, or haematochezia, with or without fever. In clinical trials, immune‑related colitis was associated with evidence of mucosal inflammation, with or without ulcerations, and lymphocytic and neutrophilic infiltration. Post‑marketing cases of cytomegalovirus (CMV) infection/reactivation have been reported in patients with corticosteroid‑refractory immune‑related colitis. Stool infections work-up should be performed upon presentation of diarrhoea or colitis to exclude infectious or other alternate etiologies.

Management recommendations for diarrhoea or colitis are based on severity of symptoms (per NCI‑CTCAE v4 severity grading classification). Patients with mild to moderate (Grade 1 or 2) diarrhoea (an increase of up to 6 stools per day) or suspected mild to moderate colitis (e.g. abdominal pain or blood in stools) may remain on ipilimumab. Symptomatic treatment (e.g. loperamide, fluid replacement) and close monitoring are advised. If mild to moderate symptoms recur or persist for 5‑7 days, the scheduled dose of ipilimumab should be withheld and corticosteroid therapy (e.g. prednisone 1 mg/kg orally once daily or equivalent) should be initiated. If resolution to Grades 0‑1 or return to baseline occurs, ipilimumab may be resumed (see section 4.2).

Ipilimumab must be permanently discontinued in patients with severe (Grade 3 or 4) diarrhoea or colitis (see section 4.2), and systemic high‑dose intravenous corticosteroid therapy should be initiated immediately. (In clinical trials, methylprednisolone 2 mg/kg/day has been used). Once diarrhoea and other symptoms are controlled, the initiation of corticosteroid taper should be based on clinical judgment. In clinical trials, rapid tapering (over periods < 1 month) resulted in recurrence of diarrhoea or colitis in some patients. Patients must be evaluated for evidence of gastrointestinal perforation or peritonitis.

The experience from clinical trials on the management of corticosteroid‑refractory diarrhoea or colitis is limited. Addition of an alternative immunosuppressive agent to the corticosteroid regimen should be considered in corticosteroid‑refractory immune‑related colitis if other causes are excluded (including Cytomegalovirus (CMV) infection/reactivation evaluated with viral PCR on biopsy, and other viral, bacterial and parasitic etiology). In clinical trials, a single dose of infliximab 5 mg/kg was added unless contraindicated. Infliximab must not be used if gastrointestinal perforation or sepsis is suspected (see the Summary of Product Characteristics for infliximab).

Immune-related colitis

Ipilimumab in combination with nivolumab

Severe diarrhoea or colitis has been observed with ipilimumab in combination with nivolumab (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. Infectious and disease-related aetiologies should be ruled out.

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

Grade 3 diarrhoea or colitis observed with ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab 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 ipilimumab in combination with nivolumab must be permanently discontinued.

Immune-related pneumonitis

Ipilimumab in combination with nivolumab

Severe pneumonitis or interstitial lung disease, including fatal cases, has been observed with ipilimumab in combination with nivolumab (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, ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab should be withheld and corticosteroids initiated at a dose of 1 mg/kg/day methylprednisolone equivalents. Upon improvement, ipilimumab in combination with nivolumab 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 ipilimumab in combination with nivolumab must be permanently discontinued.

Immune‑related hepatotoxicity

Ipilimumab as monotherapy

Ipilimumab is associated with serious immune‑related hepatotoxicity. Fatal hepatic failure has been reported in clinical trials (see section 4.8).

In patients who received ipilimumab 3 mg/kg monotherapy in MDX010‑20, time to onset of moderate to severe or fatal (Grade 2‑5) immune‑related hepatotoxicity ranged from 3 to 9 weeks from the start of treatment. With protocol‑specified management guidelines, time to resolution ranged from 0.7 to 2 weeks.

Hepatic transaminase and bilirubin must be evaluated before each dose of ipilimumab, as early laboratory changes may be indicative of emerging immune‑related hepatitis (see section 4.2). Elevations in LFTs may develop in the absence of clinical symptoms. Increases in AST and ALT or total bilirubin should be evaluated to exclude other causes of hepatic injury, including infections, tumour progression, or concomitant medication and monitored until resolution. Liver biopsies from patients who had immune‑related hepatotoxicity showed evidence of acute inflammation (neutrophils, lymphocytes, and macrophages).

For patients with Grade 2 transaminase or total bilirubin elevation, the scheduled dose of ipilimumab should be withheld, and LFTs must be monitored until resolution. Upon improvement, ipilimumab may be resumed (see section 4.2).

For patients with Grade 3 or 4 transaminase or total bilirubin elevation, treatment must be permanently discontinued (see section 4.2), and systemic high‑dose intravenous corticosteroid therapy (e.g. methylprednisolone 2 mg/kg daily or equivalent) should be initiated immediately. In such patients, LFTs must be monitored until normalization. Once symptoms have resolved and LFTs show sustained improvement or return to baseline, the initiation of corticosteroid taper should be based on clinical judgment. Tapering should occur over a period of at least 1 month. Elevations in LFTs during taper may be managed with an increase in the dose of corticosteroid and a slower taper.

For patients with significant LFT elevations that are refractory to corticosteroid therapy, addition of an alternative immunosuppressive agent to the corticosteroid regimen may be considered. In clinical trials, mycophenolate mofetil was used in patients without response to corticosteroid therapy, or who had an LFT elevation during corticosteroid tapering that was not responsive to an increase in the dose of corticosteroids (see the Summary of Product Characteristics for mycophenolate mofetil).

Ipilimumab in combination with nivolumab

Severe hepatitis has been observed with ipilimumab in combination with nivolumab (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, ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab 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 ipilimumab in combination with nivolumab must be permanently discontinued.

Immune‑related skin adverse reactions

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

Ipilimumab as monotherapy

Ipilimumab is associated with serious skin adverse reactions that may be immune-related. Rare cases of toxic epidermal necrolysis (TEN) (including Steven Johnson Syndrome) have been observed, some with fatal outcome. Rare cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also been reported in clinical trials and during post-marketing use (see section 4.8).

DRESS presents as a rash with eosinophilia associated with one or more of the following features: fever, lymphadenopathy, facial oedema, and internal organ involvement (hepatic, renal, pulmonary). DRESS may be characterised by a long latency (two to eight weeks) between medicinal product exposure and disease onset.

Ipilimumab‑induced rash and pruritus were predominantly mild or moderate (Grade 1 or 2) and responsive to symptomatic therapy. In patients who received ipilimumab 3 mg/kg monotherapy in MDX010‑20, the median time to onset of moderate to severe or fatal (Grade 2‑5) skin adverse reactions was 3 weeks (range 0.9‑16 weeks) from start of treatment. With protocol‑specified management guidelines, resolution occurred in most cases (87%), with a median time from onset to resolution of 5 weeks (range 0.6 to 29 weeks).

Ipilimumab-induced rash and pruritus should be managed based on severity. Patients with a mild to moderate (Grade 1 or 2) rash may remain on ipilimumab therapy with symptomatic treatment (e.g. antihistamines). For mild to moderate rash or mild pruritus that persists for 1 to 2 weeks and does not improve with topical corticosteroids, oral corticosteroid therapy should be initiated (e.g. prednisone 1 mg/kg once daily or equivalent).

For patients with a severe (Grade 3) rash, the scheduled dose of ipilimumab should be withheld. If initial symptoms improve to mild (Grade 1) or resolve, ipilimumab therapy may be resumed (see section 4.2).

Ipilimumab must be permanently discontinued in patients with a very severe (Grade 4) rash or severe (Grade 3) pruritus (see section 4.2), and systemic high‑dose intravenous corticosteroid therapy (e.g. methylprednisolone 2 mg/kg/day) should be initiated immediately. Once rash or pruritus is controlled, initiation of corticosteroid taper should be based on clinical judgment. Tapering should occur over a period of at least 1 month.

Ipilimumab in combination with nivolumab

Severe rash has been observed with ipilimumab in combination with nivolumab (see section 4.8). Ipilimumab in combination with nivolumab 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 ipilimumab in combination with nivolumab 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 ipilimumab in combination with nivolumab, permanent discontinuation of treatment is recommended (see section 4.2).

Immune‑related neurological reactions

Ipilimumab as monotherapy

Ipilimumab is associated with serious immune‑related neurological adverse reactions. Fatal Guillain‑Barré syndrome has been reported in clinical trials. Myasthenia gravis‑like symptoms have also been reported (see section 4.8). Patients may present with muscle weakness. Sensory neuropathy may also occur.

Unexplained motor neuropathy, muscle weakness, or sensory neuropathy lasting > 4 days must be evaluated, and non‑inflammatory causes such as disease progression, infections, metabolic syndromes and concomitant medication should be excluded. For patients with moderate (Grade 2) neuropathy (motor with or without sensory) likely related to ipilimumab, the scheduled dose should be withheld. If neurologic symptoms resolve to baseline, the patient may resume ipilimumab (see section 4.2).

Ipilimumab must be permanently discontinued in patients with severe (Grade 3 or 4) sensory neuropathy suspected to be related to ipilimumab (see section 4.2). Patients must be treated according to institutional guidelines for management of sensory neuropathy, and intravenous corticosteroids (e.g. methylprednisolone 2 mg/kg/day) should be initiated immediately.

Progressive signs of motor neuropathy must be considered immune‑related and managed accordingly. Ipilimumab must be permanently discontinued in patients with severe (Grade 3 or 4) motor neuropathy regardless of causality (see section 4.2).

Immune-related nephritis and renal dysfunction

Ipilimumab in combination with nivolumab

Severe nephritis and renal dysfunction have been observed with ipilimumab in combination with nivolumab (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, ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab should be withheld, and corticosteroids should be initiated at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, ipilimumab in combination with nivolumab 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 ipilimumab in combination with nivolumab must be permanently discontinued.

Immune‑related endocrinopathy

Ipilimumab as monotherapy

Ipilimumab can cause inflammation of the endocrine system organs, manifesting as hypophysitis, hypopituitarism, adrenal insufficiency, hypothyroidism, Type 1 diabetes mellitus and diabetic ketoacidosis (see sections 4.2 and 4.8), and patients may present with nonspecific symptoms, which may resemble other causes such as brain metastasis or underlying disease. The most common clinical presentation includes headache and fatigue. Symptoms may also include visual field defects, behavioural changes, electrolyte disturbances, and hypotension. Adrenal crisis as a cause of the patient's symptoms must be excluded. Clinical experience with ipilimumab associated endocrinopathy is limited.

For patients who received ipilimumab 3 mg/kg monotherapy in MDX010‑20, time to onset of moderate to very severe (Grade 2‑4) immune‑related endocrinopathy ranged from 7 to nearly 20 weeks from the start of treatment. Immune‑related endocrinopathy observed in clinical trials was generally controlled with immunosuppressive therapy and hormone replacement therapy.

If there are any signs of adrenal crisis such as severe dehydration, hypotension, or shock, immediate administration of intravenous corticosteroids with mineralocorticoid activity is recommended, and the patient must be evaluated for presence of sepsis or infections. If there are signs of adrenal insufficiency but the patient is not in adrenal crisis, further investigations should be considered including laboratory and imaging assessment. Evaluation of laboratory results to assess endocrine function may be performed before corticosteroid therapy is initiated. If pituitary imaging or laboratory tests of endocrine function are abnormal, a short course of high‑dose corticosteroid therapy (e.g. dexamethasone 4 mg every 6 hrs or equivalent) is recommended to treat the inflammation of the affected gland, and the scheduled dose of ipilimumab should be withheld (see section 4.2). It is currently unknown if the corticosteroid treatment reverses the gland dysfunction. Appropriate hormone replacement should also be initiated. Long‑term hormone replacement therapy may be necessary.

For symptomatic diabetes, 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. Ipilimumab must be permanently discontinued for life-threatening diabetes.

Once symptoms or laboratory abnormalities are controlled and overall patient improvement is evident, treatment with ipilimumab may be resumed and initiation of corticosteroid taper should be based on clinical judgment. Tapering should occur over a period of at least 1 month.

Ipilimumab in combination with nivolumab

Severe endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency (including secondary adrenocortical insufficiency), hypophysitis (including hypopituitarism), diabetes mellitus, and diabetic ketoacidosis have been observed with ipilimumab in combination with nivolumab (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, ipilimumab in combination with nivolumab should be withheld, and thyroid hormone replacement should be initiated as needed. For symptomatic hyperthyroidism, ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab may be resumed after corticosteroid taper, if needed. Monitoring of thyroid function should continue to ensure appropriate hormone replacement is utilised. Ipilimumab in combination with nivolumab must be permanently discontinued for life-threatening hyperthyroidism or hypothyroidism.

For symptomatic Grade 2 adrenal insufficiency, ipilimumab in combination with nivolumab should be withheld, and physiologic corticosteroid replacement should be initiated as needed. ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab may be resumed after corticosteroid taper, if needed. Ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab should be withheld, and insulin replacement should be initiated as needed. Monitoring of blood sugar should continue to ensure appropriate insulin replacement is utilised. Ipilimumab in combination with nivolumab must be permanently discontinued for life-threatening diabetes.

Infusion reaction

Ipilimumab as monotherapy or in combination with nivolumab

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

Other immune‑related adverse reactions

Ipilimumab as monotherapy

The following adverse reactions suspected to be immune‑related have been reported in patients treated with ipilimumab 3 mg/kg monotherapy in MDX010‑20: uveitis, eosinophilia, lipase elevation, and glomerulonephritis. In addition, iritis, haemolytic anaemia, amylase elevations, multi‑organ failure, and pneumonitis have been reported in patients treated with ipilimumab 3 mg/kg + gp100 peptide vaccine in MDX010‑20. Cases of Vogt-Koyanagi-Harada syndrome, serous retinal detachment, and cystitis noninfective have been reported post-marketing (see sections 4.2 and 4.8).

If severe (Grade 3 or 4), these reactions may require immediate systemic high‑dose corticosteroid therapy and discontinuation of ipilimumab (see section 4.2). For ipilimumab‑related uveitis, iritis, serous retinal detachment or episcleritis, topical corticosteroid eye drops should be considered as medically indicated. Transient vision loss has been reported in patients with ipilimumab‑related ocular inflammations.

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

Ipilimumab as monotherapy or in combination with a PD-1 or PD-L1 inhibitor

Haemophagocytic lymphohistiocytosis (HLH) has been observed with ipilimumab as monotherapy and ipilimumab in combination with a PD‑1 or PD‑L1 inhibitor (including with nivolumab). Caution should be taken when ipilimumab is administered as monotherapy or in combination with a PD‑1 or PD‑L1 inhibitor. If HLH is confirmed, administration of ipilimumab or ipilimumab in combination with a PD‑1 or PD‑L1 inhibitor should be discontinued and treatment for HLH initiated.

Ipilimumab in combination with nivolumab

The following immune-related adverse reactions were reported in less than 1% of patients treated with ipilimumab in combination with nivolumab 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, serous retinal detachment, and cystitis noninfective have been reported post-marketing (see sections 4.2 and 4.8). Transient vision loss has been reported in patients with ipilimumab‑related ocular inflammations.

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, ipilimumab in combination with nivolumab should be withheld and corticosteroids administered. Upon improvement, ipilimumab in combination with nivolumab may be resumed after corticosteroid taper. Ipilimumab in combination with nivolumab 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 ipilimumab in combination with nivolumab. 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, ipilimumab in combination with nivolumab 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, ipilimumab in combination with nivolumab should be withheld or permanently discontinued (see section 4.2).

Disease specific precautions

Melanoma

Patients with ocular melanoma, primary CNS melanoma and active brain metastases were not included in the MDX010-20 trial (see section 5.1).

Patients with ocular melanoma were not included in the CA184-169 clinical trial. However, patients with brain metastases were included in this study, if they were free of neurologic symptoms related to metastatic brain lesions and if they did not require or receive systemic corticosteroid therapy in the 10 days prior to beginning ipilimumab therapy (see section 5.1).

Patients with ocular melanoma, active brain metastases and prior therapy with ipilimumab were not included in the paediatric trial CA184070 (see section 5.1).

Patients with ocular melanoma, active brain metastases and prior therapy with CTLA-4, PD-1, PD-L1, or CD137 targeted agents were not included in the paediatric trial CA184178 (see section 5.1).

Patients with a baseline performance score ≥ 2, active brain metastases or autoimmune disease, and patients who had been receiving systemic immunosuppressants prior to study entry were excluded from the clinical trials of ipilimumab in combination with nivolumab. Patients with ocular/uveal melanoma were excluded from clinical trials of melanoma. 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.

Relative to nivolumab monotherapy, an increase in PFS for the combination of ipilimumab with nivolumab is established only in patients with low tumour PD-L1 expression. The improvement in OS was similar between ipilimumab with nivolumab 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 ipilimumab in combination with nivolumab in melanoma patients with rapidly progressing disease.

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

Renal cell carcinoma

Patients with any history of concurrent brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the clinical trials of ipilimumab in combination with nivolumab (see sections 4.5 and 5.1). In the absence of data, ipilimumab in combination with 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

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

Malignant pleural mesothelioma

Patients with primitive peritoneal, pericardial, testis, or tunica vaginalis mesothelioma, interstitial lung disease, active autoimmune disease, medical conditions requiring systemic immunosuppression, and brain metastasis (unless surgically resected or treated with stereotaxic radiotherapy and no evolution within 3 months prior to inclusion in the study) were excluded from the pivotal trial in first‑line treatment of MPM (see sections 4.5 and 5.1). In the absence of data, ipilimumab in combination with nivolumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

dMMR or MSI-H colorectal cancer

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

Oesophageal squamous cell carcinoma

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

In the first-line OSCC trial, a higher number of deaths within 4 months was observed with ipilimumab in combination with nivolumab compared to chemotherapy. Physicians should consider the delayed onset of effect of ipilimumab in combination with nivolumab before initiating treatment in patients with poorer prognostic features and/or aggressive disease (see section 5.1).

Hepatocellular carcinoma

Patients who had baseline ECOG performance score ≥ 2, prior liver transplant, Child-Pugh C liver disease, a history of concurrent brain metastases, a history of hepatic encephalopathy (within 12 months of randomization), 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, ipilimumab in combination with nivolumab 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 ipilimumab in combination with nivolumab 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 ipilimumab in combination with nivolumab in patients with poor prognostic features.

Patients with autoimmune disease

Patients with a history of autoimmune disease (other than vitiligo and adequately controlled endocrine deficiencies such as hypothyroidism), including those who require systemic immunosuppressive therapy for pre‑existing active autoimmune disease or for organ transplantation graft maintenance, were not evaluated in clinical trials. Ipilimumab is a T‑cell potentiator that enables the immune response (see section 5.1) and may interfere with immunosuppressive therapy, resulting in an exacerbation of the underlying disease or increased risk of graft rejection. Ipilimumab should be avoided in patients with severe active autoimmune disease where further immune activation is potentially imminently life threatening. In other patients with a history of autoimmune disease, ipilimumab should be used with caution after careful consideration of the potential risk-benefit on an individual basis.

Patients on controlled sodium diet

This medicinal product contains 23 mg sodium per 10 ml vial and 92 mg sodium per 40 ml vial, respectively equivalent to 1.15% and 4.60% of the WHO recommended maximum daily intake of 2 g sodium for an adult. To be taken into consideration when treating patients on a controlled sodium diet.

Concurrent administration with vemurafenib

In a Phase 1 trial, asymptomatic grade 3 increases in transaminases (ALT/AST > 5 × ULN) and bilirubin (total bilirubin > 3 × ULN) were reported with concurrent administration of ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). Based on these preliminary data, the concurrent administration of ipilimumab and vemurafenib is not recommended.

Sequential administration with vemurafenib

In a Phase 2 trial, the sequential treatment with vemurafenib followed by 10 mg/kg ipilimumab in patients with BRAF-mutated metastatic melanoma showed a higher incidence of Grade 3+ skin adverse reactions than with ipilimumab alone. Caution should be used when ipilimumab is administered following prior vemurafenib.

Paediatric population

Limited, but no long-term, safety data is available on the use of ipilimumab in adolescents 12 years of age and older.

Only very limited data are available in children younger than 12 years of age. Therefore, ipilimumab should not be used in children younger than 12 years of age.

Before initiating treatment with ipilimumab monotherapy in adolescents of 12 years and older, physicians are advised to carefully evaluate the individual patient, taking into consideration the limited available data, the observed benefits and the toxicity of ipilimumab monotherapy in the paediatric population (see sections 4.8 and 5.1).

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

Ipilimumab is a human monoclonal antibody that is not metabolised by cytochrome P450 enzymes (CYPs) or other drug metabolizing enzymes.

A drug-interaction study in adults of ipilimumab administered alone and in combination with chemotherapy (dacarbazine or paclitaxel/carboplatin) was conducted evaluating interaction with CYP isozymes (particularly CYP1A2, CYP2E1, CYP2C8, and CYP3A4) in patients with treatment-naive advanced melanoma. No clinically relevant pharmacokinetic drug‑drug interaction was observed between ipilimumab and paclitaxel/carboplatin, dacarbazine or its metabolite, 5‑aminoimidazole‑4‑carboxamide (AIC).

Other forms of interaction

Corticosteroids

The use of systemic corticosteroids at baseline, before starting ipilimumab, should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of ipilimumab. However, systemic corticosteroids or other immunosuppressants can be used after starting ipilimumab to treat immune‑related adverse reactions. The use of systemic corticosteroids after starting ipilimumab treatment does not appear to impair the efficacy of ipilimumab.

Anticoagulants

The use of anticoagulants is known to increase the risk of gastrointestinal haemorrhage. Since gastrointestinal haemorrhage is an adverse reaction with ipilimumab (see section 4.8), patients who require concomitant anticoagulant therapy should be monitored closely.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data on the use of ipilimumab in pregnant women. Animal reproduction studies have shown reproductive toxicity (see section 5.3). Human IgG1 crosses the placental barrier. The potential risk of treatment to the developing foetus is unknown. YERVOY is not recommended during pregnancy or in women of childbearing potential not using effective contraception, unless the clinical benefit outweighs the potential risk.

Breast‑feeding

Ipilimumab has been shown to be present at very low levels in milk from cynomolgus monkeys treated during pregnancy. It is unknown whether ipilimumab is secreted in human milk. Secretion of IgGs in human milk is generally limited and IgGs have a low oral bioavailability. Significant systemic exposure of the infant is not expected and no effects on the breast-fed newborn/infant are anticipated. However, because of the potential for adverse reactions in nursing infants, a decision must be made whether to discontinue breast-feeding or to discontinue from YERVOY therapy taking into account the benefit of breast-feeding for the child and the benefit of YERVOY therapy for the woman.

Fertility

Studies to evaluate the effect of ipilimumab on fertility have not been performed. Thus, the effect of ipilimumab on male and female fertility is unknown.

4.7. Effects on ability to drive and use machines

YERVOY has 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 ipilimumab does not adversely affect them.

4.8. Undesirable effects

Ipilimumab as monotherapy (see section 4.2)

a. Summary of safety profile

Ipilimumab has been administered to approximately 10,000 patients in a clinical programme evaluating its use with various doses and tumour types. Unless otherwise specified, the data below reflect exposure to ipilimumab at 3 mg/kg in clinical trials of melanoma. In the Phase 3 study MDX010‑20, (see section 5.1), patients received a median of 4 doses (range 1‑4).

Ipilimumab is most commonly associated with adverse reactions resulting from increased or excessive immune activity. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of ipilimumab (see section 4.4 for management of immune-related adverse reactions).

In patients who received 3 mg/kg ipilimumab monotherapy in MDX010‑20, the most frequently reported adverse reactions (≥ 10% of patients) were diarrhoea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite, and abdominal pain. The majority were mild to moderate (Grade 1 or 2). Ipilimumab therapy was discontinued for adverse reactions in 10% of patients.

b. Tabulated list of adverse reactions

Adverse reactions reported in patients with advanced melanoma who were treated with ipilimumab 3 mg/kg in clinical trials (n= 767) and from post-marketing surveillance are presented in Table 6.

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. Rates of immune-related adverse reactions in HLA‑A2*0201 positive patients who received ipilimumab in MDX010‑20 were similar to those observed in the overall clinical programme.

The safety profile of ipilimumab 3 mg/kg in chemotherapy-naive patients pooled across Phase 2 and 3 clinical trials (N= 75; treated), in treatment-naive patients in two retrospective observational studies (N= 273 and N= 157), and in CA184-169 (N= 362) was similar to that in previously-treated advanced melanoma.

The safety data for patients with unresectable or metastatic melanoma, treated with ipilimumab (3 mg/kg, with a minimum of 3 year follow‑up) and enrolled in multi‑national, prospective, observational study CA184143 (N= 1151) were similar to what has been reported in ipilimumab clinical trials for advanced melanoma.

Table 6: Adverse reactions in patients with advanced melanoma treated with ipilimumab 3 mg/kga

Infections and infestations

Common

sepsisb, urinary tract infection, respiratory tract infection

Uncommon

septic shockb, pneumonia

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

Common

tumour pain

Uncommon

paraneoplastic syndrome

Blood and lymphatic system disorders

Common

anaemia, lymphopaenia, thrombocytopaenia, neutropaenia

Uncommon

haemolytic anaemiab, eosinophilia

Not known

haemophagocytic lymphohistiocytosise

Immune system disorders

Uncommon

hypersensitivity

Very rare

anaphylactic reaction

Not known

solid organ transplant rejectione

Endocrine disorders

Common

hypopituitarism (including hypophysitis)c, hypothyroidismc

Uncommon

adrenal insufficiencyc, secondary adrenocortical insufficiencyd, hyperthyroidismc, hypogonadism

Rare

autoimmune thyroiditisd, thyroiditisd

Metabolism and nutrition disorders

Very common

decreased appetite

Common

dehydration, hypokalaemia, weight decreased, hyponatremia

Uncommon

alkalosis, hypophosphatemia, tumour lysis syndrome, hypocalcaemiad

Rare

type 1 diabetes mellitus (including diabetic ketoacidosis)h

Psychiatric disorders

Common

confusional state, depression

Uncommon

mental status changes, decreased libido

Nervous system disorders

Common

peripheral sensory neuropathy, dizziness, headache, lethargy, cranial neuropathy, brain oedema, peripheral neuropathy

Uncommon

Guillain‑Barré syndromeb,c, meningitis (aseptic), autoimmune central neuropathy (encephalitis)d, syncope, ataxia, tremor, myoclonus, dysarthria

Rare

myasthenia gravisd

Not known

myelitis

Eye disorders

Common

blurred vision, eye pain

Uncommon

uveitisc, vitreous haemorrhage, iritisc, eye oedemad, blepharitisd, reduced visual acuity, foreign body sensation in eyes, conjunctivitis

Rare

Vogt-Koyanagi-Harada syndromee, serous retinal detachment

Cardiac disorders

Common

arrhythmia, atrial fibrillation

Vascular disorders

Common

hypotension, flushing, hot flush

Uncommon

vasculitis, angiopathyb, peripheral ischaemia, orthostatic hypotension

Rare

temporal arteritisd

Respiratory, thoracic and mediastinal disorders

Common

dyspnoea, cough, allergic rhinitis

Uncommon

respiratory failure, acute respiratory distress syndromeb, lung infiltration, pulmonary oedema, pneumonitis

Gastrointestinal disorders

Very common

diarrhoeac, vomiting, nausea, constipation, abdominal pain

Common

gastrointestinal haemorrhage, colitisb,c, gastroesophageal reflux disease, mucosal inflammationd, gastroenteritis, stomatitis

Uncommon

gastrointestinal perforationb,c, large intestine perforationb,c, intestinal perforationb,c, peritonitisb, diverticulitis, pancreatitis, enterocolitis, gastric ulcer, large intestinal ulcer, oesophagitis, ileusd, proctitisd

Rare

pancreatic exocrine insufficiency; coeliac disease

Hepatobiliary disorders

Common

abnormal hepatic function

Uncommon

hepatic failureb,c, hepatitis, hepatomegaly, jaundice

Skin and subcutaneous tissue disorders

Very common

rashc, pruritusc

Common

dermatitis, erythema, vitiligo, urticaria, eczemad, alopecia, night sweats, dry skin

Uncommon

toxic epidermal necrolysisb,c, leukocytoclastic vasculitis, skin exfoliation, hair colour changesd

Rare

erythema multiformed, psoriasisd, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)d

Not known

pemphigoid

Musculoskeletal and connective tissue disorders

Very common

musculoskeletal painf

Common

arthralgia, myalgia, muscle spasms, arthritis

Uncommon

polymyalgia rheumatica, myositisd, muscular weaknessd

Rare

polymyositisd

Renal and urinary disorders

Common

renal failureb

Uncommon

glomerulonephritisc, autoimmune nephritisd, renal tubular acidosis, haematuriad, cystitis noninfectiveg, proteinuriad

Reproductive system and breast disorders

Uncommon

amenorrhea

General disorders and administration site conditions

Very common

fatigue, injection site reaction, pyrexia, oedema, pain

Common

chills, asthenia, influenza‑like illnessd

Uncommon

multi‑organ failureb,c, systemic inflammatory response syndromed, infusion related reaction

Investigations

Common

increased alanine aminotransferasec, increased aspartate aminotransferasec, increased blood alkaline phosphatased, increased blood bilirubin, increased lipasec

Uncommon

increased gamma-glutamyltransferased, increased blood creatinine, increased blood thyroid stimulating hormone, decreased blood cortisol, decreased blood corticotrophin, increased blood amylasec, positive antinuclear antibodyd, decreased blood testosterone

Rare

decreased blood thyroid stimulating hormoned, decreased thyroxined, abnormal blood prolactind

Adverse reaction frequencies presented in Table 6 may not be fully attributable to ipilimumab, but may contain contributions from the underlying disease.

a Frequencies are based on pooled data from 9 clinical trials investigating the ipilimumab 3 mg/kg dose in melanoma.

b Including fatal outcome.

c Additional information about these potentially inflammatory adverse reactions is provided in “Description of selected adverse reactions” and section 4.4. Data presented in those sections primarily reflect experience from a Phase 3 study, MDX010‑20.

d Data outside the 9 completed clinical trials in melanoma were included in frequency determinations.

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

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

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

h Type 1 diabetes mellitus that may be associated with diabetic ketoacidosis

Additional adverse reactions not listed in Table 6 have been reported in patients who received other doses (either < or > 3 mg/kg) of ipilimumab in clinical trials of melanoma. These additional reactions occurred at a frequency of < 1% unless otherwise noted: meningism, myocarditis, pericardial effusion, cardiomyopathy, autoimmune hepatitis, erythema nodosum, autoimmune pancreatitis, hyperpituitarism, hypoparathyroidism, infectious peritonitis, episcleritis, scleritis, Raynaud's phenomenon, palmar‑plantar erythrodysaesthesia syndrome, cytokine release syndrome, sarcoidosis, decreased blood gonadotrophin, leukopenia, polycythaemia, lymphocytosis, ocular myositis, and neurosensory hypoacusis.

The overall safety profile of ipilimumab 3 mg/kg in clinical trial CA184-169 (N=362) was consistent with that established for ipilimumab in patients treated for advanced melanoma.

Ipilimumab in combination with nivolumab (with or without chemotherapy) (see section 4.2)

a. Summary of the safety profile

When ipilimumab is administered in combination, refer to the SmPC for the other therapeutic agent(s) prior to initiation of treatment. For additional information on the safety profile of the other therapeutic agents used in combination with ipilimumab, please refer to the respective SmPC.

In the pooled dataset of ipilimumab administered in combination with nivolumab (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 ipilimumab in combination with nivolumab (with or without chemotherapy), with 1.0% fatal adverse reactions attributed to study drug. Among patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 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 ipilimumab in combination with nivolumab (with or without chemotherapy) incidence rate. Among patients treated with ipilimumab 1 mg/kg in combination with nivolumab 360 mg 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 ipilimumab in combination with nivolumab (with or without chemotherapy) incidence rate.

b. Tabulated summary of adverse reactions

Adverse reactions reported in the pooled dataset for patients treated with ipilimumab in combination with nivolumab (with or without chemotherapy) (n= 2626) and from post-marketing are presented in Table 7. 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 (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); 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 7: Adverse reactions with ipilimumab in combination with other therapeutic agents

Combination with nivolumab (with or without chemotherapy)

Infections and infestations

Very common

upper respiratory tract infection

Common

pneumonia, bronchitis, conjunctivitis

Rare

aseptic meningitis

Blood and lymphatic system disorders

Very common

anaemiab,i, thrombocytopaeniab, leucopoeniab, lymphopaeniab, neutropaeniab

Common

eosinophilia

Uncommon

febrile neutropaenia

Not known

haemophagocytic lymphohistiocytosis

Immune system disorders

Common

infusion-related reaction (including cytokine release syndrome), hypersensitivity

Rare

sarcoidosis

Not known

solid organ transplant rejectionf

Endocrine disorders

Very common

hypothyroidism

Common

hyperthyroidism, thyroiditis, adrenal insufficiency, hypophysitis, hypopituitarism, diabetes mellitus

Uncommon

diabetic ketoacidosis

Rare

hypoparathyroidism

Metabolism and nutrition disorders

Very common

decreased appetite, hyperglycaemiab, hypoglycaemiab

Common

dehydration, hypoalbuminaemia, hypophosphataemia, weight decreased

Uncommon

metabolic acidosis

Not known

tumour lysis syndromeg

Nervous system disorders

Very common

headache

Common

dizziness, peripheral neuropathy

Uncommon

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

Rare

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

Eye disorders

Common

blurred vision, dry eye

Uncommon

uveitis, episcleritis

Rare

Vogt‑Koyanagi‑Harada syndrome, serous retinal detachment

Cardiac disorders

Common

tachycardia, atrial fibrillation

Uncommon

myocarditisa, arrhythmia (including ventricular arrhythmia)a, bradycardia

Not known

pericardial disordersh

Vascular disorders

Common

hypertension

Respiratory, thoracic and mediastinal disorders

Very common

cough, dyspnoea

Common

pneumonitisa, pulmonary embolisma, pleural effusion

Gastrointestinal disorders

Very common

diarrhoea, vomiting, nausea, abdominal pain, constipation

Common

colitisa, pancreatitis, stomatitis, gastritis, dry mouth

Uncommon

duodenitis

Rare

Intestinal perforationa, pancreatic exocrine insufficiency, coeliac disease

Hepatobiliary disorders

Common

hepatitis

Skin and subcutaneous tissue disorders

Very common

rashc, pruritus

Common

alopecia, vitiligo, urticaria, dry skin, erythema

Uncommon

Stevens-Johnson syndrome, erythema multiforme, psoriasis, other lichen disordersj

Rare

toxic epidermal necrolysisa,d, lichen sclerosus

Musculoskeletal and connective tissue disorders

Very common

musculoskeletal paine, arthralgia

Common

muscle spasms, muscular weakness, arthritis

Uncommon

polymyalgia rheumatica, myopathy, myositis (including polymyositis)a

Rare

spondyloarthropathy, Sjogren's syndrome, rhabdomyolysisa

Renal and urinary disorders

Common

renal failure (including acute kidney injury)a

Uncommon

tubulointerstitial nephritis, nephritis

Rare

cystitis noninfective

General disorders and administration site conditions

Very common

fatigue, pyrexia, oedema (including peripheral oedema)

Common

chest pain, pain, chills

Investigations

Very common

increased alkaline phosphataseb, increased ASTb, increased ALTb, increased total bilirubinb, increased creatinineb, increased amylaseb, increased lipaseb, hyponatraemiab, hyperkalaemiab, hypokalaemiab, hypercalcaemiab, hypocalcaemiab

Common

hypernatraemiab, hypermagnesaemiab, increased thyroid stimulating hormone, increased gamma-glutamyltransferase

Adverse reaction frequencies presented in Table 7 may not be fully attributable to ipilimumab alone or in combination with other therapeutic agents, but may contain contributions from the underlying disease or from medicinal product used in combination.

a Fatal cases have been reported in completed or ongoing clinical studies

b Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from baseline in laboratory measurements. See “Description of selected adverse reactions; laboratory abnormalities” below.

c Rash is a composite term which includes maculopapular rash, rash erythematous, rash pruritic, rash follicular, rash macular, rash morbilliform, rash papular, rash pustular, rash papulosquamous, rash vesicular, rash generalised, exfoliative rash, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, dermatitis exfoliative, dermatitis psoriasiform, drug eruption, nodular rash, and pemphigoid.

d Reported also in studies outside the pooled dataset. The frequency is based on the programme-wide exposure.

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

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

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

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

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

j Lichen disorders is a composite term which includes lichen keratosis and lichen planus.

Description of selected adverse reactions

Except where noted, data relating to ipilimumab monotherapy are based on patients who received either ipilimumab 3 mg/kg monotherapy (n= 131) or ipilimumab 3 mg/kg in combination with gp100 (n= 380) in a Phase 3 study of advanced (unresectable or metastatic) melanoma (MDX010-20, see section 5.1).

Ipilimumab in combination 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 ipilimumab in combination with nivolumab than in those receiving nivolumab monotherapy. Table 8 presents the percentage of patients with immune-related adverse reactions who were permanently discontinued from treatment. Additionally, for patients who experienced an event, Table 8 presents the percentage of patients who required high-dose corticosteroids (at least 40 mg daily prednisone equivalents). The management guidelines for these adverse reactions are described in section 4.4.

Table 8: Immune-related adverse reactions leading to permanent discontinuation or requiring high-dose corticosteroids

Ipilimumab in combination with nivolumab (with or without chemotherapy) %

Immune-related adverse reaction leading to permanent discontinuation

Pneumonitis

2.1

Colitis

6

Hepatitis

5

Nephritis and renal dysfunction

1.1

Endocrinopathies

2.2

Skin

1.0

Hypersensitivity/Infusion reaction

0.3

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

Pneumonitis

59

Colitis

32

Hepatitis

39

Nephritis and renal dysfunction

27

Endocrinopathies

18

Skin

8

Hypersensitivity/Infusion reaction

18

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 gastrointestinal reactions

Ipilimumab is associated with serious immune‑related gastrointestinal reactions. Fatalities due to gastrointestinal perforation have been reported in < 1% of patients who received ipilimumab 3 mg/kg in combination with gp100.

In the ipilimumab 3 mg/kg monotherapy group, diarrhoea and colitis of any severity were reported in 27% and 8%, respectively. The frequency of severe (Grade 3 or 4) diarrhoea and severe (Grade 3 or 4) colitis was 5% each. The median time to onset of severe or fatal (Grade 3 to 5) immune‑related gastrointestinal reactions was 8 weeks (range 5 to 13 weeks) from the start of treatment. With protocol‑specified management guidelines, resolution (defined as improvement to mild [Grade 1] or less or to the severity at baseline) occurred in most cases (90%), with a median time from onset to resolution of 4 weeks (range 0.6 to 22 weeks). In clinical trials, immune‑related colitis was associated with evidence of mucosal inflammation, with or without ulcerations, and lymphocytic and neutrophilic infiltration.

Immune-related colitis

In patients treated with ipilimumab in combination with nivolumab (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 ipilimumab 3 mg/kg in combination with nivolumab 1 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%).

Immune-related pneumonitis

In patients treated with ipilimumab in combination with nivolumab (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+).

Immune‑related hepatotoxicity

Ipilimumab is associated with serious immune‑related hepatotoxicity. Fatal hepatic failure has been reported in < 1% of patients who received ipilimumab 3 mg/kg monotherapy.

Increases in AST and ALT of any severity were reported in 1% and 2% of patients, respectively. There were no reports of severe (Grade 3 or 4) AST or ALT elevation. Time to onset of moderate to severe or fatal (Grade 2 to 5) immune‑related hepatotoxicity ranged from 3 to 9 weeks from the start of treatment. With protocol‑specified management guidelines, time to resolution ranged from 0.7 to 2 weeks. In clinical trials, liver biopsies from patients who had immune‑related hepatotoxicity showed evidence of acute inflammation (neutrophils, lymphocytes, and macrophages).

In patients receiving ipilimumab at a higher than recommended dose in combination with dacarbazine, immune‑related hepatotoxicity occurred more frequently than in patients receiving ipilimumab 3 mg/kg monotherapy.

In patients treated with ipilimumab in combination with nivolumab (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 ipilimumab 3 mg/kg in combination with nivolumab 1 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 ipilimumab 3 mg/kg in combination with nivolumab 1 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%).

Immune‑related skin adverse reactions

Ipilimumab is associated with serious skin adverse reactions that may be immune‑related. Fatal toxic epidermal necrolysis (including SJS) has been reported in < 1% of patients who received ipilimumab in combination with gp100 (see section 5.1). Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been rarely reported with Ipilimumab in clinical studies and during post-marketing use. Incidental cases of pemphigoid have been reported during post-marketing use.

In the ipilimumab 3 mg/kg monotherapy group, rash and pruritus of any severity were each reported in 26% of patients. Ipilimumab‑induced rash and pruritus were predominantly mild (Grade 1) or moderate (Grade 2) and responsive to symptomatic therapy. The median time to onset of moderate to severe or fatal (Grade 2 to 5) skin adverse reactions was 3 weeks from start of treatment (range 0.9 to 16 weeks). With protocol‑specified management guidelines, resolution occurred in most cases (87%), with a median time from onset to resolution of 5 weeks (range 0.6 to 29 weeks).

In patients treated with ipilimumab in combination with nivolumab (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 ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg for melanoma, the incidence of rash was 65.2%, including Grade 2 (20.3%) and Grade 3 (7.8%).

Immune‑related neurological reactions

Ipilimumab is associated with serious immune‑related neurological reactions. Fatal Guillain‑Barré syndrome has been reported in < 1% of patients who received ipilimumab 3 mg/kg in combination with gp100. Myasthenia gravis‑like symptoms have also been reported in < 1% of patients who received higher doses of ipilimumab in clinical trials.

Immune-related nephritis and renal dysfunction

In patients treated with ipilimumab in combination with nivolumab (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+).

Immune‑related endocrinopathy

In the ipilimumab 3 mg/kg monotherapy group, hypopituitarism of any severity was reported in 4% of patients. Adrenal insufficiency, hyperthyroidism, and hypothyroidism of any severity were each reported in 2% of patients. The frequency of severe (Grade 3 or 4) hypopituitarism was reported in 3% of patients. Time to onset of moderate to very severe (Grade 2 to 4) immune‑related endocrinopathy ranged from 7 to nearly 20 weeks from the start of treatment. Immune‑related endocrinopathy observed in clinical trials was generally controlled with hormone replacement therapy.

In patients treated with ipilimumab in combination with nivolumab (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.

Infusion reactions

In patients treated with ipilimumab in combination with nivolumab (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 MPM treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg, the incidence of hypersensitivity/infusion reactions was 12%.

Immunogenicity

Less than 2% of patients with advanced melanoma who received ipilimumab in Phase 2 and 3 clinical trials developed antibodies against ipilimumab. None had any infusion-related or peri-infusional hypersensitivity or anaphylactic reactions. Neutralising antibodies against ipilimumab were not detected. Overall, no apparent association was observed between antibody development and adverse reactions.

Of the patients who were treated with ipilimumab in combination with nivolumab and evaluable for the presence of anti-ipilimumab antibodies, the incidence of anti-ipilimumab antibodies ranged from 6.3 to 13.7%. Neutralising antibodies against ipilimumab ranged from 0 to 0.4%. Of the patients who were treated with ipilimumab in combination with nivolumab 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 neutralising antibodies against ipilimumab was 1.6%. Of patients evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 26% 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, 37.8% with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks, and 33.8% with nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg every 6 weeks and chemotherapy. 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, 4.6% with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks and 2.6% with nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg every 6 weeks and chemotherapy.

When administered in combination with nivolumab, the CL of ipilimumab was unchanged in the presence of anti‑ipilimumab antibodies and there was no evidence of altered toxicity profile.

Laboratory abnormalities

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

Paediatric population

Ipilimumab as monotherapy

No new adverse drug reactions were reported in adolescents 12 years of age and older.

In study CA184070, no immune-related adverse reactions (irAR) ≥ Grade 3 were reported for the single patient 12 years of age and older who was treated with ipilimumab 3 mg/kg. Two (25.0%) of 8 patients treated with 5 mg/kg and 1 (11.1%) of 9 patients treated with 10 mg/kg reported Grade 3–4 events. None of the events were fatal. The types of irARs were consistent with the adult experience, with the most commonly reported irARs across all groups in the categories of gastrointestinal (0 [3 mg/kg], 62.5% [5 mg/kg], and 44.4% [10 mg/kg]), hepatic function (0 [3 mg/kg], 75.0% [5 mg/kg], 33.3% [10 mg/kg]), and skin (0 [3 mg/kg], 25.0% [5 mg/kg], 33.3% [10 mg/kg]) events. No new or unexpected irARs were observed in this study. No differences in the spectrum of irARs reported in adults and the paediatric population were evident.

In study CA184178, no new or unexpected irARs were observed, and the observed irARs were similar in frequency, intensity and organ site to what has been reported in adult studies. Two patients in the 10 mg/kg group experienced a Grade 1 and Grade 3 on-study endocrine irAR of hyperglycemia. No other endocrine abnormalities were reported.

A summary of adverse events in adolescents 12 years of age and older, as well as adults, is presented in Table 9.

Table 9: Summary of adverse events after up to four doses of 3, 5 and 10 mg/kg, all treated patients

Number of patients (%)

Age ≥ 12 to 21 years

Age 12 to < 18 years

Adults

Advanced melanoma and non-melanoma solid tumours

Advanced melanoma

Advanced melanoma

CA184070

CA184178

CA184004/022 pooled

CA184004/007/008/022 pooled

3 mg/kg

n = 1

5 mg/kg

n = 8

10 mg/kg

n = 9

3 mg/kg

n = 4

10 mg/kg n = 8

3 mg/kg

n = 111

10 mg/kg

n = 325

All deaths, n (%)

1 (100.0)

4 (50.0)

2

(22.2)

2 (50.0)

3 (37.5)

26 (23.4)

71 (21.8)

Treatment-related deaths, n (%)

0

0

0

0

0

2 (1.8)

6 (1.8)

SAEs, n (%)

1 (100.0)

7 ( 87.5)

4 ( 44.4)

1 (25.0)

6 (75.0)

50 (45.0)

168 (51.7)

SAEs, drug-related, n (%)

1 (100.0)

5 ( 62.5)

4 ( 44.4)

1 (25.0)

5 (62.5)

19 (17.1)

95 (29.2)

AEs leading to study drug discontinuation, n (%)

0

3 ( 37.5)

2 ( 22.2)

1 (25.0)

5 (62.5)

12 (10.8)

88 (27.1)

Drug-related AEs leading to study drug discontinuation, n (%)

0

3 ( 37.5)

2 ( 22.2)

1 (25.0)

5 (62.5)

9 (8.1)

61 (18.8)

irAEs, n (%)

1 (100.0)

7 ( 87.5)

7 ( 77.8)

2 (50.0)

4 (50.0)

68 (61.3)

234 (72.0)

AE, n (%)

1 (100.0)

8 (100.0)

9 (100.0)

4 (100.0)

8 (100.0)

108 (97.3)

315 (96.9)

Drug-related AEs, n (%)

1 (100.0)

7 ( 87.5)

9 (100.0)

2 (50.0)

7 (87.5)

88 (79.3)

274 (84.3)

MedDRA v.17.0 for CA184070, v.19.0 for CA184178, and V.12.1 for adult safety pool. NA = not assessed

For adults, deaths reported in this table are within 70 days of the last dose, regardless of relationship. Deaths for paediatric patients are those with on-study events within 30 days of the last dose, except for “all deaths,” which were >30 days after the last dose. In CA184178, deaths were reported at least 90 days of the last dose.

Attribution to ipilimumab reported as possible, probable, definite, or missing for CA184178 and adult safety pool, and related or missing for CA184070.

Abbreviations: SAEs = serious adverse events; AEs = adverse events; irAEs = immune-related adverse events

Ipilimumab in combination with nivolumab

The safety of ipilimumab (1 mg/kg every 3 weeks) in combination with nivolumab (1 mg/kg or 3 mg/kg for the first 4 doses, followed by nivolumab 3 mg/kg as monotherapy every 2 weeks) was evaluated in 33 paediatric patients aged ≥ 1 year to < 18 years (including 20 patients 12 to < 18 years) with recurrent or refractory solid or haematological tumours, including advanced melanoma, in clinical study CA209070. The safety profile in paediatric patients was generally similar to that seen in adults treated with ipilimumab in combination with nivolumab. No new safety signals were observed.

The most common adverse reactions (reported in at least 20% of paediatric patients) for ipilimumab in combination with nivolumab were fatigue (33.3%) and rash maculo-papular (21.2%). The majority of adverse reactions reported for ipilimumab in combination with nivolumab were of Grades 1 or 2 in severity. Ten patients (30%) had one or more Grades 3 to 4 adverse reactions.

No new safety signals were observed in clinical study CA209908 of 74 paediatric patients with high‑grade primary central nervous system (CNS) malignancies (see section 5.1) relative to data available in adult studies across indications.

Elderly

In MPM patients, there was a higher rate of serious adverse reactions and discontinuation rate due to adverse reactions in patients 75 years of age or older (68% and 35%, respectively) relative to all patients who received ipilimumab in combination with nivolumab (54% and 28%, respectively). 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 ipilimumab with nivolumab (53% and 27%, respectively).

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

4.9. Overdose

The maximum tolerated dose of ipilimumab has not been determined. In clinical trials, patients received up to 20 mg/kg without apparent toxic effects.

In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted.