Yervoy

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



 
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1. NAME OF THE MEDICINAL PRODUCT 
 
YERVOY 5 mg/ml concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each ml of concentrate contains 5 mg ipilimumab. 
One 10 ml vial contains 50 mg of ipilimumab. 
One 40 ml vial contains 200 mg of ipilimumab. 
 
Ipilimumab is a fully human anti-CTLA-4 monoclonal antibody (IgG1κ) produced in Chinese hamster 
ovary cells by recombinant DNA technology. 
 
Excipients with known effect: 
 
Each ml of concentrate contains 0.1 mmol sodium, which is 2.30 mg sodium. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion (sterile concentrate). 
 
Clear to slightly opalescent, colourless to pale yellow liquid that may contain light (few) particulates 
and has a pH of 7.0 and an osmolarity of 260-300 mOsm/kg. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Melanoma 
 
YERVOY as monotherapy 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). 
 
YERVOY in combination with nivolumab is indicated for the treatment of advanced (unresectable or 
metastatic) melanoma in adults. 
 
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. 
 



 
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4.2 Posology and method of administration 
 
Treatment must be initiated and supervised by specialist physicians experienced in the treatment of 
cancer. 
 
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 90-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 
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, 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. 
 
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 1 mg/kg over 30 minutes 
240 mg every 2 weeks over 30 minutes or 
480 mg every 4 weeks over 60 minutes 

Ipilimumab 3 mg/kg over 90 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. 
 



 
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Table 2: 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 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 - 

 
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 3A, 3B, 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 3A and 3B 
for YERVOY as monotherapy, and in Table 3C 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. 
 



 
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Table 3A 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). 

Severe or life-threatening 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) 

 ≥ Grade 3 immune-related 

reactionsc 
 ≥ Grade 2 for immune-related 

eye disorders NOT responding to 
topical immunosuppressive 
therapy 

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.  

 



 
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Table 3B 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. 

Mild to moderate Immune-related 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  

 
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. 
 



 
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Table 3C: 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 

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

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

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

Permanently discontinue treatment 

Immune-related 
nephritis and renal 
dysfunction 

Grade 2 or 3 creatinine elevation  Withhold dose(s) until creatinine returns 
to baseline and management with 
corticosteroids is complete 
 

Grade 4 creatinine elevation Permanently discontinue treatment

Immune-related 
endocrinopathies 

Symptomatic Grade 2 or 3 
hypothyroidism, hyperthyroidism, 
hypophysitis, 
Grade 2 adrenal insufficiency 
Grade 3 diabetes 

Withhold dose(s) until symptoms 
resolve and management with 
corticosteroids (if needed for symptoms 
of acute inflammation) is complete. 
Treatment should be continued in the 
presence of hormone replacement 
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 



 
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Table 3C: Recommended treatment modifications for YERVOY in combination with 
nivolumab or administration of the second phase of treatment (nivolumab 
monotherapy) following combination 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 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. 
 
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 or 90 minutes, depending on 
the dose. 
 



 
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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 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 
 
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.  



 
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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 



 
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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. 
 



 
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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. 
 



 
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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 characterized 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 



 
14 

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, and hypothyroidism (see section 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 



 
15 

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. 
 
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. 
 



 
16 

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 and serous retinal detachment 
have been reported post-marketing (see section 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, and rhabdomyolysis. Cases of 
Vogt-Koyanagi-Harada syndrome and serous retinal detachment have been reported post-marketing 
(see section 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 



 
17 

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 or 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. 
 



 
18 

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. 
 
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 
 



 
19 

Ipilimumab is a human monoclonal antibody that is not metabolized 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. 
 



 
20 

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 program 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 4. 
 
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 
program.  
 
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. 
 



 
21 

Table 4: Adverse reactions in patients with advanced melanoma treated with ipilimumab 
3 mg/kga 

Infections and infestations 
Uncommon sepsisb, septic shockb, urinary tract infection, respiratory tract infection  
Neoplasms benign, malignant and unspecified (including cysts and polyps) 
Common tumour pain 
Uncommon paraneoplastic syndrome 
Blood and lymphatic system disorders 
Common anaemia, lymphopenia  
Uncommon haemolytic anaemiab, thrombocytopenia, eosinophilia, neutropenia  
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, hypokalemia  
Uncommon hyponatremia, alkalosis, hypophosphatemia, tumour lysis syndrome, hypocalcaemiad 
Psychiatric disorders 
Common confusional state  
Uncommon mental status changes, depression, decreased libido  
Nervous system disorders 
Common peripheral sensory neuropathy, dizziness, headache, lethargy 
Uncommon Guillain-Barré syndromeb,c, meningitis (aseptic), autoimmune central neuropathy 

(encephalitis)d, syncope, cranial neuropathy, brain oedema, peripheral neuropathy, 
ataxia, tremor, myoclonus, dysarthria

Rare myasthenia gravisd 
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 
Uncommon 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 dyspnea, cough  
Uncommon respiratory failure, acute respiratory distress syndromeb, lung infiltration, pulmonary 

oedema, pneumonitis, allergic rhinitis
Gastrointestinal disorders 
Very common diarrhoeac, vomiting, nausea  
Common gastrointestinal haemorrhage, colitisb,c, constipation, gastroesophageal reflux disease, 

abdominal pain, mucosal inflammationd 



 
22 

Uncommon gastrointestinal perforationb,c, large intestine perforationb,c, intestinal perforationb,c, 
peritonitisb, gastroenteritis, diverticulitis, pancreatitis, enterocolitis, gastric ulcer, 
large intestinal ulcer, stomatitis, oesophagitis, ileusd 

Rare proctitisd 
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 
Common arthralgia, myalgia, musculoskeletal painf, muscle spasms  
Uncommon polymyalgia rheumatica, myositisd, arthritis, muscular weaknessd 
Rare polymyositisd 
Renal and urinary disorders 
Uncommon renal failureb, glomerulonephritisc, autoimmune nephritisd, renal tubular acidosis, 

haematuriad 
Rare proteinuriad 
Reproductive system and breast disorders 
Uncommon amenorrhea 
General disorders and administration site conditions 
Very common fatigue, injection site reaction, pyrexia 
Common chills, asthenia, oedema, pain, 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, weight decreased  
Uncommon increased gamma-glutamyltransferased, increased blood creatinine, increased blood 

thyroid stimulating hormone, decreased blood cortisol, decreased blood 
corticotrophin, increased lipasec, increased blood amylasec, positive antinuclear 
antibodyd, decreased blood testosterone 

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

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. 

 
Additional adverse reactions not listed in Table 4 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, 



 
23 

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 ipilimumb in patients treated for advanced melanoma. 
 
Ipilimumab in combination with nivolumab (see section 4.2) 
 
a. Summary of the safety profile 
When ipilimumab is administered in combination with nivolumab, refer to the Summary of Product 
Characteristics for nivolumab prior to initiation of treatment. For additional information on warnings 
and precautions associated with nivolumab treatment, please refer to the nivolumab SmPC. 
 
Melanoma 
In the pooled dataset of ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg in melanoma 
(n = 448) with minimum follow-up ranging from 6 to 28 months, the most frequent adverse 
reactions (≥ 10%) were rash (52%), fatigue (46%), diarrhoea (43%), pruritus (36%), nausea (26%), 
pyrexia (19%), decreased appetite (16%), hypothyroidism (16%), colitis (15%), vomiting (14%), 
arthralgia (13%), abdominal pain (13%), headache (11%), and dyspnoea (10%). The majority of 
adverse reactions were mild to moderate (Grade 1 or 2). 
 
Among the patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg in 
CA209067, 154/313 (49%) had the first onset of Grade 3 or 4 adverse reactions during the initial 
combination phase. Among the 147 patients in this group who continued treatment in the single-agent 
phase, 47 (32%) experienced at least one Grade 3 or 4 adverse reaction during the single-agent phase. 
With a minimum of 60 months follow-up from study CA209067, no new safety signals were 
identified. 
 
RCC 
In the dataset of ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in RCC (n = 547), with 
a minimum follow-up of 17.5 months, the most frequent adverse reactions (≥ 10%) were 
fatigue (48%), rash (34%), pruritus (28%), diarrhoea (27%), nausea (20%), hypothyroidism (16%), 
musculoskeletal pain (15%), arthralgia (14%), decreased appetite (14%), pyrexia (14%), 
vomiting (11%), hyperthyroidism (11%). The majority of adverse reactions were mild to moderate 
(Grade 1 or 2). 
 
Among the patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in 
CA209214, 169/547 (31%) had the first onset of Grade 3 or 4 adverse reactions during the initial 
combination phase. Among the 382 patients in this group who continued treatment in the single-agent 
phase, 144 (38%) experienced at least one Grade 3 or 4 adverse reaction during the single-agent phase. 
 
b. Tabulated summary of adverse reactions 
Adverse reactions reported in the pooled dataset for patients treated with ipilimumab 3 mg/kg in 
combination with nivolumab 1 mg/kg (n = 448) are presented in Table 5. 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. 
 



 
24 

Table 5: Adverse reactions with ipilimumab in combination with nivolumab 
 Ipilimumab 3 mg/kg in combination 

with nivolumab 1 mg/kg* 
Ipilimumab 1 mg/kg in combination 
with nivolumab 3 mg/kg** 

Infections and infestations 
Common pneumonia, upper respiratory tract 

infection 
pneumonia, upper respiratory tract 
infection, conjunctivitis 

Uncommon bronchitis bronchitis, aseptic meningitis 
Blood and lymphatic system disorders 
Common eosinophilia  
Uncommon  eosinophilia 
Not known haemophagocytic lymphohistiocytosish haemophagocytic lymphohistiocytosish 
Immune system disorders 
Common infusion related reaction, 

hypersensitivity 
infusion-related reaction, 
hypersensitivity 

Uncommon sarcoidosis  
Not known solid organ transplant rejectionh  
Endocrine disorders 
Very common hypothyroidism hypothyroidism, hyperthyroidism 
Common adrenal insufficiency, hypopituitarism, 

hypophysitis, hyperthyroidism, 
thyroiditis 

adrenal insufficiencyc, hypophysitisc, 
thyroiditis, diabetes mellitusc 

Uncommon diabetic ketoacidosisc, diabetes mellitusc diabetic ketoacidosisc, hypopituitarism 
Metabolism and nutrition disorders 
Very common decreased appetite decreased appetite 
Common dehydration dehydration 
Uncommon  metabolic acidosis 
Not known  tumour lysis syndromei   
Nervous system disorders 
Very common headache  
Common peripheral neuropathy, dizziness headache, peripheral neuropathy, 

dizziness
Uncommon Guillain-Barré syndrome, 

polyneuropathy, neuritis, peroneal nerve 
palsy, autoimmune neuropathy 
(including facial and abducens nerve 
paresis), encephalitisc

polyneuropathy, autoimmune 
neuropathy (including facial and 
abducens nerve paresis), myasthenia 
gravisc 

Eye disorders 
Common uveitis, blurred vision blurred vision 
Uncommon  uveitis 
Not known Vogt-Koyanagi-Harada syndromeh  
Rare serous retinal detachment serous retinal detachment 
Cardiac disorders 
Common tachycardia tachycardia 
Uncommon arrhythmia (including ventricular 

arrhythmia)a,d, atrial fibrillation, 
myocarditisa,f 

arrhythmia (including ventricular 
arrhythmia), myocarditisc 

Not known pericardial disordersj  
Vascular disorders 
Common hypertension hypertension 
Respiratory, thoracic and mediastinal disorders 
Very common dyspnoea  
Common pneumonitisa,c, pulmonary embolisma, 

cough 
pneumonitis, dyspnoea, pleural effusion, 
cough 



 
25 

Uncommon pleural effusion  
Gastrointestinal disorders 
Very common colitisa, diarrhoea, vomiting, nausea, 

abdominal pain
diarrhoea, vomiting, nausea 

Common stomatitis, pancreatitis, constipation, dry 
mouth 

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

Uncommon intestinal perforationa, gastritis, 
duodenitis 

gastritis 

Hepatobiliary disorders 
Common hepatitisc hepatitisc 
Skin and subcutaneous tissue disorders  

Very common rashe, pruritus rashe, pruritus 
Common vitiligo, dry skin, erythema, alopecia, 

urticaria 
dry skin, erythema, urticaria 

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

Rare toxic epidermal necrolysisa,f
, Stevens-

Johnson syndromef 
 

Musculoskeletal and connective tissue disorders 
Very common arthralgia musculoskeletal paing, arthralgia 
Common musculoskeletal paing arthritis, muscle spasms, muscular 

weakness
Uncommon spondyloarthropathy, Sjogren’s 

syndrome, arthritis, myopathy, myositis 
(including polymyositis)a,e, 
rhabdomyolysisa,f 

polymyalgia rheumatica, myositis 
(including polymyositis), 
rhabdomyolysis 

Renal and urinary disorders 
Common renal failure (including acute kidney 

injury)a,c 
renal failure (including acute kidney 
injury)c 

Uncommon tubulointerstitial nephritis tubulointerstitial nephritis 
General disorders and administration site conditions 
Very common fatigue, pyrexia fatigue, pyrexia 
Common oedema (including peripheral oedema), 

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

Uncommon chest pain  
Investigationsb 
Very common increased AST, increased ALT, 

increased total bilirubin, increased 
alkaline phosphatase, increased lipase, 
increased amylase, increased creatinine, 
hyperglycaemiac, hypoglycaemia, 
lymphopaenia, leucopoenia, 
neutropaenia, thrombocytopaenia, 
anaemia, hypocalcaemia, 
hyperkalaemia, hypokalaemia, 
hypomagnesaemia, hyponatraemia 

increased AST, increased ALT, 
increased total bilirubin, increased 
alkaline phosphatase, increased lipase, 
increased amylase, increased creatinine, 
hyperglycaemiac, hypoglycaemia, 
lymphopaenia, leucopoenia, 
neutropaeniac, thrombocytopaenia, 
anaemia, hypercalcaemia, 
hypocalcaemia, hyperkalaemia, 
hypokalaemia, hypomagnesaemia, 
hyponatraemia

Common hypercalcaemia, hypermagnesaemia, 
hypernatraemia, weight decreased 

hypermagnesaemia, hypernatraemia, 
weight decreased 

* ipilimumab in combination with nivolumab for the first 4 doses then followed by nivolumab 
monotherapy in melanoma. 

** ipilimumab in combination with nivolumab for the first 4 doses then followed by nivolumab monotherapy 
in RCC. 

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



 
26 

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

c Life-threatening cases have been reported in completed or ongoing clinical studies. 
d The frequency of adverse events in the cardiac disorders system organ class regardless of causality was 

higher in the nivolumab group than in the chemotherapy group in post-CTLA4/BRAF inhibitor metastatic 
melanoma population. Incidence rates per 100 person-years of exposure were 9.3 vs. 0; serious cardiac 
events were reported by 4.9% patients in the nivolumab group vs. 0 in the investigator´s choice group. 
The frequency of cardiac adverse events was lower in the nivolumab group than in the dacarbazine group 
in the metastatic melanoma without prior treatment population. All were considered not related to 
nivolumab by investigators except arrhythmia (atrial fibrillation, tachycardia and ventricular arrhythmia). 

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

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

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

h Post-marketing event (also see section 4.4) 
i Reported in clinical studies and in the post-marketing setting. 
j Pericardial disorders is a composite term which includes pericarditis, pericardial effusion, cardiac 

tamponade, and Dressler’s syndrome. 
 
Ipilimumab in combination with nivolumab and chemotherapy (see section 4.2) 
 
a. Summary of the safety profile 
When ipilimumab is administered in combination, refer to the Summary of Product Characteristics for 
the respective combination therapy components prior to initiation of treatment. 
 
In the dataset of ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg every 
3 weeks and 2 cycles of chemotherapy in NSCLC (n = 358), with a minimum follow-up of 
6.5 months, the most frequent adverse reactions were fatigue (36%), nausea (26%), rash (25%), 
diarrhoea (20%), pruritus (18%), decreased appetite (16%), hypothyroidism (15%), and vomiting 
(13%). The majority of adverse reactions were mild to moderate (Grade 1 or 2). Median duration of 
therapy was 6.1 months (95% CI 4.93, 7.06) for ipilimumab in combination with nivolumab and 
chemotherapy and 2.4 months (95% CI 2.30, 2.83) for chemotherapy.  
 
b. Tabulated summary of adverse reactions 
Adverse reactions reported in the dataset for patients treated with ipilimumab 1 mg/kg every 6 weeks 
in combination with nivolumab 360 mg every 3 weeks and 2 cycles of chemotherapy in NSCLC 
(n = 358) 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). Within each 
frequency grouping, adverse reactions are presented in the order of decreasing seriousness. 
 



 
27 

Table 6: Adverse reactions with ipilimumab in combination with nivolumab and 
chemotherapy 
Infections and infestations 
Common conjunctivitis, pneumonia, respiratory tract infection 
Blood and lymphatic system disorders 
Common febrile neutropaenia 
Uncommon eosinophilia 
Immune system disorders 
Common infusion-related reaction, hypersensitivity 
Endocrine disorders 
Very common hypothyroidism 
Common hyperthyroidism, adrenal insufficiency, hypophysitis, thyroiditis 
Uncommon hypopituitarism, hypoparathyroidism 
Metabolism and nutrition disorders 
Very common decreased appetite 
Common dehydration, hypoalbunaemia, hypophosphataemia 
Nervous system disorders 
Common peripheral neuropathy, dizziness 
Uncommon polyneuropathy, autoimmune neuropathy (including facial and abducens 

nerve paresis), encephalitis
Eye disorders 
Common dry eye 
Uncommon blurred vision, episcleritis 
Cardiac disorders 
Uncommon tachycardia, atrial fibrillation, bradycardia 
Vascular disorders 
Uncommon hypertension 
Respiratory, thoracic and mediastinal disorders 
Common pneumonitis, dyspnoea, cough 
Uncommon pleural effusion 
Gastrointestinal disorders 
Very common nausea, diarrhoea, vomiting 
Common constipation, stomatitis, abdominal pain, colitis, dry mouth, pancreatitis 
Hepatobiliary disorders 
Common hepatitis 
Skin and subcutaneous tissue disorders 
Very common rasha, pruritus 
Common alopecia, dry skin, erythema, urticaria 
Uncommon psoriasis, Stevens-Johnson syndrome, vitligo 
Musculoskeletal and connective tissue disorders 
Common musculoskeletal painb, arthralgia, arthritis 
Uncommon muscular weakness, muscle spasms, polymyalgia rheumatica 
Renal and urinary disorders 
Common renal failure (including acute kidney injury) 
Uncommon nephritis 
General disorders and administration site conditions 
Very common fatigue 
Common pyrexia, oedema (including peripheral oedema) 
Uncommon chills, chest pain 
Investigations 



 
28 

Very common anaemiac,d, thrombocytopaeniac, leucopoeniac, lymphopaeniac, 
neutropaeniac, increased alkaline phophatasesc, increased transaminasesc, 
increased creatininec, increased amylasec, increased lipasec, hypokalaemiac, 
hypomagnesaemiac, hyponatraemiac 

Common increased total bilirubinc, increased thyroid stimulating hormone 
Uncommon increased gamma-glutamyltransferase 

a Rash is a composite term which includes maculopapular rash, rash erythematous, rash pruritic, rash 
macular, rash morbilliform, rash papular, rash generalised, dermatitis, dermatitis acneiform, dermatitis 
allergic, dermatitis atopic, dermatitis bullous, and drug eruption. 

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

c Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from 
baseline in laboratory measurements. 

d Anaemia is a composite term which includes iron deficiency anaemia and haemoglobin decreased. 
 
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 was required in a greater proportion of patients receiving ipilimumab in combination with 
nivolumab than in those receiving nivolumab monotherapy. Table 7 presents the percentage of patients 
with immune-related adverse reactions who were permanently discontinued from treatment with 
ipilimumab in combination with nivolumab. Additionally, for patients who experienced an event, 
Table 7 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 7: Immune-related adverse reactions leading to permanent discontinuation or 
requiring high-dose corticosteroids by dosing regimen 
 
 Ipilimumab 

3 mg/kg in 
combination with 

nivolumab 
1 mg/kg in 
melanoma  

% 

Ipilimumab 
1 mg/kg in 

combination with 
nivolumab 

3 mg/kg in RCC  
% 

Ipilimumab 
1 mg/kg in 

combination with 
nivolumab 360 mg 

in combination 
with and 

chemotherapy in 
NSCLC 

% 
Immune-related adverse 
reaction leading to permanent 
discontinuation  

   

Pneumonitis 2.0 2.2 2.2 
Colitis 16 4.0 4.2 
Hepatitis 9 4.4 3.4 
Nephritis and Renal Dysfunction 1.1 1.3 1.4 
Endocrinopathies 2.7 2.9 2.0 
Skin 0.9 1.5 1.1 
Hypersensitivity/Infusion 
Reaction 

0 0 0.6 

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

   



 
29 

Pneumonitis 63 59 68 
Colitis 46 26 20 
Hepatitis 46 35 29 
Nephritis and Renal Dysfunction 17 27 24 
Endocrinopathies 27 25 8 
Skin 7 7 10 
Hypersensitivity/Infusion 
Reaction 

6 9 29 

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 3 mg/kg in combination with nivolumab 1 mg/kg in melanoma, the 
incidence of diarrhoea or colitis was 46.7% (209/448). Grade 2, Grade 3, and Grade 4 cases were 
reported in 13.6% (61/448), 15.8% (71/448), and 0.4% (2/448) of patients, respectively. No Grade 
5 cases were reported. Median time to onset was 1.2 months (range: 0.0-22.6). Resolution occurred in 
186 patients (89.4%) with a median time to resolution of 3.0 weeks (range: 0.1-159.4+). 
 
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in RCC, the 
incidence of diarrhoea or colitis was 28.2% (154/547). Grade 2 and Grade 3 cases were reported 
in 10.4% (57/547) and 4.9% (27/547) of patients, respectively. No Grade 4 or 5 cases were reported. 
Median time to onset was 1.2 months (range: 0.0-24.7). Resolution occurred in 140 patients (91.5%) 
with a median time to resolution of 2.4 weeks (range: 0.1-103.1+). 
 
In patients treated with ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg 
every 3 weeks and chemotherapy in NSCLC, the incidence of diarrhoea or colitis was 22.3% (80/358). 
Grade 2, Grade 3, Grade 4, and Grade 5 cases were reported in 7% (25/358), 5% (18/358), 0.3% 
(1/358), and 0.3% (1/358) of patients, respectively. Median time to onset was 5.1 weeks (range: 0.1-
53.6). Resolution occurred in 70 patients (87.5%) with a median time to resolution of 1.4 weeks 
(range: 0.1-76.9+). 
 
Immune-related pneumonitis 
In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg in melanoma, the 
incidence of pneumonitis including interstitial lung disease, was 7.8% (35/448). Grade 2, Grade 3, and 
Grade 4 cases were reported in 4.7% (21/448), 1.1% (5/448), and 0.2% (1/448) of patients, 
respectively. One of the Grade 3 pneumonitis cases worsened over 11 days with a fatal outcome. 
Median time to onset was 2.6 months (range: 0.7-12.6). Resolution occurred in 33 patients (94.3%) 
with a median time to resolution of 6.1 weeks (range: 0.3-35.1). 
 
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in RCC, the 
incidence of pneumonitis including interstitial lung disease was 6.2% (34/547). Grade 2 and Grade 3 



 
30 

cases were reported in 3.1% (17/547) and 1.1% (6/547), of patients, respectively. No 
Grade 4 or 5 cases were reported in this study. Median time to onset was 2.6 months (range: 
0.25-20.6). Resolution occurred in 31 patients (91.2%) with a median time to resolution of 6.1 weeks 
(range: 0.7-85.9+). 
 
In patients treated with ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg 
every 3 weeks and chemotherapy in NSCLC, the incidence of pneumonitis including interstitial lung 
disease was 5.3% (19/358). Grade 2, Grade 3, and Grade 4 cases were reported in 2.2% (8/358), 1.1% 
(4/358),and 0.6% (2/358) of patients, respectively. Median time to onset was 18.1 weeks (range: 0.6-
52.4). Resolution occurred in 14 patients (74%) with a median time to resolution of 4.3 weeks (range: 
0.7-27.9+). 
 
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 3 mg/kg in combination with nivolumab 1 mg/kg, the incidence of 
liver function test abnormalities was 29.5% (132/448). Grade 2, Grade 3, and Grade 4 cases were 
reported in 6.7% (30/448), 15.4% (69/448), and 1.8% (8/448) of patients, respectively. No Grade 5 
cases were reported. Median time to onset was 1.5 months (range: 0.0-30.1). Resolution occurred in 
124 patients (93.9%) with a median time to resolution of 5.1 weeks (range: 0.1-106.9). 
 
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in RCC, the 
incidence of liver function test abnormalities was 18.5% (101/547). Grade 2, Grade 3, and Grade 4 
cases were reported in 4.8% (26/547), 6.6% (36/547), and 1.6% (9/547) of patients, respectively. No 
Grade 5 cases were reported. Median time to onset was 2.0 months (range: 0.4-26.8). Resolution 
occurred in 86 patients (85.1%) with a median time to resolution of 6.1 weeks (range: 0.1+-82.9+). 
 
In patients treated with ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg 
every 3 weeks and chemotherapy in NSCLC, the incidence of liver function test abnormalities was 
13.4% (48/358). Grade 2, Grade 3, and Grade 4 cases were reported in 3.1% (11/358), 3.4% (12/358), 
and 1.1% (4/358) of patients, respectively. Median time to onset was 10.6 weeks (range: 1.1-68.3). 
Resolution occurred in 37 patients (80.4%) with a median time to resolution of 5 weeks (range: 0.3+-
45.0+). 
 
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 



 
31 

(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 3 mg/kg in combination with nivolumab 1 mg/kg in melanoma, the 
incidence of rash was 65.0% (291/448). Grade 2 and Grade 3 cases were reported in 20.3% (91/448) 
and 7.6% (34/448) of patients, respectively. No Grade 4 or 5 cases were reported. Median time to 
onset was 0.5 months (range: 0.0-19.4). Resolution occurred in 191 patients (65.9%) with a median 
time to resolution of 11.4 weeks (range: 0.1-150.1+). Rare cases of SJS and TEN some of them with 
fatal outcome have been observed (see sections 4.2 and 4.4). 
 
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in RCC, the 
incidence of rash was 48.8% (267/547). Grade 2 and Grade 3 cases were reported in 13.7% (75/547) 
and 3.7% (20/547) of patients, respectively. No Grade 4 or 5 cases were reported. Median time to 
onset was 0.9 months (range: 0.0-17.9). Resolution occurred in 192 patients (72.2%) with a median 
time to resolution of 11.6 weeks (range: 0.1-126.7+). 
 
In patients treated with ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg 
every 3 weeks and chemotherapy in NSCLC, the incidence of rash was 37.7% (135/358). Grade 2, 
Grade 3, and Grade 4 cases were reported in 11.5% (41/358), 4.2% (14/358), and 0.3% (1/358) of 
patients, respectively. Median time to onset was 3.3 weeks (range: 0.1-83.1). Resolution occurred in 
96 patients (71.6%) with a median time to resolution of 9.4 weeks (range: 0.1+-84.1+). 
 
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 3 mg/kg in combination with nivolumab 1 mg/kg in melanoma, the 
incidence of nephritis or renal dysfunction was 5.1% (23/448). Grade 2, Grade 3, and Grade 4 cases 
were reported in 1.6% (7/448), 0.9% (4/448), and 0.7% (3/448) of patients, respectively. No Grade 5 
cases were reported. Median time to onset was 2.6 months (range: 0.5-21.8). Resolution occurred in 
21 patients (91.3%) with a median time to resolution of 2.1 weeks (range: 0.1- 125.1+). 
 
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in RCC, the 
incidence of nephritis or renal dysfunction was 8.8% (48/547). Grade 2, Grade 3, and Grade 4 cases 
were reported in 4.4% (24/547), 0.7% (4/547), and 0.5% (3/547) of patients, respectively. No Grade 5 
cases were reported. Median time to onset was 2.1 months (range: 0.0-16.1). Resolution occurred in 
37 patients (77.1%) with a median time to resolution of 13.2 weeks (range: 0.1+-106.0+). 
 
In patients treated with ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg 
every 3 weeks and chemotherapy in NSCLC, the incidence of nephritis or renal dysfunction was 
7% (25/358). Grade 2, Grade 3, and Grade 4 cases were reported in 2.2% (8/358), 1.7% (6/358), and 
0.6 (2/358) of patients, respectively. Median time to onset was 10.6 weeks (range: 0.1-51.3). 
Resolution occurred in 14 patients (56%) with a median time to resolution of 6.3 weeks (range: 0.1+-
82.9+). 
 
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. There were no reports of severe or very severe (Grade 3 or 4) adrenal insufficiency, 
hyperthyroidism, or hypothyroidism. 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. 



 
32 

 
In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg in melanoma, the 
incidence of thyroid disorders was 25.2% (113/448). Grade 2 and Grade 3 thyroid disorders were 
reported in 14.5% (65/448) and 1.3% (6/448) of patients, respectively. 
Grade 2 and Grade 3 hypophysitis (including lymphocytic hypophysitis) occurred in 5.8% (26/448) 
and 2.0% (9/448) of patients, respectively. Grade 2 and Grade 3 hypopituitarism occurred in 0.4% 
(2/448) and 0.7% (3/448) of patients, respectively. Grade 2, Grade 3, and Grade 4 adrenal 
insufficiency (including secondary adrenocortical insufficiency) occurred in 1.6% (7/448), 1.3% 
(6/448) and 0.2% (1/448) of patients, respectively. Grade 1, Grade 2, Grade 3, and Grade 4 diabetes 
mellitus and Grade 4 diabetic ketoacidosis were each reported in 0.2% (1/448) of patients. No Grade 5 
endocrinopathy was reported. Median time to onset of these endocrinopathies was 1.9 months (range: 
0.0-28.1). Resolution occurred in 64 patients (45.4%). Time to resolution ranged 
from 0.4 to 155.4+ weeks. 
 
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in RCC, the 
incidence of thyroid disorders was 27.2% (149/547). Grade 2 and Grade 3 thyroid disorders were 
reported in 15.7% (86/547) and 1.3% (7/547) of patients, respectively. Hypophysitis occurred in 4.0% 
(22/547) of patients. Grade 2, Grade 3, and Grade 4 cases were reported in 0.5% (3/547), 2.4% 
(13/547), and 0.4% (2/547) of patients, respectively. Grade 2 hypopituitarism occurred in 0.4% 
(2/547) of patients. Grade 2, Grade 3, and Grade 4 adrenal insufficiency (including secondary 
adrenocortical insufficiency) occurred in 2.9% (16/547), 2.2% (12/547) and 0.4% (2/547) of patients, 
respectively. Diabetes mellitus including Type 1 diabetes mellitus (3 Grade 2, 2 Grade 3, and 3 
Grade 4), and diabetic ketoacidosis (1 Grade 4) were reported. No Grade 5 endocrinopathy was 
reported. Median time to onset of these endocrinopathies was 1.9 months (range: 0.0-22.3). Resolution 
occurred in 76 patients (42.7%). Time to resolution ranged from 0.4 to 130.3+ weeks. 
 
In patients treated with ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg 
every 3 weeks and chemotherapy in NSCLC, the incidence of thyroid disorders was 24% (86/358). 
Grade 2 and Grade 3 thyroid disorders were reported in 12.3% (44/358) and 0.3% (1/358) of patients, 
respectively. Hypophysitis occurred in 1.4% (5/358) of patients. Grade 2 and Grade 3 cases were 
reported in 0.6% (2/358) and 0.8% (3/358) of patients, respectively. Grade 2 hypopituitarism occurred 
in 0.3% (1/358) of patients. Grade 2 and Grade 3 adrenal insufficiency occurred in 1.7% (6/358) and 
1.4% (5/358) of patients, respectively. Diabetes mellitus including Type 1 diabetes mellitus was not 
reported. Median time to onset of these endocrinopathies was 12.1 weeks (range:1.9-58.3). Resolution 
occurred in 30 patients (35.3%). Time to resolution ranged from 1.4 to 72.4+ weeks. 
 
Infusion reactions 
 
In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg, the incidence of 
hypersensitivity/infusion reactions was 3.8% (17/448); all were Grade 1 or 2 in severity. Grade 2 cases 
were reported in 2.2% (10/448) of patients. No Grade 3-5 cases were reported. 
 
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg, the incidence of 
hypersensitivity/infusion reactions was 4.0% (22/547); all were Grade 1 or 2 in severity. Grade 2 cases 
were reported in 2.4% (13/547) of patients. No Grade 3-5 cases were reported. 
 
In patients treated with ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg 
every 3 weeks and chemotherapy in NSCLC, the incidence of hypersensitivity/infusion reactions was 
4.7% (17/358). Grade 2, Grade 3, and Grade 4 cases were reported in 2.2% (8/358), 0.3% (1/358), and 
0.3% (1/358) of patients, respectively. 
 
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 



 
33 

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 8.4%. Of the patients who were treated with ipilimumab in combination with nivolumab and 
chemotherapy and evaluable for the presence of anti-ipilimumbab 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,  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 0.5% with nivolumab 
3 mg/kg and ipilimumab 1 mg/kg every 3 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 with ipilimumab in combination with nivolumab 
In patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg in melanoma, the 
proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratory 
abnormality was as follows: 2.8% for anaemia (all Grade 3), 1.2% for thrombocytopaenia, 0.5% for 
leucopoenia, 6.7% for lymphopaenia, 0.7% for neutropaenia, 4.3% for increased alkaline phosphatase, 
12.4% for increased AST, 15.3% for increased ALT, 1.2% for increased total bilirubin, 2.4% for 
increased creatinine, 5.3% for hyperglycaemia, 8.7% for increased amylase, 19.5% for increased 
lipase, 1.2% for hypocalcaemia, 0.2% each for hypernatraemia and hypercalcaemia, 0.5% for 
hyperkalemia, 0.3% for hypermagnesaemia, 4.8% for hypokalaemia, and 9.5% for hyponatraemia. 
 
In patients treated with ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg in RCC, the 
proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratory 
abnormality was as follows: 3.0% for anaemia (all Grade 3), 0.7% for thrombocytopaenia, 0.6% for 
leucopoenia, 5.1% for lymphopaenia, 1.1% for neutropaenia, 2.0% for increased alkaline phosphatase, 
4.8% for increased AST, 6.5% for increased ALT, 1.1% for increased total bilirubin, 2.1% for 
increased creatinine, 7.2% for hyperglycaemia, 1.8% for hypoglycemia,12.2% for increased amylase, 
20.1% for increased lipase, 0.4% for hypocalcaemia, 1.3% for hypercalcaemia, 2.4% for 
hyperkalemia, 1.1% for hypermagnesaemia, 0.4% for hypomagnesaemia 1.9% for hypokalaemia, and 
9.9% for hyponatraemia. 
 
In patients treated with ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg 
every 3 weeks and chemotherapy in NSCLC, the proportion of patients who experienced a worsening 
from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 9.2% for anaemia, 4.3% for 
thrombocytopaenia, 9.8% for leucopoenia, 5.8% for lymphopaenia, 14.7% for neutropaenia, 1.2% for 
increased alkaline phosphatase, 3.5% for increased AST, 4.3% for increased ALT, 0% for increased 
total bilirubin, 1.2% for increased creatinine, 7.1% for hyperglycaemia, 0% for hypoglycaemia, 
6.7% for increased amylase, 11.9% for increased lipase, 1.4% for hypocalcaemia, 1.2% for 
hypercalcaemia, 1.7% for hyperkalemia, 0.3% for hypermagnesaemia, 1.2% for hypomagnesaemia 
3.5% for hypokalaemia, and 10.7% for hyponatraemia. 
 
Paediatric population 
 
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 



 
34 

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 8. 
 

Table 8: 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 Tumors 

Advanced Melanoma Advanced Melanoma 

CA184070 CA184178 
CA184004/ 
022Pooled 

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 

pediatric 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 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 



 
35 

 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC11. 
 
Mechanism of action 
 
Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a key regulator of T-cell activity. Ipilimumab is 
a CTLA-4 immune checkpoint inhibitor that blocks T-cell inhibitory signals induced by the CTLA-4 
pathway, increasing the number of reactive T-effector cells which mobilize to mount a direct T-cell 
immune attack against tumour cells. CTLA-4 blockade can also reduce T-regulatory cell function, 
which may contribute to an anti-tumour immune response. Ipilimumab may selectively deplete 
T-regulatory cells at the tumour site, leading to an increase in the intratumoral T-effector/ T-regulatory 
cell ratio which drives tumour cell death. 
 
Pharmacodynamic effects 
 
In patients with melanoma who received ipilimumab, the mean peripheral blood absolute lymphocyte 
counts (ALC) increased throughout the induction dosing period. In Phase 2 studies, this increase was 
dose-dependent. In MDX010-20 (see section 5.1), ipilimumab at 3 mg/kg with or without 
gp100 increased ALC throughout the induction dosing period, but no meaningful change in ALC was 
observed in the control group of patients who received an investigational gp100 peptide vaccine alone. 
In peripheral blood of patients with melanoma, a mean increase in the percent of activated HLA-DR+ 
CD4+ and CD8+ T cells was observed after treatment with ipilimumab, consistent with its mechanism 
of action. A mean increase in the percent of central memory (CCR7+ CD45RA-) CD4+ and CD8+ T 
cells and a smaller, but significant, mean increase in the percent of effector memory 
(CCR7- CD45RA-) CD8+ T cells also was observed after treatment with ipilimumab. 
 
Clinical efficacy and safety 
 
Ipilimumab in combination with nivolumab 
For additional information on clinical efficacy and safety associated with the dosing recommendations 
of nivolumab when administered as monotherapy following combination therapy with ipilimumab, 
please refer to the nivolumab SmPC. 
 
Based on modelling of dose/exposure efficacy and safety relationships, there are no clinically 
significant differences in efficacy and safety between a nivolumab dose of 240 mg every 2 weeks or 
3 mg/kg every 2 weeks. Additionally, based on these relationships, there were no clinically significant 
differences between a nivolumab dose of 480 mg every 4 weeks or 3 mg/kg every 2 weeks in 
advanced melanoma and RCC. 
 
Clinical trials with ipilimumab monotherapy 
 



 
36 

Melanoma 
 
Overall survival (OS) advantage of ipilimumab at the recommended dose of 3 mg/kg in patients with 
previously-treated advanced (unresectable or metastatic) melanoma was demonstrated in a 
Phase 3 study (MDX010-20). Patients with ocular melanoma, primary CNS melanoma, active brain 
metastases, human immunodeficiency virus (HIV), hepatitis B, and hepatitis C were not included in 
the MDX010-20 clinical trial. Clinical trials excluded patients with ECOG performance status > 1 and 
mucosal melanoma. Patients without liver metastasis who had a baseline AST > 2.5 x ULN, patients 
with liver metastasis who had a baseline AST > 5 x ULN, and patients with a baseline total 
bilirubin ≥ 3 x ULN were also excluded.  
 
For patients with a history of autoimmune disease, see also section 4.4. 
 
MDX010-20 
A Phase 3, double-blind study enrolled patients with advanced (unresectable or metastatic) melanoma 
who had previously been treated with regimens containing one or more of the following: IL-2, 
dacarbazine, temozolomide, fotemustine, or carboplatin. Patients were randomized in a 3:1:1 ratio to 
receive ipilimumab 3 mg/kg + an investigational gp100 peptide vaccine (gp100), ipilimumab 3 mg/kg 
monotherapy, or gp100 alone. All patients were HLA-A2*0201 type; this HLA type supports the 
immune presentation of gp100. Patients were enrolled regardless of their baseline BRAF mutation 
status. Patients received ipilimumab every 3 weeks for 4 doses as tolerated (induction therapy). 
Patients with apparent tumour burden increase before completion of the induction period were 
continued on induction therapy as tolerated if they had adequate performance status. Assessment of 
tumour response to ipilimumab was conducted at approximately Week 12, after completion of 
induction therapy. 
Additional treatment with ipilimumab (re-treatment) was offered to those who developed PD after 
initial clinical response (PR or CR) or after SD (per the modified WHO criteria) > 3 months from the 
first tumour assessment. The primary endpoint was OS in the ipilimumab+ gp100 group vs. the 
gp100 group. Key secondary endpoints were OS in the ipilimumab+ gp100 group vs. the ipilimumab 
monotherapy group and in the ipilimumab monotherapy group vs. the gp100 group.  
 
A total of 676 patients were randomized: 137 to the ipilimumab monotherapy group, 403 to the 
ipilimumab + gp100 group, and 136 to the gp100 alone group. The majority had received all 4 doses 
during induction. Thirty-two patients received re-treatment: 8 in the ipilimumab monotherapy 
group, 23 in the ipilimumab + gp100 group, and 1 in the gp100 group. Duration of follow-up ranged 
up to 55 months. Baseline characteristics were well balanced across groups. The median age 
was 57 years. The majority (71-73%) of patients had M1c stage disease and 37-40% of patients had an 
elevated lactate dehydrogenase (LDH) at baseline. A total of 77 patients had a history of previously 
treated brain metastases. 
 
The ipilimumab-containing regimens demonstrated a statistically significant advantage over the 
gp100 control group in OS. The hazard ratio (HR) for comparison of OS between ipilimumab 
monotherapy and gp100 was 0.66 (95% CI: 0.51, 0.87; p = 0.0026).  
 
By subgroup analysis, the observed OS benefit was consistent within most of the subgroups of patients 
(M [metastases]-stage, prior interleukin-2, baseline LDH, age, sex, and the type and number of prior 
therapy). However, for women above 50 years of age, the data supporting an OS benefit of ipilimumab 
treatment were limited. As the subgroups analysis includes only small numbers of patients, no 
definitive conclusions can be drawn from these data. 
 
Median and estimated rates of OS at 1 year and 2 years are presented in Table 9. 
 



 
37 

Table 9: Overall survival in MDX010-20  

 
Ipilimumab 3 mg/kg 

n= 137 
gp100 a 
n= 136 

Median Months (95% CI) 
10 months  
(8.0, 13.8) 

6 months  
(5.5, 8.7) 

OS at 1 year % (95% CI) 46% (37.0, 54.1) 25% (18.1, 32.9) 

OS at 2 years % (95% CI) 24% (16.0, 31.5) 14% (8.0, 20.0) 
a gp100 peptide vaccine is an experimental control.  
 
In the ipilimumab 3 mg/kg monotherapy group, median OS was 22 months and 8 months for patients 
with SD and those with PD, respectively. At the time of this analysis, medians were not reached for 
patients with CR or PR.  
 
For patients who required re-treatment, the BORR was 38% (3/8 patients) in the ipilimumab 
monotherapy group, and 0% in the gp100 group. The disease control rate (DCR) (defined as 
CR+PR+SD) was 75% (6/8 patients) and 0%, respectively. Because of the limited number of patients 
in these analyses, no definitive conclusion regarding the efficacy of ipilimumab re-treatment can be 
drawn. 
 
The development or maintenance of clinical activity following ipilimumab treatment was similar with 
or without the use of systemic corticosteroids.  
 
CA184-169 
A Phase 3, double-blind study enrolled patients with previously treated or untreated unresectable Stage 
III or Stage IV melanoma. A total of 727 patients were randomized, 362 to receive ipilimumab 
3 mg/kg and 365 to receive ipilimumab 10 mg/kg every 3 weeks for 4 doses. In the ipilimumab 10 
mg/kg group, the median OS (95% CI) was 16 months (11.63, 17.84) and in the ipilimumab 3 mg/kg 
group the median OS (95% CI) was 12 months (9.86, 13.27). Overall survival compared between 
Ipilimumab 10 mg/kg and 3 mg/kg groups showed HR = 0.84 (95% CI: 0.70, 0.99; P-value = 0.04). 
No statistically significant difference in progression free survival (PFS) was observed between the 10 
mg/kg and the 3 mg/kg groups. (HR 0.89 with a 95% CI of 0.76, 1.04 and log-rank test P-value = 
0.1548). BORR was similar in the 10 mg/kg and 3 mg/kg groups. BORR in the 10 mg/kg group was 
15.3% (95% CI: 11.8, 19.5) and in the 3 mg/kg group was 12.2% (95% CI: 9.0, 16.0). Ipilimumab 
10 mg/kg was associated with higher rates of adverse events compared with the 3 mg/kg dose. The 
frequencies of serious adverse reactions in the 10 mg/kg and 3 mg/kg groups were 37% and 18%, with 
the 3 most common serious adverse reactions being diarrhea (10.7% vs 5.5%), colitis (8.0% vs 3.0%), 
and hypophysitis (4.4% vs 1.9%). Adverse events leading to discontinuation in the 10 mg/kg and 3 
mg/kg groups occurred in 31% and 19% of patients, with AEs leading to death in 4 and 2 patients, 
respectively. 
 
At the recommended dose of 3 mg/kg median OS was similar in the subgroup of females ≥ 50 years of 
age compared to the overall population: (11.40 vs 11.53 months). Median OS in the subgroup with 
brain metastases at baseline was 5.67 months at the recommended dose of 3 mg/kg. 
 
Other studies with ipilimumab monotherapy 
 
Melanoma 
 
CA184332 and CA184338 
OS of ipilimumab 3 mg/kg monotherapy in chemotherapy-naive patients pooled across Phase 2 
and 3 clinical trials (N= 78; randomised) and in treatment-naive patients in two retrospective 
observational studies (N= 273 and N= 157) were generally consistent. In the two observational studies, 
12.1% and 33.1% of the patients had brain metastases at the time of advanced melanoma diagnosis. 
Median OS and estimated 1-year, 2-year, 3-year and 4-year survival rates are presented in Table 10. 
The estimated 1-year, 2-year and 3-year survival rates for chemotherapy-naive patients (N= 78) pooled 



 
38 

across Phase 2 and 3 clinical trials were 54.1% (95% CI: 42.5 - 65.6), 31.6% (95% CI: 20.7 - 42.9) 
and 23.7% (95% CI: 14.3 - 34.4) respectively. 
 

Table 10: Overall survival in observational studies  

 
CA184338  
n= 273 

CA184332 
n= 157 

Median OS (95% CI) 
14 months  
(12.8-18.7) 

10 months 
(7.0-12.8) 

OS at 1 year % (95% CI) 59% (52.5-64.3) 44% (35.5, 51.4) 
OS at 2 years % (95% CI) 39% (33.1-44.8) 26% (18.9-33.3) 
OS at 3 years % (95% CI) 31% (25.5-36.7) 22% (15.5-29.2) 
OS at 4 years % (95% CI) 26% (20.4-31.3) 22% (15.5-29.2) 

 
Patients with brain metastases in study CA184332 had a median OS of 7 months (95% 
CI: 5.06 - 12.81) and patients without brain metastases had a median OS of 14.1 months (95% 
CI: 9.96-Not estimated). 
 
Patients with brain metastases in study CA184338 had a median OS of 6.3 months (95% 
CI: 3.2 - 12.0) and patients without brain metastases had a median OS of 17.7 months (95% 
CI: 13.6 – 12.1). 
 
Long term survival benefit of treatment with ipilimumab (at 3mg/kg) is demonstrated through a pooled 
analysis of OS data from clinical trials in patients with previously treated and treatment naive 
advanced melanoma (N = 965). The Kaplan-Meier OS curve revealed a plateau beginning around year 
3 (OS rate = 21% [95% CI: 17-24]) that extended up to 10 years in some patients (see Figure 1). 
 
Figure 1:  Overall Survival with ipilimumab 3 mg/kg in pooled analysis 
 

 
 
 

No. at Risk 
3.0 
mg/kg 

965 429 127 73 41 29 28 12 8 4 0 

O
ve

ra
ll

 S
ur

vi
va

l 
(p

ro
po

rt
io

n)
 

3.0 
mg/kg 

Time (months) 



 
39 

 
Clinical trials with ipilimumab in combination with nivolumab 
 
Melanoma 
 
Randomised phase 3 study of receive ipilimumab in combination with nivolumab or nivolumab as 
monotherapy vs. ipilimumab as monotherapy (CA209067) 
The safety and efficacy of ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg nivolumab 
3 mg/kg vs. ipilimumab 3 mg/kg monotherapy for the treatment of advanced (unresectable or 
metastatic) melanoma were evaluated in a phase 3, randomised, double-blind study (CA209067). The 
differences between the two nivolumab-containing groups were evaluated descriptively. The study 
included adult patients with confirmed unresectable Stage III or Stage IV melanoma. Patients were to 
have ECOG performance status score of 0 or 1. Patients who had not received prior systemic 
anticancer therapy for unresectable or metastatic melanoma were enrolled. Prior adjuvant or 
neoadjuvant therapy was allowed if it was completed at least 6 weeks prior to randomisation. Patients 
with active autoimmune disease, ocular/uveal melanoma, or active brain or leptomeningeal metastases 
were excluded from the study. 
 
A total of 945 patients were randomised to receive ipilimumab in combination with nivolumab 
(n = 314), nivolumab monotherapy (n = 316), or ipilimumab monotherapy (n = 315). Patients in the 
combination arm received nivolumab 1 mg/kg over 60 minutes and ipilimumab 3 mg/kg over 
90 minutes administered intravenously every 3 weeks for the first 4 doses, followed by nivolumab 
3 mg/kg as monotherapy every 2 weeks. Patients in the nivolumab monotherapy arm received 
nivolumab 3 mg/kg every 2 weeks. Patients in the comparator arm received ipilimumab 3 mg/kg and 
nivolumab-matched placebo intravenously every 3 weeks for 4 doses followed by placebo every 
2 weeks. Randomisation was stratified by PD-L1 expression (≥ 5% vs. < 5% tumour cell membrane 
expression), BRAF status, and M stage per the American Joint Committee on Cancer (AJCC) staging 
system. Treatment was continued as long as clinical benefit was observed or until treatment was no 
longer tolerated. Tumour assessments were conducted 12 weeks after randomisation then every 
6 weeks for the first year, and every 12 weeks thereafter. The primary outcome measures were 
progression-free survival and OS. ORR and the duration of response were also assessed. 
 
Baseline characteristics were balanced across the three treatment groups. The median age was 61 years 
(range: 18 to 90 years), 65% of patients were men, and 97% were white. ECOG performance status 
score was 0 (73%) or 1 (27%). The majority of the patients had AJCC Stage IV disease (93%); 58% 
had M1c disease at study entry. Twenty-two percent of patients had received prior adjuvant therapy. 
Thirty-two percent of patients had BRAF mutation-positive melanoma; 26.5% of patients had PD-L1 
≥ 5% tumour cell membrane expression. Four percent of patients had a history of brain metastasis, and 
36% of patients had a baseline LDH level greater than ULN at study entry. Among patients with 
quantifiable tumour PD-L1 expression, the distribution of patients was balanced across the three 
treatment groups. Tumour PD-L1 expression was determined using the PD-L1 IHC 28-
8 pharmDx assay. 
 
At primary analysis (minimum follow-up 9 months) the median PFS was 6.9 months in the nivolumab 
group as compared with 2.9 months in the ipilimumab group (HR = 0.57, 99.5% CI: 0.43, 0.76; 
p < 0.0001). The median PFS was 11.5 months in the ipilimumab in combination with nivolumab 
group, as compared with 2.9 months in the ipilimumab group (HR = 0.42, 99.5% CI: 0.31, 0.57; 
p < 0.0001). 
 
PFS results from descriptive analysis (with minimum follow up of 60 months) are shown in Figure 2 
(all randomised population), Figure 3 (at the tumour PD-L1 5% cut off), and Figure 4 (at the tumour 
PD-L1 1% cut off).  
  



 
40 

Figure 2: Progression-free survival (CA209067) 

 
Progression-free survival per investigator (months) 

 
Number of subjects at risk 
Nivolumab + ipilimumab 

314 174 136 124 110 101 95 90 82 76 45 2 0 
Nivolumab 

316 151 120 106 97 84 78 73 68 65 40 1 0 
Ipilimumab 

315 78 46 34 31 28 21 18 17 15 11 1 0 
 
- - -*- - - -  Nivolumab+ipilimumab (events: 182/314), median and 95% CI: 11.50 (8.74, 19.32). 

PFS rate at 12 months and 95% CI: 49% (44, 55), PFS rate at 60 months and 95% CI: 36% (32, 42) 
──∆─── Nivolumab (events: 203/316), median and 95% CI: 6.93 (5.13, 10.18). 

PFS rate at 12 months and 95% CI: 42% (36, 47), PFS rate at 60 months and 95% CI: 29% (24, 35) 
- - -- - -  Ipilimumab (events: 261/315), median and 95% CI: 2.86 (2.79, 3.15). 

PFS rate at 12 months and 95% CI: 18% (14, 23), PFS rate at 60 months and 95% CI: 8% (5, 12) 
 
Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.42 (0.35, 0.51);  
Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.53 (0.44, 0.64);  
Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.79 (0.64, 0.96) 
  

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Figure 3: Progression-free survival by PD-L1 expression: 5% cut off (CA209067) 
PD-L1 expression < 5% 

 
Progression-free survival (months) 

 
 
 
 
 
 
 
 

 
- - -*- - - - Nivolumab+ipilimumab (events: 123/210), median and 95% CI: 11.17 (7.98, 17.51) 

 ──∆───  Nivolumab (events: 136/208), median and 95% CI: 5.39 (2.96, 7.13) 
 - - -- - -  Ipilimumab (events: 171/202), median and 95% CI: 2.83 (2.76, 3.02) 
 
   Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.42 (0.33, 0.53) 
   Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.54 (0.43, 0.68) 
   Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.77 (0.60, 0.98) 
 

PD-L1 expression ≥ 5% 

 
Progression-free survival (months) 

 
 
 
 
 
 
 
 

- - -*- - - - Nivolumab+ipilimumab (events: 36/68), median and 95% CI: 22.11 (9.72, N.A.) 
──∆───  Nivolumab (events: 46/80), median and 95% CI: 22.34 (9.46, 40.02) 
- - -- - -  Ipilimumab (events: 60/75), median and 95% CI: 3.94 (2.79, 4.21) 

 
   Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.37 (0.24, 0.56) 
   Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.42 (0.28, 0.62) 
   Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.89 (0.57, 1.37) 
  

Number of subjects at risk 
Nivolumab + ipilimumab 
210 113 87 78 71 64 59 55 52 49 33 2 0 
Nivolumab 
208 91 73 66 60 50 48 45 40 38 23 1 0 
Ipilimumab 
202 45 26 19 18 16 14 13 12 10 6 0 0 

Number of subjects at risk 
Nivolumab + ipilimumab

68 44 35 33 28 27 26 25 22 19 7 0 0 
Nivolumab 

80 52 41 36 33 30 27 25 25 24 15 0 0 
Ipilimumab 

75 21 14 10 10 9 5 5 5 5 5 1 0 

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Figure 4: Progression-free survival by PD-L1 expression: 1% cut off (CA209067)  
PD-L1 expression < 1% 

 
Progression-free survival (months) 

 
 
 
 

 
 
 
 
- - -*- - - - Nivolumab+ipilimumab (events: 73/123), median and 95% CI: 11.17 (6.93, 22.18) 
──∆───  Nivolumab (events: 82/117), median and 95% CI: 2.83 (2.76, 5.62) 
- - -- - -  Ipilimumab (events: 94/113), median and 95% CI: 2.76 (2.66, 2.86) 

 

   Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.39 (0.29, 0.54) 
   Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.59 (0.44, 0.80) 
   Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.66 (0.48, 0.91) 
 

PD-L1 expression ≥ 1% 

 
Progression-free survival (months) 

 
 
 
 
 
 
 
 
 - - -*- - - Nivolumab+ipilimumab (events: 86/155), median and 95% CI: 16.13 (8.90, 39.06) 
 ──∆───  Nivolumab (events: 100/171), median and 95% CI: 16.20 (8.11, 27.66) 
 - - -- - -  Ipilimumab (events: 137/164), median and 95% CI: 3.48 (2.83, 4.17) 
 
   Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.41 (0.31, 0.54) 
   Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.45 (0.35, 0.58) 
   Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.91 (0.68, 1.22) 
  

Number of subjects at risk 
Nivolumab + ipilimumab 
123 65 51 46 41 38 36 33 30 28 21 1 0 

Nivolumab 
117 44 35 33 30 25 23 20 17 15 8 0 0 

Ipilimumab 
113 20 12 9 9 7 5 5 4 3 3 0 0 

Number of subjects at risk 
Nivolumab + ipilimumab 
155 92 71 65 58 53 49 47 44 40 19 1 0 

Nivolumab 
171 99 79 69 63 55 52 50 48 47 30 1 0 

Ipilimumab 
164 46 28 20 19 18 14 13 13 12 8 1 0 

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43 

The final (primary) OS analysis occurred when all patients had a minimum follow-up of 28 months. 
At 28 months, median OS was not reached in the nivolumab group as compared with 19.98 months in 
the ipilimumab group (HR = 0.63, 98% CI: 0.48, 0.81; p-value: < 0.0001). Median OS was not 
reached in the ipilimumab in combination with nivolumab group as compared with the ipilimumab 
group (HR = 0.55, 98% CI: 0.42, 0.72; p-value: < 0.0001). 
 
OS results at an additional descriptive analysis undertaken at a minimum follow-up of 60 months 
show outcomes consistent with the original primary analysis. OS results from this follow-up analysis 
are shown in Figure 5 (all randomised), Figure 6 and 7 (at the tumour PD-L1 5% and 1% cut off). 
 
The OS analysis was not adjusted to account for subsequent therapies received. Subsequent systemic 
therapy was received by 34.7%, 48.1%, and 65.7% of patients in the combination, nivolumab 
monotherapy, and ipilimumab arms, respectively. Subsequent immunotherapy (including anti-PD1 
therapy, anti-CTLA-4 antibody, or other immunotherapy) was received by 17.5%, 33.2%, and 47.3% 
of patients in the combination, nivolumab monotherapy, and ipilimumab arms, respectively. 
 
Figure 5 Overall survival (CA209067) - Minimum follow-up of 60 months  

  
Overall survival (months) 

 
 
 

- - -*- - - - Nivolumab+ipilimumab (events: 152/314), median and 95% CI: N.A. (38.18, N.A.) 
OS rate and 95% CI at 12 months: 73% (68, 78), 24 months: 64% (59, 69), 36 months: 58% (52, 63), and 
60 months: 52% (46, 57) 

──∆─── Nivolumab (events: 176/316), median and 95% CI: 36.93 months (28.25, 58.71)  
OS rate and 95% CI at 12 months: 74% (69, 79), 24 months: 59% (53, 64), 36 months: 52% (46, 57), and 
60 months: 44% (39, 50) 

- - -- - -  Ipilimumab (events: 230/315), median and 95% CI: 19.94 months (16.85, 24.61) 
OS rate and 95% CI at 12 months: 67% (61, 72), 24 months: 45% (39, 50), 36 months: 34% (29, 39), and 
60 months: 26% (22, 31) 

 
Nivolumab+ipilimumab vs ipilimumab - HR (95% CI): 0.63 (0.52, 0.76);  
Nivolumab vs ipilimumab - HR (95% CI): 0.52 (0.42, 0.64);  
Nivolumab+ipilimumab vs nivolumab - HR (95% CI): 0.83 (0.67, 1.03) 

  

Number of subjects at risk 

Nivolumab+ipilimumab 

314 265 227 210 199 187 179 169 163 157 150 14 0 

Nivolumab 

316 266 231 201 181 171 158 145 141 137 130 14 0 

Ipilimumab 

315 253 203 163 135 113 100 94 87 81 73 12 0 

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Figure 6: Overall survival by PD-L1 expression: 5% cut off (CA209067) - Minimum 
follow-up of 60 months 

PD-L1 expression < 5% 

 
Overall survival (months) 

 
 
 
 
 
 
 
 
 
 

- - -*- - - - Nivolumab+ipilimumab (events: 103/210), median and 95% CI: N.A. (32.72, N.A.) 
 ──∆───  Nivolumab (events: 117/208), median and 95% CI: 35.94 months (23.06, 59.24.) 

 - - -- - -  Ipilimumab (events: 154/202), median and 95% CI: 18.40 months (13.70, 22.51) 
   Nivolumab+ipilimumab vs. ipilimumab - HR (95% CI): 0.50 (0.39, 0.65) 
   Nivolumab vs. ipilimumab - HR (95% CI): 0.62 (0.49, 0.79) 

Nivolumab+ipilimumab vs. nivolumab - HR (95% CI): 0.81 (0.62, 1.06) 
 

PD-L1 expression ≥ 5% 

 
Overall survival (months) 

 
 
 
 
 
 
 
 

- - -*- - - - Nivolumab+ipilimumab (events: 30/68), median and 95% CI: N.A. (39.06, N.A.) 
 ──∆───  Nivolumab (events: 41/80), median and 95% CI: 61.57 months (33.64, N.A.) 

 - - -- - -  Ipilimumab (events: 50/75), median and 95% CI: 28.88 months (18.10, 44.16) 
 
   Nivolumab+ipilimumab vs. ipilimumab - HR (95% CI): 0.58 (0.37, 0.91) 
   Nivolumab vs. ipilimumab - HR (95% CI): 0.63 (0.42, 0.96) 

Nivolumab+ipilimumab vs. nivolumab - HR (95% CI): 0.91 (0.657, 1.46)  

Number of subjects at risk 
Nivolumab+ipilimumab 
210 178 146 139 130 123 116 109 106 103 101 9 0 
Nivolumab 
208 169 144 123 112 108 102 92 90 88 82 9 0 
Ipilimumab 
202 158 124 99 80 69 59 57 55 50 45 5 0 

Number of subjects at risk 
Nivolumab+ipilimumab 
68 56 52 45 45 43 43 41 40 37 33 2 0 
Nivolumab 
80 76 69 61 57 53 47 44 43 41 41 5 0 
Ipilimumab 
75 66 60 46 40 34 32 29 25 24 22 5 0 

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Figure 7: Overall survival by PD-L1 expression: 1% cut off (CA209067) - Minimum follow-up 
of 60 months 

PD-L1 expression < 1% 

 
Overall survival (months) 

Number of subjects at risk 
Nivolumab+ipilimumab 

123 102 82 79 74 70 65 63 62 61 59 6 0 
Nivolumab 

117 86 73 62 57 53 49 43 43 42 41 5 0 
Ipilimumab 

113 87 71 57 44 36 33 32 31 28 27 3 0 
 - - -*- - - - Nivolumab+ipilimumab (events: 62/123), median and 95% CI: 61.44 (26.45, N.A.) 
 ──∆───  Nivolumab (events: 74/117), median and 95% CI: 23.46 months (13.01, 36.53) 

 - - -- - -  Ipilimumab (events: 86/113), median and 95% CI: 18.56 months (13.67, 23.20) 
 
   Nivolumab+ipilimumab vs. ipilimumab - HR (95% CI): 0.53 (0.38, 0.74) 
   Nivolumab vs. ipilimumab - HR (95% CI): 0.77 (0.56, 1.05) 
   Nivolumab+ipilimumab vs. nivolumab - HR (95% CI): 0.69 (0.50, 0.97) 
 

PD-L1 expression ≥ 1% 

 
Overall survival (months) 

 
 
 
 
 
 
 
 
 
 
 - - -*- - - - Nivolumab+ipilimumab (events: 71/155), median and 95% CI: N.A. (39.06, N.A.) 
 ──∆───  Nivolumab (events: 84/171), median and 95% CI: 66.99 months (39.00, N.A.) 

 - - -- - -  Ipilimumab (events: 118/164), median and 95% CI: 21.49 months (16.85, 29.08) 
 
   Nivolumab+ipilimumab vs. ipilimumab - HR (95% CI): 0.51 (0.38, 0.69) 
   Nivolumab vs. ipilimumab - HR (95% CI): 0.53 (0.40, 0.70) 

Nivolumab+ipilimumab vs. nivolumab - HR (95% CI): 0.97 (0.70, 1.32) 
  

Number of subjects at risk 
Nivolumab+ipilimumab 
155 132 116 105 101 96 94 87 84 79 75 5 0 

Nivolumab 
171 159 140 122 112 108 100 93 90 87 82 9 0 

Ipilimumab 
164 137 113 88 76 67 58 54 49 46 40 7 0 

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Minimum follow-up for the analysis of ORR was 60 months. Responses are summarised in Table 11. 
 

Table 11: Objective response (CA209067) 

 
nivolumab + 
ipilimumab  

(n = 314)

 
nivolumab  
(n = 316)

 
ipilimumab  

(n = 315)
Objective response  183 (58%) 141 (45%) 60 (19%) 

  (95% CI) (52.6, 63.8) (39.1, 50.3) (14.9, 23.8) 

 Odds ratio (vs. ipilimumab) 6.35 3.5  

  (95% CI) (4.38, 9.22) (2.46, 5.10)  

 Complete response (CR) 69 (22%) 60 (19%) 18 (6%) 

 Partial response (PR) 114 (36%) 81 (26%) 42 (13%) 

 Stable disease (SD) 38 (12%) 30 (10%) 69 (22%) 

Duration of response    

 Median (range), months 
N.A. 

(0-65.2) 
N.A.  

(0-63.3)  
14.39 

(0-61.9) 

 Proportion ≥12 months in 
duration 

67% 71% 47% 

 Proportion ≥24 months in 
duration 

57% 55% 36% 

ORR (95% CI) by tumour PD-L1 expression    

 <5% 
56% (48.7, 62.5) 

n = 210 
43% (36, 49.8) 

n = 208 
18% (12.8, 23.8) 

n = 202 

 ≥5% 
72% (59.9, 82.3) 

n = 68 
58% (45.9, 68.5) 

n = 80 
21% (12.7, 32.3) 

n = 75 

 <1% 
54% (44.4, 62.7) 

n = 123 
36% (27.2, 45.3) 

n = 117 
18% (11.2, 26.0) 

n = 113 

 ≥1% 
65% (56.4, 72) 

n = 155 
54% (46.6, 62) 

n = 171 
20% (13.7, 26.4) 

n = 164 

 
Both nivolumab-containing arms demonstrated a significant PFS and OS benefit and greater ORR 
compared with ipilimumab alone. The observed PFS results at 18 months of follow-up and ORR and 
OS results at 28 months of follow-up were consistently demonstrated across subgroups of patients 
including baseline ECOG performance status, BRAF status, M stage, age, history of brain metastases, 
and baseline LDH level. This observation was maintained with the OS results with a minimum follow-
up of 60 months. 
 
Among 131 patients who discontinued the combination due to adverse reaction after 28 months of 
follow-up, the ORR was 71% (93/131) with 20% (26/131) achieving a complete response and median 
OS was not reached. 
 
Both nivolumab-containing arms demonstrated greater objective response rates than ipilimumab 
regardless of PD-L1 expression levels. ORRs were higher for the combination of nivolumab and 
ipilimumab relative to nivolumab monotherapy across tumour PD-L1 expression levels (Table 11) 
after 60 months of follow-up, with a best overall response of complete response correlating to an 
improved survival rate. 
 
After 60 months of follow-up, median durations of response for patients with tumour PD-L1 
expression level ≥5% were not reached (range: 18.07-N.A.) in the combination arm, not reached 
(range: 26.71-N.A.) in the nivolumab monotherapy arm and 31.28 months (range: 6.08-N.A.) in the 
ipilimumab arm. At tumour PD-L1 expression <5%, median durations of response were not reached 
(range: 40.08-N.A.) in the combination arm, were not reached (range: 50.43-N.A.) in the nivolumab 
monotherapy arm and 12.75 months (range: 5.32-53.65) in the ipilimumab monotherapy arm. 



 
47 

 
No clear cut off for PD-L1 expression can reliably be established when considering the relevant 
endpoints of tumour response and PFS and OS. Results from exploratory multivariate analyses 
identified patient and tumour characteristics (ECOG performance status, M stage, baseline LDH, 
BRAF mutation status, PD-L1 status, and gender) which might contribute to the survival outcome. 
 
Efficacy by BRAF status:  
After 60 months of follow-up, BRAF[V600] mutation-positive and BRAF wild-type patients 
randomised to ipilimumab in combination with nivolumab had a median PFS of 16.76 months 
(95% CI: 8.28, 32.0) and 11.17 months (95% CI: 7.0, 18.14), while those in the nivolumab 
monotherapy arm had a median PFS of 5.6 months (95% CI: 2.79, 9.46) and 8.18 months 
(95% CI: 5.13, 19.55), respectively. BRAF[V600] mutation-positive and BRAF wild-type patients 
randomised to ipilimumab monotherapy had a median PFS of 3.38 months (95% CI: 2.79, 5.19) and 
2.83 months (95% CI: 2.76, 3.06), respectively.  
After 60 months of follow-up, BRAF[V600] mutation-positive and BRAF wild-type patients 
randomised to ipilimumab in combination with nivolumab had an ORR of 67.0% (95% CI: 57.0, 75.9; 
n = 103) and 54.0% (95% CI: 47.1, 60.9; n = 211), while those in the nivolumab monotherapy arm had 
an ORR of 37.87% (95% CI: 28.2, 48.1; n = 98) and 47.7% (95% CI: 40.9, 54.6; n = 218), 
respectively. BRAF[V600] mutation-positive and BRAF wild-type patients randomised to ipilimumab 
monotherapy had an ORR of 23.0% (95% CI: 15.2, 32.5; n = 100) and 17.2% (95% CI: 12.4, 22.9; 
n = 215),  
After 60 months of follow-up, in BRAF [V600] mutation-positive patients median OS was not reached 
in the combination arm and 45.5 months in the nivolumab monotherapy arm. Median OS for BRAF 
[V600] mutation-positive patients in the ipilimumab monotherapy arm was 24.6 months. In BRAF 
wild-type patients median OS was 39.06 months in the combination arm, 34.37 months in the 
nivolumab monotherapy arm, and 18.5 months in the ipilimumab monotherapy arm. The OS HRs for 
ipilimumab in combination with nivolumab vs. nivolumab monotherapy were 0.70 
(95% CI: 0.46, 1.05) for BRAF[V600] mutation-positive patients and 0.89 (95% CI: 0.69, 1.15) for 
BRAF wild-type patients. 
 
Randomised phase 2 study of ipilimumab in combination with nivolumab and ipilimumab (CA209069) 
Study CA209069 was a randomised, Phase 2, double-blind study comparing the combination of 
nivolumab and ipilimumab with ipilimumab alone in 142 patients with advanced (unresectable or 
metastatic) melanoma with similar inclusion criteria to study CA209067 and the primary analysis in 
patients with BRAF wild-type melanoma (77% of patients). Investigator assessed ORR was 
61% (95% CI: 48.9, 72.4) in the combination arm (n = 72) versus 11% (95% CI: 3.0, 25.4) for the 
ipilimumab arm (n = 37). The estimated 2 and 3 year OS rates were 68% (95% CI: 56, 78) and 61% 
(95% CI: 49, 71), respectively, for the combination (n = 73) and 53% (95% CI: 36, 68) and 44% 
(95% CI: 28, 60), respectively, for ipilimumab (n = 37). 
 
Renal Cell Carcinoma (RCC) 
 
Randomised phase 3 study of ipilimumab in combination with nivolumab vs. sunitinib (CA209214) 
The safety and efficacy of ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg for the 
treatment of advanced/metastatic RCC was evaluated in a phase 3, randomised, open-label study 
(CA209214). The study included patients (18 years or older) with previously untreated, advanced or 
metastatic renal cell carcinoma with a clear-cell component. The primary efficacy population included 
those intermediate/poor risk patients with at least 1 or more of 6 prognostic risk factors as per the 
International Metastatic RCC Database Consortium (IMDC) criteria (less than one year from time of 
initial renal cell carcinoma diagnosis to randomisation, Karnofsky performance status <80%, 
haemoglobin less than the lower limit of normal, corrected calcium of greater than 10 mg/dL, platelet 
count greater than the upper limit of normal, and absolute neutrophil count greater than the upper limit 
of normal). This study included patients regardless of their tumour PD-L1 status. Patients with 
Karnofsky performance status < 70% and patients with any history of or concurrent brain metastases, 
active autoimmune disease, or medical conditions requiring systemic immunosuppression were 
excluded from the study. Patients were stratified by IMDC prognostic score and region. 
 



 
48 

A total of 1096 patients were randomised in the trial, of which 847 patients had intermediate/poor-risk 
RCC and received either ipilimumab 1 mg/kg (n = 425) administered intravenously over 30 minutes in 
combination with nivolumab administered intravenously over 60 minutes every 3 weeks for 4 doses 
followed by nivolumab monotherapy 3 mg/kg every 2 weeks or sunitinib (n = 422) 50 mg daily, 
administered orally for 4 weeks followed by 2 weeks off, every cycle. Treatment was continued as 
long as clinical benefit was observed or until treatment was no longer tolerated. The first tumour 
assessments were conducted 12 weeks after randomisation and continued every 6 weeks thereafter for 
the first year and then every 12 weeks until progression or treatment discontinuation, whichever 
occurred later. Treatment beyond initial investigator-assessed RECIST, version 1.1-defined 
progression was permitted if the patient had a clinical benefit and was tolerating study drug as 
determined by the investigator. The primary efficacy outcome measures were OS, ORR and PFS as 
determined by a Blinded Independent Central Review (BICR) in intermediate/poor risk patients.  
 
Baseline characteristics were generally balanced between the two groups. The median age was 
61 years (range: 21-85) with 38%  65 years of age and 8%  75 years of age. The majority of patients 
were male (73%) and white (87%), and 31% and 69% of patients had a baseline KPS of 70 to 80% and 
90 to 100%, respectively. The median duration of time from initial diagnosis to randomisation was 
0.4 years in both the ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg and sunitinib 
groups. The median duration of treatment was 7.9 months (range: 1 day- 21.4+ months) in ipilimumab 
with nivolumab- treated patients and was 7.8 months (range: 1 days- 20.2+ months) in sunitinib-treated 
patients. Ipilimumab with nivolumab was continued beyond progression in 29% of patients. 
 
The Kaplan-Meier curves for OS (with a minimum follow-up of 24 months) in intermediate/poor risk 
patients are shown in Figure 8. 
 



 
49 

Figure 8: Kaplan-Meier curves of OS in intermediate/poor risk patients (CA209214) 
 

 
Overall Survival (Months) 

Number of Subjects at Risk 
Nivolumab + Ipilimumab 
425 399 372 348 332 317 306 282 257 201 102 33 4 0
Sunitinib   
422 387 352 316 288 253 233 216 196 147 87 36 3 0

Nivolumab + ipilimumab (events: 166/425), median and 95.0% CI: NA (32.49, NA) 

 Sunitinib (events: 209/422), median and 95.0% CI: 26.97 (22.08, 34.83) 
 
In intermediate/poor-risk patients, OS benefit was observed in the ipilimumab in combination with 
nivolumab arm vs. sunitinib regardless of tumour PD-L1 expression. Median OS for tumour PD-L1 
expression ≥ 1% was not reached for ipilimumab in combination with nivolumab, and was 19.61 
months in the sunitinib arm (HR = 0.52; 95% CI: 0.34, 0.78). For tumour PD-L1 expression < 1%, the 
median OS was 34.7 months for the ipilimumab in combination with nivolumab and was 32.2 months 
in the sunitinib arm (HR = 0.70; 95% CI: 0.54, 0.92). 
 
CA209214 also randomised 249 favourable risk patients as per IMDC criteria to nivolumab plus 
ipilimumab (n = 125) or to sunitinib (n = 124). These patients were not evaluated as part of the 
primary efficacy population. OS in favourable risk patients receiving nivolumab plus ipilimumab 
compared to sunitinib had a hazard ratio of 1.13 (95% CI: 0.64, 1.99; p = 0.6710). 
 
There are no data on the use of ipilimumab in combination with nivolumab in patients with only a non 
clear-cell histology in first line RCC. 
 
Efficacy results for the intermediate/poor risk patients are shown in Table 12. 
 

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Table 12: Efficacy results in intermediate/poor risk patients (CA209214) 
 nivolumab + ipilimumab 

(n = 425) 
sunitinib 
(n = 422) 

Overall survival    
 Events 140 (33%) 188 (45%) 

Hazard ratioa  0.63 
99.8% CI (0.44, 0.89) 
p-valueb, c < 0.0001

 
 Median (95% CI) NE (28.2, NE) 25.9 (22.1, NE) 
 Rate (95% CI)  
  At 6 months 89.5 (86.1, 92.1) 86.2 (82.4, 89.1) 
  At 12 months 80.1 (75.9, 83.6) 72.1 (67.4, 76.2) 
Progression-free survival   
 Events 228 (53.6%) 228 (54.0%) 

Hazard ratioa 0.82 
99.1% CI (0.64, 1.05) 
p-valueb,h 0.0331 

 Median (95% CI) 
 

11.6 (8.71, 15.51) 8.4 (7.03, 10.81) 

Confirmed objective response 
(BICR)  

177 (41.6%) 112 (26.5%) 

(95% CI) (36.9, 46.5) (22.4, 31.0) 
Difference in ORR (95% CI)d 16.0 (9.8, 22.2) 

p-valuee,f < 0.0001 
 

 Complete response (CR) 40 (9.4%) 5 (1.2%) 
 Partial response (PR) 137 (32.2%) 107 (25.4%) 
 Stable disease (SD) 133 (31.3%) 188 (44.5%) 
 
Median duration of responseg   
  Months (range) NE (1.4+-25.5+) 18.17 (1.3+-23.6+) 
 
Median time to response  
 Months (range) 2.8 (0.9-11.3) 3.0 (0.6-15.0) 

a Based on a stratified proportional hazards model. 
b Based on a stratified log-rank test. 
c p-value is compared to alpha 0.002 in order to achieve statistical significance. 
d Strata adjusted difference. 
e Based on the stratified DerSimonian-Laird test. 
f p-value is compared to alpha 0.001 in order to achieve statistical significance. 
g Computed using Kaplan-Meier method. 
h p-value is compared to alpha 0.009 in order to achieve statistical significance. 
“+” denotes a censored observation. 
NE = non-estimable  
 
An updated OS analysis was performed when all patients had a minimum follow-up of 24 months (see 
figure 8). At the time of this analysis, the hazard ratio was 0.66; (99.8% CI 0.48-0.91) with 166/425 
events in the combination arm and 209/422 events in the sunitinib arm. At 18 months, the OS rate was 
74.3 (95% CI 69.8-78.2) for ipilimumab in combination with nivolumab and 59.9 (95% CI 54.9-64.5) 
for sunitinib. At 24 months, the OS rate was 66.5 (95% CI 61.8-70.9) for ipilimumab in combination 
with nivolumab and 52.9 (95% CI 47.9- 57.7) for sunitinib. 
 
Patients ≥ 75 years of age represented 8% of all intermediate/poor risk patients in CA209214, and the 
combination of ipilimumab with nivolumab showed numerically less effect on OS (HR 0.97, 95% 
CI: 0.48, 1.95) in this subgroup versus the overall population. Because of the small size of this 
subgroup, no definitive conclusions can be drawn from these data. 
 



 
51 

First-line treatment of Non-Small Cell Lung Cancer 
 
Randomised phase 3 study of ipilimumab in combination with nivolumab and 2 cycles of platinum-
based chemotherapy vs. 4 cycles of platinum-based chemotherapy (CA2099LA) 

 
The safety and efficacy of ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mg 
every 3 weeks and 2 cycles of platinum-based chemotherapy were evaluated in a phase 3, randomised, 
open-label study (CA2099LA). The study included patients (18 years or older) with histologically 
confirmed non-squamous or squamous Stage IV or recurrent NSCLC (per the 7th International 
Association for the Study of Lung Cancer classification), ECOG performance status 0 or 1, and no 
prior anticancer therapy (including EGFR and ALK inhibitors). Patients were enrolled regardless of 
their tumour PD-L1 status.  
 
Patients with sensitising EGFR mutations or ALK translocations, active (untreated) brain metastases, 
carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic 
immunosuppression were excluded from the study. Patients with treated brain metastases were eligible 
if neurologically returned to baseline at least 2 weeks prior to enrolment, and either off corticosteroids, 
or on a stable or decreasing dose of < 10 mg daily prednisone equivalents. Randomisation was 
stratified by histology (squamous vs non-squamous), tumour PD-L1 expression level (≥ 1% vs < 1%), 
and gender (male vs female).  
 
A total of 719 patients were randomised to receive either ipilimumab in combination with nivolumab 
and platinum-based chemotherapy (n = 361) or platinum-based chemotherapy (n = 358). Patients in the 
ipilimumab in combination with nivolumab and platinum-based chemotherapy arm received ipilimumab 
1 mg/kg administered intravenously over 30 minutes every 6 weeks in combination with nivolumab 
360 mg administered intravenously over 30 minutes every 3 weeks and platinum-based chemotherapy 
administered every 3 weeks for 2 cycles. Patients in the chemotherapy arm received platinum-based 
chemotherapy administered every 3 weeks for 4 cycles; non-squamous patients could receive optional 
pemetrexed maintenance therapy. 
Platinum-based chemotherapy consisted of carboplatin (AUC 5 or 6) and pemetrexed 500 mg/m2; or 
cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 for non-squamous NSCLC; or carboplatin (AUC 6) and 
paclitaxel 200 mg/m2 for squamous NSCLC. 
 
Treatment continued until disease progression, unacceptable toxicity, or for up to 24 months. Treatment 
could continue beyond disease progression if the patient was clinically stable and was considered to be 
deriving clinical benefit by the investigator. Patients who discontinued combination therapy because of 
an adverse event attributed to ipilimumab were permitted to continue nivolumab monotherapy. Tumour 
assessments were performed every 6 weeks after first dose of study treatment for the first 12 months, 
then every 12 weeks until disease progression or study treatment was discontinued.  
 
CA2099LA baseline characteristics were generally balanced across all treatment groups. The median 
age was 65 years (range: 26-86) with 51% ≥ 65 years of age and 10% ≥ 75 years of age. The majority 
of patients were white (89%) and male (70%). Baseline ECOG performance status was 0 (31%) or 
1 (68%), 57% of patients with PD-L1  1% and 37% with PD-L1 < 1%, 31% had squamous and 69% 
had non-squamous histology, 17% had brain metastases, and 86% were former/current smokers. No 
patients received prior immunotherapy. 
 
CA2099LA primary efficacy outcome measure was OS. Additional efficacy endpoints were PFS, ORR, 
and duration of response as assessed by BICR. 
 
The study demonstrated a statistically significant benefit in OS, PFS, and ORR for patients randomised 
to nivolumab in combination with ipilimumab and platinum-based chemotherapy as compared to 
platinum-based chemotherapy alone at the prespecified interim analysis when 351 events were observed 
(87% of the planned number of events for final analysis). Minimum follow-up for OS was 8.1 months. 
 
Efficacy results are shown in Figure 9 (updated OS analysis with a minimum follow-up of 12.7 months) 
and Table 13 (primary analysis with a minimum follow-up of 8.1 months). 



 
52 

An updated efficacy analysis was performed when all patients had a minimum follow-up of 12.7 months 
(see Figure 9). At the time of this analysis, the hazard ratio for OS was 0.66 (95% CI: 0.55, 0.80) and 
the hazard ratio for PFS was 0.68 (95% CI: 0.57, 0.82). 
 
Figure 9: Kaplan-Meier plot of OS (CA2099LA) 

 
Overall Survival (Months) 

 
Number of Subjects at Risk 
Nivolumab + ipilimumab + chemotherapy   

 361 326 292    250        227 153 86 33 10 1 0 
Chemotherapy  

 358 319 260    208        166 116 67 26 11 0 0 
 

Nivolumab + ipilimumab + chemotherapy (events: 190/361), median and 95% CI: 15.64 (13.93, 19.98) 
Chemotherapy (events: 242/358), median and 95% CI: 10.91 (9.46, 12.55) 

 
Table 13: Efficacy results (CA2099LA) 

 
ipilimumab + nivolumab + 

chemotherapy 
(n = 361)

chemotherapy 
(n = 358) 

Overall Survival 

 Events 156 (43.2%) 195 (54.5%) 
Hazard ratio  
(96.71% CI)a 

0.69  
(0.55, 0.87)

Stratified log-rank p-valueb 0.0006 
 Median (months) 
 (95% CI) 

14.1 
(13.24, 16.16) 

10.7 
(9.46, 12.45) 

 Rate (95% CI) at 6 months 80.9 (76.4,84.6) 72.3 (67.4,76.7) 
  
Progression-free Survival 

 Events 232 (64.3%) 249 (69.6%) 
Hazard ratio  
(97.48% CI)a 

0.70  
(0.57, 0.86) 

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Table 13: Efficacy results (CA2099LA) 

 
ipilimumab + nivolumab + 

chemotherapy 
(n = 361) 

chemotherapy 
(n = 358) 

Stratified log-rank p-valuec 0.0001 
 Median (months)d 

 (95% CI) 
6.83 

(5.55, 7.66) 
4.96 

(4.27, 5.55) 
Rate (95% CI) at 6 months 51.7 (46.2, 56.8) 35.9 (30.5, 41.3) 

   
Overall Response Ratee 136 (37.7%) 90 (25.1%) 

 (95% CI) (32.7, 42.9) (20.7, 30.0) 

Stratified CMH test p-valuef 0.0003 

 Complete response (CR) 7 (1.9%) 3 (0.8%) 

 Partial response (PR) 129 (35.7%) 87 (24.3%) 
   
Duration of Response 
 Median (months)  
 (95% CI)d 

10.02 
(8.21, 13.01)

5.09 
(4.34, 7.00) 

 % with duration ≥ 6 monthsg 74 41 
a Based on a stratified Cox proportional hazard model. 
b p-value is compared with the allocated alpha of 0.0329 for this interim analysis. 
c p-value is compared with the allocated alpha of 0.0252 for this interim analysis. 
d Kaplan-Meier estimate. 
e Proportion with complete or partial response; CI based on the Clopper and Pearson Method. 
f p-value is compared with the allocated alpha of 0.025 for this interim analysis. 
g Based on Kaplan-Meier estimates of duration of response. 
CMH = Cochran-Mantel-Haenszel 
 
Subsequent systemic therapy was received by 28.8% and 41.1% of patients in the combination and 
chemotherapy arms, respectively. Subsequent immunotherapy (including anti-PD-1, anti-PD-L1, and 
anti-CTLA4) was received by 3.9% and 27.9% of patients in the combination and chemotherapy arms, 
respectively. 
 
In study CA2099LA, subgroup descriptive analysis relative to chemotherapy, OS benefit was shown 
in patients treated with ipilimumab in combination with nivolumab and chemotherapy with squamous 
histology (HR [95% CI] 0.65 [0.46, 0.93], n = 227) and in patients with non-squamous histology (HR 
[95% CI] 0.72 [0.55, 0.93], n = 492). 
 
Table 14 summarises efficacy results of OS, PFS, and ORR by tumour PD-L1 expression in pre-
specified subgroup analyses. 
 
Table 14: Efficacy results by tumour PD-L1 expression (CA2099LA) 

 

ipilimumab  
+  

nivolumab 
+ 

chemotherapy 

chemo-
therapy 

ipilimumab  
+  

nivolumab 
+ 

chemotherapy

chemo-
therapy 

ipilimumab  
+  

nivolumab 
+ 

chemotherapy 

chemo-
therapy 

ipilimumab  
+  

nivolumab 
+ 

chemotherapy

chemo-
therapy 

 
PD-L1 < 1% 

(n = 264) 
PD-L1 ≥ 1% 

(n = 406) 
PD-L1 ≥ 1% to 49% 

(n = 233) 
PD-L1 ≥ 50% 

(n = 173) 
OS Hazard 

Ratio 

(95% CI)
a

 

0.65 
(0.46, 0.92) 

0.67 
(0.51, 0.89) 

0.69 
(0.48, 0.98) 

0.64 
(0.41, 1.02) 

PFS 
Hazard 
Ratio  

(95% CI)
a

 

0.77 
(0.57, 1.03) 

0.67 
(0.53, 0.85) 

0.71 
(0.52, 0.97) 

0.59 
(0.40, 0.86) 

ORR % 31.1 20.9 41.9 27.6 37.8 24.5 48.7 30.9 

a Hazard ratio based on unstratified Cox proportional hazards model. 



 
54 

 
A total of 70 NSCLC patients aged ≥ 75 years were enrolled in study CA2099LA (37 patients in the 
ipilimumab in combination with nivolumab and chemotherapy arm and 33 patients in the chemotherapy 
arm). A HR of 1.36 (95% CI: 0.74, 2.52) in OS and a HR of 1.12 (95% CI: 0.64, 1.96) in PFS was 
observed for ipilimumab in combination with nivolumab and chemotherapy vs. chemotherapy within 
this study subgroup. ORR was 27.0% in the ipilimumab in combination with nivolumab and 
chemotherapy arm and 15.2% in the chemotherapy arm. Forty-three percent of patients aged ≥ 75 years 
discontinued treatment with ipilimumab in combination with nivolumab and chemotherapy. Efficacy 
and safety data of ipilimumab in combination with nivolumab and chemotherapy are limited in this 
patient population. 
 
In a subgroup analysis, a reduced survival benefit for ipilimumab in combination with nivolumab and 
chemotherapy compared to chemotherapy was observed in patients who were never smokers. However, 
due to the small numbers of patients, no definitive conclusions can be drawn from these data. 
 
Paediatric population 
Study CA184070 was a multi-center, Phase 1, open-label, dose-escalation study of ipilimumab in 
paediatric patients 1 year to  21 years of age with measurable/evaluable, untreatable, relapsed or 
refractory solid malignant tumors without a curative option with standard therapy. The study enrolled 
13 patients < 12 of age and 20 patients  12 years of age. Ipilimumab was administered every 3 weeks 
for 4 doses and then every 12 weeks thereafter in the absence of dose limiting toxicity (DLT) and 
disease progression. The primary endpoints were safety and pharmacokinetics (PK). Of patients 12 
years of age and older with advanced melanoma, ipilimumab 5 mg/kg was administered to three 
patients and ipilimumab 10 mg/kg was administered to two patients. Stable disease was achieved in 
two patients at the ipilimumab 5mg/kg dose, one with a duration of > 22 months. 
 
Study CA184178 was a non-randomized, multicenter, open-label Phase 2 study, in adolescent patients 
12 to < 18 years of age with previously treated or untreated, unresectable Stage III or Stage IV 
malignant melanoma. Ipilimumab was administered every 3 weeks for 4 doses. The primary efficacy 
endpoint was 1-year survival rate. Secondary efficacy endpoints of best overall response rate (BORR), 
stable disease (SD), disease control rate (DCR), and progression free survival (PFS) were based on 
mWHO criteria and determined by the investigator’s assessment. Overall survival (OS) was also 
evaluated. Tumor assessment was performed at Week 12. All patients were followed for at least 1 
year. Ipilimumab 3 mg/kg was administered to four patients and ipilimumab 10 mg/kg was 
administered to eight patients. Most patients were male (58%) and white (92%). Median age was 15 
years. Stable disease was achieved for 260 days in one patient on ipilimumab 3 mg/kg and 
approximately 14 months in one patient on ipilimumab 10 mg/kg. Two patients treated with 
ipilimumab 10 mg/kg experienced a partial response, one of which was a durable response for more 
than 1 year. Additional efficacy results are presented in Table 15. 

 

Table 15: Efficacy Results in CA184178  

 
Ipilimumab 3 mg/kg 

N= 4 
Ipilimumab 10 mg/kg 

N= 8 
1-year OS (%) (95% CI) 75% (12.8, 96.1) 62.5% (22.9, 86.1) 
BORR (%) (95% CI) 0% (0, 60.2) 25% (3.2, 65.1) 
SD (n/N)a 1/4 1/8 
DCR (%) (95% CI) 25% (0.6, 80.6) 37.5% (8.5, 75.5) 
Median PFS (months) (95% CI) 2.6 (2.3, 8.5) 2.9 (0.7,NEa) 
Median OS (months) (95% CI) 18.2 (8.9, 18.2) Not reached (5.2, NE) 

a NE= not estimable 

 
5.2 Pharmacokinetic properties 
 



 
55 

The pharmacokinetics of ipilimumab was studied in 785 patients with advanced melanoma who 
received induction doses ranging from 0.3 to 10 mg/kg administered once every 3 weeks for 4 doses. 
Cmax, Cmin and AUC of ipilimumab were found to be dose proportional within the dose range 
examined. Upon repeated dosing of ipilimumab administered every 3 weeks, CL was found to be 
time-invariant, and minimal systemic accumulation was observed as evident by an accumulation 
index 1.5 fold or less. Ipilimumab steady-state was reached by the third dose. Based on population 
pharmacokinetic analysis, the following mean (percent coefficient of variation) parameters of 
ipilimumab were obtained: terminal half-life of 15.4 days (34.4%); systemic CL of 16.8 ml/h (38.1%); 
and volume of distribution at steady-state of 7.47 l (10.1%). The mean (percent coefficient of 
variation) ipilimumab Cmin achieved at steady-state with a 3 mg/kg induction regimen was 19.4 µg/ml 
(74.6%). 
 
Ipilimumab CL increased with increasing body weight and with increasing LDH at baseline; however, 
no dose adjustment is required for elevated LDH or body weight after administration on a mg/kg basis. 
CL was not affected by age (range 23-88 years), gender, concomitant use of budesonide or 
dacarbazine, performance status, HLA-A2*0201 status, mild hepatic impairment, renal impairment, 
immunogenicity, and previous anticancer therapy. The effect of race was not examined as there was 
insufficient data in non-Caucasian ethnic groups. No controlled studies have been conducted to 
evaluate the pharmacokinetics of ipilimumab in the paediatric population or in patients with hepatic or 
renal impairment. 
 
Based on an exposure-response analysis in 497 patients with advanced melanoma, OS was 
independent of prior systemic anti-cancer therapy and increased with higher ipilimumab Cminss 
plasma concentrations. 
 
Yervoy in combination with nivolumab: When ipilimumab 1 mg/kg was administered in combination 
with nivolumab 3 mg/kg, the CL of ipilimumab was decreased by 1.5% and the CL of nivolumab was 
increased by 1% which were not considered clinically relevant. When ipilimumab 3 mg/kg was 
administered in combination with nivolumab 1 mg/kg, the CL of ipilimumab was increased by 9% and 
the CL of nivolumab was increased by 29%, which was not considered clinically relevant. 
 
When administered in combination with nivolumab, the CL of ipilimumab increased by 5.7% in the 
presence of anti-ipilimumab antibodies and the CL of nivolumab increased by 20% in the presence of 
presence of anti-nivolumab antibodies. These changes were not considered clinically relevant. 
 
Yervoy in combination with nivolumab and chemotherapy: When ipilimumab 1 mg/kg every 6 weeks 
was administered in combination with nivolumab 360 mg every 3 weeks and with 2 cycles of 
chemotherapy, the CL of ipilimumab increased approximately 22% and the CL of nivolumab 
decreased approximately 10%, which was not considered clinically relevant.  
 
Renal impairment 
 
In the population pharmacokinetic analysis of data from clinical studies in patients with metastatic 
melanoma, pre-existing mild and moderate renal impairment did not influence the CL of ipilimumab. 
Clinical and pharmacokinetic data with pre-existing severe renal impairment are limited; the potential 
need for dose adjustment cannot be determined. 
 
Hepatic impairment 
 
In the population pharmacokinetic analysis of data from clinical studies in patients with metastatic 
melanoma, pre-existing mild hepatic impairment did not influence the CL of ipilimumab. Clinical and 
pharmacokinetic data with pre-existing moderate hepatic impairment are limited; the potential need for 
dose adjustment cannot be determined. No patients with pre-existing severe hepatic impairment were 
identified in clinical studies. 
 



 
56 

Paediatric Population 
 
Based on a population PK analysis using available pooled data from 565 patients from 4 phase 2 adult 
studies (N=521) and 2 paediatric studies (N=44), CL of ipilimumab increased with increasing baseline 
body weight. Age (2-87 years) had no clinically important effect on the CL of ipilimumab. The 
estimated geometric mean CL is 8.72 mL/h in adolescent patients aged ≥12 to <18 years. Exposures in 
adolescents are comparable with those in adults receiving the same mg/kg dose. Based on the 
simulation in adults and paediatrics, comparable exposure is achieved in adults and paediatrics at the 
recommended dose of 3 mg/kg every 3 weeks. 
 
5.3 Preclinical safety data 
 
In intravenous repeat-dose toxicology studies in monkeys, ipilimumab was generally well tolerated. 
Immune-mediated adverse reactions were observed infrequently (~3%) and included colitis (which 
resulted in a single fatality), dermatitis, and infusion reaction (possibly due to acute cytokine release 
resulting from a rapid injection rate). A decrease in the weight of the thyroid and testes was seen in 
one study without accompanying histopathologic findings; the clinical relevance of this finding is 
unknown. 
 
The effects of ipilimumab on prenatal and postnatal development were investigated in a study in 
cynomolgus monkeys. Pregnant monkeys received ipilimumab every 3 weeks from the onset of 
organogenesis in the first trimester through delivery, at exposure (AUC) levels either similar to or 
higher than those associated with the clinical dose of 3 mg/kg of ipilimumab. No treatment-related 
adverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginning 
in the third trimester, both ipilimumab groups experienced higher incidences of abortion, stillbirth, 
premature delivery (with corresponding lower birth weight), and infant mortality relative to control 
animals; these findings were dose-dependent. Additionally, developmental external or visceral 
abnormalities were identified in the urogenital system of 2 infants exposed in utero to ipilimumab. 
One female infant had unilateral renal agenesis of the left kidney and ureter, and one male infant had 
an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema. The 
relationship of these malformations to treatment is unclear. 
 
Studies to evaluate the mutagenic and carcinogenic potential of ipilimumab have not been performed. 
Fertility studies have not been performed. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tris hydrochloride (2-amino-2-hydroxymethyl-1,3-propanediol hydrochloride) 
Sodium chloride 
Mannitol (E421) 
Pentetic acid (diethylenetriaminepentaacetic acid) 
Polysorbate 80  
Sodium hydroxide (for pH-adjustment) 
Hydrochloric acid (for pH-adjustment) 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products.  
 
6.3 Shelf life 
 
Unopened vial 



 
57 

3 years 
 
After opening 
From a microbiological point of view, once opened, the medicinal product should be infused or diluted 
and infused immediately. The chemical and physical in-use stability of the undiluted or diluted 
concentrate (between 1 and 4 mg/ml) has been demonstrated for 24 hrs at 25°C and 2°C to 8°C. If not 
used immediately, the infusion solution (undiluted or diluted) may be stored for up to 24 hours in a 
refrigerator (2°C to 8°C) or at room temperature (20°C to 25°C). 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C-8°C). 
Do not freeze. 
Store in the original package in order to protect from light. 
 
For storage conditions after first opening or dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
10 ml of concentrate in a vial (Type I glass) with a stopper (coated butyl rubber) and a flip-off seal 
(aluminium). Pack size of 1. 
40 ml of concentrate in a vial (Type I glass) with a stopper (coated butyl rubber) and a flip-off seal 
(aluminium). Pack size of 1. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling  
 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to asepsis. 
 
Calculating the dose: 
 
Ipilimumab monotherapy or ipilimumab in combination with nivolumab: 
The prescribed dose for the patient is given in mg/kg. Based on this prescribed dose, calculate the total 
dose to be given. More than one vial of YERVOY concentrate may be needed to give the total dose for 
the patient. 
 
 Each 10 ml vial of YERVOY concentrate provides 50 mg of ipilimumab; each 40 ml vial 

provides 200 mg of ipilimumab. 
 The total ipilimumab dose in mg = the patient’s weight in kg × the prescribed dose in mg/kg. 
 The volume of YERVOY concentrate to prepare the dose (ml) = the total dose in mg, divided 

by 5 (the YERVOY concentrate strength is 5 mg/ml). 
 
Preparing the infusion: 
Take care to ensure aseptic handling when you prepare the infusion.  
 
YERVOY can be used for intravenous administration either: 
 without dilution, after transfer to an infusion container using an appropriate sterile syringe; 

or 
 after diluting to up to 5 times the original volume of concentrate (up to 4 parts of diluent 

to 1 part of concentrate). The final concentration should range from 1 to 4 mg/ml. To dilute the 
YERVOY concentrate, you can use either: 
 sodium chloride 9 mg/ml (0.9%) solution for injection; or 
 50 mg/ml (5%) glucose solution for injection 

 



 
58 

STEP 1 
 Allow the appropriate number of vials of YERVOY to stand at room temperature for 

approximately 5 minutes. 
 Inspect the YERVOY concentrate for particulate matter or discoloration. YERVOY concentrate 

is a clear to slightly opalescent, colourless to pale yellow liquid that may contain light (few) 
particulates. Do not use if unusual amount of particles and signs of discoloration are present. 

 Withdraw the required volume of YERVOY concentrate using an appropriate sterile syringe. 
 
STEP 2 
 Transfer the concentrate into a sterile, evacuated glass bottle or intravenous bag (PVC or 

non-PVC). 
 If applicable, dilute with the required volume of sodium chloride 9 mg/ml (0.9%) solution for 

injection or 50 mg/ml (5%) glucose solution for injection. For ease of preparation, the 
concentrate can also be transferred directly into a pre-filled bag containing the appropriate 
volume of sodium chloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) glucose 
solution for injection. Gently mix the infusion by manual rotation. 

 
Administration: 
The YERVOY infusion must not be administered as an intravenous push or bolus injection. 
Administer the YERVOY infusion intravenously over a period of 30 or 90 minutes, depending on the 
dose. 
 
The YERVOY infusion should not be infused at the same time in the same intravenous line with other 
agents. Use a separate infusion line for the infusion. 
 
Use an infusion set and an in-line, sterile, non-pyrogenic, low protein binding filter (pore size 
of 0.2 μm to 1.2 μm). 
 
The YERVOY infusion is compatible with: 
 PVC infusion sets 
 Polyethersulfone (0.2 μm to 1.2 μm) and nylon (0.2 μm) in-line filters 
 
Flush the line with sodium chloride 9 mg/ml (0.9%) solution for injection or 50 mg/ml (5%) glucose 
solution for injection at the end of the infusion. 
 
Any unused medicinal product or waste material should be discarded in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBERS  
 
EU/1/11/698/001-002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 13 July 2011 
Date of latest renewal: 21 April 2016 



 
59 

 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 
  



 
60 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) 

AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 



 
61 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer(s) of the biological active substance(s) 
 
Bristol-Myers Squibb Company 
6000 Thompson Road 
East Syracuse, New York 13057 
United States 
 
Samsung Biologics Co. Ltd 
300, Songdo Bio Way (Daero)  
Yeonsu-gu, Incheon 21987 
Korea 
 
Name and address of the manufacturer(s) responsible for batch release 
 
CATALENT ANAGNI S.R.L. 
Loc. Fontana del Ceraso snc 
Strada Provinciale 12 Casilina, 41 
03012 Anagni (FR)  
Italy  
 
Swords Laboratories T/A Bristol-Myers Squibb Cruiserath Biologics 
Cruiserath Road, Mulhuddart 
Dublin 15, D15 H6EF 
Ireland 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
 Periodic safety update reports (PSURs) 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2. of the marketing 
authorisation and any agreed subsequent updates of the RMP. 
 



 
62 

An updated RMP should be submitted: 
 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
 Additional risk minimisation measures 
 
The Marketing Authorisation Holder shall ensure that all physicians who are expected to prescribe 
YERVOY are provided with/have access to the following to provide to their patients:  

 Patient Information Brochure including Alert Card 
 
Key elements for the Patient Information Brochure and Alert Card: 
 
 Brief introduction to ipilimumab and the purpose of the risk minimisation tools. 
 Information that ipilimumab can cause serious side effects in many parts of the body that can 

lead to death and need to be addressed immediately 
 Request to inform the physician of all medical conditions before treatment. 
 Description of the main symptoms of irARs and the importance of notifying their treating 

physician immediately if symptoms occur, persist or worsen. 
o Gastrointestinal: diarrhea, bloody stool, abdominal pain, nausea, or vomiting 
o Liver: yellowing of your skin or whites of your eyes 
o Skin: rash, blisters and/or peeling, mouth sores 
o Eye: blurred vision, vision changes, eye pain, 
o General: fever, headache, feeling tired, dizziness or fainting, dark urine, bleeding, 

weakness, numbness of legs, arms, or faces, changes in behavior, such as less sex drive, 
being irritable or forgetful 

 The importance of not attempting to self-treat any symptoms without consulting their 
Healthcare professional first. 

 Placeholder including the weblink of the Package Leaflet on the EMA website 
 The importance of carrying the detachable wallet-sized Patient Alert Card at all times to show it 

at all medical visits to healthcare professionals other than the prescriber (e.g. emergency 
healthcare professionals). The Card reminds patients about key symptoms that need to be 
reported immediately to the physician/nurse. It also contains prompts to enter contact details of 
the physician and to alert other physicians that the patient is treated with ipilimumab. 

 
The Marketing Authorisation Holder shall agree the format and content of the above material with the 
National Competent Authority prior to launch in the Member State. 
 
 Obligation to conduct post-authorisation measure  
 
The MAH shall complete, within the stated timeframe, the below measure: 
 

Description Due date 

Post authorisation efficacy study (PAES): In order to further elucidate the 
contribution of ipilimumab to the efficacy and toxicity of the combination 
regimen of nivolumab and ipilimumab, the MAH should conduct and 
submit the results of a randomised, clinical study comparing the efficacy 
and safety of the combination of nivolumab and ipilimumab to nivolumab 
monotherapy in previously untreated adult patients with intermediate/poor-
risk advanced renal cell carcinoma and with an appropriate spectrum of PD-
L1 expression levels. This study should be conducted according to an 
agreed protocol. 

30th September 2021 

 
  



 
63 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
  



 
64 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 
 
 



 
65 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
YERVOY 5 mg/ml concentrate for solution for infusion 
Ipilimumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml of concentrate contains 5 mg ipilimumab. 
Each vial contains 50 mg ipilimumab. 
Each vial contains 200 mg ipilimumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Tris hydrochloride, sodium chloride, mannitol (E421), pentetic acid, polysorbate 80, 
sodium hydroxide, hydrochloric acid, water for injections. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
 
50 mg/10 ml 
200 mg/40 ml 
 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
For single use only. 
 
 
8. EXPIRY DATE 
 
EXP 
 



 
66 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/11/698/001 
EU/1/11/698/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 



 
67 

SN 
<NN> 



 
68 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
YERVOY 5 mg/ml sterile concentrate 
Ipilimumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml of concentrate contains 5 mg ipilimumab. 
Each vial contains 50 mg ipilimumab. 
Each vial contains 200 mg ipilimumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Tris hydrochloride, sodium chloride, mannitol (E421), pentetic acid, polysorbate 80, 
sodium hydroxide, hydrochloric acid, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Sterile concentrate 
 
50 mg/10 ml 
200 mg/40 ml 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
IV use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
For single use only. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



 
69 

9. SPECIAL STORAGE CONDITIONS 

 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/11/698/001 
EU/1/11/698/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
  



 
70 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 
71 

Package leaflet: Information for the user 
 

YERVOY 5 mg/ml concentrate for solution for infusion 
ipilimumab 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor. 
 If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
What is in this leaflet  
 
1. What YERVOY is and what it is used for 
2. What you need to know before you use YERVOY 
3. How to use YERVOY 
4. Possible side effects 
5. How to store YERVOY 
6. Contents of the pack and other information 
 
 
1. What YERVOY is and what it is used for 
 
YERVOY contains the active substance ipilimumab, a protein which helps your immune system to 
attack and destroy cancer cells by your immune cells. 
 
Ipilimumab alone is used to treat advanced melanoma (a type of skin cancer) in adults and adolescents 
12 years of age and older. 
 
Ipilimumab in combination with nivolumab is used to treat  
 advanced melanoma (a type of skin cancer) in adults 
 advanced renal cell carcinoma (advanced kidney cancer) in adults 
 
Ipilimumab in combination with nivolumab and chemotherapy is used to treat advanced non-small cell 
lung cancer (a type of lung cancer) in adult. 
 
As YERVOY may be given in combination with  other anti-cancer medicines, it is important that you 
also read the package leaflet for these other medicines. If you have any questions about these 
medicines, please ask your doctor. 
 
2. What you need to know before you use YERVOY 
 
You should not be given YERVOY  
 if you are allergic to ipilimumab or any of the other ingredients of this medicine (listed in 

Section 6 "Contents of the pack and other information"). Talk to your doctor if you are not 
sure. 

 
Warnings and precautions 
Talk to your doctor before using YERVOY as it may cause: 

 
- Problems with your heart such as a change in the rhythm or rate of the heartbeat or an 

abnormal heart rythm. 
 

- Inflammation of the intestines (colitis) which can worsen to bleedings or bowel perforation. 
Signs and symptoms of colitis may include diarrhoea (watery, loose or soft stools), an 



 
72 

increased number of bowel movements than usual, blood in your stools or darker-coloured 
stools, pain or tenderness in your stomach area. 

 
- Problems with your lungs such as breathing difficulties or cough. These may be signs of 

inflammation of the lungs (pneumonitis or interstitial lung disease). 
 

- Inflammation of the liver (hepatitis) that can lead to liver failure. Signs and symptoms of 
hepatitis may include eye or skin yellowing (jaundice), pain on the right side of your stomach 
area, tiredness. 

 
- Inflammation of the skin that can lead to severe skin reaction (known as toxic epidermal 

necrolysis, Stevens-Johnson syndrome and Drug Reaction with Eosinophilia and Systemic 
Symptoms (DRESS)). Signs and symptoms of severe skin reaction may include such as skin 
rash with or without itching, peeling of the skin, dry skin, fever, fatigue, swelling of the face 
or lymph glands, increase of eosinophils (type of white blood cells) and effects on liver, 
kidneys or lungs. Please note that the reaction called DRESS may develop weeks or months 
after your last dose. 

 
- Inflammation of the nerves that can lead to paralysis. Symptoms of nerve problems may 

include muscle weakness, numbness or tingling in your hands or feet, loss of consciousness or 
difficulty waking up. 

 
- Inflammation or problems with your kidneys. Signs and symptoms may include abnormal 

kidney function tests, or decreased volume of urine. 
 

- Inflammation of hormone producing glands (especially the pituitary, adrenal and thyroid 
glands) that may affect how these glands work. Signs and symptoms that your glands are not 
working properly may include headaches, blurry or double vision, tiredness, decreased sexual 
drive, behavioral changes.  

 
- Diabetes (symptoms include excessive thirst, the passing of a greatly increased amount of 

urine, increase in appetite with a loss of weight, feeling tired, drowsy, weak, depressed, 
irritable and generally unwell) or diabetic ketoacidosis (acid in the blood produced from 
diabetes). 

 
- Inflammation of the muscles such as myocarditis (inflammation of the heart muscle), 

myositis (inflammation of the muscles) and rhabdomyolysis (stiffness in muscles and joints, 
muscle spasm). Signs and symptoms may include muscle pain, stiffness, weakness, chest pain, 
or severe fatigue. 

 
- Inflammation of the eyes. Signs and symptoms may include redness in the eye, pain in the 

eye, vision problems, blurry vision or temporary loss of sight. 
 

- Haemophagocytic lymphohistiocytosis. A rare disease in which our immune system makes 
too many of otherwise normal infection fighting cells called histiocytes and lymphocytes. 
Symptoms may include enlarged liver and/or spleen, skin rash, lymph node enlargement, 
breathing problems, easy bruising, kidney abnormalities, and heart problems. 

 
- Organ transplant rejection.  

 
Tell your doctor immediately if you have any of these signs or symptoms or they get worse. Do not 
try to treat your symptoms with other medicines. Your doctor may give you other medicines in 
order to prevent more severe complications and reduce your symptoms, withhold the next dose of 
YERVOY, or stop your treatment with YERVOY altogether.  
Please note that these signs and symptoms are sometimes delayed, and may develop weeks or months 
after your last dose. Before treatment, your doctor will check your general health. You will also have 
blood tests during treatment. 



 
73 

 
Check with your doctor or nurse before you are given YERVOY  
 if you have an autoimmune disease (a condition where the body attacks its own cells); 
 if you have, or have ever had, chronic viral infection of the liver, including hepatitis B (HBV) 

or hepatitis C (HCV); 
 if you have human immunodeficiency virus (HIV) infection or acquired immune deficiency 

syndrome (AIDS). 
 if you have previously experienced a severe skin adverse reaction on a prior cancer therapy. 
 if you have any history of inflammation of the lungs 
 
Children and adolescents 
YERVOY should not be used in children below 12 years of age.  
 
Other medicines and YERVOY 
Before you are given YERVOY, tell your doctor 
 if you are taking any medicines that suppress your immune system, such as corticosteroids. 

These medicines may interfere with the effect of YERVOY. However, once you are treated with 
YERVOY, your doctor may give you corticosteroids to reduce the side-effects that you may 
have with YERVOY.  

 
 if you are taking any medicines that stop your blood from clotting (anticoagulants). These 

medicines may increase the likelihood of bleeding in the stomach or intestine, which is a side-
effect of YERVOY. 

 
 if you have recently been prescribed Zelboraf (vemurafenib, another medicine for the treatment 

of skin cancer). When YERVOY is given following prior vemurafenib there may be an 
increased risk of skin side-effects. 

 
Also tell your doctor if you are taking or have recently taken any other medicines.  
 
Do not take any other medicines during your treatment without talking to your doctor first. Based on 
early data, the combination of YERVOY (ipilimumab) and vemurafenib is not recommended due to 
increased toxicity to the liver. 
 
Pregnancy and breast-feeding 
Tell your doctor if you are pregnant, if you are planning to become pregnant, or if you are 
breast-feeding.  
 
You must not use YERVOY if you are pregnant unless your doctor specifically recommends it. The 
effects of YERVOY in pregnant women are not known, but it is possible that the active substance, 
ipilimumab, could harm an unborn baby.  
 You must use effective contraception while you are being treated with YERVOY if you are a 

woman who could become pregnant.  
 If you become pregnant while using YERVOY tell your doctor. 
 
It is not known whether ipilimumab gets into breast milk. However, significant exposure of 
ipilimumab to the infant through breast milk is not expected and no effects on the breast-fed infant are 
anticipated. Ask your doctor if you can breast-feed during or after treatment with YERVOY. 
 
Driving and using machines 
Do not drive, cycle or use machines after you have been given YERVOY unless you are sure you are 
feeling well. Feeling tired or weak is a very common side effect of YERVOY. This can affect your 
ability to drive, cycle or to use machines. 
 
YERVOY contains sodium 
Tell your doctor if you are on a low-sodium (low-salt) diet before you are given YERVOY.  
 



 
74 

This medicine contains 23 mg sodium (main component of cooking/table salt) in each 10 ml vial. This 
is equivalent to 1.15% of the recommended maximum daily dietary intake of sodium for an adult. 
 
This medicine contains 92 mg sodium (main component of cooking/table salt) in each 40 ml vial. This 
is equivalent to 4.60% of the recommended maximum daily dietary intake of sodium for an adult  
 
 
3. How to use YERVOY 
 
How YERVOY is given  
YERVOY will be given to you in a hospital or clinic under the supervision of an experienced doctor.  
 
When YERVOY is given alone for the treatment of skin cancer, YERVOY will be given to you as an 
infusion (a drip) into a vein (intravenously) over a period of 90 minutes. 
 
When YERVOY is given in combination with nivolumab for the treatment of skin cancer, you will be 
given an infusion over a period of 90 minutes every 3 weeks for the first 4 doses (combination phase). 
Thereafter, nivolumab will be given as an infusion over a period of 30 or 60 minutes, every 2 weeks or 
4 weeks, depending on the dose you are receiving (single-agent phase). 
 
When YERVOY is given in combination with nivolumab the treatment of advanced kidney cancer, 
you will be given an infusion over a period of 30 minutes every 3 weeks for the first 4 doses 
(combination phase). Thereafter, nivolumab will be given as an infusion over a period 
of 30 or 60 minutes, every 2 weeks or 4 weeks, depending on the dose you are receiving (single-agent 
phase). 
 
When YERVOY is given in combination with nivolumab and chemotherapy for the treatment of 
advanced non-small cell lung cancer, you will be given an infusion over a period of 30 minutes every 
6 weeks. After completion of 2 cycles of chemotherapy, ipilimumab will be given in combination with 
nivolumab as an infusion over a period of 30 minutes every 6 weeks. 
 
How much YERVOY is given  
When YERVOY is given alone for the treatment of skin cancer, the recommended dose is 3 mg of 
ipilimumab per kilogram of your body weight.  
 
The amount of YERVOY you will be given will be calculated based on your body weight. Depending 
on your dose, some or all of the content of the YERVOY vial may be diluted with sodium 
chloride 9 mg/ml (0.9%) solution for injection or 50 mg/ml (5%) glucose solution for injection before 
use. More than one vial may be necessary to obtain the required dose. 
 
You will be treated with YERVOY once every 3 weeks, for a total of 4 doses. You may notice the 
appearance of new lesions or growth of existing lesions on your skin, which can be expected when you 
are being treated with YERVOY. Your doctor will continue giving you YERVOY for a total of 4 
doses, depending on your tolerance to the treatment. 
 
When YERVOY is given in combination with nivolumab for the treatment of skin cancer, the 
recommended dose of YERVOY is 3 mg of ipilimumab per kilogram of your body weight every 
3 weeks for the first 4 doses (combination phase). Thereafter the recommended dose of nivolumab 
is 240 mg given every 2 weeks or 480 mg given every 4 weeks (single-agent phase). 
 
When YERVOY is given in combination with nivolumab for the treatment of advanced kidney cancer, 
the recommended dose of YERVOY is 1 mg of ipilimumab per kilogram of your body weight 
every 3 weeks for the first 4 doses (combination phase). Thereafter, the recommended dose of 
nivolumab is 240 mg given every 2 weeks or 480 mg given every 4 weeks (single-agent phase). 
 



 
75 

When YERVOY is given in combination with nivolumab and chemotherapy for the treatment of 
advanced non-small cell lung cancer, you will be given an infusion over a period of 30 minutes, 
every 6 weeks. 
 
If you miss a dose of YERVOY 
It is very important for you to keep all your appointments to receive YERVOY. If you miss an 
appointment, ask your doctor when to schedule your next dose. 
 
If you stop using YERVOY 
Stopping your treatment may stop the effect of the medicine. Do not stop treatment with YERVOY 
unless you have discussed this with your doctor.  
 
If you have any further questions about your treatment or the use of this medicine, ask your doctor. 
 
When YERVOY is given in combination with nivolumab or in combination with nivolumab and 
chemotherapy, you will first be given nivolumab followed by YERVOY and then by chemotherapy. 
 
Please refer to the package leaflet of the other anti-cancer medicines in order to understand the use of 
these other medicines. If you have questions about these medicines, please ask your doctor. 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. Your 
doctor will discuss these with you and will explain the risks and benefits of your treatment.  
 
Be aware of important symptoms of inflammation 
YERVOY acts on your immune system and may cause inflammation in parts of your body. 
Inflammation may cause serious damage to your body and some inflammatory conditions may be 
life-threatening.  
 
The following side effects have been reported in patients receiving 3 mg/kg ipilimumab alone: 
 
Very common (may affect more than 1 in 10 people) 
 loss of appetite  
 diarrhoea (watery, loose or soft stools), vomiting or feeling sick (nausea)  
 skin rash, itching 
 feeling tired or weak, reaction at site of injection, fever  
 

 Tell your doctor immediately if you get any of these side effects.  
Do not try to treat your symptoms with other medicines. 

 
Common (may affect up to 1 in 10 people) 
 tumour pain 
 underactive function of the thyroid gland which can cause tiredness or weight gain, underactive 

function (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland situated at the 
base of the brain 

 dehydration 
 confusion 
 damage to the nerves (causing pain, weakness and cramps), dizziness, headache,  
 blurred vision, pain in the eye 
 low blood pressure, temporary redness of the face and neck, feeling of intense heat with 

sweating and rapid heart beat 
 shortness of breath (dyspnoea), cough  
 bleeding in the stomach or intestine, inflammation of the intestines (colitis), constipation, 

heartburn, stomach pain  
 abnormal function of the liver 
 inflammation of the inner surface lining of a particular organ 



 
76 

 inflammation and redness of the skin, skin colour change in patches (vitiligo), hives (itchy, 
bumpy rash), hair loss or thinning, excessive sweating at night, dry skin 

 pain in muscles and joints(arthralgia), muscle spasms 
 shivering, lack of energy, oedema (swelling), pain 
 flu-like illness 
 weight loss 
 

 Tell your doctor immediately if you get any of these side effects.  
Do not try to treat your symptoms with other medicines. 

 
Uncommon (may affect up to 1 in 100 people) 
 serious bacterial infection of the blood (sepsis, septic shock), inflammation around the brain or 

spinal cord, inflammation of the stomach and intestines, inflammation of bowel wall (causing 
fever, vomiting and stomach pain), urinary tract infection, infection of the respiratory tract 

 a group of symptoms due to cancer in the body such as high blood levels of calcium and 
cholesterol, and low blood levels of sugar (paraneoplastic syndrome) 

 allergic reaction 
 decreased secretion of hormones produced by adrenal glands (glands situated above the 

kidneys), overactive function of the thyroid gland, which can cause rapid heart rate, sweating 
and weight loss, defect of the glands producing sex hormones  

 decreased function of the adrenal glands caused by an underactive hypothalamus (part of the 
brain) 

 a group of metabolic complications occurring after cancer treatment characterised by high blood 
levels of potassium and phosphate, and low blood levels of calcium (tumour lysis syndrome). 

 changes in mental health, depression, lowered sex drive 
 severe and possibly fatal inflammation of the nerves causing pain, weakness or paralysis in the 

extremities (Guillain-Barré syndrome), fainting, inflammation of the nerves within the brain, 
excessive accumulation of fluid in the brain,difficulty in coordinating movements (ataxia), 
shaking, brief involuntary muscle contraction, difficulty in speaking 

 inflammation of the eye (conjunctivitis), bleeding in the eye, inflammation of the coloured part 
of the eye, reduced vision, a foreign body sensation in the eyes, swollen runny eyes, swelling of 
the eye, inflammation of the eyelids 

 irregular or abnormal heart beat 
 inflammation of the blood vessels, disease of the blood vessels, restriction in the blood supply to 

the extremities, low blood pressure when standing up 
 extreme difficulty in breathing, fluid accumulation in the lungs, inflammation of the lungs, hay 

fever 
 bowel perforation, inflammation of the membrane of the stomach wall, inflammation of the 

small intestine, inflammation of the bowel or the pancreas (pancreatitis), peptic ulcer, mouth 
ulcers and cold sores (stomatitis), inflammation of the food pipe, blockage of the intestines 

 liver failure, inflammation of the liver, enlarged liver, yellowing of the skin or eyes (jaundice) 
 severe and possibly fatal peeling of the skin (toxic epidermal necrolysis) 
 inflammation of the muscles causing pain or stiffness in the hip and shoulder, painful joints 

(arthralgia) 
 swelling of the thyroid gland, inflammation of the kidney, or the central nervous system 
 multi organ inflammation 
 inflammation of skeletal muscles 
 muscle weakness 
 kidney function failure, kidney disease 
 absence of menstrual periods 
 multi organ dysfunction, reaction related to infusion of the medicine 
 change in hair colour 
 

 Tell your doctor immediately if you get any of these side effects.  
Do not try to treat your symptoms with other medicines. 

 



 
77 

Rare (may affect up to 1 in 1,000 people) 
 inflammatory disease of blood vessels (most commonly head arteries) 
 inflammation of the anus and the rectal wall (marked by bloody stools and a frequent urge to 

defecate) 
 skin disease characterized by dry red patches covered with scales (psoriasis) 
 inflammation and redness of the skin (erythema multiforme) 
 a type of severe skin reaction characterized by rash accompanied by one or more of the 

following features: fever, swelling of the face or lymph glands, increase of eosinophils (type of 
white blood cells), effects on liver, kidneys or lungs (a reaction called DRESS). 

 loosening of membrane at the back of the eye (serous retinal detachment) 
 

 Tell your doctor immediately if you get any of these side effects.  
Do not try to treat your symptoms with other medicines. 

 
Very rare (may affect up to 1 in 10,000 people) 
 serious, potential life-threatening allergic reaction 
 

 Tell your doctor immediately if you get any of these side effects.  
Do not try to treat your symptoms with other medicines. 

 
In addition, the following uncommon (may affect up to 1 in 100 people) side effects have been 
reported in patients who received doses other than 3mg/kg of YERVOY in clinical trials: 
 
 triad of symptoms (meningism): neck stiffness, intolerance of bright light and headache, flu-like 

discomfort 
 inflammation of the heart muscle, weakness of the heart muscle, fluid around the heart 
 inflammation of the liver or the pancreas, nodules of inflammatory cells in various organs of 

your body 
 infection within the abdomen 
 painful skin lesions of the arms and legs and face (erythema nodosum) 
 overactive pituitary gland 
 decreased function of the parathyroid gland 
 inflammation of the eye, eye muscle inflammation 
 decreased hearing 
 poor blood circulation which makes toes and fingers numb or pale 
 damage to the tissues of the hands and feet resulting in redness, swelling and blisters 
 

 Tell your doctor immediately if you get any of these side effects.  
Do not try to treat your symptoms with other medicines. 

 
Other side effects that have been reported (frequency not known) include: 
 organ transplant rejection 
 a type of skin blistering disease (called pemphigoid) 
 a condition where the immune system makes too many infection-fighting cells called histiocytes 

and lymphocytes that may cause various symptoms (called haemophagocytic 
lymphohistiocytosis). Symptoms may include enlarged liver and/or spleen, skin rash, lymph 
node enlargement, breathing problems, easy bruising, kidney abnormalities, and heart problems. 

 
 Tell your doctor immediately if you get any of these side effects.  

Do not try to treat your symptoms with other medicines. 
 
Changes in test results 
YERVOY may cause changes in the results of tests carried out by your doctor. These include:  
 a variation in the number of red blood cells (which carry oxygen), white blood cells (which are 

important in fighting infection) or platelets (cells which help the blood to clot) 
 an abnormal variation of hormones and liver enzyme levels in the blood  
 abnormal liver function test 



 
78 

 abnormal levels of calcium, sodium, phosphate or potassium in the blood 
 presence of blood or proteins in the urine 
 an abnormally high alkalinity of the blood and other body tissues 
 kidneys unable to remove acids from blood normally 
 presence of antibodies in the blood against some of your own cells 
 
The following side effects have been reported with ipilimumab in combination  (the frequency and 
severity of side effects may vary with the combination of anti-cancer medicines received): 
 
Very common (may affect more than 1 in 10 people) 
 underactive thyroid gland (which can cause tiredness or weight gain), overactive thyroid gland 

(which can cause rapid heart rate, sweating and weight loss) 
 loss of appetite 
 headache 
 shortness of breath (dyspnoea) 
 inflammation of the intestines (colitis), diarrhoea (watery, loose or soft stools), vomiting or feeling 

sick (nausea), stomach pain 
 skin rash sometimes with blisters, itching 
 pain in the muscles and bones (musculoskeletal pain), painful joints (arthralgia) 
 feeling tired or weak, fever 
 

 Tell your doctor immediately if you get any of these side effects.  
Do not try to treat your symptoms with other medicines. 

 
Common (may affect up to 1 in 10 people) 
 serious lung infection (pneumonia), infections of the upper respiratory tract, inflammation of the 

eye (conjunctivitis) 
 increase of eosinophils (type of white blood cells), decrease in neutrophils with fever 
 allergic reaction, reactions related to the infusion of the medicine 
 decreased secretion of hormones produced by adrenal glands (glands situated above the kidneys), 

underactive function (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland 
situated at the base of the brain, swelling of the thyroid gland, diabetes 

 dehydration, decreased levels of albumin and phosphate in the blood 
 inflammation of the nerves (causing numbness, weakness, tingling or burning pain of the arms and 

legs), dizziness 
 inflammation of the eye which causes redness or pain, blurred vision, dry eye 
 rapid heart beat 
 high blood pressure (hypertension) 
 inflammation of the lungs (pneumonitis, characterised by coughing and difficulty breathing), 

blood clots, fluid around the lungs, cough 
 mouth ulcers and cold sores (stomatitis), inflammation of the pancreas (pancreatitis), constipation, 

dry mouth 
 inflammation of the liver 
 skin colour change in patches (vitiligo), dry skin, redness of the skin, unusual hair loss or thinning, 

hives (itchy, bumpy rash) 
 inflammation of the joints (arthritis), muscle spasm, muscle weakness 
 kidney failure (including abrupt loss of kidney function) 
 oedema (swelling), pain, chest pain, chills 
 

 Tell your doctor immediately if you get any of these side effects.  
Do not try to treat your symptoms with other medicines. 

 
Uncommon (may affect up to 1 in 100 people) 
 bronchitis 
 temporary and reversible non-infectious inflammation of the protective membranes surrounding 

the brain and spinal cord (aseptic meningitis) 



 
79 

 chronic diseases associated with a build-up of inflammatory cells in various organs and tissues, 
most commonly the lungs (sarcoidosis) 

 acid in the blood produced from diabetes (diabetic ketoacidosis) 
 decreased function of the parathyroid gland 
 increased acid levels in the blood 
 a temporary inflammation of the nerves that causes pain, weakness and paralysis in the extremities 

(Guillain-Barré syndrome); damage to nerves causing numbness and weakness (polyneuropathy); 
inflammation of the nerves; foot drop (peroneal nerve palsy); inflammation of the nerves caused 
by the body attacking itself, causing numbness, weakness, tingling or burning pain (autoimmune 
neuropathy); muscle weakness and tiredness without atrophy (myasthenia gravis) 

 inflammation of the brain 
 changes in the rhythm or rate of the heartbeat, irregular or abnormal heart beat, inflammation of 

the heart muscle, slow heart rate 
 bowel perforation, inflammation of the stomach (gastritis), inflammation of the duodenum 
 skin disease with thickened patches of red skin, often with silvery scales (psoriasis), severe 

condition of the skin that causes red, often itchy spots, similar to the rash of measles, which starts 
on the limbs and sometimes on the face and the rest of the body (erythema multiforme) 

 severe and possibly fatal peeling of the skin (Stevens-Johnson syndrome) 
 chronic disease of joints (spondyloarthropathy), disease in which the immune system attacks the 

glands that make moisture for the body, such as tears and saliva (Sjogren’s syndrome), aching 
muscles, muscle tenderness of weakness, not caused by exercise (myopathy), inflammation of the 
muscles (myositis), stiffness in muscles and joints, muscle spasm (rhabdomyolysis), inflammation 
of the muscles causing pain or stiffness (polymyalgia rheumatica) 

 inflammation of the kidney 
 

 Tell your doctor immediately if you get any of these side effects.  
Do not try to treat your symptoms with other medicines. 

 
Rare (may affect up to 1 in 1000 people) 
 severe and possibly fatal peeling of the skin (toxic epidermal necrolysis) 
 loosening of membrane at the back of the eye (serous retinal detachment) 
 

 Tell your doctor immediately if you get any of these side effects.  
Do not try to treat your symptoms with other medicines. 
 

Other side effects that have been reported (frequency not known) with ipilimumab in 
combination include: 
 organ transplant rejection 
 a group of metabolic complications occurring after cancer treatment characterised by high blood 

levels of potassium and phosphate, and low blood levels of calcium (tumour lysis syndrome) 
 an inflammatory disorder (most likely of autoimmune origin) affecting the eyes, skin and the 

membranes of the ears, brain and spinal cord (Vogt-Koyanagi-Harada syndrome)  
 Inflammation of the covering of the heart and accumulation of fluid around the heart (pericardial 

disorders) 
 a condition where the immune system makes too many infection-fighting cells called histiocytes 

and lymphocytes that may cause various symptoms (called haemophagocytic 
lymphohistiocytosis). Symptoms may include enlarged liver and/or spleen, skin rash, lymph node 
enlargement, breathing problems, easy bruising, kidney abnormalities, and heart problems. 

 
Changes in test results 
YERVOY in combination may cause changes in the results of tests carried out by your doctor. These 
include: 
 abnormal liver function tests (increased amounts of the liver enzymes aspartate aminotransferase, 

alanine aminotransferase, gamma-glutamyltransferase, or alkaline phosphatase in your blood, 
higher blood levels of the waste product bilirubin) 

 abnormal kidney function tests (increased amounts of creatinine in your blood) 
 high (hyperglycaemia) or low (hypoglycaemia) sugar levels in the blood 



 
80 

 a decreased number of red blood cells (which carry oxygen), white blood cells (which are 
important in fighting infection) or platelets (cells which help the blood to clot) 

 an increased level of the enzyme that breaks down fats and of the enzyme that breaks down starch 
 increased or decreased amount of calcium or potassium 
 increased or decreased blood levels of magnesium or sodium 
 decrease in body weight 
 increased amount of thyroid stimulating hormone 
 
Reporting of side effects 
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in 
this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store YERVOY 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and the vial label after 
EXP. The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C to 8°C). 
Do not freeze. 
Store in the original package in order to protect from light. 
 
Do not store any unused portion of the infusion solution for reuse. Any unused medicine or waste 
material should be disposed of in accordance with local requirements. 
 
 
6. Contents of the pack and other information 
 
What YERVOY contains 
 The active substance is ipilimumab. 

Each ml of concentrate contains 5 mg of ipilimumab. 
Each 10 ml vial contains 50 mg of ipilimumab. 
Each 40 ml vial contains 200 mg of ipilimumab. 

 
 The other ingredients are Tris-hydrochloride, sodium chloride (see section 2 "YERVOY 

contains sodium"), mannitol (E421), pentetic acid, polysorbate 80, sodium hydroxide, 
hydrochloric acid and water for injections. 

 
What YERVOY looks like and contents of the pack 
YERVOY concentrate for solution for infusion is clear to slightly opalescent, colourless to pale yellow 
and may contain light (few) particulates. 
 
It is available in packs containing either 1 glass vial of 10 ml or 1 glass vial of 40 ml. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 



 
81 

Manufacturer 
CATALENT ANAGNI S.R.L. 
Loc. Fontana del Ceraso snc 
Strada Provinciale 12 Casilina, 41 
03012 Anagni (FR)  
Italy  
 
Swords Laboratories T/A Bristol-Myers Squibb Cruiserath Biologics 
Cruiserath Road, Mulhuddart 
Dublin 15, D15 H6EF 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
Belgique/België/Belgien 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Lietuva 
Bristol-Myers Squibb Kft. 
Tel: +370 52 369140  

България 
Bristol-Myers Squibb Kft. 
Teл.: + 359 2 4942 480 

 

Luxembourg/Luxemburg 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Česká republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 420 221 016 111 
 

Magyarország 
Bristol-Myers Squibb Kft. 
Tel.: + 36 1 808 9433 
  

Danmark 
Bristol-Myers Squibb 
Tlf: + 45 45 93 05 06 
 

Malta 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 356 23976333 

Deutschland 
Bristol-Myers Squibb GmbH & Co. KGaA 
Tel: 0800 0752002 (+49 (0)89 121 42 350) 
 

Nederland 
Bristol-Myers Squibb B.V. 
Tel: + 31 (0)30 300 2222 

Eesti 
Bristol-Myers Squibb Kft. 
Tel: +372 640 1030 
 

Norge 
Bristol-Myers Squibb Norway Ltd 
Tlf: + 47 67 55 53 50 

Ελλάδα 
BRISTOL-MYERS SQUIBB A.E. 
Τηλ: + 30 210 6074300 
 

Österreich 
Bristol-Myers Squibb GesmbH 
Tel: + 43 1 60 14 30 
 

España 
BRISTOL-MYERS SQUIBB, S.A. 
Tel: + 34 91 456 53 00 
 

Polska 
BRISTOL-MYERS SQUIBB POLSKA SP. Z O.O. 
Tel.: + 48 22 2606400 
 

France 
Bristol-Myers Squibb SARL 
Tél: + 33 (0)1 58 83 84 96 
 

Portugal 
Bristol-Myers Squibb Farmacêutica Portuguesa, 
S.A. 
Tel: + 351 21 440 70 00 

Hrvatska 
Bristol-Myers Squibb spol. s r.o. 
Tel: +385 1 2078 508 

România 
Bristol-Myers Squibb Kft. 
Tel: + 40 (0)21 272 16 00 



 
82 

Ireland 
Bristol-Myers Squibb Pharmaceuticals uc 
Tel: + 353 (0)1 483 3625 
 

Slovenija 
Bristol-Myers Squibb spol. s r.o. 
Tel: +386 1 2355 100 

Ísland 
Bristol-Myers Squibb AB hjá Vistor hf. 
Sími: + 354 535 7000 
 

Slovenská republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 421 2 20833 600 

Italia 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 
 

Suomi/Finland 
Oy Bristol-Myers Squibb (Finland) Ab 
Puh/Tel: + 358 9 251 21 230 

Κύπρος 
BRISTOL-MYERS SQUIBB A.E. 
Τηλ: + 357 800 92666 
 

Sverige 
Bristol-Myers Squibb AB 
Tel: + 46 8 704 71 00 
 

Latvija 
Bristol-Myers Squibb Kft. 
Tel: +371 66164750 
 

United Kingdom 
Bristol-Myers Squibb Pharmaceuticals Ltd 
Tel: + 44 (0800) 731 1736 
 

 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 
------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to asepsis. 
 
Calculating the dose: 
Ipilimumab monotherapy or ipilimumab in combination with nivolumab: 
The prescribed dose for the patient is given in mg/kg. Based on this prescribed dose, calculate the 
total dose to be given. More than one vial of YERVOY concentrate may be needed to give the total 
dose for the patient. 
 
 Each 10 ml vial of YERVOY concentrate provides 50 mg of ipilimumab; each 40 ml vial 

provides 200 mg of ipilimumab. 
 The total ipilimumab dose in mg = the patient’s weight in kg × the prescribed dose in mg/kg. 
 The volume of YERVOY concentrate to prepare the dose (ml) = the total dose in mg, divided 

by 5 (the YERVOY concentrate strength is 5 mg/ml). 
 
Preparing the infusion: 
Take care to ensure aseptic handling when you prepare the infusion.  
 
YERVOY can be used for intravenous administration either: 
 without dilution, after transfer to an infusion container using an appropriate sterile syringe; 

or 
 after diluting to up to 5 times the original volume of concentrate (up to 4 parts of diluent 

to 1 part of concentrate). The final concentration should range from 1 to 4 mg/ml. To dilute the 
YERVOY concentrate, you can use either: 
 sodium chloride 9 mg/ml (0.9%) solution for injection; or 
 50 mg/ml (5%) glucose solution for injection 



 
83 

 
STEP 1 
 Allow the appropriate number of vials of YERVOY to stand at room temperature for 

approximately 5 minutes. 
 Inspect the YERVOY concentrate for particulate matter or discoloration. YERVOY concentrate 

is a clear to slightly opalescent, colourless to pale yellow liquid that may contain light (few) 
particulates. Do not use if unusual amount of particles and signs of discoloration are present. 

 Withdraw the required volume of YERVOY concentrate using an appropriate sterile syringe. 
 
STEP 2 
 Transfer the concentrate into a sterile, evacuated glass bottle or IV bag (PVC or non-PVC). 
 If applicable, dilute with the required volume of sodium chloride 9 mg/ml (0.9%) solution for 

injection or 50 mg/ml (5%) glucose solution for injection. For ease of preparation, the 
concentrate can also be transferred directly into a pre-filled bag containing the appropriate 
volume of sodium chloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) glucose 
solution for injection. Gently mix the infusion by manual rotation. 

 
Administration: 
The YERVOY infusion must not be administered as an intravenous push or bolus injection. 
Administer the YERVOY infusion intravenously over a period of 30 or 90 minutes, depending on 
the dose. 
 
The YERVOY infusion should not be infused at the same time in the same intravenous line with other 
agents. Use a separate infusion line for the infusion. 
 
Use an infusion set and an in-line, sterile, non-pyrogenic, low protein binding filter (pore size 
of 0.2 μm to 1.2 μm). 
 
The YERVOY infusion is compatible with: 
 PVC infusion sets 
 Polyethersulfone (0.2 μm to 1.2 μm) and nylon (0.2 μm) in-line filters 
 
Flush the line with sodium chloride 9 mg/ml (0.9%) solution for injection or 50 mg/ml (5%) glucose 
solution for injection at the end of the infusion. 
 
Storage conditions and shelf life: 
Unopened vial 
YERVOY must be stored in a refrigerator (2°C to 8°C). The vials must be kept in the original 
package in order to protect from light. YERVOY should not be frozen. 
 
Do not use YERVOY after the expiry date which is stated on the label and carton after EXP. The 
expiry date refers to the last day of that month. 
 
YERVOY infusion 
From a microbiological point of view, once opened, the medicine should be infused or diluted and 
infused immediately. The chemical and physical in-use stability of the undiluted or diluted infusion 
solution (between 1 and 4 mg/ml) has been demonstrated for 24 hours at room temperature (20°C 
to 25°C) or when refrigerated (2°C to 8°C). If not used immediately, the infusion solution (undiluted 
or diluted) must be used within 24 hours when stored either under refrigeration (2°C to 8°C) or at 
room temperature (20°C to 25°C). Other in-use storage time and conditions are the responsibility of 
the user. 
 
Disposal: 
Do not store any unused portion of the infusion solution for reuse. Any unused medicine or waste 
material should be disposed of in accordance with local requirements.  



 
84 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO 
THE TERMS OF THE MARKETING AUTHORISATION(S) 



 
85 

Scientific conclusions 

Taking into account the PRAC Assessment Report on the PSUR(s) for ipilimumab, the scientific 
conclusions of the CHMP are as follows:  

In view of available data on solid organ transplant rejection and haemophagocytic 
lymphohistiocytosis from clinical trial(s), the literature, spontaneous reports including in some cases 
a close temporal relationship, positive de-challenge and in view of a plausible mechanism of action, 
the PRAC considers a causal relationship between ipilimumab and solid organ transplant rejection 
and also between ipilimumab and haemophagocytic lymphohistiocytosis is at least a reasonable 
possibility. The PRAC concluded that the product information of products containing ipilimumab 
should be amended accordingly. 

The updated information is aligned with the SmPCs of other check point inhibitors. 

 
The CHMP agrees with the scientific conclusions made by the PRAC. 

 

Grounds for the variation to the terms of the marketing authorisation(s) 

On the basis of the scientific conclusions for ipilimumab the CHMP is of the opinion that the 
benefit-risk balance of the medicinal product(s) containing ipilimumab is unchanged subject to the 
proposed changes to the product information. 

The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) ANDMANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET