Nivolumab BMS

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



2 

This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nivolumab BMS 10 mg/mL concentrate for solution for infusion. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each mL of concentrate contains 10 mg of nivolumab. 
One vial of 4 mL contains 40 mg of nivolumab. 
One vial of 10 mL contains 100 mg of nivolumab. 
 
Nivolumab is produced in Chinese hamster ovary cells by recombinant DNA technology. 
 

Each mL of concentrate contains 0.1 mmol (or 2.5 mg) sodium. 
Excipient with known effect 

 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion (sterile concentrate). 
 
Clear to opalescent, colourless to pale yellow liquid that may contain few light particles. The solution 
has a pH of approximately 6.0 and an osmolality of approximately 340 mOsm/kg. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Nivolumab BMS is indicated for the treatment of locally advanced or metastatic squamous non-small 
cell lung cancer (NSCLC) after prior chemotherapy in adults. 
 
 
4.2 Posology and method of administration 
 
Treatment must be initiated and supervised by physicians experienced in the treatment of cancer. 
 

The recommended dose of Nivolumab BMS is 3 mg/kg administered intravenously over 60 minutes 
every 2 weeks. Treatment should be continued as long as clinical benefit is observed or until treatment 
is no longer tolerated by the patient.  

Posology 

 
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 Table 1. Detailed guidelines for the management of immune-related adverse 
reactions are described in section 4.4. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



3 

Table 1: Recommended treatment modifications for Nivolumab BMS 
Immune-related 
adverse reaction 

Severity Treatment modification 

Immune-related 
pneumonitis 

Grade 2 pneumonitis  Withhold Nivolumab BMS until 
symptoms resolve, radiographic 
abnormalities improve, and management 
with corticosteroids is complete 

 Grade 3 or 4 pneumonitis Permanently discontinue Nivolumab BMS 

Immune-related colitis 

Grade 2 or 3 diarrhoea or colitis Withhold Nivolumab BMS until 
symptoms resolve and management with 
corticosteroids, if needed, is complete 

Grade 4 diarrhoea or colitis Permanently discontinue 
Nivolumab BMS 

Immune-related 
hepatitis 

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

Withhold Nivolumab BMS 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 
Nivolumab BMS 

Immune-related 
nephritis and renal 
dysfunction 

Grade 2 or 3 creatinine elevation  Withhold Nivolumab BMS until 
creatinine returns to baseline and 
management with corticosteroids is 
complete 

Grade 4 creatinine elevation Permanently discontinue 
Nivolumab BMS 

Immune-related 
endocrinopathies 

Symptomatic endocrinopathies 
(including hypothyroidism, 
hyperthyroidism, hypophysitis, adrenal 
insufficiency and diabetes) 

Withhold Nivolumab BMS until 
symptoms resolve and management with 
corticosteroids (if needed for symptoms 
of acute inflammation) is complete. 
Nivolumab BMS should be continued in 
the presence of hormone replacement 
therapya as long as no symptoms are 
present 

Immune-related rash 

Grade 3 rash Withhold dose until symptoms resolve 
and management with corticosteroids is 
complete 
 

 Grade 4 rash Permanently discontinue Nivolumab BMS 
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. 

 
Nivolumab BMS should also be permanently discontinued for Grade 2 or 3 immune-related adverse 
reactions that persist despite treatment modifications (see section 4.4) or for inability to reduce 
corticosteroid dose to 10 mg prednisone or equivalent per day. 
 
Patients treated with Nivolumab BMS must be given the patient alert card and be informed about the 
risks of Nivolumab BMS (see also package leaflet). 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



4 

 
Special populations 

Paediatric population 
The safety and efficacy of Nivolumab BMS in children below 18 years of age have not been 
established. No data are available. 
 
Elderly  
No dose adjustment is required for elderly patients (≥ 65 years) (see sections 5.1 and 5.2). Data from 
patients 75 years of age or older are too limited to draw conclusions on this population. 
 
Renal impairment 
Based on the population pharmacokinetic (PK) results, no dose adjustment is required in patients with 
mild or moderate renal impairment (see section 5.2). Data from patients with severe renal impairment 
are too limited to draw conclusions on this population. 
 
Hepatic impairment 
Based on the population PK results, no dose adjustment is required in patients with mild hepatic 
impairment (see section 5.2). Data from patients with moderate or severe hepatic impairment are too 
limited to draw conclusions on these populations. Nivolumab BMS must be administered with 
caution in patients with moderate (total bilirubin > 1.5 × to 3 × the upper limit of normal [ULN] 
and any AST) or severe (total bilirubin > 3 × ULN and any AST) hepatic impairment. 
 

 
Method of administration  

Nivolumab BMS is for intravenous use only. It is to be administered as an intravenous infusion over a 
period of 60 minutes. The infusion must be administered through a sterile, non-pyrogenic, low protein 
binding in-line filter with a pore size of 0.2-1.2 µm. 
 
Nivolumab BMS must not be administered as an intravenous push or bolus injection. 
 
The total dose of Nivolumab BMS required can be infused directly as a 10 mg/mL solution or can be 
diluted to as low as 1 mg/mL with sodium chloride 9 mg/mL (0.9%) solution for injection or glucose 
50 mg/mL (5%) solution for injection.  
 
For instructions on the 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 
 
Nivolumab is associated with immune-related adverse reactions. Patients should be monitored 
continuously (at least up to 5 months after the last dose) as an adverse reaction with nivolumab may 
occur at any time during or after discontinuation of nivolumab therapy.  
 
For suspected immune-related adverse reactions, adequate evaluation should be performed to confirm 
aetiology or exclude other causes. Based on the severity of the adverse reaction, nivolumab should be 
withheld and corticosteroids administered. If immunosuppression with corticosteroids is used to treat 
an adverse reaction, a taper of at least 1 month duration should be initiated upon improvement. Rapid 
tapering may lead to worsening of the adverse reaction. Non-corticosteroid immunosuppressive 
therapy should be added if there is worsening or no improvement despite corticosteroid use.  
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. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



5 

Nivolumab must be permanently discontinued for any severe immune related adverse reaction that 
recurs and for any life threatening immune related adverse reaction. 
 

Severe pneumonitis or interstitial lung disease, including fatal cases, has been observed with 
nivolumab treatment (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. 

Immune-related pneumonitis 

 
For Grade 3 or 4 pneumonitis, 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, nivolumab should be withheld and corticosteroids initiated at 
a dose of 1 mg/kg/day methylprednisolone equivalents. Upon improvement, 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 nivolumab must be permanently discontinued. 
 

Severe diarrhoea or colitis has been observed with nivolumab treatment (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.  

Immune-related colitis 

 
For Grade 4 diarrhoea or colitis, nivolumab must be permanently discontinued, and corticosteroids 
should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents. 
 
For Grade 3 diarrhoea or colitis, nivolumab should be withheld and corticosteroids initiated at a dose 
of 1 to 2 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab may be resumed 
after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, 
nivolumab must be permanently discontinued. 
 
For Grade 2 diarrhoea or colitis, 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, 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 nivolumab must be permanently 
discontinued. 
 

Severe hepatitis has been observed with nivolumab treatment. 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. 

Immune-related hepatitis 

 
For Grade 3 or 4 transaminase or total bilirubin elevation, 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, 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, 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 nivolumab must be permanently discontinued. 
 

Severe nephritis or renal dysfunction has been observed with nivolumab treatment (see section 4.8). 
Patients should be monitored for signs and symptoms of nephritis and renal dysfunction. Most patients 

Immune-related nephritis or renal dysfunction 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



6 

present with asymptomatic increases in serum creatinine. Disease-related aetiologies should be ruled 
out. 
 
For Grade 4 serum creatinine elevation, 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, nivolumab should be withheld, and corticosteroids should 
be initiated at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, 
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 nivolumab must be permanently discontinued. 
 

Severe endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency, 
hypophysitis, diabetes mellitus, and diabetic ketoacidosis have been observed with nivolumab 
treatment.  

Immune-related endocrinopathies 

 
Patients should be monitored for clinical signs and symptoms of endocrinopathies and for 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 etiology has been identified, 
signs or symptoms of endocrinopathies should be considered immune-related. 
 
For symptomatic hypothyroidism, nivolumab should be withheld, and thyroid hormone replacement 
should be initiated as needed. For symptomatic hyperthyroidism, nivolumab should be withheld and 
methimazole should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day 
methylprednisolone equivalents should also be considered if acute inflammation of the thyroid is 
suspected. Upon improvement, nivolumab may be resumed after corticosteroid taper, if needed. 
Monitoring of thyroid function should continue to ensure appropriate hormone replacement is utilised. 
 
For symptomatic adrenal insufficiency, nivolumab should be withheld, and physiologic corticosteroid 
replacement should be initiated as needed. Monitoring of adrenal function and hormone levels should 
continue to ensure appropriate corticosteroid replacement is utilised. 
 
For symptomatic hypophysitis, 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, nivolumab may be resumed after corticosteroid taper, if needed. Monitoring of pituitary 
function and hormone levels should continue to ensure appropriate hormone replacement is utilised. 
 
For symptomatic diabetes, 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.  
 

Severe rash has been observed with nivolumab treatment that may be immune-related (see 
section 4.8). 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 prednisone 
equivalents.  

Immune-related rash 

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

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



7 

The following immune-related adverse reactions were reported in less than 1% of patients treated with 
nivolumab in clinical trials across doses and tumour types: pancreatitis, uveitis, demyelination, 
autoimmune neuropathy (including facial and abducens nerve paresis), Guillain-Barré syndrome, 
hypopituitarism, and myasthenic syndrome. 

Other immune-related adverse reactions 

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

Severe infusion reactions have been reported in clinical trials (see section 4.8). In case of a severe 
infusion reaction, nivolumab infusion must be discontinued and appropriate medical therapy 
administered. Patients with mild or moderate infusion reaction may receive nivolumab with close 
monitoring. 

Infusion reactions 

 

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

Special populations  

 

Each mL of this medicinal product contains 0.1 mmol (or 2.5 mg) sodium. To be taken into 
consideration when treating patients on a controlled sodium diet. 

Patients on controlled sodium diet 

 
Patient Alert Card 
All prescribers of Nivolumab BMS must be familiar with the Physician Information and Management 
Guidelines. The prescriber must discuss the risks of Nivolumab BMS therapy with the patient. The 
patient will be provided with the Patient Alert Card with each prescription. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Nivolumab is a human monoclonal antibody, as such pharmacokinetic interaction studies have not 
been conducted. As monoclonal antibodies are not metabolised by cytochrome P450 (CYP) enzymes 
or other drug metabolising enzymes, inhibition or induction of these enzymes by co-administered 
medicinal products is not anticipated to affect the pharmacokinetics of nivolumab.  
 

 
Other forms of interaction  

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

Systemic immunosuppression 

 
4.6 Fertility, pregnancy and lactation 
 

There are no data on the use of nivolumab in pregnant women. Studies in animals have shown 
embryofoetal toxicity (see section 5.3). Human IgG4 is known to cross the placental barrier and 
nivolumab is an IgG4; therefore nivolumab has the potential to be transmitted from the mother to the 

Pregnancy 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



8 

developing foetus. Nivolumab is not recommended during pregnancy and in women of childbearing 
potential not using effective contraception unless the clinical benefit outweighs the potential risk. 
Effective contraception should be used for at least 5 months following the last dose of 
Nivolumab BMS. 
 

It is unknown whether nivolumab is secreted in human milk. Because many medicinal products, 
including antibodies, can be secreted in human milk, a risk to the newborns/infants cannot be 
excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from 
nivolumab therapy taking into account the benefit of breast-feeding for the child and the benefit of 
therapy for the woman. 

Breast-feeding 

 

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

Fertility 

 
4.7 Effects on ability to drive and use machines 
 
Based on its pharmacodynamic properties, nivolumab is unlikely to affect the ability to drive and use 
machines. Because of potential adverse reactions such as fatigue (see section 4.8), patients should be 
advised to use caution when driving or operating machinery until they are certain that nivolumab does 
not adversely affect them. 
 
4.8 Undesirable effects 
 

Nivolumab is most commonly associated with immune-related adverse reactions. Most of these, 
including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal 
of nivolumab (see “Description of selected adverse reactions” below). 

Summary of the safety profile 

 
In the pooled dataset of two studies in squamous NSCLC (CA209017 and CA209063), the most 
frequent adverse reactions (≥ 10% of patients) were fatigue (33%), decreased appetite (15%), and 
nausea (12%). The majority of adverse reactions were mild to moderate (Grade 1 or 2).  
 

Adverse reactions reported in the pooled dataset (n=248) of CA209017 and CA209063 are presented 
in Table 2. These reactions are presented by system organ class and by frequency. Frequencies are 
defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); 
rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, adverse 
reactions are presented in the order of decreasing seriousness. 

Tabulated summary of adverse reactions 

 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



9 

Table 2: Adverse reactions in patients with squamous NSCLC treated with nivolumab 3 mg/kg 
(CA209017 and CA209063) 

Infections and infestations 
Uncommon bronchitis, upper respiratory tract infection 
Neoplasms benign, malignant and unspecified (including cysts and polyps) 
Uncommon histocytic necrotising lymphadenitis (Kikuchi lymphadenitis) 
Immune system disorders 
Uncommon anaphylactic reaction, hypersensitivity, infusion related reaction  
Endocrine disorders 
Common hypothyroidism 
Uncommon adrenal insufficiency, thyroiditis  
Metabolism and nutrition disorders 
Very common decreased appetite 
Nervous system disorders  
Common peripheral neuropathy, headache, dizziness 
Uncommon myasthenic syndrome, polyneuropathy 
Cardiac disorders 
Uncommon tachycardia 
Vascular disorders 
Uncommon vasculitis 
Respiratory, thoracic and mediastinal disorders 
Common pneumonitis, dyspnoea, cough 
Uncommon lung infiltration 
Gastrointestinal disorders 
Very common nausea 
Common diarrhoea, stomatitis, vomiting, abdominal pain, constipation, dry mouth 
Uncommon colitis, duodenal ulcer 
Skin and subcutaneous tissue disorders 
Common rash, pruritus 
Uncommon urticaria 
Musculoskeletal and connective tissue disorders 
Common musculoskeletal pain,a arthralgia 
Uncommon polymyalgia rheumatica 
Renal and urinary disorders 
Uncommon tubulointerstitial nephritis, renal failure 
General disorders and administration site conditions 
Very common fatigue 
Common pyrexia, oedema 
Investigations 
Very common increased AST,bincreased ALT,b increased alkaline phosphatase,b increased 

creatinine,b decreased lymphocytes,b decreased platelet count,b decreased 
haemoglobin,b hypercalcaemia,b hypocalcaemia,b hyperkalaemia,b 
hypokalaemia,b hypomagnesaemia,b hyponatraemiab 

Common increased total bilirubin,b decreased absolute neutrophil count,b 
hypermagnesaemia,b, hypernatraemiab 

Uncommon Increased lipase, increased amylase 
a Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest 

pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, pain in jaw, spinal pain. 
b Frequencies reflect the proportion of patients who experienced a worsening from baseline in laboratory 

measurements. See “Description of selected adverse reactions; laboratory abnormalities” below. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



10 

Data for the following immune-related adverse reactions are based on patients who received 
nivolumab 3 mg/kg in two NSCLC studies (CA209017 and CA209063, see section 5.1). The 
management guidelines for these adverse reactions are described in section 4.4. 

Description of selected adverse reactions 

 

In CA209017 and CA209063, the incidence of pneumonitis, including interstitial lung disease, was 
5.2% (13/248). Grade 2 and Grade 3 cases were reported in 2.8% (7/248) and 1.6% (4/248) of patients, 
respectively. No Grade 4 or 5 cases reported in these studies. In the phase 1 study MDX1106-03, 
pneumonitis, including a Grade 4 case in 1 patient, was reported in 3/37 patients (8.1%) with NSCLC 
receiving nivolumab 3 mg/kg. 

Immune-related pneumonitis 

 
Median time to onset was 11.6 weeks (range: 2.6-85.1). Eleven patients received high-dose 
corticosteroids (at least 40 mg prednisone equivalents) at a median initial dose of 1.1 mg/kg 
(range: 0.5-4.0) for a median total duration of 4.3 weeks (range: 0.6-13.1). Eight patients, including 
the 4 patients with a Grade 3 case, required permanent discontinuation of nivolumab due to 
pneumonitis. Resolution occurred in all 13 patients with a median time to resolution of 3.9 weeks 
(range: 0.6-13.4). 
 

In CA209017 and CA209063, the incidence of diarrhoea or colitis was 9.3% (23/248). Grade 2 and 
Grade 3 cases were reported in 2% (5/248) and 1.6% (4/248) of patients, respectively. No 
Grade 4 or 5 cases were reported in these studies. 

Immune-related colitis 

 
Median time to onset was 5.6 weeks (range: 0.1-91.0). Three patients, including 2 patients with a 
Grade 3 case, received high-dose corticosteroids (at least 40 mg prednisone equivalents) at a median 
initial dose of 0.6 mg/kg (range: 0.4-1.3) for a median duration of 2.0 weeks (range: 1.4-14.1). One 
patient required permanent discontinuation of nivolumab due to Grade 3 diarrhoea. Resolution 
occurred in 19 patients (83%) with a median time to resolution of 2.0 weeks (range: 0.1-31.0). 
 

In CA209017 and CA209063, the incidence of liver function test abnormalities was 1.2% (3/248). 
Grade 2 cases were reported in 0.4% (1/248) of patients. No Grade 3-5 cases were reported in these 
studies.  

Immune-related hepatitis 

 
Median time to onset was 25.1 weeks (range: 4.1-31.1). None of these patients received high-dose 
corticosteroids. One patient required permanent discontinuation of nivolumab due to Grade 2 increases 
in transaminases. Resolution occurred in 2 patients (67%) with a median time to resolution of 
4.1 weeks (range: 2.9-22.3+); + denotes a censored observation. 
 

In CA209017 and CA209063, the incidence of nephritis or renal dysfunction was 3.2% (8/248). 
Grade 2 and Grade 3 cases were reported in 1.2% (3/248) and 0.4% (1/248) of patients, respectively. 
No Grade 4 or 5 nephritis or renal dysfunction was reported in these studies. 

Immune-related nephritis and renal dysfunction 

 
Median time to onset was 10.5 weeks (range: 2.1-27.0). Two patients, including the one patient with a 
Grade 3 case (tubulointerstitial nephritis), received high-dose corticosteroids (at least 40 mg 
prednisone equivalents) at a median initial dose of 0.8 mg/kg (range: 0.5-1.2) for a median duration of 
5.3 weeks (range: 0.9-9.7). Resolution occurred in 5 patients (71%), including the Grade 3 case, with a 
median time to resolution of 5.9 weeks (range: 0.7- 37.6+); + denotes a censored observation. 
 

In CA209017 and CA209063, the incidence of thyroid disorders, including hypothyroidism or 
thyroiditis, was 4.4% (11/248). Grade 2 cases were reported in 3.6% (9/248) of patients. No Grade 3-5 
thyroid disorders were reported. The incidence of adrenal insufficiency was 0.4% (1/248; Grade 3). 
There were no reports of hypophysitis, diabetes mellitus, or diabetic ketoacidosis in these studies. 

Immune-related endocrinopathies 

 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



11 

Median time to onset of these endocrinopathies was 17.8 weeks (range: 6.1-33.1). Three patients, 
including the one patient with Grade 3 adrenal insufficiency, received high-dose corticosteroids (at 
least 40 mg prednisone equivalents) at a median initial dose of 1.1 mg/kg (range: 0.5-1.3) for 
2.7 weeks (range: 0.6-4.6). The Grade 3 case required permanent discontinuation of nivolumab. 
Resolution occurred in 6 patients (50%) with a median time to resolution of 20.6 weeks (0.4-47.6+); + 
denotes a censored observation.  
 

In CA209017 and CA209063, the incidence of rash was 12.1% (30/248). Grade 2 and Grade 3 cases 
were reported in 1.6% (4/248) and 0.8% (2/248) of patients, respectively. No Grade 4 or 5 rash was 
reported in these studies. 

Immune-related rash  

 
Median time to onset was 8.1 weeks (range: 0.3-51.9). None of these patients received high-dose 
corticosteroids. Two patients (1 with Grade 2 rash and 1 with Grade 3 rash) required permanent 
discontinuation of nivolumab. Resolution occurred in 24 patients (83%), including the 2 patients with 
a Grade 3 case, with a median time to resolution of 5.7 weeks (range: 0.1- 46.9+); + denotes a censored 
observation. 
 

In CA209017 and CA209063, the incidence of hypersensitivity/infusion reactions was 1.6% (4/248). 
Grade 3 anaphylactic reaction and Grade 4 hypersensitivity were each reported in 1 patient; both of 
these cases led to discontinuation and resolved with treatment. 

Infusion reactions 

 

In CA209017 and CA209063, the proportion of patients who experienced a shift from baseline to a 
Grade 3 or 4 laboratory abnormality was as follows: 13.2% for decreased lymphocytes, 9% for 
hyponatraemia, 2.9% for hypercalcaemia and hyperkalaemia, 2.5% for decreased haemoglobin (all 
Grade 3), 2.0% for hypokalaemia, 1.6% for decreased neutrophil count, 1.3% for hypomagnesaemia, 
1.2% for hypocalcaemia, 0.8% for increased total bilirubin, and 0.4% for increased AST, decreased 
platelet, hypermagnesaemia, and hypernatraemia. There was no worsening to Grade 3 or 4 in 
increased ALT, increased alkaline phosphatase, and increased creatinine. 

Laboratory abnormalities 

 
In study CA209017, hypercalcaemia was more frequently reported in the nivolumab group (31/130, 
24%) than in the docetaxel group (9/124, 7%). The exact cause is not known. Although 
hyperparathyroidism was not reported in CA209017, immune-related hyperparathyroidism might be 
considered especially if associated with hypophosphataemia (reported in 6 hypercalcemic patients in 
this study). 
 

As with all therapeutic proteins, there is a potential for an immune response to nivolumab. Of the 
497 patients who were treated with nivolumab 3 mg/kg every 2 weeks and evaluable for the presence 
of anti-product-antibodies, 51 (10.3%) patients tested positive for treatment-emergent anti-product 
antibodies by an electrochemiluminescent (ECL) assay. Only 4 (0.8%) patients were persistent 
positive. Neutralising antibodies were detected in only 5 (1.0% of the total) of the positive 
anti-product-antibody patients. There was no evidence of altered pharmacokinetic or toxicity profile 
associated with anti-product-antibody development. 

Immunogenicity 

 

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 

Reporting of suspected adverse reactions 

Appendix V. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc�


12 

4.9 Overdose 
 
No cases of overdose have been reported in clinical trials. In case of overdose, patients should be 
closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment 
instituted immediately. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies. ATC code: L01XC17. 
 

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

Mechanism of action 

 

 
Clinical efficacy and safety 

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of advanced or 
metastatic squamous NSCLC were evaluated in a phase 3, randomised, open-label study (CA209017). 
The study included patients (18 years or older) who have experienced disease progression during or 
after one prior platinum doublet-based chemotherapy regimen and an Eastern Cooperative Oncology 
Group (ECOG) performance status score of 0 or 1. Patients were enrolled regardless of their PD-L1 
status. Patients with active autoimmune disease, symptomatic interstitial lung disease, or untreated 
brain metastasis 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. 

Randomised phase 3 study vs. docetaxel (CA209017) 

 
A total of 272 patients were randomised to receive either nivolumab 3 mg/kg (N = 135) administered 
intravenously over 60 minutes every 2 weeks or docetaxel (n = 137) 75 mg/m2 every 3 weeks. 
Treatment was continued as long as clinical benefit was observed or until treatment was no longer 
tolerated. Tumour assessments, according to the Response Evaluation Criteria in Solid Tumours 
(RECIST), version 1.1, were conducted 9 weeks after randomisation and continued every 6 weeks 
thereafter. The primary efficacy outcome measure was overall survival (OS). Key secondary efficacy 
outcome measures were investigator-assessed objective response rate (ORR) and progression-free 
survival (PFS). In addition, symptom improvement and overall health status were assessed using the 
Lung Cancer Symptom Score (LCSS) average symptom burden index and the EQ-5D Visual 
Analogue Scale (EQ-VAS), respectively.  
 
Baseline characteristics were generally balanced between the two groups. The median age 
was 63 years (range: 39-85) with 44% ≥65 years of age and 11% ≥75 years of age. The majority of 
patients were white (93%) and male (76%). Thirty-one percent had progressive disease reported as the 
best response to their most recent prior regimen and 45% received nivolumab within 3 months of 
completing their most recent prior regimen. Baseline ECOG performance status score was 0 (24%) or 
1 (76%).  
 
The Kaplan-Meier curves for OS are shown in Figure 1. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



13 

Figure 1: Kaplan-Meier curves of OS (CA209017)  
 

 
Overall Survival (Months) 

Number of Subjects at Risk 
Nivolumab 3 mg/kg 

135 113 86 69 52 31 15 7 0 
Docetaxel 

137 103 68 45 30 14 7 2 0 
 Nivolumab 3 mg/kg (events : 86/135), median and 95% CI : 9.23 (7.33, 13.27) 

 Docetaxel (events : 113/137), median and 95% CI : 6.01 (5.13, 7.33) 
 
The observed OS benefit was consistently demonstrated across subgroups of patients. Survival benefit 
was observed regardless of whether patients had tumours that were designated PD-L1 negative or PD-
L1 positive (tumour membrane expression cut off of 1%, 5% or 10%). However, the role of this 
biomarker (PD-L1 expression) has not been fully elucidated. 
 
Study CA209017 included a limited number of patients ≥ 75 years (11 in the nivolumab group and 
18 in the docetaxel group). Nivolumab showed numerically less effect on OS (HR 1.85; 95% CI: 0.76, 
4.51), PFS (HR=1.76; 95%-CI: 0.77, 4.05 ) and ORR (9.1% vs 16.7%). Because of the small sample 
size, no definitive conclusions can be drawn from these data. 
 
Efficacy results are shown in Table 3. 
 

Pr
ob

ab
ili

ty
 o

f S
ur

vi
va

l 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



14 

Table 3: Efficacy results (CA209017) 
 nivolumab 

(n = 135) 
docetaxel 
(n = 137) 

Overall survival      
 Events 86 (63.7) 113 (82.5) 

Hazard ratio  0.59 
96.85% CI (0.43, 0.81) 

p-value 0.0002 
     
 Median (95% CI) months 9.23 (7.33, 13.27) 6.01 (5.13, 7.33) 
 Rate (95% CI) at 12 months 42.1 (33.7, 50.3) 23.7 (16.9, 31.1) 
Confirmed objective response  27 (20.0%) 12 (8.8%) 

(95% CI) (13.6, 27.7) (4.6, 14.8) 
Odds ratio (95% CI) 2.64 (1.27, 5.49) 

p-value 0.0083 
     

 Complete response (CR) 1 (0.7%) 0   
 Partial response (PR) 26 (19.3%) 12  (8.8%) 
 Stable disease (SD) 39 (28.9%) 47  (34.3%) 
     
Median duration of response     
  Months (range) Not reached (2.9 - 20.5+) 8.4 (1.4+ - 15.2+) 
     
Median time to response     
 Months (range) 2.2 (1.6 - 11.8) 2.1 (1.8 - 9.5) 
Progression-free survival     
 Events 105 (77.8) 122 (89.1) 

Hazard ratio  0.62  
95% CI (0.47, 0.81) 
p-value < 0.0004 

     
 Median (95% CI) (months) 3.48 (2.14, 4.86) 2.83 (2.10, 3.52) 
 Rate (95% CI) at 12 months 20.8 (14.0, 28.4) 6.4 (2.9, 11.8) 

 
The rate of disease-related symptom improvement, as measured by LCSS, was similar between the 
nivolumab group (18.5%) and the docetaxel group (21.2%). The average EQ-VAS increased over time 
for both treatment groups, indicating better overall health status for patients remaining on treatment. 
 

Study CA209063 was a single-arm, open-label study conducted in 117 patients with locally advanced 
or metastatic squamous-NSCLC after two or more lines of therapy; otherwise similar inclusion criteria 
as study CA209017 were applied. Nivolumab 3 mg/kg showed an overall response rate of 14.5% (95% 
CI: 8.7-22.2%), a median OS of 8.21 months (95% CI: 6.05-10.9 months ), and a median PFS of 
1.87 months (95% CI 1.77-3.15 months. The PFS was measured by RECIST version 1.1. The 
estimated 1-year survival rate was 41%. 

Single-arm phase 2 study (CA209063) 

 

No overall differences in safety or efficacy were reported between elderly ( ≥ 65 years) and younger 
patients (< 65 years). Data from patients 75 years of age or older are too limited to draw conclusions 
on this population. 

Safety and efficacy in elderly patients 

 

The European Medicines Agency has deferred the obligation to submit the results of studies with 
nivolumab in all subsets of the paediatric population in the treatment of malignant solid tumours (see 
section 4.2 for information on paediatric use). 

Paediatric population 

 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



15 

5.2 Pharmacokinetic properties 
 
The pharmacokinetics (PK) of nivolumab is linear in the dose range of 0.1 to 10 mg/kg. The geometric 
mean clearance (CL), terminal half-life, and average exposure at steady state at 3 mg/kg every 2 weeks 
of nivolumab were 9.5 mL/h, 26.7 days, and 75.3 µg/mL, respectively, based on a population PK 
analysis. 
 
Nivolumab CL increased with increasing body weight. Body weight normalised dosing produced 
approximately uniform steady-state trough concentration over a wide range of body weights 
(34-162 kg).  
 
The metabolic pathway of nivolumab has not been characterised. Nivolumab is expected to be 
degraded into small peptides and amino acids via catabolic pathways in the same manner as 
endogenous IgG. 
 

 
Special populations 

A population PK analysis suggested no difference in CL of nivolumab based on age, gender, race, 
tumour type, tumour size, and hepatic impairment. Although ECOG status, baseline glomerular 
filtration rate (GFR), albumin, body weight, and mild hepatic impairment had an effect on nivolumab 
CL, the effect was not clinically meaningful. 
 

The effect of renal impairment on the CL of nivolumab was evaluated in patients with mild (GFR < 90 
and ≥ 60 mL/min/1.73 m2; n = 379), moderate (GFR < 60 and ≥ 30 mL/min/1.73 m2; n = 179), or 
severe (GFR < 30 and ≥ 15 mL/min/1.73 m2; n = 2) renal impairment compared to patients with 
normal renal function (GFR ≥ 90 mL/min/1.73 m2; n = 342) in population PK analyses. No clinically 
important differences in the CL of nivolumab were found between patients with mild or moderate 
renal impairment and patients with normal renal function. Data from patients with severe renal 
impairment are too limited to draw conclusions on this population (see section 4.2).  

Renal impairment 

 

The effect of hepatic impairment on the CL of nivolumab was evaluated in patients with mild hepatic 
impairment (total bilirubin 1.0 × to 1.5 × ULN or AST > ULN as defined using the National Cancer 
Institute criteria of hepatic dysfunction; n = 92) compared to patients with normal hepatic function 
(total bilirubin and AST ≤ ULN; n = 804) in the population PK analyses. No clinically important 
differences in the CL of nivolumab were found between patients with mild hepatic impairment and 
normal hepatic function. Nivolumab has not been studied in patients with moderate (total 
bilirubin > 1.5 × to 3 × ULN and any AST) or severe hepatic impairment (total bilirubin > 3 × ULN 
and any AST) (see section 4.2). 

Hepatic impairment 

 
5.3 Preclinical safety data 
 
Blockade of PD-L1 signalling has been shown in murine models of pregnancy to disrupt tolerance 
to the foetus and to increase foetal loss. The effects of nivolumab on prenatal and postnatal 
development were evaluated in monkeys that received nivolumab twice weekly from the onset of 
organogenesis in the first trimester through delivery, at exposure levels either 8 or 35 times higher 
than those observed at the clinical dose of 3 mg/kg of nivolumab (based on AUC). There was a 
dose-dependent increase in foetal losses and increased neonatal mortality beginning in the third 
trimester. 
 
The remaining offspring of nivolumab-treated females survived to scheduled termination, with no 
treatment-related clinical signs, alterations to normal development, organ-weight effects, or gross and 
microscopic pathology changes. Results for growth indices, as well as teratogenic, neurobehavioral, 
immunological, and clinical pathology parameters throughout the 6-month postnatal period were 
comparable to the control group. However, based on its mechanism of action, foetal exposure to 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



16 

nivolumab may increase the risk of developing immune-related disorders or altering the normal 
immune response and immune-related disorders have been reported in PD-1 knockout mice. 
 
Fertility studies have not been performed with nivolumab. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium citrate dihydrate 
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. Nivolumab BMS should not be infused concomitantly in the same intravenous line with 
other medicinal products. 
 
6.3 Shelf life 
 

2 years. 
Unopened vial 

 

From a microbiological point of view, once opened, the medicinal product should be infused or diluted 
and infused immediately. 

After opening 

 
After preparation of infusion
From a microbiological point of view, the product should be used immediately. 

  

If not used immediately, chemical and physical in-use stability of Nivolumab BMS has been 
demonstrated for 24 hours at 2ºC to 8ºC protected from light and a maximum of 4 hours at 20°C-25°C 
and room light (this 4-hour period of the total 24 hours should be inclusive of the product 
administration period). 
 
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 preparation of the infusion, see section 6.3. 
 
6.5 Nature and contents of container 
 
4 mL of concentrate in a 10 mL vial (Type I glass) with a stopper (coated butyl rubber) and a dark 
blue flip-off seal (aluminium). Pack size of 1 vial. 
10 mL of concentrate in a 10 mL vial (Type I glass) with a stopper (coated butyl rubber) and a grey 
flip-off seal (aluminium). Pack size of 1 vial. 
 
Not all pack sizes may be marketed. 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



17 

 
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. 
 

 
Preparation and administration 

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 Nivolumab BMS concentrate may be needed to give the total 
dose for the patient. 

Calculating the dose 

 
 The total nivolumab dose in mg = the patient’s weight in kg × the prescribed dose in mg/kg.  
 The volume of Nivolumab BMS concentrate to prepare the dose (mL) = the total dose in mg, 

divided by 10 (the Nivolumab BMS concentrate strength is 10 mg/mL).  
 

Take care to ensure aseptic handling when you prepare the infusion. The infusion should be prepared 
in a laminar flow hood or safety cabinet using standard precautions for the safe handling of 
intravenous agents. 

Preparing the infusion 

 
Nivolumab BMS can be used for intravenous administration either: 
 without dilution, after transfer to an infusion container using an appropriate sterile syringe; or 
 after diluting to concentrations as low as 1 mg/mL. The final infusion concentration should range 

between 1 and 10 mg/mL. Nivolumab BMS concentrate may be diluted with either:  
 sodium chloride 9 mg/mL (0.9%) solution for injection; or 
 50 mg/mL (5%) glucose solution for injection.  

 
STEP 1 
 Inspect the Nivolumab BMS concentrate for particulate matter or discoloration. Do not shake the 

vial. Nivolumab BMS concentrate is a clear to opalescent, colourless to pale yellow liquid that 
may contain few light particles.  

 Withdraw the required volume of Nivolumab BMS concentrate using an appropriate sterile 
syringe.  

 
STEP 2 
 Transfer the concentrate into a sterile, evacuated glass bottle or intravenous container (PVC or 

polyolefin).  
 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. Gently mix the infusion by manual 
rotation. Do not shake. 

 

Nivolumab BMS infusion must not be administered as an intravenous push or bolus injection. 
Administration 

Administer the Nivolumab BMS infusion intravenously over a period of 60 minutes. 
Nivolumab BMS 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). 
 
Nivolumab BMS infusion is compatible with PVC and polyolefin containers, glass bottles, PVC 
infusion sets and in-line filters with polyethersulfone membranes with pore sizes of 0.2 µm to 1.2 µm. 
 
After administration of the nivolumab dose, flush the line with sodium chloride 9 mg/mL (0.9%) 
solution for injection or 50 mg/mL (5%) glucose solution for injection. 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



18 

 

Do not store any unused portion of the infusion solution for reuse. Any unused medicinal product or 
waste material should be disposed of in accordance with local requirements. 

Disposal 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH 
United Kingdom 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1026/001-002 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
 
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 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d

http://www.ema.europa.eu/�


19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER 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 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



20 

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

 
Name and address of the manufacturer of the biological active substance 
 
Lonza Biologics, Inc. 
101 International Drive 
Portsmouth, New Hampshire 
03801 
USA 
 
Name and address of the manufacturer responsible for batch release 
 
Bristol-Myers Squibb S.r.l. 
Loc. Fontana del Ceraso 
03012 Anagni (FR) 
Italy 
 
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 
 
The marketing authorisation holder shall submit the first periodic safety update report for this product 
within 6 months following authorisation. Subsequently, the marketing authorisation holder shall 
submit periodic safety update reports for this product in accordance with the requirements set out in 
the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and 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 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. 
 
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. 

 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time. 
 
• Additional risk minimisation measures  
 
Prior to launch of Nivolumab BMS in each Member State the Marketing Authorisation Holder (MAH) 
must agree about the content and format of the educational programme, including communication 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



21 

media, distribution modalities, and any other aspects of the programme, with the National Competent 
Authority.  
The educational programme is aimed at increasing the awareness about the potential immune mediated 
adverse events associated with Nivolumab BMS use, how to manage them and to enhance the 
awareness of patients or their caregivers on the signs and symptoms relevant to the early those adverse 
events. 
The MAH shall ensure that in each Member State where Nivolumab BMS is marketed, all healthcare 
professionals and patients/carers who are expected to prescribe and use Nivolumab BMS have access 
to/are provided with the following educational package: 
 

• Physician educational material 
• Patient alert card 

 
The physician educational material should contain: 

• The Summary of Product Characteristics 
• Adverse Reaction Management Guide 

 
The Adverse Reaction Management Guide shall contain the following key elements: 
 

• Relevant information (e.g. seriousness, severity, frequency, time to onset, reversibility of the 
AE as applicable) for the following safety concerns: 
o Immune-related pneumonitis 
o Immune-related colitis 
o Immune-related hepatitis 
o Immune-related nephritis or renal dysfunction 
o Immune-related endocrinopathies  
o Immune related rash 
o Other immune-related ARs 

 
• Details on how to minimise the safety concern through appropriate monitoring and management 

 
• The patient alert card shall contain the following key messages:  

 
• That Nivolumab BMS treatment may increase the risk of:  

o Immune-related pneumonitis 
o Immune-related colitis 
o Immune-related hepatitis 
o Immune-related nephritis or renal dysfunction 
o Immune-related endocrinopathies  
o Immune related rash 
o Other immune-related ARs 

 
• Signs or symptoms of the safety concern and when to seek attention from a HCP 

 
• Contact details of the Nivolumab BMS prescriber  

 
• Obligation to conduct post-authorisation measures  
 
The MAH shall complete, within the stated timeframe, the below measures: 
 
Description Due date 
1. Post-authorisation efficacy study (PAES): The MAH should submit an 
updated OS data for Study CA209017: a Phase 3, randomized study of 
nivolumab vs docetaxel in subjects with advanced or metastatic squamous 
NSCLC who have experienced disease progression during or after one prior 
platinum doublet-based chemotherapy regimen.  

The updated data 
should be submitted 
by 31st December 
2015 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



22 

2. The value of biomarkers to predict the efficacy of nivolumab should be 
further explored, specifically: 

1. To continue the exploration of the optimal cut-off for PD-L1 
positivity based on current assay method used to further elucidate its 
value as predictive of nivolumab efficacy. These analyses will be 
conducted in Studies CA 209037 and CA209066 in patients with 
advanced melanoma. 

2. To further investigate the value biomarkers other than PD-L1 
expression status at tumour cell membrane level by IHC (e.g., other 
methods / assays, and associated cut-offs, that might prove more 
sensitive and specific in predicting response to treatment based on 
PD-L1, PD-L2, tumour infiltrating lymphocytes with measurement of 
CD8+T density, RNA signature, etc.) as predictive of nivolumab 
efficacy. These additional biomarker analyses are occurring in the 
context of Study CA209-038 and Study CA209-066.  

3. To further investigate at post-approval the relation between PDL-1 
and PDL-2 expression in Phase 1 (CA209009, CA209038 and 
CA209064). 

4. To further investigate the associative analyses between PDL-1 and 
PDL-2 expression conducted in Study CA209-066. 

5. To further investigate at post-approval the possible change in PD-L1 
status of the tumour during treatment and/or tumour progression in 
Studies CA209-009, CA209-038 and CA209-064.  

 

30th September 2015 
 
 
 
 
30th September 2017 
 
 
 
 
 
 
 
31st March 2017 
 
 
31st December 2017 
 
30th September 2017 
 

 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



25 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT  
 
Nivolumab BMS 10 mg/mL concentrate for solution for infusion 
nivolumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each mL of concentrate contains 10 mg of nivolumab. 
Each vial of 4 mL contains 40 mg of nivolumab. 
Each vial of 10 mL contains 100 mg of nivolumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium citrate dihydrate, 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. 
 
40 mg/4 mL 
100 mg/10 mL 
 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intravenous 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 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



26 

EXP 
 
 
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 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1026/001 40 mg vial 
EU/1/15/1026/002 100 mg vial 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



27 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Nivolumab BMS 10 mg/mL sterile concentrate 
nivolumab 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
40 mg/4 mL 
100 mg/10 mL 
 
 
6. OTHER 
 
For single use only. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



29 

Package leaflet: Information for the user 
 

Nivolumab BMS 10 mg/mL concentrate for solution for infusion 
nivolumab 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
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.  
It is important that you keep the Alert Card with you during treatment. 
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 Nivolumab BMS is and what it is used for  
2. What you need to know before you use Nivolumab BMS 
3. How to use Nivolumab BMS 
4. Possible side effects 
5. How to store Nivolumab BMS 
6. Contents of the pack and other information 
 
 
1. What Nivolumab BMS is and what it is used for 
 
Nivolumab BMS is a medicine used to treat advanced non-small cell lung cancer (a type of lung 
cancer) in adults. It contains the active substance nivolumab, which is a monoclonal antibody, a type 
of protein designed to recognise and attach to a specific target substance in the body.  
 
Nivolumab attaches to a target protein called programmed death-1 receptor (PD-1) that can switch off 
the activity of T cells (a type of white blood cell that forms part of the immune system, the body’s 
natural defences). By attaching to PD-1, nivolumab blocks its action and prevents it from switching 
off your T cells. This helps increase their activity against the lung cancer cells. 
 
 
2. What you need to know before you use Nivolumab BMS 
 
You should not be given Nivolumab BMS 
 if you are allergic to nivolumab 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 Nivolumab BMS as it may cause: 
 Problems with your lungs such as breathing difficulties or cough. These may be signs of 

inflammation of the lungs (pneumonitis or interstitial lung disease). 
 Diarrhoea (watery, loose or soft stools) or any symptoms of inflammation of the intestines 

(colitis), such as stomach pain and mucus or blood in stool. 
 Inflammation of the liver (hepatitis). Signs and symptoms of hepatitis may include abnormal 

liver function tests, eye or skin yellowing (jaundice), pain on the right side of your stomach 
area, or tiredness. 

 Inflammation or problems with your kidneys. Signs and symptoms may include abnormal 
kidney function tests, or decreased volume of urine. 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



30 

 Problems with your hormone producing glands (including the pituitary, the thyroid and 
adrenal glands) that may affect how these glands work. Signs and symptoms that these glands 
are not working properly may include fatigue (extreme tiredness), weight change or headache 
and visual disturbances. 

 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 skin that can lead to rash and itching. 
 
Tell your doctor immediately if you have any of these signs or symptoms or if they get worse. Do 
not try to treat your symptoms with other medicines on your own. Your doctor may 
 give you other medicines in order to prevent complications and reduce your symptoms, 
 withhold the next dose of Nivolumab BMS, 
 or stop your treatment with Nivolumab BMS 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 your treatment. 
 
Check with your doctor or nurse before you are given Nivolumab BMS if: 
 you have been told that your cancer has spread to your brain 
 you have an autoimmune disease (a condition where the body attacks its own cells); 
 you have any history of inflammation of the lungs; 
 you have been taken medicines to suppress your immune system. 
 
Children and adolescents 
Nivolumab BMS should not be used in children and adolescents below 18 years of age. 
 
Other medicines and Nivolumab BMS 
Before you are given Nivolumab BMS, tell your doctor if you are taking any medicines that 
suppress your immune system, such as corticosteroids, since these medicines may interfere with the 
effect of Nivolumab BMS. However, once you are treated with Nivolumab BMS, your doctor may 
give you corticosteroids to reduce any possible side-effects that you may have during your treatment 
and this will not impact the effect of the medicine. 
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. 
 
Pregnancy and breast-feeding 
Tell your doctor if you are pregnant or think you might be, if you are planning to become pregnant, 
or if you are breast-feeding. 
 
Do not use Nivolumab BMS if you are pregnant unless your doctor specifically tells you to. The 
effects of Nivolumab BMS in pregnant women are not known, but it is possible that the active 
substance, nivolumab, could harm an unborn baby. 
 You must use effective contraception while you are being treated with Nivolumab BMS and 

for at least 5 months following the last dose of Nivolumab BMS, if you are a woman who could 
become pregnant. 

 If you become pregnant while using Nivolumab BMS tell your doctor. 
 
It is not known whether nivolumab gets into breast milk. A risk to the breast-fed infant cannot be 
excluded. Ask your doctor if you can breast-feed during or after treatment with Nivolumab BMS. 
 
Driving and using machines 
Nivolumab is unlikely to affect your ability to drive or use machines; however, use caution when 
performing these activities until you are sure that nivolumab does not adversely affect you. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



31 

Nivolumab BMS contains sodium 
Tell your doctor if you are on a low-sodium (low-salt) diet before you are given Nivolumab BMS. 
This medicine contains 2.5 mg sodium per mL of concentrate. 
 
You will also find this information in the Patient Alert Card you have been given by your doctor. It is 
important that you keep this Alert Card and show it to your partner or caregivers. 
 
 
3. How to use Nivolumab BMS 
 
How much Nivolumab BMS is given 
The amount of Nivolumab BMS you will be given will be calculated based on your body weight. The 
recommended dose is 3 mg of nivolumab per kilogram of your body weight. 
Depending on your dose, the appropriate amount of Nivolumab BMS will be diluted with sodium 
chloride 9 mg/mL (0.9%) solution for injection or glucose 50 mg/mL (5%) solution for injection 
before use. More than one vial of Nivolumab BMS may be necessary to obtain the required dose. 
 
How Nivolumab BMS is given 
You will receive treatment with Nivolumab BMS in a hospital or clinic, under the supervision of an 
experienced doctor. 
 
Nivolumab BMS will be given to you as an infusion (a drip) into a vein (intravenously) over a period 
of 60 minutes, every 2 weeks. Your doctor will continue giving you Nivolumab BMS for as long as 
you keep benefitting from it or until you no longer tolerate the treatment. 
 
If you miss a dose of Nivolumab BMS 
It is very important for you to keep all your appointments to receive Nivolumab BMS. If you miss an 
appointment, ask your doctor when to schedule your next dose. 
 
If you stop using Nivolumab BMS 
Stopping your treatment may stop the effect of the medicine. Do not stop treatment with 
Nivolumab BMS unless you have discussed this with your doctor. 
 
If you have any further questions about your treatment or on the use of this medicine, 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. Nivolumab BMS 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 and need treatment or withdrawal of 
nivolumab. 
 
The following side effects have been reported in clinical trials with nivolumab: 
 
Very common (may affect more than 1 in 10 people) 
 Decreased appetite 
 Nausea 
 Feeling tired or weak 
 
Common (may affect up to 1 in 10 people) 
 Underactive thyroid gland which can cause tiredness or weight gain 
 Inflammation of the nerves causing numbness, weakness, tingling or burning pain of the arms 

and legs, headache, dizziness 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



32 

 Inflammation of the lungs (pneumonitis), characterised by coughing and difficulty breathing, 
shortness of breath (dyspnoea), cough 

 Diarrhoea (watery, loose or soft stools), mouth ulcers and cold sores (stomatitis), vomiting, 
stomach pain, constipation, dry mouth 

 Skin rash, itching 
 Pain in the muscles, bones and joints 
 Fever, oedema (swelling) 
 
Uncommon (may affect up to 1 in 100 people) 
 Bronchitis, infections of the upper respiratory tract 
 A disease causing the inflammation or enlargement of a lymph node (Kikuchi lymphadenitis) 
 Allergic reaction, reactions related to the administration of the medicine  
 Adrenal glands not working properly, inflammation of the thyroid gland 
 A condition in which the muscles become weak and tire easily (myasthenic syndrome), damage 

to the nerves in different parts of the body that can cause decreased feeling or affect movement 
 Fast heart rate 
 Inflammation of blood vessels 
 Fluid in the lungs 
 Inflammation of the intestines (colitis), ulcer of the small intestines 
 Hives (itchy, bumpy rash) 
 Inflammation of muscles causing pain or stiffness 
 Kidney disease, kidney failure. 
 
Tell your doctor immediately if you get any of the side effects listed above. Do not try to treat your 
symptoms with other medicines on your own. 
 
Changes in test results 
Nivolumab BMS may cause changes in the results of tests carried out by your doctor. These include: 
 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) 
 Abnormal liver function tests (increased amounts of the liver enzymes aspartate 

aminotransferase, alanine aminotransferase or alkaline phosphatase in your blood, higher blood 
levels of bilirubin) 

 Abnormal kidney function tests (increased amounts of creatinine in your blood) 
 Abnormal levels of calcium, potassium, magnesium, or sodium in your blood 
 An increased level of the enzyme that breaks down lipids and of the enzyme that breaks down 

starch. 
 
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 Nivolumab BMS 
 
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. 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc�


33 

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 Nivolumab BMS contains 
 The active substance is nivolumab. 

Each mL of concentrate for solution for infusion contains 10 mg of nivolumab. 
Each vial contains either 40 mg (in 4 mL) or 100 mg (in 10 mL) of nivolumab. 
 

 The other ingredients are sodium citrate dihydrate, sodium chloride (see section 2 " 
Nivolumab BMS contains sodium"), mannitol (E421), pentetic acid, polysorbate 80, sodium 
hydroxide, hydrochloric acid and water for injections. 

 
What Nivolumab BMS looks like and contents of the pack 
Nivolumab BMS concentrate for solution for infusion (sterile concentrate) is a clear to opalescent, 
colourless to pale yellow liquid that may contain few light particles. 
 
It is available in packs containing either 1 vial of 4 mL or 1 vial of 10 mL. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Bristol-Myers Squibb Pharma EEIG 
Uxbridge Business Park 
Sanderson Road 
Uxbridge UB8 1DH 
United Kingdom 
 
Manufacturer 
Bristol-Myers Squibb S.r.l. 
Loc. Fontana del Ceraso 
03012 Anagni (FR) 
Italy 
 
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 Gyógyszerkereskedelmi Kft. 
Tel: + 370 5 2790 762 
 

България 
Bristol-Myers Squibb Gyógyszerkereskedelmi Kft. 
Teл.: + 359 800 12 400 
 

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 Gyógyszerkereskedelmi Kft. 
Tel.: + 36 1 301 9700 
 

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

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

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



34 

Deutschland 
Bristol-Myers Squibb GmbH & Co. KGaA 
Tel: + 49 89 121 42-0 
 

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

Eesti 
Bristol-Myers Squibb Gyógyszerkereskedelmi Kft. 
Tel: + 372 6827 400 
 

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 5796666 
 

France 
Bristol-Myers Squibb SARL 
Tél: + 33 (0)810 410 500 
 

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) 6311-833 
 

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

Ireland 
Bristol-Myers Squibb Pharmaceuticals Ltd 
Tel: + 353 (1 800) 749 749 
 

Slovenija 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 386 1 236 47 00 
 

Ísland 
Vistor hf. 
Sími: + 354 535 7000 
 

Slovenská republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 421 2 59298411 
 

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 Gyógyszerkereskedelmi Kft. 
Tel: + 371 67 50 21 85 
 

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 
 
------------------------------------------------------------------------------------------------------------------------- 
 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d

http://www.ema.europa.eu/�


35 

The following information is intended for healthcare professionals only: 
 
Preparation and administration of Nivolumab BMS 
 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to asepsis. 
 
Calculating the dose 
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 Nivolumab BMS concentrate may be needed to give the 
total dose for the patient. 
 
 The total nivolumab dose in mg = the patient’s weight in kg × the prescribed dose in mg/kg.  
 The volume of Nivolumab BMS concentrate to prepare the dose (mL) = the total dose in mg, 

divided by 10 (the Nivolumab BMS concentrate strength is 10 mg/mL).  
 
Preparing the infusion 
Take care to ensure aseptic handling when you prepare the infusion. The infusion should be 
prepared in a laminar flow hood or safety cabinet using standard precautions for the safe handling of 
intravenous agents. 
 
Nivolumab BMS can be used for intravenous administration either: 
 without dilution, after transfer to an infusion container using an appropriate sterile syringe; 

or 
 after diluting to concentrations as low as 1 mg/mL. The final infusion concentration should 

range between 1 and 10 mg/mL. Nivolumab BMS concentrate may be diluted with either:  
 sodium chloride 9 mg/mL (0.9%) solution for injection; or 
 50 mg/mL (5%) glucose solution for injection.  

 
STEP 1 
 Inspect the Nivolumab BMS concentrate for particulate matter or discoloration. Do not shake 

the vial. Nivolumab BMS concentrate is a clear to opalescent, colourless to pale yellow liquid 
that may contain few light particles.  

 Withdraw the required volume of Nivolumab BMS concentrate using an appropriate sterile 
syringe.  

 
STEP 2 
 Transfer the concentrate into a sterile, evacuated glass bottle or intravenous container (PVC or 

polyolefin).  
 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. Gently mix the infusion by manual 
rotation. Do not shake. 

 
Administration 
Nivolumab BMS infusion must not be administered as an intravenous push or bolus injection. 
Administer the Nivolumab BMS infusion intravenously over a period of 60 minutes. 
 
Nivolumab BMS 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). 
 
Nivolumab BMS infusion is compatible with: 
 PVC containers 
 Polyolefin containers 
 Glass bottles 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d



36 

 PVC infusion sets 
 In-line filters with polyethersulfone membranes with pore sizes of 0.2 µm to 1.2 µm. 
 
After administration of the nivolumab dose, flush the line with sodium chloride 9 mg/mL (0.9%) 
solution for injection or 50 mg/mL (5%) glucose solution for injection. 
 
Storage conditions and shelf life 
Unopened vial 
Nivolumab BMS 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. Nivolumab BMS should not be frozen. 
 
Do not use Nivolumab BMS after the expiry date which is stated on the carton and on the vial label 
after EXP. The expiry date refers to the last day of that month. 
 
Nivolumab BMS infusion 
Nivolumab BMS infusion must be completed within 24 hours of preparation. If not used immediately, 
the solution may be stored under refrigeration conditions (2°C-8°C) and protected from light for up 
to 24 hours [a maximum of 4 hours of the total 24 hours can be at room temperature (20°C-25°C) and 
room light]. 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. 

Me
dic

ina
l p

rod
uc

t n
o l

on
ge

r a
uth

ori
se

d


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER 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
	A. LABELLING
	B. PACKAGE LEAFLET