Bavencio

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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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 
 
Bavencio 20 mg/mL concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each mL of concentrate contains 20 mg of avelumab. 
One vial of 10 mL contains 200 mg of avelumab. 
 
Avelumab is a human monoclonal IgG1 antibody directed against the immunomodulatory cell surface 
ligand protein PD-L1 and produced in Chinese hamster ovary cells by recombinant DNA technology. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion (sterile concentrate). 
 
Clear, colourless to slightly yellow solution. The solution pH is in the range of 5.0 - 5.6 and the 
osmolality is between 270 and 330 mOsm/kg. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Bavencio is indicated as monotherapy for the treatment of adult patients with metastatic Merkel cell 
carcinoma (MCC). 
 
Bavencio in combination with axitinib is indicated for the first-line treatment of adult patients with 
advanced renal cell carcinoma (RCC) (see section 5.1). 
 
4.2 Posology and method of administration 
 
Treatment should be initiated and supervised by a physician experienced in the treatment of cancer. 
 
Posology 
The recommended dose of Bavencio as monotherapy is 800 mg administered intravenously over 
60 minutes every 2 weeks. 
 
Administration of Bavencio should continue according to the recommended schedule until disease 
progression or unacceptable toxicity. 
 
The recommended dose of Bavencio in combination with axitinib is 800 mg administered 
intravenously over 60 minutes every 2 weeks and axitinib 5 mg orally taken twice daily (12 hours 
apart) with or without food until disease progression or unacceptable toxicity. 
 
For information on the posology of axitinib, please refer to the axitinib product information. 
 



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Premedication 
Patients have to be premedicated with an antihistamine and with paracetamol prior to the first 
4 infusions of Bavencio. If the fourth infusion is completed without an infusion-related reaction, 
premedication for subsequent doses should be administered at the discretion of the physician. 
 
Treatment modifications 
Dose escalation or reduction is not recommended. Dosing delay or discontinuation may be required 
based on individual safety and tolerability; see Table 1. 
 
Detailed guidelines for the management of immune-related adverse reactions are described in 
section 4.4. 
 
Table 1: Guidelines for withholding or discontinuation of Bavencio 
 
Treatment-related 
adverse reaction 

Severity* Treatment modification 

Infusion-related reactions Grade 1 infusion-related reaction Reduce infusion rate by 
50% 

Grade 2 infusion-related reaction Withhold until adverse 
reactions recover to 
Grade 0-1; restart infusion 
with a 50% slower rate 

Grade 3 or Grade 4 infusion-related 
reaction 

Permanently discontinue 

Pneumonitis Grade 2 pneumonitis Withhold until adverse 
reactions recover to 
Grade 0-1 

Grade 3 or Grade 4 pneumonitis or 
recurrent Grade 2 pneumonitis 

Permanently discontinue 

Hepatitis 
 
For Bavencio in 
combination with axitinib, 
see below. 

Aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) greater 
than 3 and up to 5 times upper limit of 
normal (ULN) or total bilirubin greater 
than 1.5 and up to 3 times ULN 

Withhold until adverse 
reactions recover to 
Grade 0-1 

AST or ALT greater than 5 times ULN or 
total bilirubin greater than 3 times ULN 

Permanently discontinue 

Colitis Grade 2 or Grade 3 colitis or diarrhoea Withhold until adverse 
reactions recover to 
Grade 0-1 

Grade 4 colitis or diarrhoea or recurrent 
Grade 3 colitis 

Permanently discontinue 

Pancreatitis Suspected pancreatitis Withhold 
Confirmed pancreatitis Permanently discontinue 

Myocarditis Suspected myocarditis Withhold 
Confirmed myocarditis Permanently discontinue 

Endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, 
hyperglycaemia) 

Grade 3 or Grade 4 endocrinopathies Withhold until adverse 
reactions recover to 
Grade 0-1 

Nephritis and renal 
dysfunction 

Serum creatinine more than 1.5 and up to 
6 times ULN 

Withhold until adverse 
reactions recover to 
Grade 0-1 

Serum creatinine more than 6 times ULN Permanently discontinue 



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Treatment-related 
adverse reaction 

Severity* Treatment modification 

Other immune-related 
adverse reactions 
(including myositis, 
hypopituitarism, uveitis, 
Guillain-Barré syndrome) 

For any of the following: 
• Grade 2 or Grade 3 clinical signs 

or symptoms of an immune-related 
adverse reaction not described 
above. 

Withhold until adverse 
reactions recover to 
Grade 0-1 

For any of the following: 
• Life threatening or Grade 4 adverse 

reaction (excluding 
endocrinopathies controlled with 
hormone replacement therapy) 

• Recurrent Grade 3 immune-related 
adverse reaction 

• Requirement for 10 mg per day or 
greater prednisone or equivalent 
for more than 12 weeks 

• Persistent Grade 2 or Grade 3 
immune-mediate adverse reactions 
lasting 12 weeks or longer 

Permanently discontinue 

* Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events 
Version 4.0 (NCI-CTCAE v4.03) 
 
Treatment modifications when Bavencio is used in combination with axitinib 
If ALT or AST ≥ 3 times ULN but < 5 times ULN or total bilirubin ≥ 1.5 times ULN but < 3 times 
ULN, both Bavencio and axitinib should be withheld until these adverse reactions recover to 
Grades 0-1. If persistent (greater than 5 days), corticosteroid therapy with prednisone or equivalent 
followed by a taper should be considered. Rechallenge with Bavencio or axitinib or sequential 
rechallenge with both Bavencio and axitinib after recovery should be considered. Dose reduction 
according to the axitinib product information should be considered if rechallenging with axitinib. 
 
If ALT or AST ≥ 5 times ULN or > 3 times ULN with concurrent total bilirubin ≥ 2 times ULN or 
total bilirubin ≥ 3 times ULN, both Bavencio and axitinib should be permanently discontinued and 
corticosteroid therapy should be considered. 
 
Dose modification advice for axitinib when used with Bavencio 
When Bavencio is administered in combination with axitinib, please refer to the axitinib product 
information for recommended dose modifications for axitinib. 
 
Special populations 
 
Elderly 
No dose adjustment is needed for elderly patients (≥ 65 years) (see sections 5.1 and 5.2). 
 
Paediatric population 
The safety and efficacy of Bavencio in children and adolescents below 18 years of age have not been 
established. 
 
Renal impairment 
No dose adjustment is needed for patients with mild or moderate renal impairment (see section 5.2). 
There are insufficient data in patients with severe renal impairment for dosing recommendations. 
 
Hepatic impairment 
No dose adjustment is needed for patients with mild hepatic impairment (see section 5.2). There are 
insufficient data in patients with moderate or severe hepatic impairment for dosing recommendations. 
 



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Method of administration 
Bavencio is for intravenous infusion only. It must not be administered as an intravenous push or bolus 
injection. 
 
Bavencio has to be diluted with either sodium chloride 9 mg/mL (0.9%) solution for injection or with 
sodium chloride 4.5 mg/mL (0.45%) solution for injection. It is administered over 60 minutes as an 
intravenous infusion using a sterile, non-pyrogenic, low-protein binding 0.2 micrometre in-line or 
add-on filter. 
 
For instructions on the preparation and administration of the medicinal product, 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. 
 
Infusion-related reactions 
Infusion-related reactions, which might be severe, have been reported in patients receiving avelumab 
(see section 4.8). 
 
Patients should be monitored for signs and symptoms of infusion-related reactions including pyrexia, 
chills, flushing, hypotension, dyspnoea, wheezing, back pain, abdominal pain, and urticaria. 
 
For Grade 3 or Grade 4 infusion-related reactions, the infusion should be stopped and avelumab 
should be permanently discontinued (see section 4.2). 
 
For Grade 1 infusion-related reactions, the infusion rate should be slowed by 50% for the current 
infusion. For patients with Grade 2 infusion-related reactions, the infusion should be temporary 
discontinued until Grade 1 or resolved, then the infusion will restart with a 50% slower infusion rate 
(see section 4.2). 
 
In case of recurrence of Grade 1 or Grade 2 infusion-related reaction, the patient may continue to 
receive avelumab under close monitoring, after appropriate infusion rate modification and 
premedication with paracetamol and antihistamine (see section 4.2). 
 
In clinical trials, 98.6% (433/439) of patients with infusion-related reactions had a first 
infusion-related reaction during the first 4 infusions of which 2.7% (12/439) were Grade ≥ 3. In the 
remaining 1.4% (6/439) of patients, infusion-related reactions occurred after the first 4 infusions and 
all were of Grade 1 or Grade 2. 
 
Immune-related adverse reactions 
Most immune-related adverse reactions with avelumab were reversible and managed with temporary 
or permanent discontinuation of avelumab, administration of corticosteroids and/or supportive care. 
 
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, avelumab should be 
withheld and corticosteroids administered. If corticosteroids are used to treat an adverse reaction, a 
taper of at least 1 month duration should be initiated upon improvement. 
 
In patients, whose immune-related adverse reactions could not be controlled with corticosteroid use, 
administration of other systemic immunosuppressants may be considered. 
 



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Immune-related pneumonitis 
Immune-related pneumonitis occurred in patients treated with avelumab. One fatal case has been 
reported in patients receiving avelumab (see section 4.8). 
 
Patients should be monitored for signs and symptoms of immune-related pneumonitis and causes other 
than immune-related pneumonitis should be ruled out. Suspected pneumonitis should be confirmed 
with radiographic imaging. 
 
Corticosteroids should be administered for Grade ≥ 2 events (initial dose of 1 to 2 mg/kg/day 
prednisone or equivalent, followed by a corticosteroid taper). 
 
Avelumab should be withheld for Grade 2 immune-related pneumonitis until resolution, and 
permanently discontinued for Grade 3, Grade 4 or recurrent Grade 2 immune-related pneumonitis (see 
section 4.2). 
 
Immune-related hepatitis 
Immune-related hepatitis occurred in patients treated with avelumab. Two fatal cases have been 
reported in patients receiving avelumab (see section 4.8). 
 
Patients should be monitored for changes in liver function and symptoms of immune-related hepatitis 
and causes other than immune-related hepatitis should be ruled out. 
 
Corticosteroids should be administered for Grade ≥ 2 events (initial dose 1 to 2 mg/kg/day prednisone 
or equivalent, followed by a corticosteroid taper). 
 
Avelumab should be withheld for Grade 2 immune-related hepatitis until resolution and permanently 
discontinued for Grade 3 or Grade 4 immune-related hepatitis (see section 4.2). 
 
Immune-related colitis 
Immune-related colitis has been reported in patients receiving avelumab (see section 4.8). 
 
Patients should be monitored for signs and symptoms of immune-related colitis and causes other than 
immune-related colitis should be ruled out. Corticosteroids should be administered for Grade ≥ 2 
events (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a corticosteroid taper). 
 
Avelumab should be withheld for Grade 2 or Grade 3 immune-related colitis until resolution, and 
permanently discontinued for Grade 4 or recurrent Grade 3 immune-related colitis (see section 4.2). 
 
Immune-related pancreatitis 
Immune-related pancreatitis has been reported in patients receiving avelumab. Two fatal cases have 
been reported in patients receiving avelumab in combination with axitinib (see section 4.8). 
 
Patients should be monitored for signs and symptoms of immune-related pancreatitis. In symptomatic 
patients, obtain gastroenterology consultation and laboratory investigations (including imaging) to 
ensure the initiation of appropriate measures at an early stage. Corticosteroids should be administered 
for immune-related pancreatitis (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by 
a corticosteroid taper). 
 
Avelumab should be withheld in the event of suspected immune-related pancreatitis. Avelumab should 
be permanently discontinued if immune-related pancreatitis is confirmed (see section 4.2). 
 
Immune-related myocarditis 
Immune-related myocarditis has been reported in patients receiving avelumab. Two fatal cases have 
been reported in patients receiving avelumab in combination with axitinib (see section 4.8). 
 



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Patients should be monitored for signs and symptoms of immune-related myocarditis. In symptomatic 
patients, obtain cardiologic consultation and laboratory investigations to ensure the initiation of 
appropriate measures at an early stage. Corticosteroids should be administered for immune-related 
myocarditis (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a corticosteroid 
taper). If no improvement within 24 hours on corticosteroids, additional immunosuppression (e.g., 
mycophenolate, infliximab, anti-thymocyte globulin) should be considered. 
 
Avelumab should be withheld in the event of suspected immune-related myocarditis. Avelumab 
should be permanently discontinued if immune-related myocarditis is confirmed (see section 4.2). 
 
Immune-related endocrinopathies 
Immune-related thyroid disorders, immune-related adrenal insufficiency, and Type 1 diabetes mellitus 
have been reported in patients receiving avelumab (see section 4.8). Patients should be monitored for 
clinical signs and symptoms of endocrinopathies. Avelumab should be withheld for Grade 3 or 
Grade 4 endocrinopathies until resolution (see section 4.2). 
 
Thyroid disorders (hypothyroidism/hyperthyroidism) 
Thyroid disorders can occur at any time during treatment (see section 4.8). 
 
Patients should be monitored for changes in thyroid function (at the start of treatment, periodically 
during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. Hypothyroidism should be managed with replacement therapy and hyperthyroidism 
with anti-thyroid medicinal product, as needed. 
 
Avelumab should be withheld for Grade 3 or Grade 4 thyroid disorders (see section 4.2). 
 
Adrenal insufficiency 
Patients should be monitored for signs and symptoms of adrenal insufficiency during and after 
treatment. Corticosteroids should be administered (1 to 2 mg/kg/day prednisone intravenously or oral 
equivalent) for Grade ≥ 3 adrenal insufficiency followed by a taper until a dose of less than or equal to 
10 mg/day has been reached. 
 
Avelumab should be withheld for Grade 3 or Grade 4 symptomatic adrenal insufficiency (see 
section 4.2). 
 
Type 1 diabetes mellitus 
Avelumab can cause Type 1 diabetes mellitus, including diabetic ketoacidosis (see section 4.8). 
 
Patients should be monitored for hyperglycaemia or other signs and symptoms of diabetes. Initiate 
treatment with insulin for Type 1 diabetes mellitus. Avelumab should be withheld and anti-
hyperglycaemics in patients with Grade ≥ 3 hyperglycaemia should be administered. Treatment with 
avelumab should be resumed when metabolic control is achieved on insulin replacement therapy. 
 
Immune-related nephritis and renal dysfunction 
Avelumab can cause immune-related nephritis (see section 4.8). 
 
Patients should be monitored for elevated serum creatinine prior to and periodically during treatment. 
Corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a corticosteroid 
taper) should be administered for Grade ≥ 2 nephritis. Avelumab should be withheld for Grade 2 or 
Grade 3 nephritis until resolution to ≤ Grade 1 and permanently discontinued for Grade 4 nephritis. 
 
Other immune-related adverse reactions 
Other clinically important immune-related adverse reactions were reported in less than 1% of patients: 
myositis, hypopituitarism, uveitis, and Guillain-Barré syndrome (see section 4.8). 
 



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For suspected immune-related adverse reactions, ensure adequate evaluation to confirm aetiology or to 
rule out other causes. Based on the severity of the adverse reaction, avelumab should be withheld and 
corticosteroids to be administered. Avelumab should be resumed when the immune-related adverse 
reaction returns to Grade 1 or less following corticosteroid taper. Avelumab should be permanently 
discontinued for any Grade 3 immune-related adverse reaction that recurs and for Grade 4 
immune-related adverse reaction (see section 4.2). 
 
Hepatotoxicity (in combination with axitinib) 
Hepatotoxicity occurred in patients treated with avelumab in combination with axitinib with higher 
than expected frequencies of Grade 3 and Grade 4 ALT and AST elevation compared to avelumab 
alone (see section 4.8). 
 
Patients should be more frequently monitored for changes in liver function and symptoms as compared 
to when avelumab is used as monotherapy. 
 
Avelumab should be withheld for Grade 2 hepatotoxicity until resolution and permanently 
discontinued for Grade 3 or Grade 4 hepatotoxicity. Corticosteroids should be considered for 
Grade ≥ 2 events (see section 4.2). 
 
Patients excluded from clinical studies 
Patients with the following conditions were excluded from clinical trials: active central nervous system 
(CNS) metastasis; active or a history of autoimmune disease; a history of other malignancies within the 
last 5 years; organ transplant; conditions requiring therapeutic immune suppression or active infection 
with HIV, or hepatitis B or C. 
 
Sodium content 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 
‘sodium-free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been conducted with avelumab. 
 
Avelumab is primarily metabolised through catabolic pathways, therefore, it is not expected that 
avelumab will have pharmacokinetic drug-drug interactions with other medicinal products. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/Contraception 
Women of childbearing potential should be advised to avoid becoming pregnant while receiving 
avelumab and should use effective contraception during treatment with avelumab and for at least 
1 month after the last dose of avelumab. 
 
Pregnancy 
There are no or limited data from the use of avelumab in pregnant women. 
 
Animal reproduction studies have not been conducted with avelumab. However, in murine models of 
pregnancy, blockade of PD-L1 signalling has been shown to disrupt tolerance to the foetus and to 
result in an increased foetal loss (see section 5.3). These results indicate a potential risk, based on its 
mechanism of action, that administration of avelumab during pregnancy could cause foetal harm, 
including increased rates of abortion or stillbirth. 
 
Human IgG1 immunoglobulins are known to cross the placental barrier. Therefore, avelumab has the 
potential to be transmitted from the mother to the developing foetus. It is not recommended to use 
avelumab during pregnancy unless the clinical condition of the woman requires treatment with 
avelumab. 
 



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Breast-feeding 
It is unknown whether avelumab is excreted in human milk. Since it is known that antibodies can be 
secreted in human milk, a risk to the newborns/infants cannot be excluded. 
 
Breast-feeding women should be advised not to breast-feed during treatment and for at least 1 month 
after the last dose due to the potential for serious adverse reactions in breast-fed infants. 
 
Fertility 
The effect of avelumab on male and female fertility is unknown. 
 
Although studies to evaluate the effect of avelumab on fertility have not been conducted, there were 
no notable effects in the female reproductive organs in monkeys based on 1-month and 3-month 
repeat-dose toxicity studies (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Avelumab has negligible influence on the ability to drive and use machines. Fatigue has been reported 
following administration of avelumab (see section 4.8). Patients should be advised to use caution when 
driving or operating machinery until they are certain that avelumab does not adversely affect them. 
 
4.8 Undesirable effects 
 
Avelumab is most frequently associated with immune-related adverse reactions. Most of these, 
including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal 
of avelumab (see “Description of selected adverse reactions” below). 
 
Merkel cell carcinoma 
 
Summary of the safety profile 
The safety of avelumab as monotherapy has been evaluated in 1,738 patients with solid tumours 
including metastatic MCC receiving 10 mg/kg every 2 weeks of avelumab in clinical studies. In this 
patient population, the most common adverse reactions with avelumab were fatigue (32.4%), nausea 
(25.1%), diarrhoea (18.9%), decreased appetite (18.4%), constipation (18.4%), infusion-related 
reactions (17.1%), weight decreased (16.6%), and vomiting (16.2%). 
 
The most common Grade ≥ 3 adverse reactions were anaemia (6.0%), dyspnoea (3.9%), and 
abdominal pain (3.0%). Serious adverse reactions were immune-related adverse reactions and 
infusion-related reaction (see section 4.4). 
 
Tabulated list of adverse reactions 
Adverse reactions reported for 88 patients with metastatic MCC and for 1,650 patients in a phase I 
study in solid tumours are presented in Table 2. In both studies, avelumab was administered at 
10 mg/kg every 2 weeks. 
 
These reactions are presented by system organ class and 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. 
 



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Table 2: Adverse reactions in patients treated with avelumab as monotherapy in clinical study 
EMR100070-003 and adverse reactions from a phase I study (EMR100070-001) in solid tumours 
 
Frequency Adverse reactions 
Blood and lymphatic system disorders 
Very common Anaemia 
Common Lymphopenia 
Uncommon Thrombocytopenia, eosinophilia§ 
Immune system disorders 
Uncommon Drug hypersensitivity, hypersensitivity anaphylactic reaction, Type I 

hypersensitivity 
Endocrine disorders 
Common Hypothyroidism* 
Uncommon Adrenal insufficiency*, hyperthyroidism*, thyroiditis*, autoimmune 

thyroiditis*, adrenocortical insufficiency acute*, autoimmune 
hypothyroidism*, hypopituitarism* 

Metabolism and nutrition disorders 
Very common Decreased appetite 
Uncommon Diabetes mellitus*, Type 1 diabetes mellitus* 
Nervous system disorders 
Common Headache, dizziness, neuropathy peripheral 
Uncommon Guillain-Barré Syndrome* 
Eye disorders 
Uncommon Uveitis* 
Cardiac disorders 
Rare Myocarditis* 
Vascular disorders 
Common Hypertension, hypotension 
Uncommon Flushing 
Respiratory, thoracic and mediastinal disorders 
Very common Cough, dyspnoea 
Common Pneumonitis* 
Gastrointestinal disorders 
Very common Nausea, diarrhoea, constipation, vomiting, abdominal pain 
Common Dry mouth 
Uncommon Colitis*, autoimmune colitis*, enterocolitis*, ileus 
Rare Pancreatitis* 
Hepatobiliary disorders 
Uncommon Autoimmune hepatitis*, acute hepatic failure*, hepatic failure*, hepatitis* 
Skin and subcutaneous tissue disorders 
Common Rash*, pruritus*, rash maculo-papular*, dry skin 
Uncommon Rash pruritic*, erythema*, rash generalised*, psoriasis*, rash 

erythematous*, rash macular*, rash papular*, dermatitis exfoliative*, 
erythema multiforme*, pemphigoid*, pruritus generalised*, eczema, 
dermatitis 

Musculoskeletal and connective tissue disorders 
Very common Back pain, arthralgia 
Common Myalgia 
Uncommon Myositis* 
Renal and urinary disorders 
Uncommon Tubulo-interstitial nephritis* 
General disorders and administrative site conditions 
Very common Fatigue, pyrexia, oedema peripheral 
Common Asthenia, chills, influenza like illness 
Uncommon Systemic inflammatory response syndrome* 



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Frequency Adverse reactions 
Investigations 
Very common Weight decreased 
Common Gamma-glutamyltransferase increased, blood alkaline phosphatase 

increased, amylase increased, lipase increased, blood creatinine increased 
Uncommon Alanine aminotransferase (ALT) increased*, aspartate aminotransferase 

(AST) increased*, blood creatine phosphokinase increased*, 
transaminases increased* 

Injury, poisoning and procedural complications 
Very common Infusion related reaction 
* Immune-related adverse reaction based on medical review 
§ Reaction only observed from study EMR 100070-003 (Part B) after the data cut-off of the pooled analysis, 
hence frequency estimated 
 
Renal cell carcinoma 
 
Summary of the safety profile 
The safety of avelumab in combination with axitinib has been evaluated in 489 patients with advanced 
RCC receiving 10 mg/kg avelumab every 2 weeks and axitinib 5 mg orally twice daily in two clinical 
studies.  
 
In this patient population, the most common adverse reactions were diarrhoea (62.8%), hypertension 
(49.3%), fatigue (42.9%), nausea (33.5%), dysphonia (32.7%), decreased appetite (26.0%), 
hypothyroidism (25.2%), cough (23.7%), headache (21.3%), dyspnoea (20.9%), and arthralgia 
(20.9%). 
 
Tabulated list of adverse reactions 
Adverse reactions reported for 489 patients with advanced RCC treated in two clinical studies with 
avelumab in combination with axitinib are presented in Table 3. 
 
These reactions are presented by system organ class and 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. 
 
Table 3: Adverse reactions in patients treated with avelumab in combination with axitinib in 
clinical studies B9991002 and B9991003 
 

Frequency Adverse reactions 
Infections and infestations 
Uncommon Rash pustular 
Blood and lymphatic system disorders 
Common Anaemia, thrombocytopenia 
Uncommon Lymphopenia, eosinophilia 
Immune system disorders 
Common Hypersensitivity 
Endocrine disorders 
Very common Hypothyroidism 
Common Hyperthyroidism, adrenal insufficiency, thyroiditis 
Uncommon Autoimmune thyroiditis, hypophysitis 
Metabolism and nutrition disorders 
Very common Decreased appetite 
Common Hyperglycaemia 
Uncommon Diabetes mellitus, Type 1 diabetes mellitus 
Nervous system disorders 
Very common Headache, dizziness 



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Frequency Adverse reactions 
Common Neuropathy peripheral 
Cardiac disorders 
Uncommon Myocarditis 
Vascular disorders 
Very common Hypertension 
Common Hypotension, flushing 
Respiratory, thoracic and mediastinal disorders 
Very common Dysphonia, cough, dyspnoea 
Common Pneumonitis 
Gastrointestinal disorders 
Very common Diarrhoea, nausea, constipation, vomiting, abdominal pain 
Common Dry mouth, colitis 
Uncommon Autoimmune colitis, autoimmune pancreatitis, enterocolitis, ileus, 

pancreatitis necrotizing 
Hepatobiliary disorders 
Common Hepatic function abnormal 
Uncommon Hepatitis, hepatotoxicity, immune-mediated hepatitis, liver disorder 
Skin and subcutaneous tissue disorders 
Very common Rash, pruritus 
Common Rash pruritic, rash maculo-papular, pruritus generalized, dermatitis 

acneiform, erythema, rash macular, rash papular, rash erythematous, 
dermatitis, eczema, rash generalized 

Uncommon Drug eruption, erythema multiforme, psoriasis 
Musculoskeletal and connective tissue disorders 
Very common Arthralgia, back pain, myalgia 
Renal and urinary disorders 
Common Acute kidney injury 
General disorders and administrative site conditions 
Very common Fatigue, chills, asthenia, pyrexia 
Common Oedema peripheral, influenza like illness 
Investigations 
Very common Weight decreased, alanine aminotransferase (ALT) increased, aspartate 

aminotransferase (AST) increased 
Common Blood creatinine increased, amylase increased, lipase increased, 

gamma-glutamyltransferase increased, blood alkaline phosphatase 
increased, blood creatine phosphokinase increased, blood thyroid 
stimulating hormone decreased, transaminases increased 

Uncommon Liver function test increased 
Injury, poisoning and procedural complications 
Very common Infusion related reaction 

 
Description of selected adverse reactions 
Data for immune-related adverse reactions for avelumab as a monotherapy are based on 1,650 patients 
in the phase I study EMR100070-001 in solid tumours and 88 patients in study EMR100070-003, and 
for avelumab in combination with axitinib are based on 489 patients in study B9991002 and 
B9991003 (see section 5.1). 
 
The management guidelines for these adverse reactions are described in section 4.4. 
 
Immune-related pneumonitis 
In patients treated with avelumab as monotherapy, 1.2% (21/1,738) of patients developed 
immune-related pneumonitis. Of these patients, there was 1 (0.1%) patient with a fatal outcome, 
1 (0.1%) patient with Grade 4, and 5 (0.3%) patients with Grade 3 immune-related pneumonitis. 
 



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The median time to onset of immune-related pneumonitis was 2.5 months (range: 3 days to 
11 months). The median duration was 7 weeks (range: 4 days to more than 4 months). 
 
Avelumab was discontinued in 0.3% (6/1,738) of patients due to immune-related pneumonitis. All 
21 patients with immune-related pneumonitis were treated with corticosteroids and 17 (81%) of the 
21 patients were treated with high-dose corticosteroids for a median of 8 days (range: 1 day to 
2.3 months). Immune-related pneumonitis resolved in 12 (57%) of the 21 patients at the time of data 
cut-off. 
 
In patients treated with avelumab in combination with axitinib, 0.6% (3/489) of patients developed 
immune-related pneumonitis. Of these patients, none experienced immune-related pneumonitis 
Grade ≥ 3. 
 
The median time to onset of immune-related pneumonitis was 3.7 months (range: 2.7 months to 
8.6 months). The median duration was 2.6 months (range: 3.3 weeks to more than 7.9 months). 
 
Immune-related pneumonitis did not lead to discontinuation of avelumab in any patient. All 3 patients 
with immune-related pneumonitis were treated with high-dose corticosteroids for a median of 
3.3 months (range: 3 weeks to 22.3 months). Immune-related pneumonitis resolved in 2 (66.7%) of the 
3 patients at the time of data cut-off. 
 
Immune-related hepatitis 
In patients treated with avelumab as monotherapy, 0.9% (16/1,738) of patients developed 
immune-related hepatitis. Of these patients, there were 2 (0.1%) patients with a fatal outcome, and 
11 (0.6%) patients with Grade 3 immune-related hepatitis. 
 
The median time to onset of immune-related hepatitis was 3.2 months (range: 1 week to 15 months). 
The median duration was 2.5 months (range: 1 day to more than 7.4 months). 
 
Avelumab was discontinued in 0.5% (9/1,738) of patients due to immune-related hepatitis. All 
16 patients with immune-related hepatitis treated with corticosteroids and 15 (94%) of the 16 patients 
received high-dose corticosteroids for a median of 14 days (range: 1 day to 2.5 months). 
Immune-related hepatitis resolved in 9 (56%) of the 16 patients at the time of data cut-off. 
 
In patients treated with avelumab in combination with axitinib, 6.3% (31/489) of patients developed 
immune-related hepatitis. Of these patients, there were 18 (3.7%) patients with Grade 3 and 3 (0.6%) 
patients with Grade 4 immune-related hepatitis. 
 
The median time to onset of immune-related hepatitis was 2.3 months (range: 2.1 weeks to 
14.5 months). The median duration was 2.1 weeks (range: 2 days to 8.9 months). 
 
Avelumab was discontinued in 4.7% (23/489) of patients due to immune-related hepatitis. All 
31 patients with immune-related hepatitis were treated for hepatitis including 30 (96.8%) patients 
treated with corticosteroids and 1 patient with a non-steroidal immunosuppressant. Twenty-eight 
(90.3%) of the 31 patients received high dose corticosteroids for a median of 2.4 weeks (range: 1 day 
to 10.2 months). Immune-related hepatitis resolved in 27 (87.1%) of the 31 patients at the time of data 
cut-off. 
 
Immune-related colitis 
In patients treated with avelumab as monotherapy, 1.5% (26/1,738) of patients developed 
immune-related colitis. Of these patients, there were 7 (0.4%) patients with Grade 3 immune-related 
colitis. 
 
The median time to onset of immune-related colitis was 2.1 months (range: 2 days to 11 months). The 
median duration was 6 weeks (range: 1 day to more than 14 months). 
 



14 

Avelumab was discontinued in 0.5% (9/1,738) of patients due to immune-related colitis. All 
26 patients with immune-related colitis were treated with corticosteroids and 15 (58%) of the 
26 patients received high-dose corticosteroids for a median of 19 days (range: 1 day to 2.3 months). 
Immune-related colitis resolved in 18 (70%) of 26 patients at the time of data cut-off. 
 
In patients treated with avelumab in combination with axitinib, 2.7% (13/489) of patients developed 
immune-related colitis. Of these patients, there were 9 (1.8%) patients with Grade 3 immune-related 
colitis. 
 
The median time to onset of immune-related colitis was 5.1 months (range: 2.3 weeks to 14 months). 
The median duration was 1.6 weeks (range: 1 day to more than 9 months). 
 
Avelumab was discontinued in 0.4% (2/489) of patients due to immune-related colitis. All 13 patients 
with immune-related colitis were treated with corticosteroids and 12 (92.3%) of the 13 patients 
received high-dose corticosteroids for a median of 2.3 weeks (range: 5 days to 4.6 months). 
Immune-related colitis resolved in 10 (76.9%) of 13 patients at the time of data cut-off. 
 
Immune-related pancreatitis 
In patients treated with avelumab as monotherapy, immune-related pancreatitis occurred in less than 
1% (1/4,000) of patients across clinical trials in multiple tumour types and in 0.6% (3/489) of patients 
receiving avelumab in combination with axitinib including 2 (0.4%) patients with fatal outcome. 
 
Immune-related myocarditis 
In patients treated with avelumab as monotherapy, immune-related myocarditis occurred in less than 
1% (5/4,000) of patients across clinical trials in multiple tumour types and in 0.6% (3/489) of patients 
receiving avelumab in combination with axitinib including 2 (0.4%) patients with fatal outcome. 
 
Immune-related endocrinopathies 
Thyroid disorders 
In patients treated with avelumab as monotherapy, 6% (98/1,738) of patients developed 
immune-related thyroid disorders, including 90 (5%) patients with hypothyroidism, 7 (0.4%) with 
hyperthyroidism, and 4 (0.2%) with thyroiditis. Of these patients, there were 3 (0.2%) patients with 
Grade 3 immune-related thyroid disorders. 
 
The median time to onset of thyroid disorders was 2.8 months (range: 2 weeks to 13 months). The 
median duration was not estimable (range: 1 day to more than 26 months). 
 
Avelumab was discontinued in 0.1% (2/1,738) of patients due to immune-related thyroid disorders. 
Thyroid disorders resolved in 7 (7%) of the 98 patients at the time of data cut-off. 
 
In patients treated with avelumab in combination with axitinib, 24.7% (121/489) of patients developed 
immune-related thyroid disorders, including 111 (22.7%) patients with hypothyroidism, 17 (3.5%) 
with hyperthyroidism, and 7 (1.4%) with thyroiditis. Of these patients, there were 2 (0.4%) patients 
with Grade 3 immune-related thyroid disorders. 
 
The median time to onset of thyroid disorders was 2.8 months (range: 3.6 weeks to 19.3 months). The 
median duration was not estimable (range: 8 days to more than 23.9 months). 
 
Avelumab was discontinued in 0.2% (1/489) of patients due to immune-related thyroid disorders. 
Thyroid disorders resolved in 15 (12.4%) of the 121 patients at the time of data cut-off. 
 
Adrenal insufficiency 
In patients treated with avelumab as monotherapy, 0.5% (8/1,738) of patients developed 
immune-related adrenal insufficiency. Of these patients, there was 1 (0.1%) patient with Grade 3 
immune-related adrenal insufficiency. 
 



15 

The median time to onset of immune-related adrenal insufficiency was 2.5 months (range: 1 day to 
8 months). The median duration was not estimable (range: 2 days to more than 6 months). 
 
Avelumab was discontinued in 0.1% (2/1,738) of patients due to immune-related adrenal 
insufficiency. All 8 patients with immune-related adrenal insufficiency were treated with 
corticosteroids, 4 (50%) of the 8 patients received high-dose systemic corticosteroids (≥ 40 mg 
prednisone or equivalent) followed by a taper for a median of 1 day (range: 1 day to 24 days). Adrenal 
insufficiency resolved in 1 patient with corticoid treatment at the time of data cut-off. 
 
In patients treated with avelumab in combination with axitinib, 1.8% (9/489) of patients developed 
immune-related adrenal insufficiency. Of these patients, there were 2 (0.4%) patients with Grade 3 
immune-related adrenal insufficiency. 
 
The median time to onset of immune-related adrenal insufficiency was 5.5 months (range: 3.6 weeks 
to 8.7 months). The median duration was 2.8 months (range: 3 days to more than 15.5 months). 
 
Immune-related adrenal insufficiency did not lead to discontinuation of avelumab in any patient. Eight 
(88.9%) patients with immune-related adrenal insufficiency were treated with corticosteroids and 2 
(25%) of the 8 patients received high-dose corticosteroids (≥ 40 mg prednisone or equivalent) for a 
median of 8 days (range: 5 days to 11 days). Adrenal insufficiency resolved in 4 (44.4%) of the 
9 patients at the time of data cut-off. 
 
Type 1 diabetes mellitus 
In patients treated with avelumab as monotherapy, Type 1 diabetes mellitus without an alternative 
aetiology occurred in 0.1% (2/1,738) of patients including two Grade 3 reactions that led to permanent 
discontinuation of avelumab. 
 
In patients treated with avelumab in combination with axitinib, Type 1 diabetes mellitus without an 
alternative aetiology occurred in 1.0% (5/489) of patients. Of these patients, there was 1 (0.2%) patient 
with Grade 3 Type 1 diabetes mellitus. 
 
The median time to onset of Type 1 diabetes mellitus was 1.9 months (range: 1.1 months to 
7.3 months). 
 
Avelumab was discontinued in 0.2% (1/489) of patients due to Type 1 diabetes mellitus. All 5 patients 
with Type 1 diabetes mellitus were treated with insulin. Type 1 diabetes mellitus did not resolve in any 
of the patients at the time of data cut-off. 
 
Immune-related nephritis and renal dysfunction 
In patients treated with avelumab as monotherapy, immune-related nephritis occurred in 0.1% 
(1/1,738) of patients receiving avelumab leading to permanent discontinuation of avelumab. 
 
In patients treated with avelumab in combination with axitinib, immune-related nephritis occurred in 
0.4% (2/489) of patients. Of these patients, there were 2 (0.4%) patients with Grade 3 immune-related 
nephritis. 
 
The median time to onset of immune-related nephritis was 1.2 months (range: 2.9 weeks to 
1.8 months). The median duration was 1.3 weeks (range: more than 4 days to 1.3 weeks). 
 
Immune-related nephritis did not lead to discontinuation of avelumab in any patient. All 2 patients 
with immune-related nephritis were treated with high-dose corticosteroids for a median of 1.1 weeks 
(range: 3 days to 1.9 weeks). Immune-related nephritis resolved in 1 (50%) of the 2 patients at the time 
of data cut-off. 
 



16 

Hepatotoxicity (in combination with axitinib) 
In patients treated with avelumab in combination with axitinib, Grades 3 and Grade 4 increased ALT 
and increased AST were reported in 9% and 7% of patients, respectively. 
 
In patients with ALT ≥ 3 times ULN (Grades 2-4, n=82), ALT resolved to Grades 0-1 in 92%. 
 
Among the 73 patients who were rechallenged with either avelumab (59%) or axitinib (85%) 
monotherapy or with both (55%), 66% had no recurrence of ALT ≥ 3 times ULN. 
 
Immunogenicity 
Of 1,738 patients treated with avelumab 10 mg/kg as an intravenous infusion every 2 weeks, 
1,627 were evaluable for treatment-emergent anti-drug antibodies (ADA) and 96 (5.9%) tested 
positive. In ADA positive patients, there may be an increased risk for infusion-related reactions (about 
40% and 25% in ADA ever-positive and ADA never-positive patients, respectively). Based on data 
available, including the low incidence of immunogenicity, the impact of ADA on pharmacokinetics, 
efficacy and safety is uncertain, while the impact of neutralizing antibodies (nAb) is unknown. 
 
Of the 480 patients with at least one valid ADA result at any time point treated with avelumab 
10 mg/kg as an intravenous infusion every 2 weeks in combination with axitinib 5 mg twice daily, 453 
were evaluable for treatment-emergent ADA and 66 (14.6%) tested positive. A new ADA method with 
improved sensitivity and drug tolerance was used in the RCC population. Overall, there was no 
evidence of altered pharmacokinetic profile, increased incidence of infusion reactions or effects on 
efficacy with anti-avelumab antibody development. 
 
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. 
 
4.9 Overdose 
 
Three patients were reported to be overdosed with 5% to 10% above the recommended dose of 
avelumab. The patients had no symptoms, did not require any treatment for the overdose, and 
continued on avelumab therapy. 
 
In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions. 
The treatment is directed to the management of symptoms. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other antineoplastic agents, monoclonal antibodies, ATC code: 
L01XC31. 
 
Mechanism of action 
Avelumab is a human immunoglobulin G1 (IgG1) monoclonal antibody directed against programmed 
death ligand 1 (PD-L1). Avelumab binds PD-L1 and blocks the interaction between PD-L1 and the 
programmed death 1 (PD-1) and B7.1 receptors. This removes the suppressive effects of PD-L1 on 
cytotoxic CD8+ T-cells, resulting in the restoration of anti-tumour T-cell responses. Avelumab has also 
shown to induce natural killer (NK) cell-mediated direct tumour cell lysis via antibody-dependent 
cell-mediated cytotoxicity (ADCC). 
 

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


17 

Clinical efficacy and safety 
 
Merkel cell carcinoma (study EMR100070-003) 
The efficacy and safety of avelumab was investigated in the single arm, multi-centre study 
EMR100070-003 with two parts. Part A was conducted in patients with histologically confirmed 
metastatic MCC, whose disease had progressed on or after chemotherapy administered for distant 
metastatic disease, with a life expectancy of more than 3 months. Part B included patients with 
histologically confirmed metastatic MCC who were treatment-naïve to systemic therapy in the 
metastatic setting. 
 
Patients with active or a history of central nervous system (CNS) metastasis; active or a history of 
autoimmune disease; a history of other malignancies within the last 5 years; organ transplant; 
conditions requiring therapeutic immune suppression or active infection with HIV, or hepatitis B or C 
were excluded. 
 
Patients received avelumab at a dose of 10 mg/kg every 2 weeks until disease progression or 
unacceptable toxicity. Patients with radiological disease progression not associated with significant 
clinical deterioration, defined as no new or worsening symptoms, no change in performance status for 
greater than two weeks, and no need for salvage therapy could continue treatment. 
 
Tumour response assessments were performed every 6 weeks, as assessed by an Independent Endpoint 
Review Committee (IERC) using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. 
 
Study 003 Part A – previously-treated patients 
The major efficacy outcome measure was confirmed best overall response (BOR); secondary efficacy 
outcome measures included duration of response (DOR), progression-free survival (PFS), and overall 
survival (OS). 
 
An efficacy analysis was conducted in all 88 patients after a minimum follow-up of 36 months. Patients 
received a median of 7 doses of avelumab (range: 1 dose to 95 doses), and the median duration of 
treatment was 17 weeks (range: 2 weeks to 208 weeks). 
 
Of the 88 patients, 65 (74%) were male, the median age was 73 years (range 33 years to 88 years), 
81 (92%) patients were Caucasian, and 49 (56%) patients and 39 (44%) patients with an Eastern 
Cooperative Oncology Group (ECOG) performance status 0 and 1, respectively. 
 
Overall, 52 (59%) patients were reported to have had 1 prior anti-cancer therapy for MCC, 26 (30%) 
with 2 prior therapies, and 10 (11%) with 3 or more prior therapies. Forty-seven (53%) of the patients 
had visceral metastases. 
 
Table 4 summarises efficacy endpoints in patients receiving avelumab at the recommended dose for 
study EMR100070-003, Part A with a minimum follow-up of 36 months. Overall survival was 
evaluated in an analysis with a minimum follow-up of 44 months. The median OS was 12.6 months 
(95% CI 7.5, 17.1). 
 



18 

Table 4: Response to avelumab 10 mg/kg every 2 weeks in patients with metastatic MCC in study 
EMR100070-003 (Part A)* 
 

Efficacy endpoints (Part A) 
(per RECIST v1.1, IERC) 

Results 
(N=88) 

Objective response rate (ORR) 
 Response rate, CR+PR** n (%) 
 (95% CI) 

 
29 (33.0%) 
(23.3, 43.8) 

Confirmed best overall response (BOR) 
 Complete response (CR)** n (%) 
 Partial response (PR)** n (%) 

 
10 (11.4%) 
19 (21.6%) 

Duration of response (DOR)a 
 Median, months 
 (95% CI) 
 Minimum, maximum (months) 
 ≥ 6 months by K-M, (95% CI) 
 ≥ 12 months by K-M, (95% CI) 
 ≥ 24 months by K-M, (95% CI) 
 ≥ 36 months by K-M, (95% CI) 

 
40.5 

(18, not estimable) 
2.8, 41.5+ 

93% (75, 98) 
71% (51, 85) 
67% (47, 82) 
52% (26, 73) 

Progression-free survival (PFS) 
 Median PFS, months 
 (95% CI) 
 6-month PFS rate by K-M, (95% CI) 
 12-month PFS rate by K-M, (95% CI) 
 24-month PFS rate by K-M, (95% CI) 
 36-month PFS rate by K-M, (95% CI) 

 
2.7 

(1.4, 6.9) 
40% (29, 50) 
29% (19, 39) 
26% (17, 36) 
21% (12, 32) 

CI: Confidence interval; RECIST: Response Evaluation Criteria in Solid Tumours; IERC: 
Independent Endpoint Review Committee; K-M: Kaplan-Meier; +denotes a censored value 
* Efficacy data with a minimum follow-up of 36 months (cut-off date 14 September 2018) 
** CR or PR was confirmed at a subsequent tumour assessment 
a Based on number of patients with confirmed response (CR or PR) 

 
The median time to response was 6 weeks (range: 6 weeks to 36 weeks) after the first dose of 
avelumab. Twenty-two out of 29 (76%) patients with response were reported to have responded within 
7 weeks after the first dose of avelumab. 
 
The Kaplan-Meier curve of PFS of the 88 patients (Part A) with metastatic MCC is presented in 
Figure 1. 
 



19 

Figure 1: Kaplan-Meier estimates of progression-free survival (PFS) per RECIST v1.1, IERC 
(Part A, minimum follow-up of 36 months) 
 

 
 
Tumour samples were evaluated for PD-L1 tumour cell expression, and for Merkel cell polyomavirus 
(MCV) using an investigational immunohistochemistry (IHC) assay. Table 5 summarises the objective 
response rates by the PD-L1 expression and MCV status of patients with metastatic MCC in study 
EMR100070-003 (Part A). 
 
Table 5: Objective response rates by PD-L1 expression and MCV tumour status in patients with 
metastatic MCC in study EMR100070-003 (Part A) 
 

 Avelumab 
ORR (95% CI)* 

PD-L1 expression at cut-off of ≥ 1% N=74a 
 Positive (n=58) 36.2% (24.0, 49.9) 
 Negative (n=16) 18.8% (4.0, 45.6) 
IHC-MCV tumour status N=77b 
 Positive (n=46) 28.3% (16.0, 43.5) 
 Negative (n=31) 35.5% (19.2, 54.6) 

IHC: Immunohistochemistry; MCV: Merkel cell polyomavirus; ORR: objective response rate 
* ORR (cut-off date 14 September 2018) 
a Based on data from patients evaluable for PD-L1 
b Based on data from patients evaluable for MCV by immunohistochemistry (IHC) 

 
Study 003 Part B – patients who have not received systemic therapy in the metastatic setting 
The major efficacy outcome measure was durable response, defined as objective response (complete 
response (CR) or partial response (PR)) with a duration of at least 6 months; secondary outcome 
measures included BOR, DOR, PFS, and OS. 
 
The primary analysis for Part B included 116 patients who received at least one dose of avelumab with 
a minimum follow-up of 15 months at the time of the data cut-off (cut-off date 02 May 2019). 
 
Of the 116 patients, 81 (70%) were male, the median age was 74 years (range: 41 to 93 years), 75 
(65%) were white, and 72 (62%) and 44 (38%) had an ECOG performance status of 0 and 1 
respectively.  
 

# At Risk
088 43 32 30 27 24 21 20 20 20 20 17 15 14 10 10 10 8 5 2 2 2 1

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0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Progression Free Survival by IERC (months) 

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48

Product-Limit Survival Estimate (N=88)



20 

Table 6 summarises the primary analysis of efficacy endpoints including an estimate of the 24-month 
rates by Kaplan-Meier for DOR, and PFS in patients receiving avelumab at the recommended dose for 
study EMR100070-003, Part B. 
 
Table 6: Primary analysis of response to avelumab 10 mg/kg every 2 weeks in patients with 
metastatic MCC in study EMR100070-003 (Part B)* 
 

Efficacy endpoints (Part B) 
(per RECIST v1.1, IERC) 

Results 
(N=116) 

Durable response 
 ≥ 6 months 
 (95% CI) 

 
30.2% 

(22.0, 39.4) 
Objective response rate (ORR) 
 Response rate, CR+PR** n (%) 
 (95% CI) 

 
46 (39.7%) 
(30.7, 49.2) 

Confirmed best overall response (BOR) 
 Complete response (CR)** n (%) 
 Partial response (PR)** n (%) 

 
19 (16.4%) 
27 (23.3%) 

Duration of response (DOR)a 
 Median, months 
 (95% CI) 
 Minimum, maximum (months) 
 ≥ 3 months by K-M, (95% CI) 
 ≥ 6 months by K-M, (95% CI) 
 ≥ 12 months by K-M, (95% CI) 
 ≥ 18 months by K-M, (95% CI) 
 ≥ 24 months by K-M, (95% CI) 

 
18.2 

(11.3, not estimable) 
1.2, 28.3 

89% (75, 95) 
78% (63, 87) 
66% (50, 78) 
52% (34, 67) 
45% (25, 63) 

Progression-free survival (PFS) 
 Median PFS, months 
 (95% CI) 
 3-month PFS rate by K-M, (95% CI) 
 6-month PFS rate by K-M, (95% CI) 
 12-month PFS rate by K-M, (95% CI) 
 24-month PFS rate by K-M, (95% CI) 

 
4.1 

(1.4, 6.1) 
51% (42, 60) 
41% (32, 50) 
31% (23, 40) 
20% (12, 30) 

CI: Confidence interval; RECIST: Response Evaluation Criteria in Solid Tumours; IERC: 
Independent Endpoint Review Committee; K-M: Kaplan-Meier 
* Efficacy data with a minimum follow-up of 15 months (cut-off date 02 May 2019) 
** CR or PR was confirmed at a subsequent tumour assessment 
a Based on number of patients with confirmed response (CR or PR) 

 
Figure 2 presents the Kaplan-Meier curve for PFS from the primary analysis with 116 patients 
enrolled into Part B with a minimum follow-up of 15 months. 
 



21 

Figure 2: Kaplan-Meier estimates of progression-free survival (PFS) per RECIST v1.1, IERC 
(Part B, N=116) 
 

 
 
Tumour samples were evaluated for PD-L1 tumour cell expression, and for MCV using an 
investigational IHC assay. Table 7 summarises the objective response rates by PD-L1 expression and 
MCV status of patients with metastatic MCC in study EMR100070-003 (Part B). 
 
Table 7: Objective response rates by PD-L1 expression and MCV tumour status in patients with 
metastatic MCC in study EMR100070-003 (Part B) 
 

 Avelumab 
ORR (95% CI)* 

PD-L1 expression at cut-off of ≥ 1% N=108a 
 Positive (n=21) 61.9% (38.4, 81.9) 
 Negative (n=87) 33.3% (23.6, 44.3) 
IHC-MCV tumour status N=107b 
 Positive (n=70) 34.3% (23.3, 46.6) 
 Negative (n=37) 48.6% (31.9, 65.6) 

IHC: Immunohistochemistry; MCV: Merkel cell polyomavirus; ORR: objective response rate 
* ORR (cut-off date 02 May 2019) 
a Based on data from patients evaluable for PD-L1 
b Based on data from patients evaluable for MCV by IHC 

 
Renal cell carcinoma (study B9991003) 
The efficacy and safety of avelumab in combination with axitinib was demonstrated in study 
B9991003, a randomised, multicentre, open-label study of avelumab in combination with axitinib in 
886 patients with untreated advanced or metastatic RCC with a clear-cell component. 
 
Patients were included irrespective of prognostic risk groups or tumour PD-L1 expression and had to 
have at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumours 
(RECIST) version 1.1 that was not been previously irradiated. Patients with prior systemic therapy 
directed at advanced or metastatic RCC; prior systemic immunotherapy treatment with IL-2, IFN-α, 
anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies, or active brain metastasis; active autoimmune 
disease that might deteriorate when receiving an immunostimulatory agents; a history of other 
malignancies within the last 5 years; organ transplant were ineligible. 
 

# At Risk
0116 60 56 45 39 24 18 10 8 5 4 3

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0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Progression Free Survival by IERC (months) 

0 2 4 6 8 10 12 14 16 18 20 22 24

Product-Limit Survival Estimate (N=116)



22 

Randomization was stratified according to Eastern Cooperative Oncology Group (ECOG) 
Performance Status (PS) (0 vs. 1) and region (United States vs. Canada/Western Europe vs. the rest of 
the world). Patients were randomised (1:1) to one of the following treatment arms: 
• Avelumab 10 mg/kg intravenous infusion every 2 weeks in combination with axitinib 5 mg 

twice daily orally (N=442). Patients who tolerated axitinib 5 mg twice daily without Grade 2 or 
greater axitinib-related adverse events for 2 consecutive weeks could increase to 7 mg and then 
subsequently to 10 mg twice daily. Axitinib could be interrupted or reduced to 3 mg twice daily 
and subsequently to 2 mg twice daily to manage toxicity. 

• Sunitinib 50 mg once daily orally for 4 weeks followed by 2 weeks off (N=444) until 
radiographic or clinical progression or unacceptable toxicity. 

 
Treatment with avelumab and axitinib continued until RECIST v1.1-defined progression of disease by 
Blinded Independent Central Review (BICR) assessment or unacceptable toxicity. Administration of 
avelumab and axitinib was permitted beyond RECIST-defined disease progression based on 
investigator’s assessment of the patient’s benefit-risk and clinical condition, including performance 
status, clinical symptoms, adverse events and laboratory data. The majority (n=160, 71.4%) of the 
patients with progressive disease continued treatment with both medicinal products after progression. 
Assessment of tumour status was performed at baseline, after randomisation at 6 weeks, then every 
6 weeks thereafter up to 18 months after randomisation, and every 12 weeks thereafter until 
documented confirmed disease progression by BICR. 
 
The primary efficacy endpoints were progression-free survival (PFS), as assessed by BICR using 
RECIST v1.1 and overall survival (OS) in the first-line treatment of patients with advanced RCC who 
have PD-L1-positive tumours (PD-L1 expression level ≥ 1%). The key secondary endpoints were PFS 
based on BICR assessment per RECIST v1.1 and OS irrespective of PD-L1 expression. PD-L1 status 
was determined by immunohistochemistry. Additional secondary endpoints included objective 
response (OR), time to response (TTR) and duration of response (DOR). 
 
The study population characteristics were: median age of 61 years (range: 27.0 to 88.0), 38% of patients 
were 65 years or older, 75% were male, 75% were White, and the ECOG performance score was 0 
(63%) or 1 (37%). 
 
Patient distribution by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) 
risk groups was 21% favourable, 62% intermediate, and 16% poor. Patient distribution by Memorial 
Sloan–Kettering Cancer Center (MSKCC) risk groups was 22% favourable, 65% intermediate, and 
11% poor. 
 
Efficacy results are presented in Table 8 and Figure 3 based on a data cut-off date of 28 January 2019. 
With a median OS follow-up of 19 months, OS data were immature with 27% deaths. The observed 
hazard ratio (HR) for OS was 0.80 (95% CI: 0.616, 1.027) for avelumab in combination with axitinib 
compared to sunitinib. 
 



23 

Table 8: Efficacy results from study B9991003 in patients irrespective of PD-L1 expression 
 

Efficacy endpoints 
(Based on BICR assessment) 

Avelumab plus axitinib 
(N=442) 

Sunitinib 
(N=444) 

Progression-free survival (PFS)   
 Events (%) 229 (52) 258 (58) 
 Median in months (95% CI) 13.3 (11.1, 15.3) 8.0 (6.7, 9.8) 
 Hazard ratio (95% CI) 0.69 (0.574, 0.825) 
 p-value* < 0.0001 
 12-month PFS rate by K-M, (95% CI)** 52.4% (47.4, 57.2) 39.2% (34.1, 44.2) 
 18-month PFS rate by K-M, (95% CI)** 43.9% (38.8, 49.0) 29.3% (24.2, 34.6) 
Confirmed objective response rate (ORR)   
 Objective response rate (ORR) n (%) 232 (52.5) 121 (27.3) 
 (95% CI) 47.7, 57.2 23.2, 31.6 
 Complete response (CR) n (%) 17 (3.8) 9 (2.0) 
 Partial response (PR) n (%) 215 (48.6) 112 (25.2) 
Time to response (TTR)   
 Median, months (range) 2.7 (1.2, 20.7) 4.0 (1.2, 18.0) 
Duration of response (DOR)   
 Median, months (95% CI) 18.5 (17.8, NE) NE (16.4, NE) 

BICR: Blinded Independent Central Review; CI: Confidence interval; NE: Not estimable. 
* 1-sided p-value based on stratified log-rank. 
** CIs are derived using the log-log transformation with back transformation to untransformed scale. 
 
Figure 3: Kaplan-Meier estimates for progression-free survival based on BICR assessment in 
patients irrespective of PD-L1 expression 
 

 
 
Improvement of PFS was observed across pre-specified subgroups. 



24 

 
Figure 4: Forest plot of progression-free survival based on BICR assessment in patients 
irrespective of PD-L1 expression 
 

 
 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Bavencio in all subsets of the paediatric population for the treatment of Merkel cell carcinoma and 
renal cell carcinoma (see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Avelumab pharmacokinetics (PK) was assessed using a population PK approach for avelumab as 
monotherapy and avelumab in combination with axitinib. 
 
Based on a population PK analysis for avelumab as monotherapy and in combination with axitinib, 
there are no expected clinically meaningful differences in exposure of avelumab between settings 
administered every 2 weeks at 800 mg or 10 mg/kg. 
 
Distribution 
Avelumab is expected to be distributed in the systemic circulation and to a lesser extent in the 
extracellular space. The volume of distribution at steady state was 4.72 L. 
 
Consistent with a limited extravascular distribution, the volume of distribution of avelumab at steady 
state is small. As expected for an antibody, avelumab does not bind to plasma proteins in a specific 
manner. 
 



25 

Elimination 
Based on a population pharmacokinetic analysis from 1,629 patients, the value of total systemic 
clearance (CL) is 0.59 L/day. In the supplemental analysis, avelumab CL was found to decrease over 
time: the largest mean maximal reduction (% coefficient of variation [CV%]) from baseline value with 
different tumour types was approximately 32.1% (CV 36.2%). 
 
Steady-state concentrations of avelumab were reached after approximately 4 to 6 weeks (2 to 3 cycles) 
of repeated dosing at 10 mg/kg every 2 weeks, and systemic accumulation was approximately 
1.25-fold. 
 
The elimination half-life (t½) at the recommended dose is 6.1 days based on the population PK 
analysis. 
 
Linearity/non-linearity 
The exposure of avelumab increased dose-proportionally in the dose range of 10 mg/kg to 20 mg/kg 
every 2 weeks. 
 
When avelumab 10 mg/kg was administered in combination with axitinib 5 mg, the respective 
exposures of avelumab and axitinib were unchanged compared to the single agents. There was no 
evidence to suggest a clinically relevant change of avelumab clearance over time in patients with 
advanced RCC. 
 
Special populations 
A population pharmacokinetic analysis suggested no difference in the total systemic clearance of 
avelumab based on age, gender, race, PD-L1 status, tumour burden, renal impairment and mild or 
moderate hepatic impairment. 
 
Total systemic clearance increases with body weight. Steady-state exposure was approximately 
uniform over a wide range of body weights (30 to 204 kg) for body weight normalised dosing. 
 
Renal impairment 
No clinically important differences in the clearance of avelumab were found between patients with 
mild (glomerular filtration rate (GFR) 60 to 89 mL/min, Cockcroft-Gault Creatinine Clearance 
(CrCL); n=623), moderate (GFR 30 to 59 mL/min, n=320) and patients with normal (GFR 
≥ 90 mL/min, n=671) renal function. 
 
Avelumab has not been studied in patients with severe renal impairment (GFR 15 to 29 mL/min). 
 
Hepatic impairment 
No clinically important differences in the clearance of avelumab were found between patients with 
mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin between 1 and 1.5 times ULN, 
n=217) and normal hepatic function (bilirubin and AST ≤ ULN, n=1,388) in a population PK analysis. 
Hepatic impairment was defined by National Cancer Institute (NCI) criteria of hepatic dysfunction. 
 
Avelumab has not been studied in patients with moderate hepatic impairment (bilirubin between 1.5 
and 3 times ULN) or severe hepatic impairment (bilirubin > 3 times ULN). 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose 
toxicity in Cynomolgus monkeys administered intravenously doses of 20, 60 or 140 mg/kg once a 
week for1 month and 3 months, followed by a 2-month recovery period after the 3-month dosing 
period. Perivascular mononuclear cell cuffing was observed in the brain and spinal cord of monkeys 
treated with avelumab at ≥ 20 mg/kg for 3 months. Although there was no clear dose-response 
relationship, it cannot be excluded that this finding was related to avelumab treatment. 
 



26 

Animal reproduction studies have not been conducted with avelumab. The PD-1/PD-L1 pathway is 
thought to be involved in maintaining tolerance to the foetus throughout pregnancy. Blockade of 
PD-L1 signalling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and 
to result in an increase in foetal loss. These results indicate a potential risk that administration of 
avelumab during pregnancy could cause foetal harm, including increased rates of abortion or stillbirth. 
 
No studies have been conducted to assess the potential of avelumab for carcinogenicity or 
genotoxicity. 
 
Fertility studies have not been conducted with avelumab. In 1-month and 3-month repeat-dose 
toxicology studies in monkeys, there were no notable effects in the female reproductive organs. Many 
of the male monkeys used in these studies were sexually immature and thus no explicit conclusions 
regarding effects on male reproductive organs can be made. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol 
Glacial acetic acid 
Polysorbate 20 
Sodium hydroxide 
Water for injections 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
Unopened vial 
2 years 
 
After opening 
From a microbiological point of view, once opened, the medicinal product should be diluted and 
infused immediately. 
 
After preparation of infusion 
Chemical and physical in-use stability of the diluted solution has been demonstrated for 24 hours at 
20°C to 25°C and room light. From a microbiological point of view, unless the method of dilution 
precludes the risk of microbial contamination, the diluted solution should be infused immediately. If 
not used immediately, in-use storage times and conditions prior to use are the responsibility of the 
user. 
 
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 dilution of the medicinal product, see section 6.3. 
 



27 

6.5 Nature and contents of container 
 
10 mL of concentrate in a vial (Type I glass) with a halobutyl rubber stopper and an aluminium seal 
fitted with a removable plastic cap. 
 
Pack size of 1 vial. 
 
6.6 Special precautions for disposal and other handling 
 
Bavencio is compatible with polyethylene, polypropylene, and ethylene vinyl acetate infusion bags, 
glass bottles, polyvinyl chloride infusion sets and in-line filters with polyethersulfone membranes with 
pore sizes of 0.2 micrometre. 
 
Handling instructions 
An aseptic technique for the preparation of the solution for infusion should be used. 
 
• The vial should be visually inspected for particulate matter and discoloration. Bavencio is a 

clear, colourless to slightly yellow solution. If the solution is cloudy, discoloured, or contains 
particulate matters, the vial should be discarded. 

• An infusion bag of appropriate size (preferably 250 mL) containing either sodium chloride 
9 mg/mL (0.9%) solution for injection or with sodium chloride 4.5 mg/mL (0.45%) solution for 
injection should be used. The required volume of Bavencio should be withdrawn from the 
vial(s) and transferred to the infusion bag. Any partially used or empty vials have to be 
discarded. 

• The diluted solution should be mixed by gently inverting the bag in order to avoid foaming or 
excessive shearing of the solution. 

• The solution should be inspected to ensure it is clear, colourless, and free of visible particles. 
The diluted solution should be used immediately once prepared. 

• Do not co-administer other medicinal products through the same intravenous line. Administer 
the solution for infusion using a sterile, non-pyrogenic, low-protein binding 0.2 micrometre 
in-line or add-on filter as described in section 4.2. 

 
After administration of Bavencio, the line should be flushed with either sodium chloride 9 mg/mL 
(0.9%) solution for injection or with sodium chloride 4.5 mg/mL (0.45%) solution for injection. 
 
Do not freeze or shake the diluted solution. If refrigerated, allow the diluted solution in the intravenous 
bags to come to room temperature prior to use. 
 
Disposal 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/17/1214/001 
 
 



28 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 18 September 2017 
Date of latest renewal: 20 June 2019 
 
 
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. 
 
  

http://www.ema.europa.eu/


29 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 

 



30 

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

 
Name and address of the manufacturer of the biological active substance 
 
Merck Serono SA 
Succursale de Corsier-sur-Vevey 
Chemin du Fenil - Zone Industrielle B 
1804 Corsier-sur-Vevey 
Switzerland 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Merck Serono S.p.A. 
Via Delle Magnolie 15 (loc. frazione Zona Industriale) 
70026 - Modugno (BA) 
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 (PSURs) 
 
The requirements for submission of PSURs 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. 
 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 
6 months following authorisation. 
 
 
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. 
 
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. 

 



31 

• Additional risk minimisation measures 
 
Prior to launch of Bavencio in each Member State the marketing authorisation holder (MAH) must 
agree about the content and format of the educational programme, including communication media, 
distribution modalities, and any other aspects of the programme, with the National Competent 
Authority. 
 
The educational programme is aimed at increasing awareness and providing information concerning 
the signs and symptoms of certain important identified risks of avelumab, including immune-related 
pneumonitis, hepatitis, colitis, pancreatitis, myocarditis, thyroid disorders, adrenal insufficiency, 
type 1 diabetes mellitus, nephritis and renal dysfunction, myositis, hypopituitarism, uveitis, Guillain-
Barre syndrome and infusion related reactions, and how to manage them. 
 
The MAH shall ensure that in each Member State where Bavencio is marketed, all patients/carers who 
are expected to use Bavencio have access to/are provided with the following educational package: 
• Patient Information Brochure 
• Patient Alert Card 
 
The patient educational material should contain 
• The package leaflet 
• Patient Information brochure 
• Patient Alert Card 
 
The Patient Information brochure shall contain the following key messages: 
• Brief introduction to the tool and its purpose 
• Brief introduction to Bavencio treatment 
• Recommendation to consult the package leaflet 
• Information that avelumab can cause serious side effects during or after treatment, that need to 

be treated right away and warning message on the importance of being aware of signs and 
symptoms while receiving avelumab treatment 

• Reminder of the importance to consult their doctor before any change of treatment or in case of 
side effect 

 
The Patient Alert Card shall contain the following key messages: 
• Brief introduction to avelumab (indication and purpose of this tool) 
• Description of the main signs and symptoms of the following safety concerns and reminder of 

the importance of notifying their treating physician immediately if symptoms occur, persist or 
worsen: 

o Immune-Related Pneumonitis 
o Immune-Related Hepatitis 
o Immune-Related Colitis 
o Immune-Related Pancreatitis 
o Immune-Related Myocarditis 
o Immune-Related Endocrinopathies (diabetes mellitus, thyroid disorders, adrenal 

insufficiency) 
o Immune-related nephritis and renal dysfunction 
o Other immune-related adverse reactions including myositis, hypopituitarism, uveitis 

and Guillain-Barre Syndrome 
o Infusion-Related Reactions 

• Warning message for patients on the importance of consulting their doctor immediately in case 
they develop any of the listed signs and symptoms and on the important not attempting to treat 
themselves. 

• Reminder to carry the Patient Alert Card at all times and to show it to all healthcare 
professionals that may treat them. 



32 

• The card should also prompt to enter contact details of the physician and include a warning 
message for healthcare professionals treating the patient at any time, including in conditions of 
emergency, that the patient is using Bavencio. 

 
  



33 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



34 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



35 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Bavencio 20 mg/mL concentrate for solution for infusion 
avelumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each mL of concentrate contains 20 mg of avelumab. 
One vial of 10 mL contains 200 mg of avelumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Mannitol, glacial acetic acid, polysorbate 20, sodium hydroxide, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion. 
 
200 mg/10 mL 
 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use after dilution 
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 
 
 



36 

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 
 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1214/001 
 
 
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 
SN 
NN 



37 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Bavencio 20 mg/mL sterile concentrate 
avelumab 
IV after dilution 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
200 mg/10 mL 
 
 
6. OTHER 
 
 
  



38 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



39 

Package leaflet: Information for the patient 
 

Bavencio 20 mg/mL concentrate for solution for infusion 
avelumab 

 
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. 
• 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 Bavencio is and what it is used for 
2. What you need to know before you use Bavencio 
3. How to use Bavencio 
4. Possible side effects 
5. How to store Bavencio 
6. Contents of the pack and other information 
 
 
1. What Bavencio is and what it is used for 
 
Bavencio contains the active substance avelumab, a monoclonal antibody (a type of protein) that 
attaches to a specific target in the body called PD-L1. 
 
PD-L1 is found on the surface of certain tumour cells, and helps protect them from the immune system 
(the body’s natural defences). Bavencio binds to PD-L1, and blocks this protective effect, allowing the 
immune system to attack the tumour cells. 
 
Bavencio is used in adults to treat: 
• Merkel cell carcinoma (MCC), a rare type of skin cancer, when it is metastatic (has spread to 

other parts of the body). 
• Renal cell carcinoma (RCC), a type of kidney cancer, when it is advanced (has spread beyond 

the kidney or to other parts of the body). 
 
For renal cell cancer, Bavencio is to be used in combination with axitinib. 
 
It is important that you also read the package leaflet for the medicine containing axitinib. If you have 
any questions about axitinib, ask your doctor. 
 
 
2. What you need to know before you use Bavencio 
 
Do not use Bavencio 
if you are allergic to avelumab or any of the other ingredients of this medicine (listed in section 6). 
 



40 

Warnings and precautions 
 
Blood tests and weight checks: 
Your doctor will check your general health before and during treatment with Bavencio. 
You will have blood tests during your treatment and your doctor will monitor your weight before and 
during treatment. 
 
Talk to your doctor before receiving Bavencio: 
It may cause side effects (see section 4). Please note that in some cases symptoms may be delayed, and 
may develop after your last dose. If you suffer from any of these you should seek urgent medical 
attention: 
• infusion-related reactions; 
• problems due to inflammation of your lungs (pneumonitis); 
• inflammation of your liver (hepatitis) or other liver problems; 
• inflammation of your intestines (colitis), diarrhoea (watery, loose or soft stools) or more bowel 

movements than usual; 
• inflammation of your pancreas (pancreatitis); 
• inflammation of your heart (myocarditis); 
• problems with your hormone producing glands (the thyroid, adrenal and pituitary glands) that 

may affect how these glands work; 
• Type 1 diabetes, including acid in the blood produced from diabetes (diabetic ketoacidosis); 
• problems with your kidneys; 
• inflammation of your muscles (myositis). 
 
If you experience any of these symptoms when taking Bavencio do not try to treat them on your own 
with other medicines. Your doctor may 
• give you other medicines in order to prevent complications and reduce your symptoms, 
• withhold the next dose of Bavencio, 
• or stop your treatment with Bavencio altogether. 
 
Check with your doctor or nurse before you receive Bavencio if: 
• you have an autoimmune disease (a condition where the body attacks its own cells); 
• you have human immunodeficiency virus (HIV) infection or acquired immune deficiency 

syndrome (AIDS); 
• you have ever had chronic viral infection of the liver, including hepatitis B (HBV) or hepatitis C 

(HCV); 
• you receive medicines to suppress your immune system; 
• you have had an organ transplant. 
 
Children and adolescents 
Bavencio has not been studied in children and adolescents below 18 years of age. 
 
Other medicines and Bavencio 
Tell your doctor if you are taking, have recently taken or might take any other medicines. 
 
Pregnancy 
Bavencio can cause harm to your unborn baby. If you are pregnant, think you may be pregnant or are 
planning to have a baby, ask your doctor for advice before taking this medicine. 
 
You must not use Bavencio if you are pregnant unless your doctor specifically recommends it. 
 
If you are a woman who could become pregnant, you must use effective contraceptives while you are 
being treated with Bavencio and for at least 1 month after your last dose. 
 



41 

Breast-feeding 
If you are breast-feeding, tell your doctor. 
 
Do not breast-feed while receiving Bavencio and for at least 1 month after your last dose. 
 
It is unknown if Bavencio passes into your breast milk. A risk to the breast-fed child cannot be 
excluded. 
 
Driving and using machines 
Do not drive or use machines after you have received Bavencio if you are not feeling well enough. 
Tiredness is a very common side effect of Bavencio and can affect your ability to drive or to use 
machines. 
 
Bavencio has a low sodium content 
Bavencio contains less than 1 mmol sodium (23 mg) in each dose and therefore is essentially 
sodium-free. 
 
 
3. How to use Bavencio 
 
You will receive Bavencio in a hospital or clinic, under the supervision of an experienced doctor. 
 
How much Bavencio you will receive 
The recommended dose of avelumab is 800 mg every 2 weeks. Your doctor will decide how many 
treatments you need. 
 
How you will receive Bavencio 
You will receive Bavencio as an infusion (a drip) into a vein (intravenously) over a period of 1 hour. 
Bavencio will be added to an infusion bag containing a sodium chloride solution before use. 
 
Before you receive Bavencio 
For at least the first 4 treatments, you will receive paracetamol and an antihistamine before being 
given Bavencio, to help to prevent possible side effects related to the infusion. Depending on how 
your body responds to treatment, your doctor may decide to continue giving you these medicines 
before all of your Bavencio treatments. 
 
If you miss a dose of Bavencio 
It is very important for you to keep all your appointments to receive Bavencio. If you miss an 
appointment, ask your doctor when to schedule your next dose. 
 
If you stop receiving Bavencio 
Do not stop treatment with Bavencio unless you have discussed this with your doctor. Stopping your 
treatment may stop the effect of the medicine. 
 
If you have any further questions 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. Some side 
effects may happen weeks or months after your last dose. 
 
Bavencio acts on your immune system and may cause inflammation in parts of your body (see 
section 2). Inflammation may cause serious damage to your body and some inflammatory conditions 
may lead to death and need treatment or withdrawal of Bavencio. 
 



42 

Seek urgent medical attention if you experience inflammation in any part of your body or if you 
have any of the following signs or symptoms, or if they get worse. 
 
• Signs of infusion-related reactions such as shortness of breath or wheezing, chills or shaking, 

bumpy rash or skin wheals, flushing, low blood pressure (dizziness, fatigue, nausea) fever, 
back pain, and abdominal pain. This is very common. 

 
• Signs of inflammation of hormone producing glands (which may affect how the glands work) 

may include extreme tiredness, rapid heartbeat, increased sweating, changes in mood or 
behaviour, such as irritability or forgetfulness, feeling cold, very low blood pressure (fainting, 
dizziness, fatigue, nausea), weight change or headache. This is very common for thyroid 
gland, common for adrenal glands, and uncommon for pituitary gland. 

 
• Signs of inflammation of the lungs (pneumonitis) may be breathing difficulties or cough. This 

is common. 
 
• Signs of inflammation of the intestines (colitis) may include diarrhoea (loose stools) or more 

bowel movements than usual, blood in your stools or dark, tarry, sticky stools, or severe 
stomach (abdomen) pain or tenderness. This is common. 

 
• Signs of liver problems, including inflammation of the liver (hepatitis) may include yellowing 

of your skin (jaundice) or the whites of your eyes, severe nausea or vomiting, pain on the 
right side of your stomach area (abdomen), drowsiness, dark urine (tea coloured), bleeding 
or bruising more easily than normal, feeling less hungry than usual, tiredness or abnormal 
liver function tests. This is common. 

 
• Signs of inflammation of the pancreas (pancreatitis) may include abdominal pain, nausea and 

vomiting. This is uncommon. 
 
• Signs of inflammation of the heart (myocarditis) may include trouble breathing, dizziness or 

fainting, fever, chest pain and chest tightness or flu like symptoms. This is uncommon. 
 
• Signs of type 1 diabetes may include feeling more hungry or thirsty than usual, needing to 

urinate more often, weight loss, and feeling tired. This is uncommon. 
 
• Signs of inflammation of the kidney may include abnormal kidney function tests, urinating 

less than usual, blood in your urine, or swelling in your ankles. This is uncommon. 
 
• Signs of inflammation of the muscles (myositis) may include muscle pain or weakness. This is 

uncommon. 
 
Do not try to treat yourself with other medicines. 
 
Other side effects 
 
Some side effects may not have symptoms and may only be discovered through blood tests. 
 
The following side effects have been reported in clinical trials with avelumab alone: 
 
Very common (may affect more than 1 in 10 people) 
• Decrease in the number of red blood cells 
• Nausea, loose stools, constipation, vomiting 
• Belly pain, back pain, joint pain 
• Cough, shortness of breath 
• Feeling tired or weak 
• Fever 



43 

• Swelling in the arms, feet or legs 
• Weight loss, feeling less hungry 
 
Common (may affect up to 1 in 10 people) 
• Decrease in the number of a type of white blood cells (lymphocytes) 
• Increases or decreases in blood pressure 
• Headache, dizziness 
• Feeling cold 
• Dryness in the mouth 
• Increased pancreatic enzymes in the blood 
• Skin rash, itching 
• Muscle pain 
• Flu-like illness (includes feeling of fever, muscle aches) 
• Numbness, tingling, weakness, burning sensation in arms or legs 
 
Uncommon (may affect up to 1 in 100 people) 
• Decrease in the number of platelets in the blood 
• Redness in the skin 
• Bowel occlusion 
• Red, itchy, scaly patches on the skin 
• Inflammatory reaction of the whole body (Systemic inflammatory response syndrome) 
• Inflammation of the eye 
• Increased liver enzymes in the blood 
• Increase in the number of a type of white blood cells (eosinophils) 
• Increased muscle enzyme in the blood 
• Guillain-Barré Syndrome (an immune system disorder that causes nerve inflammation and can 

result in pain, numbness, muscle weakness and difficulty walking) 
 
The following side effects have been reported in clinical trials with avelumab in combination with 
axitinib: 
 
Very common (may affect more than 1 in 10 people) 
• Loose stools, nausea, constipation, vomiting 
• Increases in blood pressure 
• Feeling tired or weak 
• Hoarseness, cough, shortness of breath 
• Feeling less hungry, weight loss 
• Headache, dizziness 
• Joint pain, back pain, belly pain, muscle pain 
• Increased liver enzymes in the blood 
• Feeling cold 
• Skin rash, itching 
• Fever 
 
Common (may affect up to 1 in 10 people) 
• Red, itchy, scaly patches on the skin, acne-like rash 
• Swelling in the arms, feet or legs 
• Dryness in the mouth 
• Increased pancreatic enzymes in the blood 
• Decreased kidney function 
• Decrease in the number of red blood cells 
• Decreases in blood pressure 
• Increased glucose in the blood 
• Flu-like illness (includes feeling of fever, muscle aches) 



44 

• Increased muscle enzyme in the blood 
• Decrease in the number of platelets in the blood 
• Numbness, tingling, weakness, burning sensation in arms or legs 
• Redness in the skin 
 
Uncommon (may affect up to 1 in 100 people) 
• Decrease in the number of a type of white blood cells (lymphocytes) 
• Increase in the number of a type of white blood cells (eosinophils) 
• Bowel occlusion 
 
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 Bavencio 
 
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 vial label and carton 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 concentrate or of the diluted 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 Bavencio contains 
 
The active substance is avelumab. 
 
One vial of 10 mL contains 200 mg of avelumab. Each mL of concentrate contains 20 mg of 
avelumab. 
 
The other ingredients are mannitol, glacial acetic acid, polysorbate 20, sodium hydroxide, water for 
injections (see section 2 “Bavencio has a low sodium content”). 
 
What Bavencio looks like and contents of the pack 
Bavencio is a clear, colourless to slightly yellow concentrate for solution for infusion (sterile 
concentrate). 
 
The pack size is 1 glass vial per carton. 
 
Marketing Authorisation Holder 
Merck Europe B.V. 
Gustav Mahlerplein 102 
1082 MA Amsterdam 
The Netherlands 

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


45 

 
Manufacturer 
Merck Serono S.p.A. 
Via Delle Magnolie 15 (loc. frazione Zona Industriale) 
70026 - Modugno (BA) 
Italy 
 
This leaflet was last revised in 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
 
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The following information is intended for healthcare professionals only: 
 
Handling instructions 
 
Preparation and administration 
An aseptic technique for the preparation of the solution for infusion should be used. 
 
• The vial should be visually inspected for particulate matter and discoloration. Bavencio is a 

clear, colourless to slightly yellow solution. If the solution is cloudy, discoloured, or contains 
particulate matters, the vial should be discarded. 

• An infusion bag of appropriate size (preferably 250 mL) containing either sodium chloride 
9 mg/mL (0.9%) solution for injection or with sodium chloride 4.5 mg/mL (0.45%) solution for 
injection should be used. The required volume of Bavencio should be withdrawn from the 
vial(s) and be transferred to the infusion bag. Any partially used or empty vials have to be 
discarded. 

• The diluted solution should be mixed by gently inverting the bag in order to avoid foaming or 
excessive shearing of the solution. 

• The solution should be inspected to ensure it is clear, colourless, and free of visible particles. 
The diluted solution should be used immediately once prepared. 

• Do not co-administer other medicinal products through the same intravenous line. Administer 
the infusion using a sterile, non-pyrogenic, low-protein binding 0.2 micrometre in-line or add-
on filter. 

 
After administration of Bavencio, the line should be flushed with either sodium chloride 9 mg/mL 
(0.9%) solution for injection or with sodium chloride 4.5 mg/mL (0.45%) solution for injection. 
 
Do not freeze or shake the diluted solution. If refrigerated, allow the diluted solution in the intravenous 
bags to come to room temperature prior to use. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	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
	A. LABELLING
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