Aybintio

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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 

 

Aybintio 25 mg/ml concentrate for solution for infusion. 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each ml of concentrate contains 25 mg of bevacizumab*. 

Each 4 ml vial contains 100 mg of bevacizumab. 

Each 16 ml vial contains 400 mg of bevacizumab. 

For dilution and other handling recommendations, see section 6.6. 

 
*Bevacizumab is a recombinant humanised monoclonal antibody produced by DNA technology in Chinese 

Hamster Ovary cells. 

 
For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Concentrate for solution for infusion. 

 
Clear to slightly opalescent, colourless to pale brown liquid. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Aybintio in combination with fluoropyrimidine-based chemotherapy is indicated for treatment of adult 

patients with metastatic carcinoma of the colon or rectum. 

 
Aybintio in combination with paclitaxel is indicated for first-line treatment of adult patients with metastatic 

breast cancer. For further information as to human epidermal growth factor receptor 2 (HER2) status, 

please refer to section 5.1. 

 

Aybintio in combination with capecitabine is indicated for first-line treatment of adult patients with 

metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or 

anthracyclines is not considered appropriate. Patients who have received taxane and 

anthracyclinecontaining regimens in the adjuvant setting within the last 12 months should be excluded 

from treatment with Aybintio in combination with capecitabine. For further information as to HER2 status, 

please refer to section 5.1. 

 
Aybintio, in addition to platinum-based chemotherapy, is indicated for first-line treatment of adult patients 

with unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly 

squamous cell histology. 

 
Aybintio, in combination with erlotinib, is indicated for first-line treatment of adult patients with 

unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer with Epidermal 

Growth Factor Receptor (EGFR) activating mutations (see section 5.1). 

 



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Aybintio in combination with interferon alfa-2a is indicated for first line treatment of adult patients with 

advanced and/or metastatic renal cell cancer. 

 
Aybintio, in combination with carboplatin and paclitaxel is indicated for the front-line treatment of adult 

patients with advanced (International Federation of Gynecology and Obstetrics (FIGO) stages III B, III C 

and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer (see section 5.1).  

 

Aybintio, in combination with carboplatin and gemcitabine or in combination with carboplatin and 

paclitaxel, is indicated for treatment of adult patients with first recurrence of platinum-sensitive epithelial 

ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab 

or other VEGF inhibitors or VEGF receptor-targeted agents. 

 

Aybintio, in combination with topotecan, or pegylated liposomal doxorubicin is indicated for the treatment 

of adult patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal 

cancer who received no more than two prior chemotherapy regimens and who have not received prior 

therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents (see section 5.1). 

 
Aybintio, in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients 

who cannot receive platinum therapy, is indicated for the treatment of adult patients with persistent, 

recurrent, or metastatic carcinoma of the cervix (see section 5.1). 

 

4.2 Posology and method of administration 

 

Aybintio must be administered under the supervision of a physician experienced in the use of antineoplastic 

medicinal products. 

 

Posology 

 

Metastatic carcinoma of the colon or rectum (mCRC) 

 

The recommended dose of Aybintio, administered as an intravenous infusion, is either 5 mg/kg or 

10 mg/kg of body weight given once every 2 weeks or 7.5 mg/kg or 15 mg/kg of body weight given once 

every 3 weeks. 

 

It is recommended that treatment be continued until progression of the underlying disease or until 

unacceptable toxicity. 

 
Metastatic breast cancer (mBC) 

 
The recommended dose of Aybintio is 10 mg/kg of body weight given once every 2 weeks or 15 mg/kg of 

body weight given once every 3 weeks as an intravenous infusion. 

 

It is recommended that treatment be continued until progression of the underlying disease or until 

unacceptable toxicity. 

 

Non-small cell lung cancer (NSCLC) 

 

First-line treatment of non-squamous NSCLC in combination with platinum-based chemotherapy 

 
Aybintio is administered in addition to platinum-based chemotherapy for up to 6 cycles of treatment 

followed by Aybintio as a single agent until disease progression. 

 

The recommended dose of Aybintio is 7.5 mg/kg or 15 mg/kg of body weight given once every 3 weeks as 

an intravenous infusion. 

 

Clinical benefit in NSCLC patients has been demonstrated with both 7.5 mg/kg and 15 mg/kg doses (see 

section 5.1). 



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It is recommended that treatment be continued until progression of the underlying disease or until 

unacceptable toxicity. 
 

First-line treatment of non-squamous NSCLC with EGFR activating mutations in combination with 

erlotinib 

 
EGFR mutation testing should be performed prior to initiation of treatment with the combination of 

Aybintio and erlotinib. It is important that a well-validated and robust methodology is chosen to avoid false 

negative or false positive determinations. 

 

The recommended dose of Aybintio when used in addition to erlotinib is 15 mg/kg of body weight given 

once every 3 weeks as an intravenous infusion. 

 

It is recommended that the treatment with Aybintio in addition to erlotinib is continued until disease 

progression. 

 
For the posology and method of administration of erlotinib, please refer to the full erlotinib prescribing 

information. 

 
Advanced and/or metastatic renal cell cancer (mRCC) 

 
The recommended dose of Aybintio is 10 mg/kg of body weight given once every 2 weeks as an 

intravenous infusion. 

 

It is recommended that treatment be continued until progression of the underlying disease or until 

unacceptable toxicity. 

 

Epithelial ovarian, fallopian tube and primary peritoneal cancer 

 

Front-line treatment  

Aybintio is administered in addition to carboplatin and paclitaxel for up to 6 cycles of treatment followed 

by continued use of Aybintio as single agent until disease progression or for a maximum of 15 months or 

until unacceptable toxicity, whichever occurs earlier. The recommended dose of Aybintio is 15 mg/kg of 

body weight given once every 3 weeks as an intravenous infusion. 

 
Treatment of platinum-sensitive recurrent disease  

Aybintio is administered in combination with either carboplatin and gemcitabine for 6 cycles and up to 10 

cycles or in combination with carboplatin and paclitaxel for 6 cycles and up to 8 cycles, followed by 

continued use of Aybintio as single agent until disease progression. The recommended dose of Aybintio is 

15 mg/kg of body weight given once every 3 weeks as an intravenous infusion. 

 

Treatment of platinum-resistant recurrent disease  

Aybintio is administered in combination with one of the following agents - topotecan (given weekly) or 

pegylated liposomal doxorubicin. The recommended dose of Aybintio is 10 mg/kg of body weight given 

once every 2 weeks as an intravenous infusion. When Aybintio is administered in combination with 

topotecan (given on days 1-5, every 3 weeks), the recommended dose of Aybintio is 15 mg/kg of body 

weight given once every 3 weeks as an intravenous infusion. It is recommended that treatment be continued 

until disease progression or unacceptable toxicity (see section 5.1, study MO22224). 

 
Cervical Cancer 

 

Aybintio is administered in combination with one of the following chemotherapy regimens: paclitaxel and 

cisplatin or paclitaxel and topotecan. 

 

The recommended dose of Aybintio is 15 mg/kg of body weight given once every 3 weeks as an 

intravenous infusion. 

 



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It is recommended that treatment be continued until progression of the underlying disease or until 

unacceptable toxicity (see section 5.1). 

 
Special populations 

 
Elderly patients 

No dose adjustment is required in the patients ≥ 65 years of age. 

 
Patients with renal impairment 

The safety and efficacy have not been studied in patients with renal impairment (see section 5.2). 

 
Patients with hepatic impairment 

The safety and efficacy have not been studied in patients with hepatic impairment (see section 5.2). 

 

Paediatric population 

The safety and efficacy of bevacizumab in children aged less than 18 years old have not been established. 

Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology 

can be made. 

 
There is no relevant use of bevacizumab in the paediatric population in the indications for treatment of 

cancers of the colon, rectum, breast, lung, ovarian, fallopian tube, peritoneum, cervix and kidney. 

 

Method of administration  

 

Aybintio is for intravenous use. The initial dose should be delivered over 90 minutes as an intravenous 

infusion. If the first infusion is well tolerated, the second infusion may be administered over 60 minutes. If 

the 60-minute infusion is well tolerated, all subsequent infusions may be administered over 30 minutes. 

 
It should not be administered as an intravenous push or bolus. 

 
Dose reduction for adverse reactions is not recommended. If indicated, therapy should either be 

permanently discontinued or temporarily suspended as described in section 4.4. 

 

Precautions to be taken before handling or administering the medicinal product 

 
For instructions on dilution of the medicinal product before administration, see section 6.6. Aybintio 

infusions should not be administered or mixed with glucose solutions. This medicinal product must not be 

mixed with other medicinal products except those mentioned in section 6.6. 

 

4.3 Contraindications 

 

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
• Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or 

humanised antibodies. 

• Pregnancy (see section 4.6). 
 

4.4 Special warnings and precautions for use 

 

Traceability 

In order to improve the traceability of biological medicinal products, the trade name and the batch number 

of the administered product should be clearly recorded (or stated) in the patient file. 

 
Gastrointestinal (GI) perforations and fistulae (see section 4.8) 

Patients may be at an increased risk for the development of gastrointestinal perforation and gall bladder 

perforation when treated with bevacizumab. Intra-abdominal inflammatory process may be a risk factor for 

gastrointestinal perforations in patients with metastatic carcinoma of the colon or rectum, therefore, caution 

should be exercised when treating these patients. Prior radiation is a risk factor for GI perforation in 



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patients treated for persistent, recurrent or metastatic cervical cancer with bevacizumab and all patients 

with GI perforation had a history of prior radiation. Therapy should be permanently discontinued in 

patients who develop gastrointestinal perforation. 

 
GI-vaginal fistulae in study GOG-0240 

Patients treated for persistent, recurrent, or metastatic cervical cancer with bevacizumab are at increased 

risk of fistulae between the vagina and any part of the GI tract (Gastrointestinal-vaginal fistulae). Prior 

radiation is a major risk factor for the development of GI-vaginal fistulae and all patients with GI-vaginal 

fistulae had a history of prior radiation. Recurrence of cancer within the field of prior radiation is an 

additional important risk factor for the development of GI-vaginal fistulae. 

 

Non-GI fistulae (see section 4.8) 

Patients may be at increased risk for the development of fistulae when treated with bevacizumab. 

Permanently discontinue Aybintio in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula 

[US National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE v.3)]. 

Limited information is available on the continued use of bevacizumab in patients with other fistulae. 

In cases of internal fistula not arising in the gastrointestinal tract, discontinuation of Aybintio should be 

considered. 

 
Wound healing complications (see section 4.8) 

Bevacizumab may adversely affect the wound healing process. Serious wound healing complications, 

including anastomotic complications, with a fatal outcome have been reported. Therapy should not be 

initiated for at least 28 days following major surgery or until the surgical wound is fully healed. In patients 

who experienced wound healing complications during therapy, treatment should be withheld until the 

wound is fully healed. Therapy should be withheld for elective surgery. 

 
Necrotising fasciitis, including fatal cases, has rarely been reported in patients treated with bevacizumab. 

This condition is usually secondary to wound healing complications, gastrointestinal perforation or fistula 

formation. Aybintio therapy should be discontinued in patients who develop necrotising fasciitis, and 

appropriate treatment should be promptly initiated. 

 
Hypertension (see section 4.8) 

An increased incidence of hypertension was observed in bevacizumab-treated patients. Clinical safety data 

suggest that the incidence of hypertension is likely to be dose-dependent. Pre-existing hypertension should 

be adequately controlled before starting Aybintio treatment. There is no information on the effect of 

bevacizumab in patients with uncontrolled hypertension at the time of initiating therapy. 

 

Monitoring of blood pressure is generally recommended during therapy. 

 
In most cases hypertension was controlled adequately using standard antihypertensive treatment 

appropriate for the individual situation of the affected patient. The use of diuretics to manage hypertension 

is not advised in patients who receive a cisplatin-based chemotherapy regimen. Aybintio should be 

permanently discontinued if medically significant hypertension cannot be adequately controlled with 

antihypertensive therapy, or if the patient develops hypertensive crisis or hypertensive encephalopathy. 

 
Posterior reversible encephalopathy syndrome (PRES) (see section 4.8) 

There have been rare reports of bevacizumab-treated patients developing signs and symptoms that are 

consistent with PRES, a rare neurologic disorder, which can present with the following signs and 

symptoms among others: seizures, headache, altered mental status, visual disturbance, or cortical blindness, 

with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, 

preferably magnetic resonance imaging (MRI). In patients developing PRES, treatment of specific 

symptoms including control of hypertension is recommended along with discontinuation of Aybintio. The 

safety of reinitiating bevacizumab therapy in patients previously experiencing PRES is not known. 

 
Proteinuria (see section 4.8) 

Patients with a history of hypertension may be at increased risk for the development of proteinuria when 

treated with bevacizumab. There is evidence suggesting that all Grade (US National Cancer Institute- 

Common Terminology Criteria for Adverse Events [NCI-CTCAE v.3]) proteinuria may be related to the 



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dose. Monitoring of proteinuria by dipstick urinalysis is recommended prior to starting and during therapy. 

Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of patients treated with bevacizumab. 

Therapy should be permanently discontinued in patients who develop nephrotic syndrome (NCI-CTCAE 

v.3). 

 
Arterial thromboembolism (see section 4.8) 

In clinical trials, the incidence of arterial thromboembolic reactions including cerebrovascular accidents 

(CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs) was higher in patients 

receiving bevacizumab in combination with chemotherapy compared to those who received chemotherapy 

alone. 

 

Patients receiving bevacizumab plus chemotherapy, with a history of arterial thromboembolism, diabetes or 

age greater than 65 years have an increased risk of developing arterial thromboembolic reactions during 

therapy. Caution should be taken when treating these patients with Aybintio. 

 
Therapy should be permanently discontinued in patients who develop arterial thromboembolic reactions. 

 
Venous thromboembolism (see section 4.8) 

Patients may be at risk of developing venous thromboembolic reactions, including pulmonary embolism 

under bevacizumab treatment. 

 

Patients treated for persistent, recurrent, or metastatic cervical cancer with bevacizumab in combination 

with paclitaxel and cisplatin may be at increased risk of venous thromboembolic events. 

 

Aybintio should be discontinued in patients with life-threatening (Grade 4) thromboembolic reactions, 

including pulmonary embolism (NCI-CTCAE v.3). Patients with thromboembolic reactions ≤ Grade 3 need 

to be closely monitored (NCI-CTCAE v.3). 

 
Haemorrhage 

Patients treated with bevacizumab have an increased risk of haemorrhage, especially tumour-associated 

haemorrhage. Aybintio should be discontinued permanently in patients who experience Grade 3 or 4 

bleeding during bevacizumab therapy (NCI-CTCAE v.3) (see section 4.8). 

 
Patients with untreated CNS metastases were routinely excluded from clinical trials with bevacizumab, 

based on imaging procedures or signs and symptoms. Therefore, the risk of CNS haemorrhage in such 

patients has not been prospectively evaluated in randomised clinical trials (see section 4.8). Patients should 

be monitored for signs and symptoms of CNS bleeding, and Aybintio treatment discontinued in cases of 

intracranial bleeding. 

 
There is no information on the safety profile of bevacizumab in patients with congenital bleeding diathesis, 

acquired coagulopathy or in patients receiving full dose of anticoagulants for the treatment of 

thromboembolism prior to starting bevacizumab treatment, as such patients were excluded from clinical 

trials. Therefore, caution should be exercised before initiating therapy in these patients. However, patients 

who developed venous thrombosis while receiving therapy did not appear to have an increased rate of 

Grade 3 or above bleeding when treated with a full dose of warfarin and bevacizumab concomitantly 

(NCI-CTCAE v.3). 

 
Pulmonary haemorrhage/haemoptysis 

Patients with non-small cell lung cancer treated with bevacizumab may be at risk of serious, and in some 

cases fatal, pulmonary haemorrhage/haemoptysis. Patients with recent pulmonary haemorrhage/ 

haemoptysis (> 2.5 ml of red blood) should not be treated with bevacizumab. 

 

Aneurysms and artery dissections 

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation 

of aneurysms and/or artery dissections. Before initiating Aybintio, this risk should be carefully considered 

in patients with risk factors such as hypertension or history of aneurysm. 

 



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Congestive heart failure (CHF) (see section 4.8) 

Reactions consistent with CHF were reported in clinical trials. The findings ranged from asymptomatic 

declines in left ventricular ejection fraction to symptomatic CHF, requiring treatment or hospitalisation. 

Caution should be exercised when treating patients with clinically significant cardiovascular disease such 

as pre-existing coronary artery disease, or congestive heart failure with bevacizumab. 

 
Most of the patients who experienced CHF had metastatic breast cancer and had received previous 

treatment with anthracyclines, prior radiotherapy to the left chest wall or other risk factors for CHF were 

present. 

 
In patients in AVF3694g who received treatment with anthracyclines and who had not received 

anthracyclines before, no increased incidence of all Grade CHF was observed in the anthracycline + 

bevacizumab group compared to the treatment with anthracyclines only. CHF Grade 3 or higher reactions 

were somewhat more frequent among patients receiving bevacizumab in combination with chemotherapy 

than in patients receiving chemotherapy alone. This is consistent with results in patients in other studies of 

metastatic breast cancer who did not receive concurrent anthracycline treatment (NCI-CTCAE v.3) (see 

section 4.8). 

 
Neutropenia and infections (see section 4.8) 

Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia 

(including some fatalities) have been observed in patients treated with some myelotoxic chemotherapy 

regimens plus bevacizumab in comparison to chemotherapy alone. This has mainly been seen in 

combination with platinum- or taxane-based therapies in the treatment of NSCLC, mBC, and in 

combination with paclitaxel and topotecan in persistent, recurrent, or metastatic cervical cancer. 

 
Hypersensitivity reactions/infusion reactions (see section 4.8) 

Patients may be at risk of developing infusion/hypersensitivity reactions. Close observation of the patient 

during and following the administration of bevacizumab is recommended as expected for any infusion of a 

therapeutic humanised monoclonal antibody. If a reaction occurs, the infusion should be discontinued and 

appropriate medical therapies should be administered. A systematic premedication is not warranted. 

 
Osteonecrosis of the jaw (ONJ) (see section 4.8) 

Cases of ONJ have been reported in cancer patients treated with bevacizumab, the majority of whom had 

received prior or concomitant treatment with intravenous bisphosphonates, for which ONJ is an identified 

risk. Caution should be exercised when bevacizumab and intravenous bisphosphonates are administered 

simultaneously or sequentially. 

 

Invasive dental procedures are also an identified risk factor. A dental examination and appropriate 

preventive dentistry should be considered prior to starting the treatment with Aybintio. In patients who 

have previously received or are receiving intravenous bisphosphonates invasive dental procedures should 

be avoided, if possible. 

 
Intravitreal use 

Aybintio is not formulated for intravitreal use. 

 
Eye disorders 

Individual cases and clusters of serious ocular adverse reactions have been reported following unapproved 

intravitreal use of bevacizumab compounded from vials approved for intravenous administration in cancer 

patients. These reactions included infectious endophthalmitis, intraocular inflammation such as sterile 

endophthalmitis, uveitis and vitritis, retinal detachment, retinal pigment epithelial tear, intraocular pressure 

increased, intraocular haemorrhage such as vitreous haemorrhage or retinal haemorrhage and conjunctival 

haemorrhage. Some of these reactions have resulted in various degrees of visual loss, including permanent 

blindness. 

 



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Systemic effects following intravitreal use 

A reduction of circulating VEGF concentration has been demonstrated following intravitreal anti-VEGF 

therapy. Systemic adverse reactions including non-ocular haemorrhages and arterial thromboembolic 

reactions have been reported following intravitreal injection of VEGF inhibitors. 

 
Ovarian failure/fertility 

 

Bevacizumab may impair female fertility (see sections 4.6 and 4.8). Therefore fertility preservation 

strategies should be discussed with women of child-bearing potential prior to starting treatment with 

bevacizumab. 

 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Effect of antineoplastic agents on bevacizumab pharmacokinetics 

No clinically relevant interaction of co-administered chemotherapy on bevacizumab pharmacokinetics was 

observed based on the results of population pharmacokinetic analyses. There were neither statistically 

significant nor clinically relevant differences in bevacizumab clearance in patients receiving bevacizumab 

monotherapy compared to patients receiving bevacizumab in combination with interferon alfa-2a, erlotinib 

or chemotherapies (IFL, 5-FU/LV, carboplatin/paclitaxel, capecitabine, doxorubicin or 

cisplatin/gemcitabine). 

 
Effect of bevacizumab on the pharmacokinetics of other antineoplastic agents 

No clinically relevant interaction of bevacizumab was observed on the pharmacokinetics of 

co-administered interferon alfa 2a, erlotinib (and its active metabolite OSI-420), or the chemotherapies 

irinotecan (and its active metabolite SN38), capecitabine, oxaliplatin (as determined by measurement of 

free and total platinum), and cisplatin. Conclusions on the impact of bevacizumab on gemcitabine 

pharmacokinetics cannot be drawn. 

 
Combination of bevacizumab and sunitinib malate 

In two clinical trials of metastatic renal cell carcinoma, microangiopathic haemolytic anaemia (MAHA) 

was reported in 7 of 19 patients treated with bevacizumab (10 mg/kg every two weeks) and sunitinib 

malate (50 mg daily) combination. 

 
MAHA is a haemolytic disorder which can present with red cell fragmentation, anaemia, and 

thrombocytopenia. In addition, hypertension (including hypertensive crisis), elevated creatinine, and 

neurological symptoms were observed in some of these patients. All of these findings were reversible upon 

discontinuation of bevacizumab and sunitinib malate (see Hypertension, Proteinuria, PRES in section 4.4). 

 
Combination with platinum- or taxane-based therapies (see sections 4.4 and 4.8) 

Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia 

(including some fatalities) have been observed mainly in patients treated with platinum- or taxane-based 

therapies in the treatment of NSCLC and mBC. 

 
Radiotherapy 

The safety and efficacy of concomitant administration of radiotherapy and bevacizumab has not been 

established. 

 
EGFR monoclonal antibodies in combination with bevacizumab chemotherapy regimens 

No interaction studies have been performed. EGFR monoclonal antibodies should not be administered for 

the treatment of mCRC in combination with bevacizumab-containing chemotherapy. Results from the 

randomised phase III studies, PACCE and CAIRO-2, in patients with mCRC suggest that the use of 

anti-EGFR monoclonal antibodies panitumumab and cetuximab, respectively, in combination with 

bevacizumab plus chemotherapy, is associated with decreased PFS and/or OS, and with increased toxicity 

compared with bevacizumab plus chemotherapy alone. 

 

 



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4.6 Fertility, pregnancy and lactation 

 
Women of childbearing potential 

Women of childbearing potential have to use effective contraception during (and up to 6 months after) 

treatment. 

 
Pregnancy 

There are no clinical trial data on the use of bevacizumab in pregnant women. Studies in animals have 

shown reproductive toxicity including malformations (see section 5.3). IgGs are known to cross the 

placenta, and bevacizumab is anticipated to inhibit angiogenesis in the foetus, and thus is suspected to 

cause serious birth defects when administered during pregnancy. In the post-marketing setting, cases of 

foetal abnormalities in women treated with bevacizumab alone or in combination with known embryotoxic 

chemotherapeutics have been observed (see section 4.8). Bevacizumab is contraindicated in pregnancy (see 

section 4.3). 

 
Breast-feeding 

It is not known whether bevacizumab is excreted in human milk. As maternal IgG is excreted in milk and 

bevacizumab could harm infant growth and development (see section 5.3), women must discontinue 

breast-feeding during therapy and not breast-feed for at least six months following the last dose of 

bevacizumab. 

 
Fertility 

Repeat dose toxicity studies in animals have shown that bevacizumab may have an adverse effect on 

female fertility (see section 5.3). In a phase III trial in the adjuvant treatment of patients with colon cancer, 

a substudy with premenopausal women has shown a higher incidence of new cases of ovarian failure in the 

bevacizumab group compared to the control group. After discontinuation of bevacizumab treatment, 

ovarian function recovered in the majority of patients. Long term effects of the treatment with bevacizumab 

on fertility are unknown. 

 

4.7 Effects on ability to drive and use machines 

 

Bevacizumab has no or negligible influence on the ability to drive and use machines. However, 

somnolence and syncope have been reported with bevacizumab use (see table 1 in section 4.8). If patients 

are experiencing symptoms that affect their vision or concentration, or their ability to react, they should be 

advised not to drive and use machines until symptoms abate. 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

The overall safety profile of bevacizumab is based on data from over 5,700 patients with various 

malignancies, predominantly treated with bevacizumab in combination with chemotherapy in clinical trials. 

 
The most serious adverse reactions were: 

• Gastrointestinal perforations (see section 4.4). 
• Haemorrhage, including pulmonary haemorrhage/haemoptysis, which is more common in non-small 

cell lung cancer patients (see section 4.4). 

• Arterial thromboembolism (see section 4.4). 

 
The most frequently observed adverse reactions across clinical trials in patients receiving bevacizumab 

were hypertension, fatigue or asthenia, diarrhoea and abdominal pain. 

 
Analyses of the clinical safety data suggest that the occurrence of hypertension and proteinuria with 

bevacizumab therapy are likely to be dose-dependent. 

 

Tabulated list of adverse reactions 

The adverse reactions listed in this section fall into the following frequency categories: very common 

(≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very 

rare (<1/10,000); not known (cannot be estimated from the available data). 



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Tables 1 and 2 list adverse reactions associated with the use of bevacizumab in combination with different 

chemotherapy regimens in multiple indications, by MedDRA system organ class. 

 
Table 1 provides all adverse reactions by frequency that were determined to have a causal relationship with 

bevacizumab through: 

• comparative incidences noted between clinical trial treatment arms (with at least a 10% difference 
compared to the control arm for NCI-CTCAE Grade 1-5 reactions or at least a 2% difference 

compared to the control arm for NCI-CTCAE Grade 3-5 reactions, 

• post-authorisation safety studies, 
• spontaneous reporting, 
• epidemiological studies\non-interventional or observational studies, 
• or through an evaluation of individual case reports. 
 

Table 2 provides the frequency of severe adverse reactions. Severe reactions are defined as adverse events 

with at least a 2% difference compared to the control arm in clinical studies for NCI-CTCAE Grade 3-5 

reactions. Table 2 also includes adverse reactions which are considered by the MAH to be clinically 

significant or severe. 

 
Post-marketing adverse reactions are included in both Tables 1 and 2, where applicable. Detailed 

information about these post-marketing reactions are provided in Table 3. 

 
Adverse reactions are added to the appropriate frequency category in the tables below according to the 

highest incidence seen in any indication. 

Within each frequency category, adverse reactions are presented in the order of decreasing seriousness. 

 
Some of the adverse reactions are reactions commonly seen with chemotherapy; however, bevacizumab 

may exacerbate these reactions when combined with chemotherapeutic agents. Examples include 

palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine, 

peripheral sensory neuropathy with paclitaxel or oxaliplatin, nail disorders or alopecia with paclitaxel, and 

paronychia with erlotinib. 

 

Table 1. Adverse reactions by frequency 

System organ 

class 
Very common Common Uncommon Rare Very rare 

Frequency not 

known 

Infections and 

infestations 

 Sepsis, 

Abscessb,d, 

Cellulitis, 

Infection, 

Urinary tract 

infection 

 Necrotising 

fasciitisa 

  

Blood and 

lymphatic 

system 

disorders 

Febrile 

neutropenia, 

Leucopenia, 

Neutropeniab, 

Thrombocytopenia 

Anaemia, 

Lymphopenia 

    

Immune system 

disorders 

 Hypersensitivity, 

Infusion 

reactionsa,b,d 

    

Metabolism and 

nutrition 

disorders 

Anorexia 

Hypomagnesaemia 

Hyponatraemia 

Dehydration     

Nervous system 

disorders 

Peripheral sensory 

neuropathyb, 

Dysarthria, 

Headache, 

Dysguesia 

Cerebrovascular 

accident, 

Syncope, 

Somnolence 

 Posterior 

reversible 

encephalopathy 

syndromea,b,d 

Hypertensive 

encephalopathya 

 



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System organ 

class 
Very common Common Uncommon Rare Very rare 

Frequency not 

known 

Eye disorders Eye disorder, 

Lacrimation 

increased 

     

Cardiac 

disorders 

 Congestive heart 

failureb,d, 

Supraventricular 

tachycardia 

    

Vascular 

disorders 

Hypertensionb,d, 

Thromboembolism 

(venous)b,d 

Thromboembolism 

(arterial)b,d, 

Haemorrhageb,d, 

Deep vein 

thrombosis 

   Renal thrombotic 

microangiopathya,b, 

Aneurysms and 

artery dissections 

Respiratory, 

thoracic and 

mediastinal 

disorders 

Dyspnoea, 

Rhinitis 

Epistaxis 

Cough 

Pulmonary 

haemorrhage/ 

Haemoptysisb,d, 

Pulmonary 

embolism, 

Hypoxia, 

Dysphoniaa 

   Pulmonary 

hypertensiona, 

Nasal septum 

perforationa 

Gastrointestinal 

disorders 

Rectal 

haemorrhage, 

Stomatitis, 

Constipation, 

Diarrhoea, 

Nausea, 

Vomiting, 

Abdominal pain 

Gastrointestinal 

perforationb,d, 

Intestinal 

perforation, 

Ileus, 

Intestinal 

obstruction, 

Recto-vaginal 

fistulaed,e, 

Gastrointestinal 

disorder,  

Proctalgia 

   Gastrointestinal 

ulcera 

Hepatobiliary 

disorders 

     Gallbladder 

perforationa,b 

Skin and 

subcutaneous 

tissue disorders 

Wound healing 

complicationsb,d, 

Exfoliative 

dermatitis, 

Dry skin, 

Skin discoloration 

Palmar-plantar 

erythrodysaesthesia 

syndrome 

    

Musculoskeletal 

and connective 

tissue disorders 

Arthralgia, 

Myalgia 

Fistulab,d, 

Muscular 

weakness, 

Back pain 

   Osteonecrosis of 

the jawa,b, 

Non-mandibular 

osteonecrosisa,f 

Renal and 

urinary 

disorders 

Proteinuriab,d      

Reproductive 

system and 

breast disorders 

Ovarian failureb,c,d Pelvic pain     

Congenital, 

familial, and 

genetic disorder 

     Foetal 

abnormalitiesa,b 



13 

System organ 

class 
Very common Common Uncommon Rare Very rare 

Frequency not 

known 

General 

disorders and 

administration 

site conditions 

Asthenia, 

Fatigue, 

Pyrexia, 

Pain, 

Mucosal 

inflammation 

Lethargy     

Investigations Weight decreased      

When events were noted as both all grade and grade 3-5 adverse drug reactions in clinical trials, the highest frequency observed in 

patients has been reported. Data are unadjusted for the differential time on treatment. 

a For further information please refer to Table 3 ‘Adverse reactions reported in post-marketing setting’. 
b Terms represent a group of events that describe a medical concept rather than a single condition or MedDRA (Medical 

Dictionary for Regulatory Activities) preferred term. This group of medical terms may involve the same underlying 

pathophysiology (e.g. arterial thromboembolic reactions include cerebrovascular accident, myocardial infarction, transient 

ischaemic attack and other arterial thromboembolic reactions). 
c Based on a substudy from NSABP C-08 with 295 patients. 
d For additional information refer below within section “Description of selected serious adverse reactions”. 
e Recto-vaginal fistulae are the most common fistulae in the GI-vaginal fistula category. 
f Observed in paediatric population only 

 

Table 2. Severe adverse reactions by frequency 

System organ 

class 
Very common Common Uncommon Rare Very rare 

Frequency not 

known 

Infections and 

infestations 

 Sepsis,  

Cellulitis, 

Abscessa,b, 

Infection, 

Urinary tract infection 

   Necrotising 

fasciitisc 

Blood and 

lymphatic system 

disorders 

Febrile neutropenia, 

Leucopenia, 

Neutropeniaa, 

Thrombocytopenia 

Anaemia, 

Lymphopenia 

    

Immune system 

disorders 

     Hypersensitivity, 

Infusion 

reactionsa,b,c 

Metabolism and 

nutrition disorders 

 Dehydration, 

Hyponatraemia 

    

Nervous system 

disorders 

Peripheral sensory 

neuropathya 

Cerebrovascular 

accident, 

Syncope, 

Somnolence, 

Headache 

   Posterior reversible 

encephalopathy 

syndromea,b,c, 

Hypertensive 

encephalopathyc 

 

Cardiac disorders  Congestive heart 

failurea,b, 

Supraventricular 

tachycardia 

    

Vascular disorders Hypertensiona,b Thromboembolism 

arteriala,b, 

Haemorrhagea,b, 

Thromboembolism 

(venous)a,b 

Deep vein thrombosis 

   Renal thrombotic 

microangiopathyb,c, 

Aneurysms and 

artery dissections 



14 

System organ 

class 
Very common Common Uncommon Rare Very rare 

Frequency not 

known 

Respiratory, 

thoracic and 

mediastinal 

disorders 

 Pulmonary 

haemorrhage/ 

Haemoptysisa,b, 

Pulmonary embolism, 

Epistaxis, 

Dyspnoea, 

Hypoxia 

   Pulmonary 

hypertensionc, 

Nasal septum 

perforationc 

Gastrointestinal 

disorders 

Diarrhoea, 

Nausea, 

Vomiting, 

Abdominal pain 

Intestinal perforation, 

Ileus, 

Intestinal obstruction,  

Recto-vaginal fistulaec,d, 

Gastrointestinal 

disorder, 

Stomatitis, 

Proctalgia 

   Gastrointestinal 

perforationa,b, 

Gastrointestinal 

ulcerc, 

Rectal 

haemorrhage 

Hepatobiliary 

disorders 

     Gallbladder 

perforationb,c 

Skin and 

subcutaneous tissue 

disorders 

 Wound healing 

complicationsa,b, 

Palmar-plantar 

erythrodysaesthesia 

syndrome 

    

Musculoskeletal 

and connective 

tissue disorders 

 Fistulaa,b, 

Myalgia, 

Arthralgia, 

Muscular weakness, 

Back pain 

   Osteonecrosis of 

the jawb,c 

Renal and urinary 

disorders 

 Proteinuriaa,b     

Reproductive 

system and breast 

disorders 

 Pelvic pain    Ovarian failurea,b 

Congenital, 

familial, and 

genetic disorder 

     Foetal 

abnormalitiesa,c 

General disorders 

and administration 

site conditions 

Asthenia, 

Fatigue 

Pain, 

Lethargy, 

Mucosal inflammation 

    

Table 2 provides the frequency of severe adverse reactions. Severe reactions are defined as adverse events with at least a 2% 

difference compared to the control arm in clinical studies for NCI-CTCAE Grade 3-5 reactions. 

Table 2 also includes adverse reactions which are considered by the MAH to be clinically significant or severe. 

These clinically significant adverse reactions were reported in clinical trials but the grade 3-5 reactions did not meet the threshold 

of at least a 2% difference compared to the control arm. Table 2 also includes clinically significant adverse reactions that were 

observed only in the post-marketing setting, therefore, the frequency and NCI-CTCAE grade is not known. These clinically 

significant reactions have therefore been included in Table 2 within the column entitled “Frequency Not Known.” 
a Terms represent a group of events that describe a medical concept rather than a single condition or MedDRA (Medical Dictionary 

for Regulatory Activities) preferred term. This group of medical terms may involve the same underlying pathophysiology (e.g. 

arterial thromboembolic reactions include cerebrovascular accident, myocardial infarction, transient ischaemic attack and other 

arterial thromboembolic reactions). 
b For additional information refer below within section “Description of selected serious adverse reactions”. 
c For further information please refer to Table 3 ‘Adverse reactions reported in post-marketing setting’. 
d Recto-vaginal fistulae are the most common fistulae in the GI-vaginal fistula category. 

 

 



15 

Description of selected serious adverse reactions 

 

Gastrointestinal (GI) perforations and fistulae (see section 4.4) 

Bevacizumab has been associated with serious cases of gastrointestinal perforation. 

 
Gastrointestinal perforations have been reported in clinical trials with an incidence of less than 1% in 

patients with non-squamous non-small cell lung cancer, up to 1.3% in patients with metastatic breast 

cancer, up to 2.0% in patients with metastatic renal cell cancer or in patients with ovarian cancer, and up to 

2.7% (including gastrointestinal fistula and abscess) in patients with metastatic colorectal cancer. From a 

clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), GI 

perforations (all grade) were reported in 3.2% of patients, all of whom had a history of prior pelvic 

radiation. 

 

The occurrence of those events varied in type and severity, ranging from free air seen on the plain 

abdominal X-ray, which resolved without treatment, to intestinal perforation with abdominal abscess and 

fatal outcome. In some cases underlying intra-abdominal inflammation was present, either from gastric 

ulcer disease, tumour necrosis, diverticulitis, or chemotherapy-associated colitis. 

 
Fatal outcome was reported in approximately a third of serious cases of gastrointestinal perforations, which 

represents between 0.2%-1% of all bevacizumab treated patients. 

 
In bevacizumab clinical trials, gastrointestinal fistulae (all grade) have been reported with an incidence of 

up to 2% in patients with metastatic colorectal cancer and ovarian cancer, but were also reported less 

commonly in patients with other types of cancer. 

 
GI-vaginal fistulae in study GOG-0240 

In a trial of patients with persistent, recurrent or metastatic cervical cancer, the incidence of GI-vaginal 

fistulae was 8.3% in bevacizumab-treated patients and 0.9% in control patients, all of whom had a history 

of prior pelvic radiation. The frequency of GI-vaginal fistulae in the group treated with 

bevacizumab + chemotherapy was higher in patients with recurrence within the field of prior radiation 

(16.7%) compared with patients with no prior radiation and/ or no recurrence inside the field of prior 

radiation (3.6%). The corresponding frequencies in the control group receiving chemotherapy alone were 

1.1% vs. 0.8%, respectively. Patients who develop GI-vaginal fistulae may also have bowel obstructions 

and require surgical intervention as well as diverting ostomies. 

 
Non-GI fistulae (see section 4.4) 

Bevacizumab use has been associated with serious cases of fistulae including reactions resulting in death. 

 
From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (GOG-240), 1.8% of 

bevacizumab-treated patients and 1.4% of control patients were reported to have had non-gastrointestinal 

vaginal, vesical, or female genital tract fistulae. 

 
Uncommon (≥ 0.1% to < 1%) reports of fistulae that involve areas of the body other than the 

gastrointestinal tract (e.g. bronchopleural and biliary fistulae) were observed across various indications. 

Fistulae have also been reported in post-marketing experience. 

 
Reactions were reported at various time points during treatment ranging from one week to greater than 

1 year from initiation of bevacizumab, with most reactions occurring within the first 6 months of therapy. 

 
Wound healing (see section 4.4) 

As bevacizumab may adversely impact wound healing, patients who had major surgery within the last 

28 days were excluded from participation in phase III clinical trials. 

 
In clinical trials of metastatic carcinoma of the colon or rectum, there was no increased risk of 

post- operative bleeding or wound healing complications observed in patients who underwent major 

surgery 28-60 days prior to starting bevacizumab. An increased incidence of post-operative bleeding or 

wound healing complication occurring within 60 days of major surgery was observed if the patient was 



16 

being treated with bevacizumab at the time of surgery. The incidence varied between 10% (4/40) and 20% 

(3/15). 

 
Serious wound healing complications, including anastomotic complications, have been reported, some of 

which had a fatal outcome. 

 
In locally recurrent and metastatic breast cancer trials, Grade 3-5 wound healing complications were 

observed in up to 1.1% of patients receiving bevacizumab compared with up to 0.9% of patients in the 

control arms (NCI-CTCAE v.3). 

 
In clinical trials of ovarian cancer, Grade 3-5 wound healing complications were observed in up to 1.8% of 

patients in the bevacizumab arm versus 0.1% in the control arm (NCI-CTCAE v.3). 

 

Hypertension (see section 4.4) 

In clinical trials, with the exception of study JO25567, the overall incidence of hypertension (all grades) 

ranged up to 42.1% in the bevacizumab containing arms compared with up to 14% in the control arms. The 

overall incidence of NCI-CTC Grade 3 and 4 hypertension in patients receiving bevacizumab ranged from 

0.4% to 17.9%. Grade 4 hypertension (hypertensive crisis) occurred in up to 1.0% of patients treated with 

bevacizumab and chemotherapy compared to up to 0.2% of patients treated with the same chemotherapy 

alone. 

 
In study JO25567, all grade hypertension was observed in 77.3% of the patients who received bevacizumab 

in combination with erlotinib as first-line treatment for non-squamous NSCLC with EGFR activating 

mutations, compared to 14.3% of patients treated with erlotinib alone. Grade 3 hypertension was 60.0% in 

patients treated with bevacizumab in combination with erlotinib compared to 11.7% in patients treated with 

erlotinib alone. There were no grade 4 or 5 hypertension events. 

 
Hypertension was generally adequately controlled with oral anti-hypertensives such as 

angiotensin-converting enzyme inhibitors, diuretics and calcium-channel blockers. It rarely resulted in 

discontinuation of bevacizumab treatment or hospitalisation. 

 
Very rare cases of hypertensive encephalopathy have been reported, some of which were fatal. 

 
The risk of bevacizumab-associated hypertension did not correlate with the patients’ baseline 

characteristics, underlying disease or concomitant therapy. 

 
Posterior reversible encephalopathy syndrome (see section 4.4) 

There have been rare reports of bevacizumab-treated patients developing signs and symptoms that are 

consistent with PRES, a rare neurological disorder. Presentation may include seizures, headache, altered 

mental status, visual disturbance, or cortical blindness, with or without associated hypertension. The 

clinical presentation of PRES is often nonspecific, and therefore the diagnosis of PRES requires 

confirmation by brain imaging, preferably MRI. 

 
In patients developing PRES, early recognition of symptoms with prompt treatment of specific symptoms 

including control of hypertension (if associated with severe uncontrolled hypertension) is recommended in 

addition to discontinuation of bevacizumab therapy. Symptoms usually resolve or improve within days 

after treatment discontinuation, although some patients have experienced some neurologic sequelae. The 

safety of reinitiating bevacizumab therapy in patients previously experiencing PRES is not known. 

 
Across clinical trials, 8 cases of PRES have been reported. Two of the eight cases did not have radiological 

confirmation via MRI. 

 
Proteinuria (see section 4.4) 

In clinical trials, proteinuria has been reported within the range of 0.7% to 54.7% of patients receiving 

bevacizumab. 

 



17 

Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic 

syndrome, with the great majority as Grade 1 proteinuria (NCI-CTCAE v.3). Grade 3 proteinuria was 

reported in up to 10.9% of treated patients. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 

1.4% of treated patients. Testing for proteinuria is recommended prior to start of bevacizumab therapy. In 

most clinical trials urine protein levels of ≥ 2g/24 hrs led to the holding of bevacizumab until recovery to 

< 2g/24 hrs. 

 
Haemorrhage (see section 4.4) 

In clinical trials across all indications the overall incidence of NCI-CTCAE v.3 Grade 3-5 bleeding 

reactions ranged from 0.4% to 6.9% in bevacizumab treated patients, compared with up to 4.5% of patients 

in the chemotherapy control group. 

 

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), 

grade 3-5 bleeding reactions have been reported in up to 8.3% of patients treated with bevacizumab in 

combination with paclitaxel and topotecan compared with up to 4.6% of patients treated with paclitaxel and 

topotecan. 

 
The haemorrhagic reactions that have been observed in clinical trials were predominantly 

tumour-associated haemorrhage (see below) and minor mucocutaneous haemorrhage (e.g. epistaxis). 

 
Tumour-associated haemorrhage (see section 4.4) 

Major or massive pulmonary haemorrhage/haemoptysis has been observed primarily in trials in patients 

with non-small cell lung cancer (NSCLC). Possible risk factors include squamous cell histology, treatment 

with antirheumatic/anti-inflammatory substances, treatment with anticoagulants, prior radiotherapy, 

bevacizumab therapy, previous medical history of atherosclerosis, central tumour location and cavitation of 

tumours prior to or during therapy. The only variables that showed statistically significant correlations with 

bleeding were bevacizumab therapy and squamous cell histology. Patients with NSCLC of known 

squamous cell histology or mixed cell type with predominant squamous cell histology were excluded from 

subsequent phase III trials, while patients with unknown tumour histology were included. 

 
In patients with NSCLC excluding predominant squamous histology, all Grade reactions were seen with a 

frequency of up to 9.3% when treated with bevacizumab plus chemotherapy compared with up to 5% in the 

patients treated with chemotherapy alone. Grade 3-5 reactions have been observed in up to 2.3% of patients 

treated with bevacizumab plus chemotherapy as compared with < 1% with chemotherapy alone 

(NCI-CTCAE v.3). Major or massive pulmonary haemorrhage/haemoptysis can occur suddenly and up to 

two thirds of the serious pulmonary haemorrhages resulted in a fatal outcome. 

 
Gastrointestinal haemorrhages, including rectal bleeding and melaena have been reported in colorectal 

cancer patients, and have been assessed as tumour-associated haemorrhages. 

 
Tumour-associated haemorrhage was also seen rarely in other tumour types and locations, including cases 

of central nervous system (CNS) bleeding in patients with CNS metastases (see section 4.4). 

 
The incidence of CNS bleeding in patients with untreated CNS metastases receiving bevacizumab has not 

been prospectively evaluated in randomised clinical trials. In an exploratory retrospective analysis of data 

from 13 completed randomised trials in patients with various tumour types, 3 patients out of 91 (3.3%) 

with brain metastases experienced CNS bleeding (all Grade 4) when treated with bevacizumab, compared 

to 1 case (Grade 5) out of 96 patients (1%) that were not exposed to bevacizumab. In two subsequent 

studies in patients with treated brain metastases (which included around 800 patients), one case of Grade 2 

CNS haemorrhage was reported in 83 subjects treated with bevacizumab (1.2%) at the time of interim 

safety analysis (NCI-CTCAE v.3). 

 

Across all clinical trials, mucocutaneous haemorrhage has been seen in up to 50% of bevacizumab-treated 

patients. These were most commonly NCI-CTCAE v.3 Grade 1 epistaxis that lasted less than 5 minutes, 

resolved without medical intervention and did not require any changes in the bevacizumab treatment 

regimen. Clinical safety data suggest that the incidence of minor mucocutaneous haemorrhage (e.g. 

epistaxis) may be dose-dependent. 



18 

 
There have also been less common reactions of minor mucocutaneous haemorrhage in other locations, such 

as gingival bleeding or vaginal bleeding. 

 
Thromboembolism (see section 4.4) 

Arterial thromboembolism: An increased incidence of arterial thromboembolic reactions was observed in 

patients treated with bevacizumab across indications, including cerebrovascular accidents, myocardial 

infarction, transient ischaemic attacks, and other arterial thromboembolic reactions. 

 

In clinical trials, the overall incidence of arterial thromboembolic reactions ranged up to 3.8% in the 

bevacizumab containing arms compared with up to 2.1% in the chemotherapy control arms. Fatal outcome 

was reported in 0.8% of patients receiving bevacizumab compared to 0.5% in patients receiving 

chemotherapy alone. Cerebrovascular accidents (including transient ischaemic attacks) were reported in up 

to 2.7% of patients treated with bevacizumab in combination with chemotherapy compared to up to 0.5% 

of patients treated with chemotherapy alone. Myocardial infarction was reported in up to 1.4% of patients 

treated with bevacizumab in combination with chemotherapy compared to up to 0.7% of patients treated 

with chemotherapy alone. 

 
In one clinical trial evaluating bevacizumab in combination with 5-fluorouracil/folinic acid, AVF2192g, 

patients with metastatic colorectal cancer who were not candidates for treatment with irinotecan were 

included. In this trial arterial thromboembolic reactions were observed in 11% (11/100) of patients 

compared to 5.8% (6/104) in the chemotherapy control group. 

 
Venous thromboembolism: The incidence of venous thromboembolic reactions in clinical trials was similar 

in patients receiving bevacizumab in combination with chemotherapy compared to those receiving the 

control chemotherapy alone. Venous thromboembolic reactions include deep venous thrombosis, 

pulmonary embolism and thrombophlebitis. 

 
In clinical trials across indications, the overall incidence of venous thromboembolic reactions ranged from 

2.8% to 17.3% of bevacizumab-treated patients compared with 3.2% to 15.6% in the control arms. 

 
Grade 3-5 (NCI-CTCAE v.3) venous thromboembolic reactions have been reported in up to 7.8% of 

patients treated with chemotherapy plus bevacizumab compared with up to 4.9% in patients treated with 

chemotherapy alone (across indications, excluding persistent, recurrent, or metastatic cervical cancer). 

 
From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), 

grade 3-5 venous thromboembolic events have been reported in up to 15.6% of patients treated with 

bevacizumab in combination with paclitaxel and cisplatin compared with up to 7.0% of patients treated 

with paclitaxel and cisplatin. 

 
Patients who have experienced a venous thromboembolic reaction may be at higher risk for a recurrence if 

they receive bevacizumab in combination with chemotherapy versus chemotherapy alone. 

 
Congestive heart failure (CHF) 

In clinical trials with bevacizumab, congestive heart failure (CHF) was observed in all cancer indications 

studied to date, but occurred predominantly in patients with metastatic breast cancer. In four phase III trials 

(AVF2119g, E2100, BO17708 and AVF3694g) in patients with metastatic breast cancer CHF Grade 3 

(NCI-CTCAE v.3) or higher was reported in up to 3.5% of patients treated with bevacizumab in 

combination with chemotherapy compared with up to 0.9% in the control arms. For patients in study 

AVF3694g who received anthracyclines concomitantly with bevacizumab, the incidences of Grade 3 or 

higher CHF for the respective bevacizumab and control arms were similar to those in the other studies in 

metastatic breast cancer: 2.9% in the anthracycline + bevacizumab arm and 0% in the anthracycline + 

placebo arm. In addition, in study AVF3694g the incidences of all Grade CHF were similar between the 

anthracycline + bevacizumab (6.2%) and the anthracycline + placebo arms (6.0%). 

 
Most patients who developed CHF during mBC trials showed improved symptoms and/or left ventricular 

function following appropriate medical therapy. 



19 

 
In most clinical trials of bevacizumab, patients with pre-existing CHF of NYHA (New York Heart 

Association) II-IV were excluded, therefore, no information is available on the risk of CHF in this 

population. 

 
Prior anthracyclines exposure and/or prior radiation to the chest wall may be possible risk factors for the 

development of CHF. 

 

An increased incidence of CHF has been observed in a clinical trial of patients with diffuse large B- cell 

lymphoma when receiving bevacizumab with a cumulative doxorubicin dose greater than 300 mg/m2. This 

phase III clinical trial compared rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone 

(R-CHOP) plus bevacizumab to R- CHOP without bevacizumab. While the incidence of CHF was, in both 

arms, above that previously observed for doxorubicin therapy, the rate was higher in the R-CHOP plus 

bevacizumab arm. These results suggest that close clinical observation with appropriate cardiac 

assessments should be considered for patients exposed to cumulative doxorubicin doses greater than 300 

mg/m2 when combined with bevacizumab. 

 
Hypersensitivity reactions/infusion reactions (see section 4.4 and Post-marketing experience below) 

In some clinical trials anaphylactic and anaphylactoid-type reactions were reported more frequently in 

patients receiving bevacizumab in combination with chemotherapy than with chemotherapy alone. The 

incidence of these reactions in some clinical trials of bevacizumab is common (up to 5% in 

bevacizumab-treated patients). 

 
Infections 

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), 

grade 3-5 infections have been reported in up to 24% of patients treated with bevacizumab in combination 

with paclitaxel and topotecan compared with up to 13% of patients treated with paclitaxel and topotecan. 

 
Ovarian failure/fertility (see sections 4.4 and 4.6) 

In NSABP C-08, a phase III trial of bevacizumab in adjuvant treatment of patients with colon cancer, the 

incidence of new cases of ovarian failure, defined as amenorrhoea lasting 3 or more months, FSH 

level ≥ 30 mIU/ml and a negative serum β-HCG pregnancy test, has been evaluated in 295 premenopausal 

women. New cases of ovarian failure were reported in 2.6% patients in the mFOLFOX-6 group compared 

to 39% in the mFOLFOX-6 + bevacizumab group. After discontinuation of bevacizumab treatment, 

ovarian function recovered in 86.2% of these evaluable women. Long term effects of the treatment with 

bevacizumab on fertility are unknown. 

 
Laboratory abnormalities 

Decreased neutrophil count, decreased white blood cell count and presence of urine protein may be 

associated with bevacizumab treatment. 

 
Across clinical trials, the following Grade 3 and 4 (NCI-CTCAE v.3) laboratory abnormalities occurred in 

patients treated with bevacizumab with at least a 2% difference compared to the corresponding control 

groups: hyperglycaemia, decreased haemoglobin, hypokalaemia, hyponatraemia, decreased white blood 

cell count, increased international normalised ratio (INR). 

 
Clinical trials have shown that transient increases in serum creatinine (ranging between 1.5-1.9 times 

baseline level), both with and without proteinuria, are associated with the use of bevacizumab. The 

observed increase in serum creatinine was not associated with a higher incidence of clinical manifestations 

of renal impairment in patients treated with bevacizumab. 

 
Other special populations 

 
Elderly patients 

In randomised clinical trials, age > 65 years was associated with an increased risk of developing arterial 

thromboembolic reactions, including cerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) 

and myocardial infarctions (MIs). Other reactions with a higher frequency seen in patients over 65 were 



20 

Grade 3-4 leucopenia and thrombocytopenia (NCI-CTCAE v.3); and all Grade neutropenia, diarrhoea, 

nausea, headache and fatigue as compared to those aged ≤ 65 years when treated with bevacizumab (see 

sections 4.4 and 4.8 under Thromboembolism). In one clinical trial, the incidence of hypertension of grade 

≥ 3 was two fold higher in patients aged > 65 years than in the younger age group (<65 years). In a study 

of platinum-resistant recurrent ovarian cancer patients, alopecia, mucosal inflammation, peripheral sensory 

neuropathy, proteinuria and hypertension were also reported and occurred at a rate at least 5% higher in the 

CT + BV arm for bevacizumab-treated patients ≥ 65 years of age compared with bevacizumab-treated 

patients aged < 65 years. 

No increase in the incidence of other reactions, including gastrointestinal perforation, wound healing 

complications, congestive heart failure, and haemorrhage was observed in elderly patients (> 65 years) 

receiving bevacizumab as compared to those aged ≤ 65 years treated with bevacizumab. 

 
Paediatric population 

The safety and efficacy of bevacizumab in children less than 18 years old have not been established. 

 
In study BO25041 of bevacizumab added to postoperative radiation therapy (RT) with concomitant and 

adjuvant temozolomide in paediatric patients with newly diagnosed supratentorial, infratentorial, 

cerebellar, or peduncular high-grade glioma, the safety profile was comparable with that observed in other 

tumour types in adults treated with bevacizumab. 

 
In study BO20924 of bevacizumab with current standard of care in rhabdomyosarcoma and 

non-rhabdomyosarcoma soft tissue sarcoma, the safety profile of bevacizumab-treated children was 

comparable with that observed in adults treated with bevacizumab. 

 
Bevacizumab is not approved for use in patients under the age of 18 years. In published literature reports, 

cases of non-mandibular osteonecrosis have been observed in patients under the age of 18 years treated 

with bevacizumab. 

 

Post-marketing experience 

 
Table 3. Adverse reactions reported in post-marketing setting 

System organ class 

(SOC) 
Reactions (frequency*) 

Infections and infestations 
Necrotising fasciitis, usually secondary to wound healing complications, 

gastrointestinal perforation or fistula formation (rare) (see also section 4.4) 

Immune system disorders Hypersensitivity reactions and infusion reactions (not known); with the 

following possible co-manifestations: dyspnoea/difficulty breathing, 

flushing/redness/rash, hypotension or hypertension, oxygen desaturation, chest 

pain, rigors and nausea/vomiting (see also section 4.4 and Hypersensitivity 

reactions/infusion reactions above) 

Nervous system disorders Hypertensive encephalopathy (very rare) (see also section 4.4 and 

Hypertension in section 4.8) 

Posterior Reversible Encephalopathy Syndrome (PRES), (rare) (see also 

section 4.4) 

Vascular disorders Renal thrombotic microangiopathy, which may be clinically manifested as 

proteinuria (not known) with or without concomitant sunitinib use. For further 

information on proteinuria see section 4.4 and Proteinuria in section 4.8. 

Respiratory, thoracic and 

mediastinal disorders 

Nasal septum perforation (not known) 

Pulmonary hypertension (not known) 

Dysphonia (common) 

Gastrointestinal disorders Gastrointestinal ulcer (not known) 

Hepatobiliary disorders Gall bladder perforation (not known) 

Musculoskeletal and Cases of Osteonecrosis of the Jaw (ONJ) have been reported in patients treated 



21 

System organ class 

(SOC) 
Reactions (frequency*) 

connective tissue disorders with bevacizumab, most of which occurred in patients who had identified risk 

factors for ONJ, in particular exposure to intravenous bisphosphonates and/or a 

history of dental disease requiring invasive dental procedures (see also section 

4.4) 

Cases of non-mandibular osteonecrosis have been observed in 

bevacizumab-treated paediatric patients (see section 4.8, Paediatric 

population). 

Congenital, familial, and 

genetic disorder 

Cases of foetal abnormalities in women treated with bevacizumab alone or in 

combination with known embryotoxic chemotherapeutics have been observed 

(see section 4.6) 

* if specified, the frequency has been derived from clinical trial data 
 

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 

 

The highest dose tested in humans (20 mg/kg of body weight, intravenous every 2 weeks) was associated 

with severe migraine in several patients. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1 Pharmacodynamic properties 

 
Pharmacotherapeutic group: antineoplastic and immunomodulating agents, antineoplastic agents, other 

antineoplastic agents, monoclonal antibodies, ATC code: L01X C07 

 

Aybintio is a biosimilar medicinal product. Detailed information is available on the website of the 

European Medicines Agency http://www.ema.europa.eu. 

 
Mechanism of action 

Bevacizumab binds to vascular endothelial growth factor (VEGF), the key driver of vasculogenesis and 

angiogenesis, and thereby inhibits the binding of VEGF to its receptors, Flt-1 (VEGFR-1) and KDR 

(VEGFR-2), on the surface of endothelial cells. Neutralising the biological activity of VEGF regresses the 

vascularisation of tumours, normalises remaining tumour vasculature, and inhibits the formation of new 

tumour vasculature, thereby inhibiting tumour growth. 
 

Pharmacodynamic effects 

Administration of bevacizumab or its parental murine antibody to xenotransplant models of cancer in nude 

mice resulted in extensive anti-tumour activity in human cancers, including colon, breast, pancreas and 

prostate. Metastatic disease progression was inhibited and microvascular permeability was reduced. 

 
Clinical efficacy and safety 

 
Metastatic carcinoma of the colon or rectum (mCRC) 

 

The safety and efficacy of the recommended dose (5 mg/kg of body weight every two weeks) in metastatic 

carcinoma of the colon or rectum were studied in three randomised, active-controlled clinical trials in 

combination with fluoropyrimidine-based first-line chemotherapy. Bevacizumab was combined with two 

chemotherapy regimens: 

 

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


22 

• AVF2107g: A weekly schedule of irinotecan/bolus 5-fluorouracil/folinic acid (IFL) for a total of 
4 weeks of each 6 week-cycle (Saltz regimen). 

• AVF0780g: In combination with bolus 5-fluorouracil/folinic acid (5-FU/FA) for a total of 6 weeks 
of each 8 week-cycle (Roswell Park regimen). 

• AVF2192g: In combination with bolus 5-FU/FA for a total of 6 weeks of each 8 week-cycle 
(Roswell Park regimen) in patients who were not optimal candidates for first-line irinotecan 

treatment. 

 

Three additional studies with bevacizumab have been conducted in mCRC patients: first-line (NO16966), 

second-line with no previous bevacizumab treatment (E3200), and second-line with previous bevacizumab 

treatment following disease progression in first-line (ML18147). In these studies, bevacizumab was 

administered at the following dosing regimens in combination with FOLFOX-4 (5-FU/LV/oxaliplatin), 

XELOX (capecitabine/oxaliplatin), and fluoropyrimidine/irinotecan and fluoropyrimidine/oxaliplatin: 

 

• NO16966: Bevacizumab 7.5 mg/kg of body weight every 3 weeks in combination with oral 
capecitabine and intravenous oxaliplatin (XELOX) or bevacizumab 5 mg/kg every 2 weeks in 

combination with leucovorin plus 5-fluorouracil bolus, followed by 5-fluorouracil infusion, with 

intravenous oxaliplatin (FOLFOX-4). 

• E3200: Bevacizumab 10 mg/kg of body weight every 2 weeks in combination with leucovorin and 
5-fluorouracil bolus, followed by 5-fluorouracil infusion, with intravenous oxaliplatin (FOLFOX-4) 

in bevacizumab-naïve patients. 

• ML18147: Bevacizumab 5.0 mg/kg of body weight every 2 weeks or bevacizumab 7.5 mg/kg of 
body weight every 3 weeks in combination with fluoropyrimidine/irinotecan or 

fluoropyrimidine/oxaliplatin in patients with disease progression following first-line treatment with 

bevacizumab. Use of irinotecan- or oxaliplatin-containing regimen was switched depending on 

first-line usage of either oxaliplatin or irinotecan. 

 
AVF2107g 

This was a phase III randomised, double-blind, active-controlled clinical trial evaluating bevacizumab in 

combination with IFL as first-line treatment for metastatic carcinoma of the colon or rectum. 

Eight hundred and thirteen patients were randomised to receive IFL + placebo (Arm 1) or 

IFL + bevacizumab (5 mg/kg every 2 weeks, Arm 2). A third group of 110 patients received bolus 

5-FU/FA + bevacizumab (Arm 3). Enrolment in Arm 3 was discontinued, as pre-specified, once safety of 

bevacizumab with the IFL regimen was established and considered acceptable. All treatments were 

continued until disease progression. The overall mean age was 59.4 years; 56.6% of patients had an ECOG 

performance status of 0, 43% had a value of 1 and 0.4% had a value of 2. 15.5% had received prior 

radiotherapy and 28.4% prior chemotherapy. 

 
The primary efficacy variable of the trial was overall survival. The addition of bevacizumab to IFL resulted 

in statistically significant increases in overall survival, progression-free survival and overall response rate 

(see Table 4). The clinical benefit, as measured by overall survival, was seen in all pre-specified patient 

subgroups, including those defined by age, sex, performance status, location of primary tumour, number of 

organs involved and duration of metastatic disease. 
 

The efficacy results of bevacizumab in combination with IFL-chemotherapy are displayed in Table 4. 



23 

Table 4 . Efficacy results for trial AVF2107g 

 AVF2107g 

Arm 1 

IFL + placebo 

Arm 2 

IFL + bevacizumaba 

Number of patients 411 402 

Overall survival 

Median time (months) 15.6 20.3 

95% CI 14.29 – 16.99 18.46 – 24.18 

Hazard ratiob 0.660 

(p-value = 0.00004) 

Progression-free survival 

Median time (months) 6.2 10.6 

Hazard ratio 0.54 

(p-value < 0.0001) 

Overall response rate 

Rate (%) 34.8 44.8 

 (p-value = 0.0036) 
a 5 mg/kg every 2 weeks. 
b Relative to control arm. 

 

Among the 110 patients randomised to Arm 3 (5-FU/FA + bevacizumab) prior to discontinuation of this 

arm, the median overall survival was 18.3 months and the median progression free survival was 

8.8 months. 

 
AVF2192g 

This was a phase II randomised, double-blind, active-controlled clinical trial evaluating the efficacy and 

safety of bevacizumab in combination with 5-FU/FA as first-line treatment for metastatic colorectal cancer 

in patients who were not optimal candidates for first-line irinotecan treatment. One hundred and five 

patients were randomised to 5-FU/FA + placebo arm and 104 patients to 5-FU/FA + bevacizumab (5 mg/kg 

every 2 weeks) arm. All treatments were continued until disease progression. The addition of bevacizumab 

5 mg/kg every two weeks to 5-FU/FA resulted in higher objective response rates, significantly longer 

progression-free survival, and a trend in longer survival as compared to 5-FU/FA chemotherapy alone. 

 
AVF0780g 

This was a phase II randomised, active-controlled, open-labelled clinical trial investigating bevacizumab in 

combination with 5-FU/FA as first-line treatment of metastatic colorectal cancer. The median age was 64 

years. 19% of the patients had received prior chemotherapy and 14% prior radiotherapy. 

Seventy-one patients were randomised to receive bolus 5-FU/FA or 5-FU/FA + bevacizumab (5 mg/kg 

every 2 weeks). A third group of 33 patients received bolus 5-FU/FA + bevacizumab (10 mg/kg every 

2 weeks). Patients were treated until disease progression. The primary endpoints of the trial were objective 

response rate and progression-free survival. The addition of bevacizumab 5 mg/kg every two weeks to 

5-FU/FA resulted in higher objective response rates, longer progression-free survival, and a trend in longer 

survival, compared with 5-FU/FA chemotherapy alone (see Table 5). These efficacy data are consistent 

with the results from trial AVF2107g. 

 
The efficacy data from trials AVF0780g and AVF2192g investigating bevacizumab in combination with 

5-FU/FA-chemotherapy are summarised in Table 5. 



24 

Table 5. Efficacy results for trials AVF0780g and AVF2192g 

 AVF0780g AVF2192g 

5-FU/FA 
5-FU/FA + 

bevacizumaba 

5-FU/FA + 

bevacizumabb 

5-FU/FA + 

placebo 

5-FU/FA + 

bevacizumab 

Number of patients 36 35 33 105 104 

Overall survival 

Median time (months) 13.6 17.7 15.2 12.9 16.6 

95% CI    10.35 - 16.95 13.63 - 19.32 

Hazard ratioc - 0.52 1.01  0.79 

p-value  0.073 0.978  0.16 

Progression-free survival 

Median time (months) 5.2 9.0 7.2 5.5 9.2 

Hazard ratio  0.44 0.69  0.5 

p-value - 0.0049 0.217  0.0002 

Overall response rate 

Rate (percent) 16.7 40.0 24.2 15.2 26 

95% CI 7.0 − 33.5 24.4 − 57.8 11.7 – 42.6 9.2 - 23.9 18.1 - 35.6 

p-value  0.029 0.43  0.055 

Duration of response 

Median time (months) NR 9.3 5.0 6.8 9.2 

25–75 percentile (months) 5.5 − NR 6.1 − NR 3.8 – 7.8 5.59 - 9.17 5.88 - 13.01 
a 5 mg/kg every 2 weeks. 
b 10 mg/kg every 2 weeks.  
c Relative to control arm.  

NR = not reached. 

 

NO16966 
This was a phase III randomised, double-blind (for bevacizumab), clinical trial investigating bevacizumab 

7.5 mg/kg in combination with oral capecitabine and IV oxaliplatin (XELOX), administered on a 3-weekly 

schedule; or bevacizumab 5 mg/kg in combination with leucovorin with 5-fluorouracil bolus, followed by 

5-fluorouracil infusional, with IV oxaliplatin (FOLFOX-4), administered on a 2-weekly schedule. The trial 

contained two parts: an initial unblinded 2-arm part (Part I) in which patients were randomised to two 

different treatment groups (XELOX and FOLFOX-4) and a subsequent 2 x 2 factorial 4-arm part (Part II) 

in which patients were randomised to four treatment groups (XELOX + placebo, FOLFOX-4 + placebo, 

XELOX + bevacizumab, FOLFOX-4 + bevacizumab). In Part II, treatment assignment was double-blind 

with respect to bevacizumab. 

 
Approximately 350 patients were randomised into each of the 4 trial arms in the Part II of the trial. 



25 

Table 6. Treatment regimens in trial NO16966 (mCRC) 

 Treatment Starting dose Schedule 

FOLFOX-4 

or 

FOLFOX-4 + 

bevacizumab 

Oxaliplatin 

Leucovorin 

5-Fluorouracil 

85 mg/m2 IV 2 h 

200 mg/m2 IV 2 h 

400 mg/m2  IV bolus, 

600 mg/m2 IV 22 h 

Oxaliplatin on day 1 

Leucovorin on day 1 and 2 

5-fluorouracil IV bolus/infusion, each 

on days 1 and 2 

Placebo or 

bevacizumab 

5 mg/kg IV 30-90 min Day 1, prior to FOLFOX-4, every 2 

weeks 

XELOX 

or 

XELOX + 

bevacizumab 

Oxaliplatin 

Capecitabine 

130 mg/m2 IV 2 h 

1000 mg/m2 oral bid 

Oxaliplatin on day 1 

Capecitabine oral bid for 2 weeks 

(followed by 1 week off treatment) 

Placebo or 

bevacizumab 

7.5 mg/kg IV 30-90 min Day 1, prior to XELOX, q 3 weeks 

5-Fluorouracil: IV bolus injection immediately after leucovorin 

 

The primary efficacy parameter of the trial was the duration of progression-free survival. In this trial, there 

were two primary objectives: to show that XELOX was non-inferior to FOLFOX-4 and to show that 

bevacizumab in combination with FOLFOX-4 or XELOX chemotherapy was superior to chemotherapy 

alone. Both co-primary objectives were met: 

 
● Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4-containing arms in 

the overall comparison was demonstrated in terms of progression-free survival and overall survival 

in the eligible per-protocol population. 

 
● Superiority of the bevacizumab-containing arms versus the chemotherapy alone arms in the overall 

comparison was demonstrated in terms of progression-free survival in the ITT population (Table 7). 

 
Secondary PFS analyses, based on ‘on-treatment’-based response assessments, confirmed the significantly 

superior clinical benefit for patients treated with bevacizumab (analyses shown in Table 7), consistent with 

the statistically significant benefit observed in the pooled analysis. 



26 

Table 7. Key efficacy results for the superiority analysis (ITT population, trial NO16966) 

Endpoint (months) FOLFOX-4 

or XELOX 

+ placebo (n=701) 

FOLFOX-4 

or XELOX 

+ bevacizumab 

(n=699) 

P-value 

Primary endpoint 

Median PFS** 8.0 9.4 0.0023 

Hazard ratio (97.5% CI) a 0.83 (0.72–0.95)  

Secondary endpoints 

Median PFS (on treatment)** 7.9 10.4 < 0.0001 

Hazard ratio (97.5% CI) 0.63 (0.52-0.75)  

Overall response rate 

(invest. assessment)** 

49.2 % 46.5 %  

Median overall survival* 19.9 21.2 0.0769 

Hazard ratio (97.5% CI) 0.89 (0.76-1.03)  

* Overall survival analysis at clinical cut-off 31 January 2007 

** Primary analysis at clinical cut-off 31 January 2006 
a relative to control arm 

 
In the FOLFOX treatment subgroup, the median PFS was 8.6 months in placebo and 9.4 months in 

bevacizumab treated patients, HR = 0.89, 97.5% CI = [0.73; 1.08]; p-value = 0.1871, the corresponding 

results in the XELOX treatment subgroup being 7.4 vs. 9.3 months, HR = 0.77, 97.5% CI = [0.63; 0.94]; 

p-value = 0.0026. 

 
The median overall survival was 20.3 months in placebo and 21.2 months in bevacizumab treated patients 

in the FOLFOX treatment subgroup, HR=0.94, 97.5% CI = [0.75; 1.16]; p-value = 0.4937, the 

corresponding results in the XELOX, treatment subgroup being 19.2 vs. 21.4 months, HR = 0.84, 97.5% CI 

= [0.68; 1.04]; p-value = 0.0698. 

 
ECOG E3200 

This was a phase III randomised, active-controlled, open-label trial investigating bevacizumab 10 mg/kg in 

combination with leucovorin with 5-fluorouracil bolus and then 5-fluorouracil infusional, with IV 

oxaliplatin (FOLFOX-4), administered on a 2-weekly schedule in previously-treated patients (second line) 

with advanced colorectal cancer. In the chemotherapy arms, the FOLFOX-4 regimen used the same doses 

and schedule as shown in Table 6 for trial NO16966. 

 
The primary efficacy parameter of the trial was overall survival, defined as the time from randomisation to 

death from any cause. Eight hundred and twenty-nine patients were randomised (292 FOLFOX-4, 293 

bevacizumab + FOLFOX-4 and 244 bevacizumab monotherapy). The addition of bevacizumab to 

FOLFOX-4 resulted in a statistically significant prolongation of survival. Statistically significant 

improvements in progression-free survival and objective response rate were also observed (see Table 8). 



27 

Table 8. Efficacy results for trial E3200 

 E3200 

FOLFOX-4 FOLFOX-4 + bevacizumaba 

Number of patients 292 293 

Overall survival 

Median (months) 10.8 13.0 

95% CI 10.12 – 11.86 12.09 – 14.03 

Hazard ratiob 0.751 

(p-value = 0.0012) 

Progression-free survival 

Median (months) 4.5 7.5 

Hazard ratio 0.518 

(p-value < 0.0001) 

Objective response rate 

Rate 8.6% 22.2% 

 (p-value < 0.0001) 
a 10 mg/kg every 2 weeks 
b Relative to control arm 

 
No significant difference was observed in the duration of overall survival between patients who received 

bevacizumab monotherapy compared to patients treated with FOLFOX-4. Progression-free survival and 

objective response rate were inferior in the bevacizumab monotherapy arm compared to the FOLFOX-4 

arm. 

 
ML18147 

This was a Phase III randomised, controlled, open-label trial investigating bevacizumab 5.0 mg/kg every 

2 weeks or 7.5 mg/kg every 3 weeks in combination with fluoropyrimidine-based chemotherapy versus 

fluoropyrimidine-based chemotherapy alone in patients with mCRC who have progressed on a first-line 

bevacizumab-containing regimen. 

 

Patients with histologically confirmed mCRC and disease progression were randomised 1:1 within 3 

months after discontinuation of bevacizumab first-line therapy to receive fluoropyrimidine/oxaliplatin- or 

fluoropyrimidine/irinotecan-based chemotherapy (chemotherapy switched depending on first-line 

chemotherapy) with or without bevacizumab. Treatment was given until progressive disease or 

unacceptable toxicity. The primary outcome measure was overall survival defined as the time from 

randomisation until death from any cause. 

 

A total of 820 patients were randomised. The addition of bevacizumab to fluoropyrimidine-based 

chemotherapy resulted in a statistically significant prolongation of survival in patients with mCRC who 

have progressed on a first-line bevacizumab-containing regimen (ITT = 819) (see Table 9). 



28 

Table 9. Efficacy results for study ML18147 (ITT population) 

 ML18147 

 
fluoropyrimidine/irinotecan 

or 

fluoropyrimidine/oxaliplatin 

based chemotherapy 

fluoropyrimidine/irinotecan 

or 

fluoropyrimidine/oxaliplatin 

based chemotherapy 

+ bevacizumaba 

Number of Patients 410 409 

Overall Survival 

Median (months) 9.8 11.2 

Hazard ratio (95% 

confidence interval) 

0.81 (0.69, 0.94)  

(p-value = 0.0062) 

Progression-Free Survival 

Median (months) 4.1 5.7 

Hazard ratio (95% 

confidence interval) 

0.68 (0.59, 0.78)  

(p-value < 0.0001) 

Objective Response Rate (ORR) 

Patients included in analysis 406 404 

Rate 3.9% 5.4% 

 (p-value = 0.3113) 
a 5.0 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks 

 
Statistically significant improvements in progression-free survival were also observed. Objective response 

rate was low in both treatment arms and the difference was not significant. 

 
Study E3200 used a 5 mg/kg/week equivalent dose of bevacizumab in bevacizumab-naïve patients, while 

study ML18147 used a 2.5 mg/kg/week equivalent dose of bevacizumab in bevacizumab-pretreated 

patients. A cross-trial comparison of the efficacy and safety data is limited by differences between these 

studies, most notably in patient populations, previous bevacizumab exposure and chemotherapy regimens. 

Both the 5 mg/kg/week and 2.5 mg/kg/week equivalent doses of bevacizumab provided a statistically 

significant benefit with regards to OS (HR 0.751 in study E3200; HR 0.81 in study ML18147) and PFS 

(HR 0.518 in study E3200; HR 0.68 in study ML18147). In terms of safety, there was a higher overall 

incidence of Grade 3-5 AEs in study E3200 relative to study ML18147. 

 
Metastatic breast cancer (mBC) 

 

Two large Phase III trials were designed to investigate the treatment effect of bevacizumab in combination 

with two individual chemotherapy agents, as measured by the primary endpoint of PFS. A clinically 

meaningful and statistically significant improvement in PFS was observed in both trials. 

 
Summarised below are PFS results for the individual chemotherapy agents included in the indication: 

 
• Study E2100 (paclitaxel) 

• Median PFS increase 5.6 months, HR 0.421 (p < 0.0001, 95% CI 0.343; 0.516) 

• Study AVF3694g (capecitabine) 

• Median PFS increase 2.9 months, HR 0.69 (p = 0.0002, 95% CI 0.56; 0.84) 

 
Further details of each study and the results are provided below. 

 



29 

ECOG E2100 

Trial E2100 was an open-label, randomised, active controlled, multicentre clinical trial evaluating 

bevacizumab in combination with paclitaxel for locally recurrent or metastatic breast cancer in patients 

who had not previously received chemotherapy for locally recurrent and metastatic disease. Patients were 

randomised to paclitaxel alone (90 mg/m2 IV over 1 hour once weekly for three out of four weeks) or in 

combination with bevacizumab (10 mg/kg IV infusion every two weeks). Prior hormonal therapy for the 

treatment of metastatic disease was allowed. Adjuvant taxane therapy was allowed only if it was completed 

at least 12 months prior to trial entry. Of the 722 patients in the trial, the majority of patients had 

HER2-negative disease (90%), with a small number of patients with unknown (8%) or confirmed 

HER2-positive status (2%), who had previously been treated with or were considered unsuitable for 

trastuzumab therapy. Furthermore, 65% of patients had received adjuvant chemotherapy including 19% 

prior taxanes and 49% prior anthracyclines. Patients with central nervous system metastases, including 

previously treated or resected brain lesions, were excluded. 

 
In trial E2100, patients were treated until disease progression. In situations where early discontinuation of 

chemotherapy was required, treatment with bevacizumab as a single agent continued until disease 

progression. The patient characteristics were similar across the trial arms. The primary endpoint of this trial 

was progression free survival (PFS), based on trial investigators’ assessment of disease progression. In 

addition, an independent review of the primary endpoint was also conducted. The results of this trial are 

presented in Table 10. 

 
Table 10. Trial E2100 efficacy results 

Progression-free survival 

 Investigator assessment* IRF assessment 

 Paclitaxel 

 
(n=354) 

Paclitaxel/ 

bevacizumab 

(n=368) 

Paclitaxel 

 
(n=354) 

Paclitaxel/ 

bevacizumab 

(n=368) 

Median PFS (months) 5.8 11.4 5.8 11.3 

HR 

(95% CI) 

0.421 

(0.343; 0.516) 

0.483 

(0.385; 0.607) 

p-value < 0.0001 < 0.0001 

Response rates (for patients with measurable disease) 

 Investigator assessment IRF assessment 

 Paclitaxel 

 
(n=273) 

Paclitaxel/ 

bevacizumab 

(n=252) 

Paclitaxel 

 
(n=243) 

Paclitaxel/ 

bevacizumab 

(n=229) 

% pts with objective 

response 
23.4 48.0 22.2 49.8 

p-value < 0.0001 < 0.0001 

* primary analysis 

 

Overall survival 

 
Paclitaxel 

(n=354) 

Paclitaxel/ 

bevacizumab 

(n=368) 

Median OS (months) 24.8 26.5 

HR 

(95% CI) 

0.869 

(0.722; 1.046) 

p-value 0.1374 

 



30 

The clinical benefit of bevacizumab as measured by PFS was seen in all pre-specified subgroups tested 

(including disease-free interval, number of metastatic sites, prior receipt of adjuvant chemotherapy and 

oestrogen receptor (ER) status). 

 

AVF3694g 

Study AVF3694g was a Phase III, multicentre, randomised, placebo-controlled trial designed to evaluate 

the efficacy and safety of bevacizumab in combination with chemotherapy compared to chemotherapy plus 

placebo as first-line treatment for patients with HER2-negative metastatic or locally recurrent breast cancer. 

 
Chemotherapy was chosen at the investigator's discretion prior to randomisation in a 2:1 ratio to receive 

either chemotherapy plus bevacizumab or chemotherapy plus placebo. The choices of chemotherapy 

included capecitabine, taxane (protein-bound paclitaxel, docetaxel), and anthracycline-based agents 

(doxorubicin/ cyclophosphamide, epirubicin/ cyclophosphamide, 5-fluorouracil/ doxorubicin/ 

cyclophosphamide, 5-fluorouracil/epirubicin/cyclophosphamide) given every three weeks (q3w). 

bevacizumab or placebo was administered at a dose of 15 mg/kg q3w. 

 
This study included a blinded treatment phase, an optional open-label post-progression phase, and a 

survival follow-up phase. During the blinded treatment phase, patients received chemotherapy and 

medicinal product (bevacizumab or placebo) every 3 weeks until disease progression, treatment-limiting 

toxicity, or death. On documented disease progression, patients who entered the optional open-label phase 

could receive open-label bevacizumab together with a wide-range of second line therapies. 

 
Statistical analyses were performed independently for 1) patients who received capecitabine in combination 

with bevacizumab or placebo; 2) patients who received taxane-based or anthracycline-based chemotherapy 

in combination with bevacizumab or placebo. The primary endpoint of the study was PFS by investigator 

assessment. In addition, the primary endpoint was also assessed by an independent review committee 

(IRC). 

 
The results of this study from the final protocol defined analyses for progression free survival and response 

rates for the independently powered capecitabine cohort of Study AVF3694g are presented in Table 11 

Results from an exploratory overall survival analysis which include an additional 7 months of follow-up 

(approximately 46% of patients had died) are also presented. The percentage of patients who received 

bevacizumab in the open-label phase was 62.1% in the capecitabine + placebo arm and 49.9% in the 

capecitabine + bevacizumab arm. 



31 

Table 11. Efficacy results for study AVF3694g: – Capecitabinea and bevacizumab/Placebo (Cap + 

bevacizumab/Pl) 

Progression-free survivalb 

 Investigator Assessment IRC Assessment 

 Cap + Pl 

(n=206) 

Cap +  

bevacizumab 

(n=409) 

Cap + Pl 

(n=206) 

Cap + 

bevacizumab 

(n=409) 

Median PFS (months) 5.7 8.6 6.2 9.8 

Hazard ratio vs placebo 

arm (95% CI) 

0.69 (0.56; 0.84) 0.68 (0.54; 0.86) 

p-value 0.0002 0.0011 

Response rate (for patients with measurable disease)b 

 Cap + Pl (n=161) Cap + bevacizumab (n=325) 

% pts with objective 

response 

23.6 35.4 

p-value 0.0097 

Overall survivalb 

HR (95% CI) 0.88 (0.69; 1.13) 

p-value (exploratory) 0.33 
a 1000 mg/m2 oral twice daily for 14 days administered every 3 weeks 
b Stratified analysis included all progression and death events except those where non-protocol therapy (NPT) was 

initiated prior to documented progression; data from those patients were censored at the last tumour assessment prior 

to starting NPT. 
 

 

An unstratified analysis of PFS (investigator assessed) was performed that did not censor for non- protocol 

therapy prior to disease progression. The results of these analyses were very similar to the primary PFS 

results. 
 

Non-small cell lung cancer (NSCLC) 

 

First-line treatment of non-squamous NSCLC in combination with platinum-based chemotherapy 

The safety and efficacy of bevacizumab, in addition to platinum-based chemotherapy, in the first-line 

treatment of patients with non-squamous non-small cell lung cancer (NSCLC), was investigated in trials 

E4599 and BO17704. An overall survival benefit has been demonstrated in trial E4599 with a  

15 mg/kg/q3wk dose of bevacizumab. Trial BO17704 has demonstrated that both 7.5 mg/kg/q3wk and  

15 mg/kg/q3wk bevacizumab doses increase progression free survival and response rate. 

 
E4599 

E4599 was an open-label, randomised, active-controlled, multicentre clinical trial evaluating bevacizumab 

as first-line treatment of patients with locally advanced (stage IIIb with malignant pleural effusion), 

metastatic or recurrent NSCLC other than predominantly squamous cell histology. 

 

Patients were randomised to platinum-based chemotherapy (paclitaxel 200 mg/m2) and carboplatin AUC = 

6.0, both by IV infusion (PC) on day 1 of every 3-week cycle for up to 6 cycles or PC in combination with 

bevacizumab at a dose of 15 mg/kg IV infusion day 1 of every 3-week cycle. After completion of six cycles 

of carboplatin-paclitaxel chemotherapy or upon premature discontinuation of chemotherapy, patients on the 

bevacizumab + carboplatin–paclitaxel arm continued to receive bevacizumab as a single agent every  

3 weeks until disease progression. 878 patients were randomised to the two arms. 

 



32 

During the trial, of the patients who received trial treatment, 32.2% (136/422) of patients received 

7-12 administrations of bevacizumab and 21.1% (89/422) of patients received 13 or more administrations 

of bevacizumab. 

 
The primary endpoint was duration of survival. Results are presented in Table 12. 

 
Table 12. Efficacy results for trial E4599 

 Arm 1 

Carboplatin/ Paclitaxel 

Arm 2 

Carboplatin/ Paclitaxel + 

bevacizumab 

15 mg/kg q 3 weeks 

Number of patients 444 434 

Overall survival 

Median (months) 10.3 12.3 

Hazard ratio 0.80 (p=0.003) 

95% CI (0.69; 0.93) 

Progression-free survival 

Median (months) 4.8 6.4 

Hazard ratio 0.65 (p < 0.0001) 

95% CI (0.56; 0.76) 

Overall response rate 

Rate (percent) 12.9 29.0 (p < 0.0001) 

 

In an exploratory analysis, the extent of bevacizumab benefit on overall survival was less pronounced in 

the subgroup of patients who did not have adenocarcinoma histology. 

 
BO17704 

Trial BO17704 was a randomised, double-blind phase III trial of bevacizumab in addition to cisplatin and 

gemcitabine versus placebo, cisplatin and gemcitabine in patients with locally advanced (stage IIIb with 

supraclavicular lymph node metastases or with malignant pleural or pericardial effusion), metastatic or 

recurrent non-squamous NSCLC, who had not received prior chemotherapy. The primary endpoint was 

progression free survival, secondary endpoints for the trial included the duration of overall survival. 

 

Patients were randomised to platinum-based chemotherapy, cisplatin 80 mg/m2 intravenous infusion 

on day 1 and gemcitabine 1250 mg/m2 intravenous infusion on days 1 and 8 of every 3-week cycle for up 

to 6 cycles (CG) with placebo or CG with bevacizumab at a dose of 7.5 or 15 mg/kg IV infusion day 1 of 

every 3-week cycle. In the bevacizumab-containing arms, patients could receive bevacizumab as a 

single-agent every 3 weeks until disease progression or unacceptable toxicity. Trial results show that 94% 

(277 / 296) of eligible patients went on to receive single agent bevacizumab at cycle 7. A high proportion 
of patients (approximately 62%) went on to receive a variety of non-protocol specified anti-cancer 

therapies, which may have impacted the analysis of overall survival. 

 



33 

The efficacy results are presented in Table 13. 

 
Table 13. Efficacy results for trial BO17704 

 Cisplatin/Gemcitabine 

+ placebo 

Cisplatin/Gemcitabine 

+ bevacizumab 

7.5 mg/kg q 3 weeks 

Cisplatin/Gemcitabine 

+ bevacizumab 

15 mg/kg q 3 weeks 

Number of patients 347 345 351 

Progression-free 

survival 

   

Median (months)  6.1 6.7  

(p=0.0026) 

6.5  

(p=0.0301) 

Hazard ratio  0.75 

[0.62; 0.91] 

0.82 

[0.68; 0.98] 

Best overall response 

ratea 

20.1% 34.1% 

(p < 0.0001) 
30.4% 

(p=0.0023) 
a Patients with measurable disease at baseline 

 

Overall survival 

Median (months)  13.1 13.6 

(p=0.4203) 

13.4 

(p=0.7613) 

Hazard ratio  0.93 

[0.78; 1.11] 

1.03 

[0.86; 1.23] 

 

First-line treatment of non-squamous NSCLC with EGFR activating mutations in combination with 

erlotinib 

 
JO25567 

Study JO25567 was a randomized, open-label, multi-center Phase II study conducted in Japan to evaluate 

the efficacy and safety of bevacizumab used in addition to erlotinib in patients with non-squamous NSCLC 

with EGFR activating mutations (exon 19 deletion or exon 21 L858R mutation) who had not received prior 

systemic therapy for Stage IIIB/IV or recurrent disease. 

 

The primary endpoint was progression-free survival (PFS) based on independent review assessment. 

Secondary endpoints included overall survival, response rate, disease control rate, duration of response, 

and safety. 

 

EGFR mutation status was determined for each patient prior to patient screening and 154 patients were 

randomised to receive either erlotinib + bevacizumab (erlotinib 150 mg oral daily + bevacizumab 

[15 mg/kg IV every 3 weeks]) or erlotinib monotherapy (150 mg oral daily) until disease progression (PD) 

or unacceptable toxicity. In the absence of PD, discontinuation of one component of study treatment in the 

erlotinib + bevacizumab arm did not lead to discontinuation of the other component of study treatment as 

specified in the study protocol. 

 



34 

The efficacy results of the study are presented in Table 14. 
 

Table 14. Efficacy results for study JO25567 

 

  

Erlotinib 

N = 77# 

Erlotinib + bevacizumab 

N = 75# 

PFS^ (months)    

Median 9.7 16.0 

HR (95% CI) 0.54 (0.36; 0.79) 

p-value 0.0015 

Overall Response Rate   

Rate (n) 63.6% (49) 69.3% (52) 

p-value 0.4951 

Overall Survival* (months)    

Median 47.4 47.0 

HR (95% CI) 0.81 (0.53; 1.23) 

p-value 0.3267 

#  A total of 154 patients (ECOG Performance Status 0 or 1) were randomized. However two of the randomized 

patients discontinued the study before receiving any study treatment 

^  Blinded independent review (protocol-defined primary analysis) 

*  Exploratory analysis: final OS analysis at clinical cut off on 31 October 2017, approx. 59% of patients had died. 

CI, confidence interval; HR, Hazard ratio from unstratified Cox regression analysis; NR, not reached. 

 
Advanced and/or metastatic renal cell cancer (mRCC) 

 

Bevacizumab in combination with interferon alfa-2a for the first-line treatment of advanced and/ or 

metastatic renal cell cancer (BO17705) 

 

This was a phase III randomised double-blind trial conducted to evaluate the efficacy and safety of 

bevacizumab in combination with interferon (IFN) alfa-2a versus IFN alfa-2a alone as first-line treatment 

in mRCC. The 649 randomised patients (641 treated) had Karnofsky Performance Status (KPS) of ≥ 70%, 

no CNS metastases and adequate organ function. Patients were nephrectomised for primary renal cell 

carcinoma. Bevacizumab 10 mg/kg was given every 2 weeks until disease progression. IFN alfa-2a was 

given up to 52 weeks or until disease progression at a recommended starting dose of 9 MIU three times a 

week, allowing a dose reduction to 3 MIU three times a week in 2 steps. Patients were stratified according 

to country and Motzer score and the treatment arms were shown to be well balanced for the prognostic 

factors. 

 
The primary endpoint was overall survival, with secondary endpoints for the trial including 

progression-free survival. The addition of bevacizumab to IFN-alpha-2a significantly increased PFS and 

objective tumour response rate. These results have been confirmed through an independent radiological 

review. However, the increase in the primary endpoint of overall survival by 2 months was not significant 

(HR= 0.91). A high proportion of patients (approximately 63% IFN/placebo; 55% bevacizumab/IFN) 

received a variety of non-specified post-trial anti-cancer therapies, including antineoplastic agents, which 

may have impacted the analysis of overall survival. 



35 

The efficacy results are presented in Table 15. 

 
Table 15. Efficacy results for trial BO17705 

 BO17705 

Placebo + IFNa BVb + IFNa 

Number of patients 322 327 

Progression-free survival   

Median (months)  5.4 10.2 

Hazard ratio 

95% CI 

0.63 

0.52, 0.75 

(p-value < 0.0001) 

Objective response rate (%) in Patients with 

measurable disease 

  

N 289 306 

Response rate 12.8% 31.4% 

 (p-value < 0.0001) 
a Interferon alfa-2a 9 MIU 3x/week 
b Bevacizumab 10 mg/kg q 2 wk 

 

Overall survival   

Median (months) 21.3 23.3 

Hazard ratio 

95% CI 

0.91 

0.76, 1.10 

(p-value 0.3360) 

 

An exploratory multivariate Cox regression model using backward selection indicated that the following 

baseline prognostic factors were strongly associated with survival independent of treatment: gender, white 

blood cell count, platelets, body weight loss in the 6 months prior to trial entry, number of metastatic sites, 

sum of longest diameter of target lesions, Motzer score. Adjustment for these baseline factors resulted in a 

treatment hazard ratio of 0.78 (95% CI [0.63; 0.96], p=0.0219), indicating a 22% reduction in the risk of 

death for patients in the bevacizumab + IFN alfa-2a arm compared to IFN alfa-2a arm. 

 
Ninety seven (97) patients in the IFN alfa-2a arm and 131 patients in the bevacizumab arm reduced the 

dose of IFN alfa-2a from 9 MIU to either 6 or 3 MIU three times a week as pre-specified in the protocol. 

Dose-reduction of IFN alfa-2a did not appear to affect the efficacy of the combination of bevacizumab and 

IFN alfa-2a based on PFS event free rates over time, as shown by a sub-group analysis. The 131 patients in 

the bevacizumab + IFN alfa-2a arm who reduced and maintained the IFN alfa-2a dose at 6 or 3 MIU during 

the trial, exhibited at 6, 12 and 18 months PFS event free rates of 73, 52 and 21% respectively, as 

compared to 61, 43 and 17% in the total population of patients receiving bevacizumab + IFN alfa-2a. 

 
AVF2938 

This was a randomised, double-blind, phase II clinical trial investigating bevacizumab 10 mg/kg in a 

2 weekly schedule with the same dose of bevacizumab in combination with 150 mg daily erlotinib, in 

patients with metastatic clear cell RCC. A total of 104 patients were randomised to treatment in this trial, 

53 to bevacizumab 10 mg/kg every 2 weeks plus placebo and 51 to bevacizumab 10 mg/kg every 2 weeks 

plus erlotinib 150 mg daily. The analysis of the primary endpoint showed no difference between the 

bevacizumab + Placebo arm and the bevacizumab + Erlotinib arm (median PFS 8.5 versus 9.9 months). 

Seven patients in each arm had an objective response. The addition of erlotinib to bevacizumab did not 

result in an improvement in OS (HR = 1.764; p=0.1789), duration of objective response (6.7 vs 9.1 

months) or time to symptom progression (HR = 1.172; p=0.5076). 



36 

AVF0890 

This was a randomised phase II trial conducted to compare the efficacy and safety of bevacizumab versus 

placebo. A total of 116 patients were randomised to receive bevacizumab 3 mg/kg every 2 weeks (n=39), 

10 mg/kg every 2 weeks; (n=37), or placebo (n=40). An interim analysis showed there was a significant 

prolongation of the time to progression of disease in the 10 mg/kg group as compared with the placebo 

group (hazard ratio, 2.55; p < 0.001). There was a small difference, of borderline significance, between the 

time to progression of disease in the 3 mg/kg group and that in the placebo group (hazard ratio, 1.26; 

p=0.053). Four patients had objective (partial) response, and all of these had received the 10 mg/kg dose 

bevacizumab; the ORR for the 10 mg/kg dose was 10%. 

 
Epithelial ovarian, fallopian tube and primary peritoneal cancer 

 
Front-line treatment of ovarian cancer 

 
The safety and efficacy of bevacizumab in the front-line treatment of patients with epithelial ovarian, 

fallopian tube or primary peritoneal cancer were studied in two phase III trials (GOG-0218 and BO17707) 

that evaluated the effect of the addition of bevacizumab to carboplatin and paclitaxel compared to the 

chemotherapy regimen alone. 

 
GOG-0218 

The GOG-0218 study was a phase III multicentre, randomised, double-blind, placebo-controlled, three arm 

study evaluating the effect of adding bevacizumab to an approved chemotherapy regimen (carboplatin and 

paclitaxel) in patients with advanced ( Stages IIIB, IIIC and IV according to FIGO staging version dated 

1988) epithelial ovarian, fallopian tube or primary peritoneal cancer. 

 
Patients who had received prior therapy with bevacizumab or prior systemic anticancer therapy for ovarian 

cancer (e.g. chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy, or hormonal 

therapy) or previous radiotherapy to the abdomen or pelvis were excluded from the study. 

 
A total of 1873 patients were randomised in equal proportions to the following three arms: 

 
• CPP arm: Five cycles of placebo (started cycle 2) in combination with carboplatin (AUC 6) and 

paclitaxel (175 mg/m2) for 6 cycles followed by placebo alone, for a total of up to 15 months of therapy 

• CPB15 arm: Five cycles of bevacizumab (15 mg/kg q3w started cycle 2) in combination with 

carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles followed by placebo alone, for a total of 

up to 15 months of therapy 

• CPB15+ arm: Five cycles of bevacizumab (15 mg/kg q3w started cycle 2) in combination with 

carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles followed by continued use of 

bevacizumab (15 mg/kg q3w) as single agent for a total of up to 15 months of therapy. 

 
The majority of patients included in the study were White (87% in all three arms); the median age was  

60 years in CPP and CPB15 arms and 59 years in CPB15+ arm; and 29% of patients in CPP or CPB15 and 

26% in CPB15+ were over 65 years of age. Overall approximately 50% of patients had a GOG PS of 0 at 

baseline, 43% a GOG PS score of 1, and 7% a GOG PS score of 2. Most patients had EOC (82% in CPP 

and CPB15, 85% in CPB15+) followed by PPC (16% in CPP, 15% in CPB15, 13% in CPB15+) and FTC 

(1% in CPP, 3% in CPB15, 2% in CPB15+). The majority of patients had serous adenocarcinoma 

histologic type (85% in CPP and CPB15, 86% in CPB15+). Overall approximately 34% of patients were 

FIGO Stage III optimally debulked with gross residual disease, 40% Stage III sub-optimally debulked, and 

26% were Stage IV patients. 

 

The primary endpoint was PFS based on investigator’s assessment of disease progression based on 

radiological scans or CA 125 levels, or symptomatic deterioration per protocol. In addition, a prespecified 

analysis of the data censoring for CA-125 progression events was conducted, as well as an independent 

review of PFS as determined by radiological scans. 

 

The trial met its primary objective of PFS improvement. Compared to patients treated with chemotherapy 

(carboplatin and paclitaxel) alone in the front-line setting, patients who received bevacizumab at a dose of 



37 

15 mg/kg q3w in combination with chemotherapy and continued to receive bevacizumab alone (CPB15+), 

had a clinically meaningful and statistically significant improvement in PFS. 

 

In patients who only received bevacizumab in combination with chemotherapy and did not continue to 

receive bevacizumab alone (CPB15), no clinically meaningful benefit in PFS was observed. 

 

The results of this study are summarised in Table 16. 

 

Table 16. Efficacy results from study GOG-0218 
Progression-free survival1 

 CPP 

(n = 625) 

CPB15  

(n = 625) 

CPB15+  

(n = 623) 

Median PFS (months)  10.6 11.6 14.7 

Hazard Ratio (95% CI)2  0.89  

(0.78, 1.02) 

0.70  

(0.61, 0.81) 

p-value3, 4  0.0437 < 0.0001 

Objective response Rate5 

 

 

CPP 

(n = 396) 

CPB15  

(n = 393) 

CPB15 +  

(n = 403) 

% pts with objective 

response 

63.4 66.2 

 

66.0 

 

p-value  0.2341 0.2041 

Overall survival6 
 
 

 

CPP 

(n = 625) 

CPB15  

(n = 625) 

CPB15 + 

(n = 623) 

Median OS (months)  40.6 38.8 43.8 

Hazard Ratio (95% CI)2  1.07 (0.91, 1.25) 0.88 (0.75, 1.04) 

p-value3  0.2197 0.0641 

1 Investigator assessed GOG protocol-specified PFS analysis (neither censored for CA-125 progressions nor censored 

for NPT prior to disease progression) with data cut-off date of 25 February, 2010. 
2 Relative to the control arm; stratified hazard ratio. 
3 One-sided log-rank p-value 
4 Subject to a p-value boundary of 0.0116. 
5 Patients with measurable disease at baseline. 
6 Final overall survival analysis performed when 46.9% of the patients had died. 

 

Prespecified PFS analyses were conducted, all with a cut-off date of 29 September 2009. The results of 

these prespecified analyses are as follows: 

 

• The protocol specified analysis of investigator-assessed PFS (without censoring for CA-125 
progression or non-protocol therapy [NPT]) shows a stratified hazard ratio of 0.71 (95% CI: 

0.61-0.83, 1-sided log-rank p-value < 0.0001) when CPB15+ is compared with CPP, with a median 

PFS of 10.4 months in the CPP arm and 14.1 months in the CPB15+ arm. 

 

• The primary analysis of investigator-assessed PFS (censoring for CA-125 progressions and NPT) 
shows a stratified hazard ratio of 0.62 (95% CI: 0.52-0.75, 1-sided log-rank p-value < 0.0001) when 

CPB15+ is compared with CPP, with a median PFS of 12.0 months in the CPP arm and 18.2 months 

in the CPB15+ arm. 

 

• The analysis of PFS as determined by the independent review committee (censoring for NPT) shows 
a stratified hazard ratio of 0.62 (95% CI: 0.50-0.77, 1-sided log-rank p-value < 0.0001) when 

CPB15+ is compared with CPP, with a median PFS of 13.1 in the CPP arm and 19.1 months in the 

CPB15+ arm. 

 

PFS subgroup analyses by disease stage and debulking status are summarised in Table 17. These results 

demonstrate robustness of the analysis of PFS as shown in Table 16. 

 



38 

Table 17. PFS1 results by disease stage and debulking status from study GOG-0218 
Randomised patients stage III optimally debulked disease 2,3 

 

 

CPP 

(n = 219) 

CPB15  

(n = 204) 

CPB15+ 

(n = 216) 

Median PFS (months)  12.4 14.3 17.5 

Hazard ratio (95% CI)4  0.81  

(0.62, 1.05) 

0.66 

(0.50, 0.86) 

Randomised patients with stage III suboptimally debulked disease3 

 

 

CPP 

(n = 253) 

CPB15 

(n = 256) 

CPB15+ 

(n = 242) 

Median PFS (months)  10.1 10.9 13.9 

Hazard ratio (95% CI)4  0.93  

(0.77, 1.14) 

0.78 

(0.63, 0.96) 

Randomised patients with stage IV disease 

 

 

CPP 

(n = 153) 

CPB15 

(n = 165) 

CPB15+ 

(n = 165) 

Median PFS (months)  9.5 10.4 12.8 

Hazard Ratio (95% CI)4  0.90  

(0.70, 1.16) 

0.64  

(0.49, 0.82) 
1 Investigator assessed GOG protocol-specified PFS analysis (neither censored for CA-125 progressions nor censored 

for NPT prior to disease progression) with data cut-off date of 25 February, 2010 
2 With gross residual disease. 
3 3.7% of the overall randomised patient population had Stage IIIB disease. 
4 Relative to the control arm. 

 

BO17707 (ICON7) 

BO17707 was a Phase III, two arm, multicentre, randomised, controlled, open-label study comparing the 

effect of adding bevacizumab to carboplatin plus paclitaxel in patients with FIGO stage I or IIA (Grade 3 or 

clear cell histology only; n = 142), or FIGO stage IIB - IV (all Grades and all histological types, n = 1386) 

epithelial ovarian, fallopian tube or primary peritoneal cancer following surgery (NCI-CTCAE v.3). FIGO 

staging version dated 1988 was used in this trial. 

 
Patients who had received prior therapy with bevacizumab or prior systemic anticancer therapy for ovarian 

cancer (e.g. chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy, or hormonal 

therapy) or previous radiotherapy to the abdomen or pelvis were excluded from the study. 

 
A total of 1528 patients were randomised in equal proportions to the following two arms: 

 

• CP arm: Carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles of 3 weeks duration 
• CPB7.5+ arm: Carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles of 3 weeks plus 

bevacizumab (7.5 mg/kg q3w) for up to 12 months (Bevacizumab was started at cycle 2 of 

chemotherapy if treatment was initiated within 4 weeks of surgery or at cycle 1 if treatment was 

initiated more than 4 weeks after surgery). 

 

The majority of patients included in the study were White (96%), the median age was 57 years in both 

treatment arms, 25% of patients in each treatment arm were 65 years of age or over, and approximately 

50% of patients had an ECOG PS of 1; 7% of patients in each treatment arm had an ECOG PS of 2. The 

majority of patients had EOC (87.7%) followed by PPC (6.9%) and FTC (3.7%) or a mixture of the three 

origins (1.7%). Most patients were FIGO Stage III (both 68%) followed by FIGO Stage IV (13% and 

14%), FIGO Stage II (10% and 11%) and FIGO Stage I (9% and 7%). The majority of the patients in 

each treatment arm (74% and 71%) had poorly differentiated (Grade 3) primary tumours at baseline. The 

incidence of each histologic sub-type of EOC was similar between the treatment arms; 69% of patients 

in each treatment arm had serous adenocarcinoma histologic type. 

 
The primary endpoint was PFS as assessed by the investigator using RECIST. 

 
The trial met its primary objective of PFS improvement. Compared to patients treated with 

chemotherapy (carboplatin and paclitaxel) alone in the front-line setting, patients who received 



39 

bevacizumab at a dose of 7.5 mg/kg q3w in combination with chemotherapy and continued to receive 

bevacizumab for up to 18 cycles had a statistically significant improvement in PFS. 

 
The results of this study are summarised in Table 18. 

 
Table 18. Efficacy results from study BO17707 (ICON7) 
Progression-free survival 

 

 

CP 

(n = 764) 

CPB7.5+ 

(n =764) 

Median PFS (months)2 16.9 19.3 

Hazard ratio [95% CI]2 0.86 [0.75; 0.98] 

(p-value = 0.0185) 

Objective response rate1 

 

 

CP 

(n = 277) 

CPB7.5+ 

(n =272) 

Response rate 54.9% 64.7% 

(p-value = 0.0188) 
Overall Survival3 

 

 

CP 

(n = 764) 

CPB7.5+ 

(n = 764) 

Median (months)  58.0 57.4 

Hazard ratio [95% CI] 0.99 [0.85; 1.15] 
(p-value = 0.8910) 

1 In patients with measurable disease at baseline. 
2 Investigator assessed PFS analysis with data cut-off date of 30 November 2010. 
3 Final overall survival analysis performed when 46.7% of the patients had died with data cut-off date of 31 March 

2013. 

 

The primary analysis of investigator-assessed PFS with a data cut-off date of 28 February 2010 shows an 

unstratified hazard ratio of 0.79 (95% CI: 0.68-0.91, 2-sided log-rank p-value 0.0010) with a median PFS 

of 16.0 months in the CP arm and 18.3 months in the CPB7.5+ arm. 

 
PFS subgroup analyses by disease stage and debulking status are summarised in Table 19. These results 

demonstrate robustness of the primary analysis of PFS as shown in Table 18. 

 



40 

Table 19. PFS1 results by disease stage and debulking status from study BO17707 (ICON7) 

Randomised patients stage III optimally debulked disease 2,3 

 

 

CP 

(n = 368) 

CPB7.5+  

(n = 383) 

Median PFS (months) 17.7 19.3 

Hazard ratio (95% CI)4  0.89  

(0.74, 1.07) 

Randomised patients with stage III suboptimally debulked disease3 

 

 

CP 

(n = 154) 

CPB7.5+ 

(n = 140) 

Median PFS (months) 10.1 16.9 

Hazard ratio (95% CI)4  0.67  

(0.52, 0.87) 

Randomised patients with stage IV disease 

 

 

CP 

(n = 97) 

CPB7.5+ 

(n = 104) 

Median PFS (months) 10.1 13.5 

Hazard Ratio (95% CI)4  0.74  

(0.55, 1.01) 
1 Investigator assessed PFS analysis with data cut-off date of 30 November 2010. 
2 With or without gross residual disease. 
3 5.8% of the overall randomised patient population had Stage IIIB disease. 
4 Relative to the control arm. 

 
Recurrent ovarian cancer 

 
The safety and efficacy of bevacizumab in the treatment of recurrent epithelial ovarian, fallopian tube or 

primary peritoneal cancer was studied in three phase III trials (AVF4095g, MO22224 and GOG-0213) with 

different patient populations and chemotherapy regimens. 

 
• AVF4095g evaluated the efficacy and safety of bevacizumab in combination with carboplatin and 

gemcitabine, followed by bevacizumab as a single agent in patients with platinum-sensitive recurrent 

epithelial ovarian, fallopian tube or primary peritoneal cancer. 

• GOG-0213 evaluated the efficacy and safety of bevacizumab in combination with carboplatin and 

paclitaxel, followed by bevacizumab as a single agent in patients with platinum-sensitive recurrent 

epithelial ovarian, fallopian tube or primary peritoneal cancer. 

•  MO22224 evaluated the efficacy and safety of bevacizumab in combination with paclitaxel, 

topotecan, or pegylated liposomal doxorubicin in patients with platinum-resistant recurrent epithelial 

ovarian, fallopian tube or primary peritoneal cancer. 

 
AVF4095g 

The safety and efficacy of bevacizumab in the treatment of patients with platinum-sensitive, recurrent 

epithelial ovarian, fallopian tube or primary peritoneal cancer, who have not received prior chemotherapy in 

the recurrent setting or prior bevacizumab treatment, was studied in a phase III randomised, double-blind, 

placebo-controlled trial (AVF4095g). The study compared the effect of adding bevacizumab to carboplatin 

and gemcitabine chemotherapy and continuing bevacizumab as a single agent to progression, to carboplatin 

and gemcitabine alone. 

 

Only patients with histologically documented ovarian, primary peritoneal, or fallopian tube carcinoma that 

had recurred > 6 months after platinum-based chemotherapy and who had not received chemotherapy in the 

recurrent setting and who have not received prior therapy with bevacizumab or other VEGF inhibitors or 

VEGF receptor–targeted agents were included in the study. 

 

A total of 484 patients with measurable disease were randomised 1:1 to either: 

• Carboplatin (AUC4, Day 1) and gemcitabine (1000 mg/m2 on Days 1 and 8) and concurrent placebo 

every 3 weeks for 6 and up to 10 cycles followed by placebo (every 3 weeks) alone until disease 

progression or unacceptable toxicity 



41 

• Carboplatin (AUC4, Day 1) and gemcitabine (1000 mg/m2
 on Days 1 and 8) and concurrent 

bevacizumab (15 mg/kg Day 1) every 3 weeks for 6 and up to 10 cycles followed by bevacizumab 

(15 mg/kg every 3 weeks) alone until disease progression or unacceptable toxicity 
 

The primary endpoint was progression-free survival based on investigator assessment using modified 

RECIST 1.0. Additional endpoints included objective response, duration of response, overall survival and 

safety. An independent review of the primary endpoint was also conducted. 

 

The results of this study are summarised in Table 20. 

 

Table 20. Efficacy results from study AVF4095g 

Progression-free survival 

 Investigator Assessment IRC Assessment 

 Placebo+ C/G 

(n=242) 

Bevacizumab + C/G 

(n=242) 

Placebo+ C/G 

(n=242) 

Bevacizumab + C/G 

(n=242) 

Not censored for NPT  

Median PFS 

(months) 
8.4 12.4 8.6 12.3 

Hazard ratio 

(95% CI) 
0.524 [0.425, 0.645] 0.480 [0.377, 0.613] 

p –value < 0.0001 < 0.0001 

Censored for NPT  

Median PFS 

(months) 
8.4 12.4 8.6 12.3 

Hazard ratio 

(95% CI) 
0.484 [0.388, 0.605] 0.451 [0.351, 0.580] 

p –value < 0.0001 < 0.0001 

Objective response rate 

 Investigator Assessment IRC Assessment 

 Placebo+ C/G 

(n = 242) 

Bevacizumab + C/G 

(n = 242) 

Placebo+ C/G 

(n = 242) 

Bevacizumab + C/G 

(n = 242) 

% pts with objective 

response 
57.4% 78.5% 53.7% 74.8% 

p –value < 0.0001 < 0.0001 

Overall survival 

 Placebo+ C/G 

(n = 242) 

Bevacizumab + C/G 

(n = 242) 

Median OS 

(months) 
32.9 33.6 

Hazard Ratio 

(95% CI) 
0.952 [0.771, 1.176] 

p–value 0.6479 

 

PFS subgroup analyses depending on recurrence since last platinum therapy are summarised in Table 21. 



42 

Table 21. Progression-free survival by time from last platinum therapy to recurrence 

 Investigator Assessment 

Time from last platinum therapy 

to recurrence 

Placebo + C/G 

(n = 242) 

Bevacizumab + C/G 

(n = 242) 

6-12 months (n=202)   

Median 8.0 11.9 

Hazard ratio (95% CI) 0.41 (0.29 - 0.58) 

> 12 months (n=282)   

Median 9.7 12.4 

Hazard ratio (95% CI) 0.55 (0.41 – 0.73) 

 

GOG-0213 

GOG-0213, a phase III randomized controlled open label trial, studied the safety and efficacy of 

bevacizumab in the treatment of patients with platinum-sensitive, recurrent epithelial ovarian, fallopian 

tube or primary peritoneal cancer, who have not received prior chemotherapy in the recurrent setting. 

There was no exclusion criterion for prior anti-angiogenic therapy. The study evaluated the effect of 

adding bevacizumab to carboplatin+paclitaxel and continuing bevacizumab as a single agent until 

disease progression or unacceptable toxicity compared to carboplatin+paclitaxel alone. 

 
A total of 673 patients were randomized in equal proportions to the following two treatment arms: 

• CP arm: Carboplatin (AUC5) and paclitaxel (175 mg/m2 IV) every 3 weeks for 6 and up to  
8 cycles. 

• CPB arm: Carboplatin (AUC5) and paclitaxel (175 mg/m2 IV) and concurrent bevacizumab  
(15 mg/kg) every 3 weeks for 6 and up to 8 cycles, followed by bevacizumab (15 mg/kg every  

3 weeks) alone until disease progression or unacceptable toxicity. 

 
Most patients in both the CP arm (80.4%) and the CPB arm (78.9%) were White. The median age was 

60.0 years in the CP arm and 59.0 years in the CPB arm. The majority of patients (CP: 64.6%;  

CPB: 68.8%) were in the age category < 65 years. At baseline, most patients in both treatment arms 

had a GOG PS of 0 (CP: 82.4%: CPB; 80.7%) or 1 (CP: 16.7%: CPB; 18.1%). A GOG PS of 2 at 

baseline was reported in 0.9% of patients in the CP arm and in 1.2% of patients in the CPB arm. 

 
The primary efficacy endpoint was overall survival (OS). The main secondary efficacy endpoint was 

progression-free survival (PFS). Results are presented in Table 22. 



43 

Table 22. Efficacy results1,2 from study GOG-0213 

Primary Endpoint 

Overall Survival (OS) CP 

(n=336) 

CPB 

(n=337) 

Median OS (months) 37.3 42.6 

Hazard ratio (95% CI) (eCRF)a 0.823 [CI: 0.680, 0.996] 

p-value 0.0447 

Hazard ratio (95% CI) 

(registration form)b 

0.838 [CI: 0.693, 1.014] 

p-value 0.0683 

Secondary Endpoint 

Progression-free survival (PFS) CP 

(n=336) 

CPB  

(n=337) 

Median PFS (months) 10.2 13.8 

Hazard ratio (95% CI) 0.613 [CI: 0.521, 0.721] 

p-value <0.0001 
1 Final Analysis 2 Tumour assessments and response evaluations were determined by the investigators using the 

GOG 

RECIST criteria (Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228Y247). 

 
a Hazard ratio was estimated from Cox proportional hazards models stratified by the duration of platinum free-interval prior 

to enrolling onto this study per eCRF (electronic case report form) and secondary surgical debulking status Yes/No 

(Yes=randomized to undergo cytoreduction or randomized to not undergo cytoreduction; No= not a candidate or did not 

consent to cytoreduction). b stratified by the duration of treatment free-interval prior to enrolling onto this study per the 

registration form, and secondary surgical debulking status Yes/No. 

 
The trial met its primary objective of OS improvement. Treatment with bevacizumab at 15 mg/kg 

every 3 weeks in combination with chemotherapy (carboplatin and paclitaxel) for 6 and up to 8 cycles, 

followed by bevacizumab until disease progression or unacceptable toxicity resulted, when data were 

derived from eCRF, in a clinically meaningful and statistically significant improvement in OS 

compared to treatment with carboplatin and paclitaxel alone. 

 
MO22224 

Study MO22224 evaluated the efficacy and safety of bevacizumab in combination with chemotherapy 

for platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. This 

study was designed as an open-label, randomized, two-arm Phase III evaluation of bevacizumab plus 

chemotherapy (CT+BV) versus chemotherapy alone (CT). 

 

A total of 361 patients were enrolled into this study and administered either chemotherapy (paclitaxel, 

topotecan, or pegylated liposomal doxorubicin (PLD) alone or in combination with bevacizumab: 

 
• CT Arm (chemotherapy alone): 

• Paclitaxel 80 mg/m2
 
as a 1-hour IV infusion on Days 1, 8, 15, and 22 every 4 weeks. 

• Topotecan 4 mg/m2 as a 30-minute IV infusion on Days 1, 8, and 15 every 4 weeks. 

Alternatively, a 1.25 mg/m2 dose could be administered over 30 minutes on Days 1–5 every 

3 weeks. 

• PLD 40 mg/m2
 
as a 1 mg/min IV infusion on Day 1 only every 4 weeks. After Cycle 1, the 

drug could be delivered as a 1-hour infusion. 

• CT+BV Arm (chemotherapy plus bevacizumab): 
• The chosen chemotherapy was combined with bevacizumab 10 mg/kg IV every 2 weeks (or 

bevacizumab 15 mg/kg every 3 weeks if used in combination with topotecan 1.25 mg/m2 on 

Days 1–5 every 3 weeks). 



44 

Eligible patients had epithelial ovarian, fallopian tube or primary peritoneal cancer that progressed 

within < 6 months of previous platinum therapy consisting of a minimum of 4 platinum therapy cycles. 

Patients should have had a life expectancy of ≥ 12 weeks and no prior radiotherapy to the pelvis or 

abdomen. Most patients were FIGO Stage IIIC or Stage IV. The majority of patients in both arms had 

an ECOG Performance Status (PS) of 0 (CT: 56.4% vs. CT + BV: 61.2%). The percentage of patients 

with an ECOG PS of 1 or ≥ 2 was 38.7% and 5.0% in the CT arm, and 29.8% and 9.0% in the CT + 

BV arm. Information on race exists for 29.3% of patients and nearly all patients were white. The 

median age of patients was 61.0 (range: 25−84) years. A total of 16 patients (4.4%) were > 75 years 

old. The overall rates of discontinuation due to adverse events were 8.8% in the CT arm and 43.6% in 

the CT + BV arm (mostly due to Grade 2-3 adverse events) and the median time to discontinuation in 

the CT + BV arm was 5.2 months compared with 2.4 months in the CT arm. The rates of 

discontinuation due to adverse events in the subgroup of patients > 65 years old were 8.8% in the CT 

arm and 50.0% in the CT + BV arm. The HR for PFS was 0.47 (95% CI: 0.35, 0.62) and 0.45 (95% 

CI: 0.31, 0.67) for the < 65 and ≥ 65 subgroups, respectively. 

 

The primary endpoint was progression-free survival, with secondary endpoints including objective 

response rate and overall survival. Results are presented in Table 23. 

 
Table 23. Efficacy results from study MO22224 

Primary Endpoint 

Progression-Free Survival* 

 CT (n=182) CT+BV (n=179) 

Median (months) 3.4 6.7 

Hazard ratio (95% CI) 0.379 [0.296, 0.485] 

p-value <0.0001 

Secondary Endpoints 

Objective Response Rate** 

 CT (n=144) CT+BV (n=142) 

% patients with objective response 18 (12.5%) 40 (28.2%) 

p –value 0.0007 

Overall Survival (final analysis)***  

 CT (n=182) CT+BV (n=179) 

Median OS (months) 13.3 16.6 

Hazard Ratio (95% CI) 0.870 [0.678, 1.116] 

p-value 0.2711 

All analyses presented in this table are stratified analyses. 

* Primary analysis was performed with a data cut-off date of 14 November 2011. 

** Randomized Patients with Measurable Disease at Baseline. 

*** The final analysis of overall survival was performed when 266 deaths, which account for 73.7% of enrolled 

patients, were observed. 

 
The trial met its primary objective of PFS improvement. Compared to patients treated with 

chemotherapy (paclitaxel, topotecan or PLD) alone in the recurrent platinum-resistant setting, patients 

who received bevacizumab at a dose of 10 mg/kg every 2 weeks (or 15 mg/kg every 3 weeks if used in 

combination with 1.25 mg/m2 topotecan on Days 1–5 every 3 weeks) in combination with 

chemotherapy and continued to receive bevacizumab until disease progression or unacceptable 

toxicity, had a statistically significant improvement in PFS. The exploratory PFS and OS analyses by 

chemotherapy cohort (paclitaxel, topotecan and PLD) are summarized in Table 24. 

 



45 

Table 24. Exploratory PFS and OS analyses by chemotherapy cohort 

 CT CT+BV 

Paclitaxel n=115 

Median PFS (months) 3.9 9.2 

Hazard ratio (95% CI) 0.47 [0.31, 0.72] 

Median OS (months) 13.2 22.4 

Hazard ratio (95% CI) 0.64 [0.41, 0.99] 

Topotecan n=120 

Median PFS (months) 2.1 6.2 

Hazard ratio (95% CI) 0.28 [0.18, 0.44] 

Median OS (months) 13.3 13.8 

Hazard ratio (95% CI) 1.07 [0.70, 1.63] 

PLD n=126 

Median PFS (months) 3.5 5.1 

Hazard ratio (95% CI) 0.53 [0.36, 0.77] 

Median OS (months) 14.1 13.7 

Hazard ratio (95% CI) 0.91 [0.61, 1.35] 

 
Cervical Cancer 

 

GOG-0240 

The efficacy and safety of bevacizumab in combination with chemotherapy (paclitaxel and cisplatin or 

paclitaxel and topotecan) in the treatment for patients with persistent, recurrent or metastatic 

carcinoma of the cervix was evaluated in study GOG-0240, a randomised, four-arm, open label, 

multi-centre phase III trial. 

 
A total of 452 patients were randomised to receive either: 

 
• Paclitaxel 135 mg/m2 IV over 24 hours on Day 1 and cisplatin 50 mg/m2 IV on Day 2, every 

3 weeks (q3w); or 

Paclitaxel 175 mg/m2 IV over 3 hours on Day 1 and cisplatin 50 mg/m2 IV on Day 2 (q3w); or 

Paclitaxel 175 mg/m2 IV over 3 hours on Day 1 and cisplatin 50 mg/m2 IV on Day 1 (q3w) 

 
• Paclitaxel 135 mg/m2 IV over 24 hours on Day 1 and cisplatin 50 mg/m2 IV on Day 2 plus 

bevacizumab 15 mg/kg IV on Day 2 (q3w); or 

Paclitaxel 175 mg/m2 IV over 3 hours on Day 1 and cisplatin 50 mg/m2 IV on Day 2 plus 

bevacizumab 15 mg/kg IV on Day 2 (q3w); or 

Paclitaxel 175 mg/m2 IV over 3 hours on Day 1 and cisplatin 50 mg/m2 IV on Day 1 plus 

bevacizumab 15 mg/kg IV on Day 1 (q3w) 

 
• Paclitaxel 175 mg/m2 IV over 3 hours on Day 1 and topotecan 0.75 mg/m2 IV over 30 minutes 

on days 1-3 (q3w) 

 

• Paclitaxel 175 mg/m2 IV over 3 hours on Day 1 and topotecan 0.75 mg/m2 IV over 30 minutes 
on Days 1-3 plus bevacizumab 15 mg/kg IV on Day 1 (q3w) 

 
Eligible patients had persistent, recurrent or metastatic squamous cell carcinoma, adenosquamous 

carcinoma, or adenocarcinoma of the cervix which was not amenable to curative treatment with 



46 

surgery and/or radiation therapy and who have not received prior therapy with bevacizumab or other 

VEGF inhibitors or VEGF receptor–targeted agents. 

 

The median age was 46.0 years (range: 20−83) in the Chemo alone group and 48.0 years (range: 

22−85) in the Chemo+bevacizumab group; with 9.3% of patients in the Chemo alone group and 7.5% 

of patients in the Chemo+bevacizumab group over the age of 65 years. 

 

Of the 452 patients randomized at baseline, the majority of patients were white (80.0% in the Chemo 

alone group and 75.3% in the Chemo+bevacizumab group), had squamous cell carcinoma (67.1% in 

the Chemo alone group and 69.6% in the  Chemo+bevacizumab group), had persistent/recurrent 

disease (83.6% in the Chemo alone group and 82.8% in the Chemo+bevacizumab group), had 1-2 

metastatic sites (72.0% in the Chemo alone group and 76.2% in the Chemo+bevacizumab group), had 

lymph node involvement (50.2% in the Chemo alone group and 56.4% in the  Chemo+bevacizumab 

group), and had a platinum free interval ≥ 6 months (72.5% in the Chemo alone group and 64.4% in 

the Chemo+bevacizumab group). 

 
The primary efficacy endpoint was overall survival. Secondary efficacy endpoints included 

progression-free survival and objective response rate. Results from the primary analysis and the 

follow-up analysis are presented by bevacizumab Treatment and by Trial Treatment in Table 25 and 

Table 26, respectively. 

 
Table 25. Efficacy results from study GOG-0240 by Bevacizumab Treatment 

 Chemotherapy 

(n=225) 

Chemotherapy + bevacizumab 

(n=227) 

Primary Endpoint 

Overall Survival - Primary analysis6 

Median (months)1 12.9 16.8 

Hazard ratio [95% CI] 0.74 [0.58, 0.94] (p-value5 = 0.0132) 

Overall survival - Follow-up analysis7 

Median (months)1 13.3 16.8 

Hazard ratio [95% CI] 0.76 [0.62, 0.94] 

(p-value5,8 = 0.0126) 

Secondary Endpoints 

Progression-free survival – Primary analysis6 

Median PFS (months)1 6.0 8.3 

Hazard ratio [95% CI] 0.66 [0.54, 0.81] (p-value5 <0.0001) 

Best overall response – Primary analysis6 

Responders (Response rate2) 76 (33.8 %) 103 (45.4 %) 

95% CI for response rates3 [27.6%, 40.4%] [38.8%, 52.1%] 

Difference in response rates 11.60% 

95% CI for difference in response rates4 [2.4%, 20.8%] 

p-value (Chi-squared Test) 0.0117 
1 Kaplan-Meier estimates 
2 Patients and percentage of patients with best overall response of confirmed CR or PR; percentage calculated on 

patients with measurable disease at baseline 
3 95% CI for one sample binomial using Pearson-Clopper method 
4 Approximate 95% CI for difference of two rates using Hauck-Anderson method 

5 log-rank test (stratified) 



47 

6 Primary analysis was performed with a data cut-off date of 12 December 2012 and is considered the final 

analysis 
7 Follow-up analysis was performed with a data cut-off date of 07 March 2014 
8 p-value displayed for descriptive purpose only 

 

Table 26. Overall survival results from study GOG-0240 by Trial Treatment 

Treatment 

Comparison 

Other 

Factor 

Overall survival – Primary 

analysis1 

Hazard ratio (95% CI) 

Overall survival – Follow-up 

analysis2 

Hazard ratio (95% CI) 

Bevacizumab 

vs. 

No 

bevacizumab 

Cisplatin+ 

Paclitaxel 

0.72 (0.51, 1.02) 

(17.5 vs.14.3 months; p = 0.0609) 

0.75 (0.55, 1.01) 

(17.5 vs.15.0 months; p = 0.0584) 

Topotecan+ 

Paclitaxel 

0.76 (0.55, 1.06) 

(14.9 vs. 11.9 months; p = 

0.1061) 

0.79 (0.59, 1.07) 

(16.2 vs. 12.0 months; p = 0.1342) 

Topotecan + 

Paclitaxel vs. 

Cisplatin + 

Paclitaxel 

Bevacizumab 

 

1.15 (0.82, 1.61) 

(14.9 vs. 17.5 months; p = 

0.4146) 

1.15 (0.85, 1.56) 

(16.2 vs 17.5 months; p = 0.3769) 

No 

bevacizumab  

1.13 (0.81, 1.57) 

(11.9 vs.14.3 months; p = 0.4825) 

1.08 (0.80, 1.45) 

(12.0 vs 15.0 months; p = 0.6267) 

1 Primary analysis was performed with a data cut-off date of 12 December 2012 and is considered the final 

analysis 
2 Follow-up analysis was performed with a data cut-off date of 07 March 2014; all p-values are displayed for 

descriptive purpose only 

 
Paediatric population 

The European Medicines Agency has waived the obligation to submit the results of studies, in all 

subsets of the paediatric population, in breast carcinoma, adenocarcinoma of the colon and rectum, 

lung carcinoma (small cell and non-small cell carcinoma), kidney and renal pelvis carcinoma 

(excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal 

medullary carcinoma and rhabdoid tumour of the kidney), ovarian carcinoma (excluding 

rhabdomyosarcoma and germ cell tumours), fallopian tube carcinoma (excluding rhabdomyosarcoma 

and germ cell tumours), peritoneal carcinoma (excluding blastomas and sarcomas) and cervix and 

corpus uteri carcinoma. 

 
High-grade glioma 

Anti-tumour activity was not observed in two earlier studies among a total of 30 children aged  

> 3 years old with relapsed or progressive high-grade glioma when treated with bevacizumab and 

irinotecan (CPT-11). There is insufficient information to determine the safety and efficacy of 

bevacizumab in children with newly-diagnosed high-grade glioma. 

 
In a single-arm study (PBTC-022), 18 children with recurrent or progressive non-pontine high-grade 

glioma (including 8 with glioblastoma [WHO Grade IV], 9 with anaplastic astrocytoma [Grade III] and 

1 with anaplastic oligodendroglioma [Grade III]) were treated with bevacizumab (10 mg/kg) two weeks 

apart and then with bevacizumab in combination with CPT-11 (125-350 mg/m²) once every two weeks 

until progression. There were no objective (partial or complete) radiological responses (MacDonald 

criteria). Toxicity and adverse reactions included arterial hypertension and fatigue as well as CNS 

ischaemia with acute neurological deficit. 

 
In a retrospective single institution series, 12 consecutive (2005 to 2008) children with relapsed or 

progressive high-grade glioma (3 with WHO Grade IV, 9 with Grade III) were treated with 

bevacizumab (10 mg/kg) and irinotecan (125 mg/m²) every 2 weeks. There were no complete responses 

and 2 partial responses (MacDonald criteria). 

 
In a randomized phase II study (BO25041) a total of 121 patients aged ≥ 3 years to <18 years with 

newly diagnosed supratentorial or infratentorial cerebellar or peduncular high-grade glioma (HGG) 



48 

were treated with post operative radiation therapy (RT) and adjuvant temozolomide (T) with and 

without bevacizumab: 10 mg/kg every 2 weeks IV. 

 

The study did not meet its primary endpoint of demonstrating a significant improvement of EFS 

(Central Radiology Review Committee (CRRC)-assessed) when bevacizumab was added to the RT/T 

arm compared with RT/T alone (HR = 1.44; 95% CI: 0.90, 2.30). These results were consistent with 

those from various sensitivity analyses and in clinically relevant subgroups. The results for all 

secondary endpoints (investigator assessed EFS, and ORR and OS) were consistent in showing no 

improvement associated with the addition of bevacizumab to the RT/T arm compared with the RT/T 

arm alone. 

 
Addition of bevacizumab to RT/T did not demonstrate clinical benefit in study BO25041 in  

60 evaluable children patients with newly diagnosed supratentorial or infratentorial cerebellar or 

peduncular high-grade glioma (HGG) (see section 4.2 for information on paediatric use). 

 
Soft tissue sarcoma 

In a randomized phase II study (BO20924) a total of 154 patients aged ≥ 6 months to <18 years with 

newly diagnosed metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma were 

treated with standard of care (Induction IVADO/IVA+/- local therapy followed by Maintenance 

Vinorelbine and cyclophosphamide) with or without bevacizumab (2.5 mg/kg/week) for a total 

duration of treatment of approximately 18 months. At the time of the final primary analysis, the 

primary endpoint of EFS by independent central review did not show a statistically significant 

difference between the two treatment arms, with HR of 0.93 (95% CI: 0.61, 1.41; p-value = 0.72). 

The difference in ORR per independent central review was 18% (CI: 0.6%, 35.3%) between the two 

treatment arms in the few patients who had evaluable tumor at baseline and had a confirmed response 

prior to receiving any local therapy: 27/75 patients (36.0%, 95% CI: 25.2%, 47.9%) in the Chemo arm 

and 34/63 patients (54.0%, 95% CI: 40.9%, 66.6%) in the Bv + Chemo arm. The secondary endpoint 

of Overall Survival (OS) was not mature. Until mature OS results and safety data are available no 

definitive conclusion can be drawn on the benefit/risk balance. 

 
Addition of bevacizumab to standard of care did not demonstrate clinical benefit in clinical trial 

BO20924, in 71 evaluable children (from age 6 months to less than 18 years old) patients with 

metastatic Rhabdomyosarcoma and non-Rhabdomyosarcoma Soft Tissue Sarcoma (see section 4.2 for 

information on paediatric use). 

 
The incidence of AEs, including Grade ≥ 3 AEs and SAEs, was similar between the two treatment 

arms. No AEs leading to death occurred in either treatment arm; all deaths were attributed to disease 

progression. Bevacizumab addition to multimodal standard of care treatment seemed to be tolerated in 

this paediatric population. 

 

 

5.2 Pharmacokinetic properties 

 

The pharmacokinetic data for bevacizumab are available from ten clinical trials in patients with solid 

tumours. In all clinical trials, bevacizumab was administered as an IV infusion. The rate of infusion 

was based on tolerability, with an initial infusion duration of 90 minutes. The pharmacokinetics of 

bevacizumab was linear at doses ranging from 1 to 10 mg/kg. 

 
Distribution 

The typical value for central volume (Vc) was 2.73 L and 3.28 L for female and male patients 

respectively, which is in the range that has been described for IgGs and other monoclonal antibodies. 

The typical value for peripheral volume (Vp) was 1.69 L and 2.35 L for female and male patients 

respectively, when bevacizumab is co-administered with anti-neoplastic agents. After correcting for 

body weight, male patients had a larger Vc (+ 20%) than female patients. 
 

 

 



49 

Biotransformation 

Assessment of bevacizumab metabolism in rabbits following a single IV dose of 125I-bevacizumab 

indicated that its metabolic profile was similar to that expected for a native IgG molecule which does 

not bind VEGF. The metabolism and elimination of bevacizumab is similar to endogenous IgG i.e. 

primarily via proteolytic catabolism throughout the body, including endothelial cells, and does not rely 

primarily on elimination through the kidneys and liver. Binding of the IgG to the FcRn receptor results 

in protection from cellular metabolism and the long terminal half-life. 

 
Elimination 

The value for clearance is, on average, equal to 0.188 and 0.220 L/day for female and male patients, 

respectively. After correcting for body weight, male patients had a higher bevacizumab clearance  

(+ 17%) than females. According to the two-compartmental model, the elimination half-life is 18 days 

for a typical female patient and 20 days for a typical male patient. 

 
Low albumin and high tumour burden are generally indicative of disease severity. Bevacizumab 

clearance was approximately 30% faster in patients with low levels of serum albumin and 7% faster in 

subjects with higher tumour burden when compared with a typical patient with median values of 

albumin and tumour burden. 

 

Pharmacokinetics in special populations 

The population pharmacokinetics were analysed in adult and pediatric patients to evaluate the effects 

of demographic characteristics. In adults, the results showed no significant difference in the 

pharmacokinetics of bevacizumab in relation to age. 

 
Renal impairment 

No trials have been conducted to investigate the pharmacokinetics of bevacizumab in renally impaired 

patients since the kidneys are not a major organ for bevacizumab metabolism or excretion. 

 
Hepatic impairment 

No trials have been conducted to investigate the pharmacokinetics of bevacizumab in patients with 

hepatic impairment since the liver is not a major organ for bevacizumab metabolism or excretion. 

 
Paediatric population 

The pharmacokinetics of bevacizumab were evaluated in 152 children, adolescents and young adults 

(7 months to 21 years, 5.9 to 125 kg) across 4 clinical studies using a population pharmacokinetic 

model. The pharmacokinetic results show that the clearance and volume of distribution of 

bevacizumab were comparable between paediatric and young adult patients when normalised by body 

weight, with exposure trending lower as body weight decreased. Age was not associated with the 

pharmacokinetics of bevacizumab when body weight was taken into account. 

 
The pharmacokinetics of bevacizumab was well characterized by the paediatric population PK model 

for 70 patients in Study BO20924 (1.4 to 17.6 years; 11.6 to 77.5 kg) and 59 patients in Study 

BO25041 (1 to 17 years; 11.2 to 82.3 kg). In Study BO20924, bevacizumab exposure was generally 

lower compared to a typical adult patient at the same dose. In Study BO25041, bevacizumab exposure 

was similar compared to a typical adult at the same dose. In both studies, bevacizumab exposure 

trended lower as body weight decreased. 

 

5.3 Preclinical safety data 

 

In studies of up to 26 weeks duration in cynomolgus monkeys, physeal dysplasia was observed in 

young animals with open growth plates, at bevacizumab average serum concentrations below the 

expected human therapeutic average serum concentrations. In rabbits, bevacizumab was shown to 

inhibit wound healing at doses below the proposed clinical dose. Effects on wound healing were 

shown to be fully reversible. 

 



50 

Studies to evaluate the mutagenic and carcinogenic potential of bevacizumab have not been 

performed. 

No specific studies in animals have been conducted to evaluate the effect on fertility. An adverse effect 

on female fertility can however be expected as repeat dose toxicity studies in animals have shown 

inhibition of the maturation of ovarian follicles and a decrease/absence of corpora lutea and associated 

decrease in ovarian and uterus weight as well as a decrease in the number of menstrual cycles. 

 

Bevacizumab has been shown to be embryotoxic and teratogenic when administered to rabbits. 

Observed effects included decreases in maternal and foetal body weights, an increased number of 

foetal resorptions and an increased incidence of specific gross and skeletal foetal malformations. 

Adverse foetal outcomes were observed at all tested doses, of which the lowest dose resulted in 

average serum concentrations approximately 3 times larger than in humans receiving 5 mg/kg every  

2 weeks. Information on foetal malformations observed in the post marketing setting are provided in 

section 4.6 Fertiliy, Pregnancy and Lactation and 4.8 Undesirable Effects. 

 
 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Trehalose dihydrate 

Sodium acetate trihydrate 

Acetic acid 

Polysorbate 20 

Water for injections 

 

6.2 Incompatibilities 

 

This medicinal product must not be mixed with other medicinal products except those mentioned in 

section 6.6. 

 
A concentration dependent degradation profile of bevacizumab was observed when diluted with 

glucose solutions (5%). 

 

6.3 Shelf life 

 

Unopened vial 

 
3 years. 

 

Diluted medicinal product 

 

Chemical and physical in-use stability has been demonstrated for 48 hours at 2°C to 30°C in sodium 

chloride 9 mg/ml (0.9%) solution for injection. From a microbiological point of view, the product 

should be used immediately. If not used immediately, in-use storage times and conditions are the 

responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless 

dilution has taken place in controlled and validated aseptic conditions. 

 

6.4 Special precautions for storage 

 

Store in a refrigerator (2°C-8°C). 

Do not freeze. 

Keep the vial in the outer carton in order to protect from light. 

 
For storage conditions after dilution of the medicinal product, see section 6.3. 

 

6.5 Nature and contents of container 



51 

 

4 ml solution in a vial (Type I glass) with a stopper (butyl rubber) containing 100 mg of bevacizumab. 

16 ml solution in a vial (Type I glass) with a stopper (butyl rubber) containing 400 mg of 

bevacizumab.  

Pack of 1 vial. 

 

6.6 Special precautions for disposal and other handling 

 

Aybintio should be prepared by a healthcare professional using aseptic technique to ensure the sterility 

of the prepared solution. 

 
The necessary amount of bevacizumab should be withdrawn and diluted to the required administration 

volume with sodium chloride 9 mg/ml (0.9%) solution for injection. The concentration of the final 

bevacizumab solution should be kept within the range of 1.4 mg/ml to 16.5 mg/ml. In the majority of 

the occasions the necessary amount of Aybintio can be diluted with 0.9 % sodium chloride solution for 

injection to a total volume of 100 ml. 

 
Parenteral medicinal products should be inspected visually for particulate matter and discolouration 

prior to administration. 

 
No incompatibilities between Aybintio and polyvinyl chloride or polyolefine bags or infusion sets have 

been observed. 

 
Aybintio is for single-use only, as the product contains no preservatives. Any unused medicinal 

product or waste material should be disposed in accordance with local requirements. 
 

 

7. MARKETING AUTHORISATION HOLDER 

 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10 

2616 LR Delft 

The Netherlands 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/20/1454/001 – 100 mg/4 ml vial  

EU/1/20/1454/002 – 400 mg/16 ml vial 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation:  

 

10. DATE OF REVISION OF THE TEXT 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

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

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


52 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 

SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR 

BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 

PRODUCT 

 



53 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer of the biological active substance 

 

Biogen (Denmark) Manufact. ApS 

Biogen Allé 1 

Hillerød, 3400, 

Denmark 

 

Name and address of the manufacturer responsible for batch release 

 

Biogen (Denmark) Manufact. ApS 

Biogen Allé 1 

Hillerød, 3400, 

Denmark 

 

 

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. 

 

 

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. 

 

 



54 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 



55 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 



56 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Aybintio 25 mg/ml concentrate for solution for infusion  

bevacizumab 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each vial contains 100 mg bevacizumab. 

 

 

3. LIST OF EXCIPIENTS 

 

Trehalose dihydrate, sodium acetate trihydrate, acetic acid, polysorbate 20, water for injections 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Concentrate for solution for infusion  

1 vial of 4 ml 

100 mg/4 ml 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For 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 

 

 

8. EXPIRY DATE 

 

EXP 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in a refrigerator.  

Do not freeze. 

Keep the vial in the outer carton. 



57 

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 

 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

The Netherlands  

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/20/1454/001  

 

 

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  

 



58 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

VIAL  

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Aybintio 25 mg/ml sterile concentrate  

bevacizumab 

IV after dilution 

 

 

2. METHOD OF ADMINISTRATION 

 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

100 mg/4 ml 

 

 

6. OTHER 

 

 

 

 



59 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Aybintio 25 mg/ml concentrate for solution for infusion  

bevacizumab 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each vial contains 400 mg bevacizumab. 

 

 

3. LIST OF EXCIPIENTS 

 

Trehalose dihydrate, sodium acetate trihydrate, acetic acid, polysorbate 20, water for injections 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Concentrate for solution for infusion  

1 vial of 16 ml 

400 mg/16 ml 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For 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 

 

 

8. EXPIRY DATE 

 

EXP 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in a refrigerator.  

Do not freeze. 

Keep the vial in the outer carton. 



60 

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 

 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

The Netherlands  

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/20/1454/002  

 

 

13. BATCH NUMBER 

 

Lot  

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including Braille accepted. 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 

NN  

 



61 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

VIAL  

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Aybintio 25 mg/ml sterile concentrate  

bevacizumab 

IV after dilution 

 

 

2. METHOD OF ADMINISTRATION 

 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

400 mg/16 ml 

 

 

6. OTHER 

 

 

 



62 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



63 

Package leaflet: Information for the user 

 

Aybintio 25 mg/ml concentrate for solution for infusion 

bevacizumab 

 

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, pharmacist or nurse.  
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 

 

1. What Aybintio is and what it is used for  

2. What you need to know before you use Aybintio  

3. How to use Aybintio 

4. Possible side effects  

5. How to store Aybintio  

6. Contents of the pack and other information 

 

 

1. What Aybintio is and what it is used for 

 

Aybintio contains the active substance bevacizumab, which is a humanised monoclonal antibody (a 

type of protein that is normally made by the immune system to help defend the body from infection 

and cancer). Bevacizumab binds selectively to a protein called human vascular endothelial growth 

factor (VEGF), which is found on the lining of blood and lymph vessels in the body. The VEGF 

protein causes blood vessels to grow within tumours, these blood vessels provide the tumour with 

nutrients and oxygen. Once bevacizumab is bound to VEGF, tumour growth is prevented by blocking 

the growth of the blood vessels which provide the nutrients and oxygen to the tumour. 

 

Aybintio is a medicine used for the treatment of adult patients with advanced cancer in the large 

bowel, i.e., in the colon or rectum. Aybintio will be administered in combination with chemotherapy 

treatment containing a fluoropyrimidine medicine. 

 

Aybintio is also used for the treatment of adult patients with metastatic breast cancer. When used for 

patients with breast cancer, it will be administered with a chemotherapy medicinal product called 

paclitaxel or capecitabine. 

 

Aybintio is also used for the treatment of adult patients with advanced non-small cell lung cancer. 

Aybintio will be administered together with a chemotherapy regimen containing platinum. 

 

Aybintio is also used for the treatment of adult patients with advanced non-small cell lung cancer 

when cancer cells have specific mutations of a protein called epidermal growth factor receptor 

(EGFR). 

Aybintio will be administered in combination with erlotinib. 

 

Aybintio is also used for treatment of adult patients with advanced kidney cancer. When used for 

patients with kidney cancer, it will be administered with another type of medicine called interferon. 

 



64 

Aybintio is also used for the treatment of adult patients with advanced epithelial ovarian, fallopian 

tube, or primary peritoneal cancer. When used for patients with epithelial ovarian, fallopian tube, or 

primary peritoneal cancer, it will be administered in combination with carboplatin and paclitaxel. 

When used for those adult patients with advanced epithelial ovarian, fallopian tube, or primary 

peritoneal cancer whose disease has come back at least 6 months after the last time they were treated 

with a chemotherapy regimen containing a platinum agent, Aybintio will be administered in 

combination with carboplatin and gemcitabine or with carboplatin and paclitaxel. 

 

When used for those adult patients with advanced epithelial ovarian, fallopian tube, or primary 

peritoneal cancer whose disease has come back before 6 months after the last time they were treated 

with a chemotherapy regimen containing a platinum agent, Aybintio will be administered in 

combination with topotecan or pegylated liposomal doxorubicin. 

 

Aybintio is also used for the treatment of adult patients with persistent, recurrent or metastatic cervical 

cancer. Aybintio will be administered in combination with paclitaxel and cisplatin or, alternatively, 

paclitaxel and topotecan in patients who cannot receive platinum therapy. 

 

 

2. What you need to know before you use Aybintio 

 

Do not use Aybintio if 

- you are allergic (hypersensitive) to bevacizumab or to any of the other ingredients of this 

medicine (listed in section 6). 

- you are allergic (hypersensitive) to Chinese hamster ovary (CHO) cell products or to other 

recombinant human or humanised antibodies. 

- you are pregnant. 

 

Warnings and precautions  

 
Talk to your doctor, pharmacist or nurse before using Aybintio: 

 

● It is possible that Aybintio may increase the risk of developing holes in the gut wall. If you 
have conditions causing inflammation inside the abdomen (e.g. diverticulitis, stomach 

ulcers, colitis associated with chemotherapy), please discuss this with your doctor. 

 

● Aybintio may increase the risk of developing an abnormal connection or passageway 
between two organs or vessels. The risk of developing connections between the vagina and 

any parts of the gut can increase if you have persistent, recurrent or metastatic cervical 

cancer. 

 

● This medicine can increase the risk of bleeding or increase the risk of problems with wound 
healing after surgery. If you are going to have an operation, if you have had major surgery 

within the last 28 days or if you still have an unhealed wound following surgery, you should 

not receive this medicine. 

 

● Aybintio may increase the risk of developing serious infections of the skin or deeper layers 
under the skin, especially if you had holes in the gut wall or problems with wound healing. 

 

● Aybintio can increase the incidence of high blood pressure. If you have high blood 
pressure which is not well controlled with blood pressure medicines, please consult your 

doctor as it is important to make sure that your blood pressure is under control before 

starting Aybintio treatment. 

 

● If you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) 
or a tear in a blood vessel wall. 

 

● This medicine increases the risk of having protein in your urine especially if you already 



65 

have high blood pressure. 

 

● The risk of developing blood clots in your arteries (a type of blood vessel) can increase if 
you are over 65 years old, if you have diabetes, or if you have had previous blood clots in 

your arteries. Please talk to your doctor since blood clots can lead to heart attack and 

stroke. 

 

● Aybintio can also increase the risk of developing blood clots in your veins (a type of blood 
vessel). 

● This medicine may cause bleeding, especially tumour-related bleeding. Please consult your 
doctor if you or your family tend to suffer from bleeding problems or you are taking 

medicines to thin the blood for any reason. 

 

● It is possible that Aybintio may cause bleeding in and around your brain. Please discuss this 
with your doctor if you have metastatic cancer affecting your brain. 

 

● It is possible that Aybintio can increase the risk of bleeding in your lungs, including 
coughing or spitting blood. Please discuss with your doctor if you noticed this previously. 

 

● Aybintio can increase the risk of developing a weak heart. It is important that your doctor 
knows if you have ever received anthracyclines (for example doxorubicin, a specific type of 

chemotherapy used to treat some cancers) or had radiotherapy to your chest, or if you have 

heart disease. 

 

● This medicine may cause infections and a decreased number of your neutrophils (a type 
of blood cell important for your protection against bacteria). 

 

● It is possible that Aybintio can cause hypersensitivity and/or infusion reactions (reactions 
related to your injection of the medicine). Please let your doctor, pharmacist or nurse know if 

you have previously experienced problems after injections, such as dizziness/feeling of 

fainting, breathlessness, swelling or skin rash. 

 

● A rare neurological side effect named posterior reversible encephalopathy syndrome (PRES) 
has been associated with Aybintio treatment. If you have headache, vision changes, 

confusion or seizure with or without high blood pressure, please contact your doctor. 

 

Please consult your doctor, even if these above statements were only applicable to you in the past.  

 

Before you are given Aybintio or while you are being treated with Aybintio: 

● if you have or have had pain in the mouth, teeth and/or jaw, swelling or sores inside the 
mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth tell your 

doctor and dentist immediately. 

● if you need to undergo an invasive dental treatment or dental surgery, tell your dentist that 
you are being treated with Aybintio, in particular when you are also receiving or have 

received an injection of bisphosphonate into your blood. 

 

You may be advised to have a dental check-up before you start treatment with Aybintio. 

 

 

Children and adolescents 

 

Aybintio use is not recommended in children and adolescents under the age of 18 years because the 

safety and benefit have not been established in these patient populations. 

 

Death of bone tissue (osteonecrosis) in bones other than the jaw have been reported in patients under 

18 years old when treated with Aybintio.



66 

Other medicines and Aybintio 

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 

medicines. 

 

Combinations of Aybintio with another medicine called sunitinib malate (prescribed for renal and 

gastrointestinal cancer) may cause severe side effects. Discuss with your doctor to make sure that you 

do not combine these medicine. 

 

Tell your doctor if you are using platinum- or taxane-based therapies for lung or metastatic breast 

cancer. These therapies in combination with Aybintio may increase the risk of severe side effects. 

  

Please tell your doctor if you have recently received, or are receiving, radiotherapy. 

 

Pregnancy, breast-feeding and fertility 

You must not use this medicine if you are pregnant. Aybintio may cause damage to your unborn baby 

as it may stop the formation of new blood vessels. Your doctor should advise you about using 

contraception during treatment with Aybintio and for at least 6 months after the last dose of Aybintio. 

 

Tell your doctor straightaway if you are pregnant, become pregnant during treatment with this 

medicine, or plan to become pregnant in the near future. 

 

You must not breast-feed your baby during treatment with Aybintio and for at least 6 months after the 

last dose of Aybintio, as this medicine may interfere with the growth and development of your baby. 

 

Aybintio may impair female fertility. Please consult your doctor for more information. Ask your 

doctor, pharmacist or nurse for advice before taking any medicine. 

 

 

Driving and using machines 

Aybintio has not been shown to reduce your ability to drive or to use any tools or machines. However, 

sleepiness and fainting have been reported with Aybintio use. If you experience symptoms that affect 

your vision or concentration, or your ability to react, do not drive and use machines until symptoms 

disappear. 

 

Important information about some of the ingredients of Aybintio 

This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 
‘sodium-free’. 

 

 

3. How to use Aybintio 

 

Dosage and frequency of administration 

The dose of Aybintio needed depends on your body weight and the kind of cancer to be treated. The 

recommended dose is 5 mg, 7.5 mg, 10 mg or 15 mg per kilogram of your body weight. Your doctor 

will prescribe a dose of Aybintio that is right for you. You will be treated with Aybintio once every 2 

or 3 weeks. The number of infusions that you receive will depend on how you are responding to 

treatment; you should continue to receive this medicine until Aybintio fails to stop your tumour 

growing. Your doctor will discuss this with you. 

 

Method and route of administration 

Aybintio is a concentrate for solution for infusion. Depending on the dose prescribed for you, some or 

all of the contents of the Aybintio vial will be diluted with sodium chloride solution before use. A 

doctor or nurse will give you this diluted Aybintio solution by intravenous infusion (a drip into your 

vein). The first infusion will be given to you over 90 minutes. If this is well-tolerated the second 

infusion may be given over 60 minutes. Later infusions may be given to you over 30 minutes. 

 

 



67 

The administration of Aybintio should be temporarily discontinued 

● if you develop severe high blood pressure requiring treatment with blood pressure medicines, 

● if you have problems with wound healing following surgery, 

● if you undergo surgery. 

 

The administration of Aybintio should be permanently discontinued if you develop 

● severe high blood pressure which cannot be controlled by blood pressure medicines; or a 

sudden severe rise in blood pressure, 

● presence of protein in your urine accompanied by swelling of your body, 

● a hole in your gut wall, 

● an abnormal tube-like connection or passage between the windpipe and the gullet, between 

internal organs and skin, between the vagina and any parts of the gut or between other tissues 

that are not normally connected (fistula), and are judged by your doctor to be severe, 

● serious infections of the skin or deeper layers under the skin, 

● a blood clot in your arteries, 

● a blood clot in the blood vessels of your lungs, 

● any severe bleeding. 

 

If too much Aybintio is given 

● you may develop a severe migraine. If this happens you should talk to your doctor, pharmacist 

or nurse immediately. 

 

If a dose of Aybintio is missed 

● your doctor will decide when you should be given your next dose of Aybintio. You should 

discuss this with your doctor. 

 

If you stop treatment with Aybintio 

Stopping your treatment with Aybintio may stop the effect on tumour growth. Do not stop treatment 

with Aybintio unless you have discussed this with your doctor. 

 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. 

 

The side effects listed below were seen when Aybintio was given together with chemotherapy. This 

does not necessarily mean that these side effects were strictly caused by Aybintio. 

 

Allergic reactions 

If you have an allergic reaction, tell your doctor or a member of the medical staff straight away. The 

signs may include: difficulty in breathing or chest pain. You could also experience redness or flushing 

of the skin or a rash, chills and shivering, feeling sick (nausea) or being sick (vomiting). 

 

You should seek help immediately if you suffer from any of the below mentioned side effects. 

 

Severe side effects, which may be very common (affects more than 1 user in 10), include: 

• high blood pressure, 

• feeling of numbness or tingling in hands or feet, 

• decreased number of cells in the blood, including white cells that help to fight against 

infections (this may be accompanied by fever), and cells that help the blood to clot, 

• feeling weak and having no energy, 

• tiredness, 



68 

• diarrhoea, nausea, vomiting and abdominal pain. 

 

Severe side effects, which may be common (affects 1 to 10 users in 100), include: 

• perforation of the gut, 

• bleeding, including bleeding in the lungs in patients with non-small cell lung cancer, 

• blocking of the arteries by a blood clot, 

• blocking of the veins by a blood clot, 

• blocking of the blood vessels of the lungs by a blood clot, 

• blocking of the veins of the legs by a blood clot, 

• heart failure, 

• problems with wound healing after surgery, 

• redness, peeling, tenderness, pain, or blistering on the fingers or feet, 

• decreased number of red cells in the blood, 

• lack of energy, 

• stomach and intestinal disorder,  

• muscle and joint pain, muscular weakness, 

• dry mouth in combination with thirst and/or reduced or darkened urine, 

• inflammation of the moist lining of mouth and gut, lungs and air passages, reproductive, and 

urinary tracts, 

• sores in the mouth and the tube from the mouth to the stomach, which may be painful and 

cause difficulty swallowing, 

• pain, including headache, back pain and pain in the pelvis and anal regions, 

• localised pus collection, 

• infection, and in particular infection in the blood or bladder, 

• reduced blood supply to the brain or stroke, 

• sleepiness, 

• nose bleed, 

• increase in heart rate (pulse), 

• blockage in the gut or bowel, 

• abnormal urine test (protein in the urine), 

• shortness of breath or low levels of oxygen in the blood, 

• infections of the skin or deeper layers under the skin, 

• fistula: abnormal tube-like connection between internal organs and skin or other tissues that 

are not normally connected, including connections between vagina and the gut in patients with 

cervical cancer. 

 

Severe side effects of unknown frequency (frequency cannot be estimated from the available data), 

include: 

• serious infections of the skin or deeper layers under the skin, especially if you had holes in the 

gut wall or problems with wound healing, 

• allergic reactions (the signs may include difficulty breathing, facial redness, rash, low blood 

pressure or high blood pressure, low oxygen in your blood, chest pain, or nausea/vomiting), 

• a negative effect on a woman’s ability to have children (see the paragraphs below the list of 

side effects for further recommendations), 

• a brain condition with symptoms including seizures (fits), headache, confusion, and changes in 

vision (Posterior Reversible Encephalopathy Syndrome or PRES), 

• symptoms that suggest changes in normal brain function (headaches, vision changes, 

confusion, or seizures), and high blood pressure, 

• an enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall 

(aneurysms and artery dissections), 

• clogging of a very small blood vessel(s) in the kidney, 

• abnormally high blood pressure in the blood vessels of the lungs which makes the right side of 

the heart work harder than normal, 

• a hole in the cartilage wall separating the nostrils of the nose, 

• a hole in the stomach or intestines, 



69 

• an open sore or hole in the lining of the stomach or small intestine (the signs may include 

abdominal pain, feeling bloated, black tarry stools or blood in your stools (faeces) or blood in 

your vomit), 

• bleeding from the lower part of the large bowel, 

• lesions in the gums with an exposed jaw bone that does not heal and may be associated with 

pain and inflammation of the surrounding tissue (see the paragraphs below the list of side 

effects for further recommendations), 

• hole in the gall bladder (symptoms and signs may include abdominal pain, fever, and 

nausea/vomiting). 

 

You should seek help as soon as possible if you suffer from any of the below mentioned side 

effects. 

 

Very common (affects more than 1 user in 10) side effects, which were not severe, include: 

• constipation, 

• loss of appetite, 

• fever, 

• problems with the eyes (including increased production of tears), 

• changes in speech, 

• change in the sense of taste, 

• runny nose, 

• dry skin, flaking and inflammation of the skin, change in skin colour, 

• loss of body weight, 

• nose bleeds. 

 

Common (affects 1 to 10 users in 100) side effects, which were not severe, include: 

• voice changes and hoarseness. 

 

Patients older than 65 years have an increased risk of experiencing the following side effects : 

• blood clot in the arteries which can lead to a stroke or a heart attack, 

• reduction in the number of white cells in the blood, and cells that help the blood clot, 

• diarrhoea, 

• sickness, 

• headache, 

• fatigue, 

• high blood pressure. 

 

Aybintio may also cause changes in laboratory tests carried out by your doctor. These include a 

decreased number of white cells in the blood, in particular neutrophils (one type of white blood cell 

which helps protect against infections) in the blood; presence of protein in the urine; decreased blood 

potassium, sodium or phosphorous (a mineral); increased blood sugar; increased blood alkaline 

phosphatase (an enzyme); increased serum creatinine (a protein measured by a blood test to see how 

well your kidneys are working); decreased haemoglobin (found in red blood cells, which carry 

oxygen), which may be severe. 

 

Pain in the mouth, teeth and/or jaw, swelling or sores inside the mouth, numbness or a feeling of 

heaviness in the jaw, or loosening of a tooth. These could be signs and symptoms of bone damage in 

the jaw (osteonecrosis). Tell your doctor and dentist immediately if you experience any of them. 

 

Pre-menopausal women (women who have a menstrual cycle) may notice that their periods become 

irregular or are missed and may experience impaired fertility. If you are considering having children 

you should discuss this with your doctor before your treatment starts. 

 

Aybintio has been developed and made to treat cancer by injecting it into the bloodstream. It has not 

been developed or made for injection into the eye. It is therefore not authorised to be used in this way. 

When Aybintio is injected directly into the eye (unapproved use), the following side effects may occur: 

 



70 

• Infection or inflammation of the eye globe, 

• Redness of the eye, small particles or spots in your vision (floaters), eye pain, 

• Seeing flashes of light with floaters, progressing to a loss of some of your vision, 

• Increased eye pressure, 

• Bleeding in the eye. 

 

Reporting of side effects 

If you get any side effects, talk to your doctor, pharmacist or nurse. 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 Aybintio 

 

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 outer carton and on the vial label 

after the abbreviation EXP. The expiry date refers to the last day of that month. 

  

Store in a refrigerator (2C–8C). Do not freeze. 

Keep the vial in the outer carton in order to protect from light. 

 

Infusion solutions should be used immediately after dilution. Do not use Aybintio if you notice any 

particulate matter or discolouration prior to administration. If not used immediately, in-use storage 

times and conditions are the responsibility of the user and would normally not be longer than 24 hours 

at 2°C to 8°C, unless the infusion solutions have been prepared in a sterile environment.  

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help to protect the environment. 

 

6. Contents of the pack and other information 

 

What Aybintio contains  

- The active substance is bevacizumab. Each ml of concentrate contains 25 mg of bevacizumab, 
corresponding to 1.4 to 16.5 mg/ml when diluted as recommended. 

Each 4 ml vial contains 100 mg of bevacizumab, corresponding to 1.4 mg/ml when diluted as 

recommended. 

Each 16 ml vial contains 400 mg of bevacizumab, corresponding to 16.5 mg/ml when diluted as 

recommended 

- The other ingredients are trehalose dihydrate, sodium acetate trihydrate, acetic acid,  
polysorbate 20, and water for injections 

 

What Aybintio looks like and contents of the pack 

Aybintio is a concentrate for solution for infusion. The concentrate is a clear, colourless to pale brown 

liquid in a glass vial with a rubber stopper. Each vial contains 100 mg bevacizumab in 4 ml of solution 

or 400 mg bevacizumab in 16 ml of solution. Each pack of Aybintio contains one vial. 

 

Marketing Authorisation Holder  

Samsung Bioepis NL B.V. 

Olof Palmestraat 10 

2616 LR Delft 

The Netherlands 

 

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


71 

Manufacturer 

Biogen (Denmark) Manufact. ApS 

Biogen Allé 1 

Hillerød, 3400, 

Denmark 

 

  

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Nederland/Pays-Bas/Niederlande  

Lietuva 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Nyderlandai 

 

България 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Нидерландия 

Luxembourg/Luxemburg 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Holland/Niederlande 

 

Česká republika 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Nizozemsko 

Magyarország 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Hollandia 

 

Danmark 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Holland 

Tlf: + 45 8083 0425 

 

Malta 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Olanda 

Deutschland 

MSD SHARP & DOHME GMBH 

Tel: 0800 673 673 673 (+49 (0) 89 4561 2612) 

e-mail@msd.de 

 

Nederland 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Nederland 

Eesti 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Holland 

Norge 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Nederland 

Tlf: +47 80 02 50 72 

 

Ελλάδα 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Ολλανδία 

 

Österreich 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Niederlande 

España 

Merck Sharp & Dohme de España, S.A. 

Tel: +34 91 321 06 00 

msd_info@merck.com 

 

Polska 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Holandia 

 

France 

MSD France 

Tél: + 33 (0) 1 80 46 40 40 

 

Portugal 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Países Baixos 

 

mailto:e-mail@msd.de
mailto:msd_info@merck.com


72 

Hrvatska 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Nizozemska 

 

Ireland 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Netherlands 

 

România 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Olanda 

 

Slovenija 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Nizozemska 

 

Ísland 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Holland 

Slovenská republika 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Holandsko 

 

Italia 

MSD Italia S.r.l. 

Tel: +39 06 361911 

medicalinformation.it@merck.com 

 

Suomi/Finland 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Alankomaat/Nederländerna  

Κύπρος 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Ολλανδία 

 

Sverige 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Nederländerna 

 

Latvija 

Samsung Bioepis NL B.V. 

Olof Palmestraat 10, 2616 LR Delft 

Nīderlande 

United Kingdom 

Merck Sharp & Dohme Limited 

Tel: +44 (0) 1992 467272 

medicalinformationuk@merck.com  

 

  

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 

 

This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 

 

mailto:medicalinformation.it@merck.com
mailto:medicalinformationuk@merck.com

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET