Equidacent

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
  



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Equidacent 25 mg/mL concentrate for solution for infusion. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each mL of concentrate contains 25 mg of bevacizumab*. 
 
Each vial of 4 mL of concentrate contains 100 mg of bevacizumab.  
Each vial of 16 mL of concentrate 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. 
 
Excipient(s) with known effect 
Each vial of 4 mL of concentrate contains 191 mg sorbitol (E420).  
Each vial of 16 mL of concentrate contains 764 mg sorbitol (E420). 
 
For the full list of excipients see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion. 
 
Clear to opalescent, colourless to pale brownish-yellowish solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Bevacizumab in combination with fluoropyrimidine-based chemotherapy is indicated for treatment of 
adult patients with metastatic carcinoma of the colon or rectum. 
 
Bevacizumab 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. 
 
Bevacizumab 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 anthracycline- 
containing regimens in the adjuvant setting within the last 12 months should be excluded from 
treatment with Equidacent in combination with capecitabine. For further information as to HER2 
status, please refer to section 5.1. 
 
Bevacizumab, 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. 
 



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Bevacizumab, 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). 
 
Bevacizumab in combination with interferon alfa-2a is indicated for first-line treatment of adult 
patients with advanced and/or metastatic renal cell cancer. 
 
Bevacizumab, 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 
IIIB, IIIC and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer (see section 5.1). 
 
Bevacizumab, 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. 
 
Bevacizumab, 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 
 
Equidacent 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 Equidacent, 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 Equidacent 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 
 
Equidacent is administered in addition to platinum-based chemotherapy for up to 6 cycles of 
treatment followed by Equidacent as a single agent until disease progression. 
 
The recommended dose of Equidacent 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 
Equidacent 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 Equidacent 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 Equidacent 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 Equidacent 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: Equidacent is administered in addition to carboplatin and paclitaxel for up to 6 
cycles of treatment followed by continued use of Equidacent as single agent until disease progression 
or for a maximum of 15 months or until unacceptable toxicity, whichever occurs earlier. 
 
The recommended dose of Equidacent is 15 mg/kg of body weight given once every 3 weeks as an 
intravenous infusion. 
 
Treatment of platinum-sensitive recurrent disease: Equidacent 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 Equidacent as single agent 
until disease progression. The recommended dose of Equidacent is 15 mg/kg of body weight given 
once every 3 weeks as an intravenous infusion. 
 
Cervical cancer 
 
Equidacent is administered in combination with one of the following chemotherapy regimens: 
paclitaxel and cisplatin or paclitaxel and topotecan. 
 
The recommended dose of Equidacent is 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 (see section 5.1). 
 

Special populations 
 

Elderly: No dose adjustment is required in the elderly. 
 



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Renal impairment: The safety and efficacy have not been studied in patients with renal impairment 
(see section 5.2). 
 
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 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 
 
Equidacent 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. Equidacent 
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 
 
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 patients treated for persistent, recurrent or metastatic cervical cancer with 
Equidacent 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 
 



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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 Equidacent 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 
Equidacent 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. Equidacent 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 Equidacent 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. 
Equidacent 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 
Equidacent. The safety of reinitiating bevacizumab therapy in patients previously experiencing PRES 
is not known. 
 
Proteinuria (see section 4.8) 
 



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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 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 Equidacent. 
 
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. 
 
Equidacent 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. Equidacent 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 Equidacent 
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 
 



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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 Equidacent, this risk should be 
carefully considered in patients with risk factors such as hypertension or history of aneurysm. 
 
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 Equidacent. In patients 
who have previously received or are receiving intravenous bisphosphonates invasive dental 
procedures should be avoided, if possible. 



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Intravitreal use 
 
Equidacent 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. 
 
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 childbearing potential prior to starting treatment with 
bevacizumab. 
 
Excipients with known effect 
 
Sorbitol 

This medicinal product contains sorbitol (E420). Patients with hereditary fructose intolerance (HFI) 
should not take/be given this medicinal product. 
 
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. 



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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. 
 
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). Equidacent 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 



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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). 
 
Tables 1 and 2 list adverse reactions associated with the use of bevacizumab in combination with 
different chemotherapy regimens in multiple indications. 
 
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. 



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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 
Thrombocytopeni
a 

Anaemia, 
Lymphopenia 

    

Immune system 
disorders 

 Hypersensitivity, 
Infusion 
reactionsa,b,d 

    

Metabolism 
and nutrition 
disorders 

Anorexia 
Hypomagnesaemi
a Hyponatraemia 

Dehydration     

Nervous system 
disorders 

Peripheral sensory 
neuropathyb, 
Dysarthria, 
Headache, 
Dysguesia 

Cerebrovascular 
accident, Syncope, 
Somnolence 

 Posterior 
reversible 
encephalopath
y syndromea,b,d 

Hypertensive 
encephalo- 
pathya 

 

Eye disorders Eye disorder, 
Lacrimation 
increased 

     

Cardiac 
disorders 

 Congestive heart 
failureb,d, 
Supraventricular 
tachycardia 

    

Vascular 
disorders 

Hypertensionb,d, 
Thromboembolis
m (venous)b,d 

Thromboembolis
m (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 

   Gastrointestinal 
ulcera 



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System organ 
class 

Very common Common Uncommon Rare Very rare Frequency not 
known 

disorder, 
Proctalgia 

Hepatobiliary 
disorders 

     Gallbladder 
perforationa,b 

Skin and 
subcutaneous 
tissue disorders 

Wound healing 
complicationsb,d, 
Exfoliative 
dermatitis, Dry 
skin, Skin 
discolouration 

Palmar-plantar 
erythrodysaesthesi
a syndrome 

    

Musculoskeleta
l 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 
disorders 

     Foetal 
abnormalitiesa,b 

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 

Febrile 
neutropenia, 
Leucopenia, 

Anaemia, 
Lymphopenia 

    



14  

System 
organ class 

Very common Common Uncommon Rare Very 
rare 

Frequency not 
known 

system 
disorders 

Neutropeniaa, 
Thrombocytop
enia 

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 Thromboemboli
sm arteriala,b, 
Haemorrhagea,b, 
Thromboemboli
sm (venous)a,b, 
Deep vein 
thrombosis 

   Renal 
thrombotic 
microangiopathy
b,c Aneurysms 
and artery 
dissections 

Respiratory, 
thoracic and 
mediastinal 
disorders 

 Pulmonary 
haemorrhage/ 
Haemoptysisa,b, 
Pulmonary 
embolism, 
Epistaxis, 
Dyspnoea, 
Hypoxia 

   Pulmonary 
hypertensionc, 
Nasal septum 
perforationc 

Gastro-
intestinal 
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 
erythro-
dysaesthesia 
syndrome 

    

Musculo- 
skeletal and 

 Fistulaa,b, 
Myalgia, 

   Osteonecrosis of 
the jawb,c 



15  

System 
organ class 

Very common Common Uncommon Rare Very 
rare 

Frequency not 
known 

connective 
tissue 
disorders 

Arthralgia, 
Muscular 
weakness, Back 
pain 

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 
administratio
n 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. 
 
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. 



16  

 
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 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. 
 



17  

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. 
 
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 



18  

to 1.4% of treated patients. Testing for proteinuria is recommended prior to start of Equidacent 
therapy. In most clinical trials urine protein levels of ≥ 2g/24 hrs led to stopping treatment with 
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 



19  

treatment regimen. Clinical safety data suggest that the incidence of minor mucocutaneous 
haemorrhage (e.g. epistaxis) may be dose-dependent. 
 
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 



20  

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. 
 
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 Equidacent 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 



21  

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 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 post-operative 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 metastatic rhabdomyosarcoma and 
non-rhabdomyosarcoma soft tissue sarcoma, the safety profile of bevacizumab-treated children was 
comparable with that observed in adults treated with bevacizumab. 
 
Equidacent 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 



22  

System organ class 
(SOC) Reactions (frequency*) 

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 
connective tissue disorders 

Cases of osteonecrosis of the jaw (ONJ) have been reported in patients 
treated 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. 
 
Equidacent 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 

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


23  

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 
 
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: 
 
• 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. 



24  

 
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. 
 
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. 
 



25  

The efficacy data from trials AVF0780g and AVF2192g investigating bevacizumab in combination 
with 5-FU/FA chemotherapy are summarised in table 5. 
 
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. 
 
  



26  

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 
1,000 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. 
 
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 



27  

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). 
 
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 



28  

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). 
 
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) 



29  

• 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. 
 
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. 
 
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. 
 



32  

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 1,250 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. 
 
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] 



33  

 Cisplatin/Gemcitabine 
+ placebo 

Cisplatin/Gemcitabine 
+ bevacizumab 

7.5 mg/kg q 3 weeks 

Cisplatin/Gemcitabine 
+ bevacizumab 

15 mg/kg q 3 weeks 
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 randomised, open-label, multi-centre 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. 
 
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 randomised. However two of 
the randomised 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. 



34  

 
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 alfa-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. 
 
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 
 Placebo + IFNa BVb + IFNa 
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), 



35  

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 subgroup 
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). 
 

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 anti-cancer 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 1,873 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 



36  

• 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 suboptimally 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 pre-
specified 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 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 



37  

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. 
 
Pre-specified PFS analyses were conducted, all with a cut-off date of 29 September 2009. The results 
of these pre-specified 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 disease2,3 
 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 0.66 

(0.62, 1.05) (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 0.78 

(0.77, 1.14) (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 0.64 

(0.70, 1.16) (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 = 1,386) 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 anti-cancer 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 1,528 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. 
 



39  

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 
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. 
 
Table 19. PFS1 results by disease stage and debulking status from study BO17707 (ICON7) 
 

Randomised patients stage III optimally debulked disease2,3 
 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 CPB7.5+ 



40  

(n = 97) (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 phase III trials (AVF4095g 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. 

 
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 (AUC 4, day 1) and gemcitabine (1,000 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. 

• Carboplatin (AUC 4, day 1) and gemcitabine (1,000 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. 
 
  



41  

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. 
 
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 randomised 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 



42  

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 randomised 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. 
 
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 = randomised to undergo cytoreduction or 
randomised 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. 

 
  



43  

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. 
 
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 
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 randomised 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 23 and 24, 
respectively. 
 



44  

Table 23. 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). 
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. 
  



45  

Table 24. 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 randomised 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) 



46  

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 event free 
survival (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 randomised 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 tumour 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 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 adverse events, including grade ≥ 3 adverse events and serious adverse events, was 
similar between the two treatment arms. No adverse events 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. 
 
Biotransformation 



47  

 
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 paediatric 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 characterised by the paediatric population PK model 
for 70 paediatric 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 



48  

inhibit wound healing at doses below the proposed clinical dose. Effects on wound healing were 
shown to be fully reversible. 
 
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 
sections 4.6 and 4.8. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium L-glutamate  
Sorbitol (E420)  
Polysorbate 80 
Hydrochloric acid (for pH-adjustment)  
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. 



49  

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 
 
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 
 
Equidacent 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 Equidacent 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 Equidacent and polyvinyl chloride or polyolefin bags or infusion sets 
have been observed. 
 
Equidacent 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 
 
Centus Biotherapeutics Europe Limited 
South Bank House, Barrow Street 
Dublin 4 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/20/1472/001 
EU/1/20/1472/002 
 
 
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 (EMA): http://www.ema.europa.eu.  

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


50  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 

 
 



51  

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

 
Name and address of the manufacturer of the biological active substance 
 
Kyowa Kirin Co., Ltd. 
Takasaki Plant, 100-1 Hagiwara-machi,  
Takasaki, Gunma, 370-0013,  
Japan 
 
Name and address of the manufacturer responsible for batch release 
 
Geryon Pharma Ireland Limited 
Skybridge House, Corballis Road North, Dublin Airport, 
Swords, Co. Dublin, K67 P6K2, 
Ireland 
 
 
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. 

 
 
 
 
 
 
 
 



52  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



53  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



54  

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Equidacent 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 
 
Contains: sodium L-glutamate, sorbitol (E420), polysorbate 80, hydrochloric acid, 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 
 
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. 
Store in the original carton in order to protect from light. 
 
 



55  

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 
 
Centus Biotherapeutics Europe Limited 
South Bank House, Barrow Street 
Dublin 4 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/20/1472/001 
 
 
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 
  



56  

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Equidacent 25 mg/mL sterile concentrate  
bevacizumab 
IV  
 
 
2. METHOD OF ADMINISTRATION 
 
IV after dilution 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
100 mg/4 mL 
 
 
6. OTHER 
 
  



57  

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Equidacent 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 
 
Contains: sodium L-glutamate, sorbitol (E420), polysorbate 80, hydrochloric acid, 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 
 
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. 
Store in the original carton in order to protect from light. 
 
 



58  

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 
 
Centus Biotherapeutics Europe Limited 
South Bank House, Barrow Street 
Dublin 4 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/20/1472/002 
 
 
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 
  



59  

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Equidacent 25 mg/mL sterile concentrate  
bevacizumab 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
IV after dilution 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
400 mg/16 mL 
 
 
6. OTHER 
  



60  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B.  PACKAGE LEAFLET 
  



61  

Package leaflet: Information for the user 
 

Equidacent 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 Equidacent is and what it is used for 
2. What you need to know before you use Equidacent 
3. How to use Equidacent 
4. Possible side effects 
5. How to store Equidacent 
6. Contents of the pack and other information 
 
 
1. What Equidacent is and what it is used for 
 
Equidacent 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. 
 
Advanced cancer in the large bowel 
Equidacent is a medicine used for the treatment of adult patients with advanced cancer in the large 
bowel, i.e., in the colon or rectum. Equidacent will be administered in combination with chemotherapy 
treatment containing a fluoropyrimidine medicine. 
 
Breast cancer which has spread (metastatic) 
Equidacent 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. 
 
Advanced non-small cell lung cancer  
Equidacent is also used for the treatment of adult patients with advanced non-small cell lung cancer. 
Equidacent will be administered together with a chemotherapy regimen containing platinum. 
 
Equidacent 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). Equidacent will be administered in combination with erlotinib. 
 



62  

Advanced kidney cancer 
Equidacent 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. 
 
Advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer 
Equidacent 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, Equidacent will be administered in 
combination with carboplatin and gemcitabine or with carboplatin and paclitaxel. 
 
Cervical cancer which does not go away, comes back or has spread  
Equidacent is also used for the treatment of adult patients with persistent, recurrent or metastatic 
cervical cancer. Equidacent 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 Equidacent 
 
Do not use Equidacent 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 Equidacent: 
 
 It is possible that Equidacent 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. 

 
 Equidacent 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. 

 
 Equidacent 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. 

 
 Equidacent 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. 
 
 Equidacent 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 Equidacent 
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. 



63  

 
 Equidacent increases the risk of having protein in your urine especially if you already 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. 

 
 Equidacent 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 Equidacent 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 Equidacent can increase the risk of bleeding in your lungs, including coughing or 
spitting blood. Please discuss with your doctor if you noticed this previously. 

 
 Equidacent 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 Equidacent 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 Equidacent 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 Equidacent or while you are being treated with Equidacent: 
 
 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 Equidacent, 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 Equidacent. 
 
Children and adolescents 
 
Equidacent 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. 
 



64  

Death of bone tissue (osteonecrosis) in bones other than the jaw have been reported in patients under 
18 years old when treated with bevacizumab. 
 
Other medicines and Equidacent 
 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. 
 
Combinations of Equidacent 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 Equidacent 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. Equidacent 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 Equidacent and for 

at least 6 months after the last dose of Equidacent. 
 
Tell your doctor straight away 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 Equidacent and for at least 6 months after 
the last dose of Equidacent, as this medicine may interfere with the growth and development of your 
baby. 
 
Equidacent 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 
 
Equidacent 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 Equidacent use. If you experience 
symptoms that affect your vision or concentration, or your ability to react, do not drive or use 
machines until symptoms disappear. 
 
Equidacent contains sorbitol  
 
Each Equidacent vial of 4 mL of concentrate contains 191 mg sorbitol and each Equidacent vial of 16 
mL of concentrate contains 764 mg sorbitol. Sorbitol is a source of fructose. If you have hereditary 
fructose intolerance (HFI), a rare genetic disorder, you must not receive this medicine. Patients with 
HFI cannot break down fructose, which may cause serious side effects. You must tell your doctor 
before receiving this medicine if you have HFI. 
 
Important information about some of the ingredients of Equidacent 
This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-
free’. 
 
 
3. How to use Equidacent 
 



65  

 
Dosage and frequency of administration 
 
The dose of Equidacent 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 Equidacent that is right for you.  
 You will be treated with Equidacent 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 Equidacent fails to stop your tumour growing. 
Your doctor will discuss this with you. 

 
Method and route of administration 
 
Equidacent is a concentrate for solution for infusion. Depending on the dose prescribed for you, some 
or all of the contents of the Equidacent vial will be diluted with sodium chloride solution before use. 
A doctor or nurse will give you this diluted Equidacent 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. 
 
The administration of Equidacent 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 Equidacent 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 Equidacent 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 Equidacent is missed 
 
 your doctor will decide when you should be given your next dose of Equidacent. You should 

discuss this with your doctor. 
 
If you stop treatment with Equidacent 
 
Stopping your treatment with Equidacent may stop the effect on tumour growth. Do not stop 
treatment with Equidacent unless you have discussed this with your doctor. 
 



66  

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 Equidacent was given together with chemotherapy. This 
does not necessarily mean that these side effects were strictly caused by Equidacent. 
 
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 (may affect more than 1 in 10 people), 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, 
 diarrhoea, nausea, vomiting and abdominal pain. 
 
Severe side effects, which may be common (may affect up to 1 in 10 people), 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, 



67  

 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, 
 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 (may affect more than 1 in 10 people) 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 (may affect up to 1 in 10 people) side effects, which were not severe, include: 
 voice changes and hoarseness. 



68  

 
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. 
 
Equidacent 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. 
 
Equidacent 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 Equidacent is injected directly into the eye (unapproved use), the following side effects 
may occur: 
 
 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 Equidacent 
 
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. 
 

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


69  

Infusion solutions should be used immediately after dilution. Do not use Equidacent if you notice any 
particulate matter or discolouration prior to administration. 
 
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 Equidacent 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 sodium L-glutamate, sorbitol (E420), polysorbate 80, hydrochloric acid 
and water for injections. 

 
What Equidacent looks like and contents of the pack 
 
Equidacent is a concentrate for solution for infusion. The concentrate is a clear to opalescent, 
colourless to pale brownish-yellowish solution 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 
Equidacent contains one vial. 
 
Marketing Authorisation Holder 
Centus Biotherapeutics Europe Limited 
South Bank House, Barrow Street 
Dublin 4 
Ireland 
 
Manufacturer  
Geryon Pharma Ireland Limited 
Skybridge House, Corballis Road North, Dublin Airport, 
Swords, Co. Dublin, K67 P6K2, 
Ireland 
 
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. 

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

	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