Zirabev

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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

Zirabev 25 mg/ml concentrate for solution for infusion.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of concentrate contains 25 mg of bevacizumab*. 
Each 4 ml vial contains 100 mg of bevacizumab.
Each 16 ml vial contains 400 mg of bevacizumab.
For dilution and other handling recommendations, see section 6.6.

*Bevacizumab is a recombinant humanised monoclonal antibody produced by DNA technology in 
Chinese Hamster Ovary cells.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate).

Clear to slightly opalescent, colourless to pale brown liquid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Zirabev in combination with fluoropyrimidine-based chemotherapy is indicated for treatment of adult 
patients with metastatic carcinoma of the colon or rectum.

Zirabev 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.

Zirabev 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 Zirabev in combination with capecitabine. For further information as to 
HER2 status, please refer to section 5.1.

Zirabev, 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.

Zirabev in combination with interferon alfa-2a is indicated for first line treatment of adult patients 
with advanced and/or metastatic renal cell cancer.

Zirabev, in combination with carboplatin and paclitaxel is indicated for the front-line treatment of 
adult patients with advanced (International Federation of Gynecology and Obstetrics (FIGO) stages 
III B, III C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer (see section 5.1).



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Zirabev, 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.

Zirabev in combination with topotecan, or pegylated liposomal doxorubicin is indicated for the 
treatment of adult patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or 
primary peritoneal cancer who received no more than two prior chemotherapy regimens and who have 
not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor–targeted 
agents (see Section 5.1).

Zirabev, 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

Zirabev 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 Zirabev, 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 Zirabev 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

Zirabev is administered in addition to platinum-based chemotherapy for up to 6 cycles of treatment 
followed by Zirabev as a single agent until disease progression.

The recommended dose of Zirabev 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).

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



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Advanced and/or metastatic renal cell cancer (mRCC)

The recommended dose of Zirabev 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: Zirabev is administered in addition to carboplatin and paclitaxel for up to 6 cycles 
of treatment followed by continued use of Zirabev as single agent until disease progression or for a 
maximum of 15 months or until unacceptable toxicity, whichever occurs earlier. 
The recommended dose of Zirabev is 15 mg/kg of body weight given once every 3 weeks as an 
intravenous infusion. 

Treatment of platinum-sensitive recurrent disease: Zirabev 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 Zirabev as single agent until 
disease progression. The recommended dose of Zirabev is 15 mg/kg of body weight given once every 
3 weeks as an intravenous infusion. 

Treatment of platinum-resistant recurrent disease: Zirabev is administered in combination with one of 
the following agents – topotecan (given weekly) or pegylated liposomal doxorubicin. The 
recommended dose of Zirabev is 10 mg/kg of body weight given once every 2 weeks as an intravenous
infusion. When Zirabev is administered in combination with topotecan (given on days 1-5, every 3 
weeks), the recommended dose of Zirabev is 15 mg/kg of body weight given once every 3 weeks as an 
intravenous infusion. It is recommended that treatment be continued until disease progression or 
unacceptable toxicity (see section 5.1, study MO22224).

Cervical cancer

Zirabev is administered in combination with one of the following chemotherapy regimens: paclitaxel 
and cisplatin or paclitaxel and topotecan.

The recommended dose of Zirabev 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 patients
No dose adjustment is required in the elderly.

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

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

Paediatric population

The safety and efficacy of bevacizumab in children 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.



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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

Zirabev 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. Zirabev
infusions should not be administered or mixed with glucose solutions. This medicinal product must 
not be mixed with other medicinal products except those mentioned in section 6.6.

4.3 Contraindications

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

human or humanised antibodies.
 Pregnancy (see section 4.6).

4.4 Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the trade name and the batch 
number of the administered product should be clearly recorded (or stated) in the patient file.

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

Patients may be at an increased risk for the development of gastrointestinal perforation and gall 
bladder perforation when treated with bevacizumab. Intra-abdominal inflammatory process may be a 
risk factor for gastrointestinal perforations in patients with metastatic carcinoma of the colon or 
rectum, therefore, caution should be exercised when treating these patients. Prior radiation is a risk 
factor for GI perforation in patients treated for persistent, recurrent or metastatic cervical cancer with 
bevacizumab and all patients with GI perforation had a history of prior radiation. Therapy should be 
permanently discontinued in patients who develop gastrointestinal perforation.

GI-vaginal fistulae in study GOG-0240

Patients treated for persistent, recurrent, or metastatic cervical cancer with bevacizumab are at 
increased risk of fistulae between the vagina and any part of the GI tract (Gastrointestinal-vaginal 
fistulae). Prior radiation is a major risk factor for the development of GI-vaginal fistulae and all 
patients with GI- vaginal fistulae had a history of prior radiation. Recurrence of cancer within the field 
of prior radiation is an additional important risk factor for the development of GI-vaginal fistulae.

Non-GI fistulae (see section 4.8)

Patients may be at increased risk for the development of fistulae when treated with bevacizumab. 
Permanently discontinue Zirabev in patients with tracheoesophageal (TE) fistula or any Grade 4 
fistula [US National Cancer Institute-Common Terminology Criteria for Adverse Events 



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(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 Zirabev 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. Zirabev 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 Zirabev 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. Zirabev
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.

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 Zirabev, this risk should be 
carefully considered in patients with risk factors such as hypertension or history of aneurysm.

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

Proteinuria (see section 4.8)

Patients with a history of hypertension may be at increased risk for the development of proteinuria 
when treated with bevacizumab. There is evidence suggesting that all Grade (US National Cancer 
Institute- Common Terminology Criteria for Adverse Events [NCI-CTCAE v.3]) proteinuria may be 
related to the dose. Monitoring of proteinuria by dipstick urinalysis is recommended prior to starting 



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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 Zirabev.

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.

Zirabev 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. Zirabev should be discontinued permanently in patients who 
experience Grade 3 or 4 bleeding during Zirabev 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 Zirabev
treatment discontinued in cases of intracranial bleeding.

There is no information on the safety profile of bevacizumab in patients with congenital bleeding 
diathesis, acquired coagulopathy or in patients receiving full dose of anticoagulants for the treatment 
of thromboembolism prior to starting bevacizumab treatment, as such patients were excluded from 
clinical trials. Therefore, caution should be exercised before initiating therapy in these patients. 
However, patients who developed venous thrombosis while receiving therapy did not appear to have 
an increased rate of Grade 3 or above bleeding when treated with a full dose of warfarin and 
bevacizumab concomitantly (NCI-CTCAE v.3).

Pulmonary haemorrhage/haemoptysis

Patients with non-small cell lung cancer treated with bevacizumab may be at risk of serious, and in 
some cases fatal, pulmonary haemorrhage/haemoptysis. Patients with recent pulmonary 
haemorrhage/haemoptysis (> 2.5 ml of red blood) should not be treated with Zirabev.



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Congestive heart failure (CHF) (see section 4.8)

Reactions consistent with CHF were reported in clinical trials. The findings ranged from 
asymptomatic declines in left ventricular ejection fraction to symptomatic CHF, requiring treatment or 
hospitalisation. Caution should be exercised when treating patients with clinically significant 
cardiovascular disease such as pre-existing coronary artery disease, or congestive heart failure with 
Zirabev.

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 Zirabev 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 Zirabev. In patients who 
have previously received or are receiving intravenous bisphosphonates invasive dental procedures 
should be avoided, if possible.

Intravitreal use

Zirabev 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 



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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 child-bearing potential prior to starting treatment with 
Zirabev.

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 alpha 2a, erlotinib (and its active metabolite OSI-420), or the 
chemotherapies irinotecan (and its active metabolite SN38), capecitabine, oxaliplatin (as determined 
by measurement of free and total platinum), and cisplatin. Conclusions on the impact of 
bevacizumab on gemcitabine pharmacokinetics cannot be drawn.

Combination of bevacizumab and sunitinib malate

In two clinical trials of metastatic renal cell carcinoma, microangiopathic haemolytic anaemia 
(MAHA) was reported in 7 of 19 patients treated with bevacizumab (10 mg/kg every two weeks) 
and sunitinib malate (50 mg daily) combination.

MAHA is a haemolytic disorder which can present with red cell fragmentation, anaemia, and 
thrombocytopenia. In addition, hypertension (including hypertensive crisis), elevated creatinine, and 
neurological symptoms were observed in some of these patients. All of these findings were reversible 
upon discontinuation of bevacizumab and sunitinib malate (see Hypertension, Proteinuria, PRES in 
section 4.4).

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

Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe 
neutropenia (including some fatalities) have been observed mainly in patients treated with platinum-
or taxane-based therapies in the treatment of NSCLC and mBC.

Radiotherapy

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



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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). Bevacizumab is 
contraindicated in pregnancy (see section 4.3).

Breast-feeding

It is not known whether bevacizumab is excreted in human milk. As maternal IgG is excreted in milk 
and bevacizumab could harm infant growth and development (see section 5.3), women must
discontinue breast-feeding during therapy and not breast-feed for at least six months following the last 
dose of bevacizumab.

Fertility

Repeat dose toxicity studies in animals have shown that bevacizumab may have an adverse effect on 
female fertility (see section 5.3). In a phase III trial in the adjuvant treatment of patients with colon 
cancer, a substudy with premenopausal women has shown a higher incidence of new cases of ovarian 
failure in the bevacizumab group compared to the control group. After discontinuation of 
bevacizumab treatment, ovarian function recovered in the majority of patients. Long term effects of 
the treatment with bevacizumab on fertility are unknown.

4.7 Effects on ability to drive and use machines

Bevacizumab has no or negligible influence on the ability to drive and use machines. However, 
somnolence and syncope have been reported with bevacizumab use (see table 1 in section 4.8). If 
patients are experiencing symptoms that affect their vision or concentration, or their ability to react, 
they should be advised not to drive and use machines until symptoms abate.

4.8 Undesirable effects

Summary of the safety profile

The overall safety profile of bevacizumab is based on data from over 5,700 patients with various 
malignancies, predominantly treated with bevacizumab in combination with chemotherapy in clinical 
trials.

The most serious adverse reactions were:



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 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 
reactions with at least a 2% difference compared to the control arm in clinical studies for 
NCI-CTCAE Grade 3-5 reactions. Table 2 also includes adverse reactions which are considered by 
the MAH to be clinically significant or severe.

Post-marketing adverse reactions are included in both Tables 1 and 2, where applicable. Detailed 
information about these post-marketing reactions are provided in Table 3.

Adverse reactions are added to the appropriate frequency category in the tables below according 
to the highest incidence seen in any indication.

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

Some of the adverse reactions are reactions commonly seen with chemotherapy; however, 
bevacizumab may exacerbate these reactions when combined with chemotherapeutic agents. 
Examples include palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal 
doxorubicin or capecitabine, peripheral sensory neuropathy with paclitaxel or oxaliplatin, nail 
disorders or alopecia with paclitaxel, and paronychia with erlotinib.



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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, 
Thrombo-cytopenia

Anaemia, 
Lymphopenia

Immune system 
disorders

Hypersensitivity, 
Infusion 
reactionsa,b,d

Metabolism and 
nutrition disorders

Anorexia,
Hypomagnesaemia,
Hyponatraemia

Dehydration

Nervous system 
disorders

Peripheral sensory 
neuropathyb, 
Dysarthria, 
Headache, 
Dysguesia

Cerebrovascular 
accident, Syncope, 
Somnolence

Posterior 
reversible 
encephalo-
pathy 
syndromea,b,d

Hypertensive 
encephalo-
pathya

Eye disorders Eye disorder, 
Lacrimation 
increased

Cardiac disorders Congestive heart 
failureb,d, 
Supraventricular 
tachycardia

Vascular disorders Hypertensionb,d, 
Thrombo-embolism 
(venous)b,d

Thrombo-
embolism 
(arterial)b,d, 
Haemorrhageb,d, 
Deep vein 
thrombosis

Aneurysms and 
artery dissections,
Renal thrombotic
microangiopathya,b

Respiratory, thoracic 
and mediastinal 
disorders

Dyspnoea, Rhinitis,
Epistaxis, Cough

Pulmonary 
haemorrhage/ 
Haemoptysisb,d, 
Pulmonary 
embolism, 
Hypoxia, 
Dysphoniaa

Pulmonary 
hypertensiona, 
Nasal septum 
perforationa



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System organ
class

Very common Common Uncommon Rare Very rare Frequency not 
known

Gastrointestinal 
disorders

Rectal 
haemorrhage, 
Stomatitis, 
Constipation, 
Diarrhoea, Nausea, 
Vomiting, 
Abdominal pain

Gastrointestinal 
perforationb,d, 
Intestinal 
perforation, Ileus,
Intestinal 
obstruction, 
Recto-vaginal 
fistulaed,e, 
Gastrointestinal 
disorder, 
Proctalgia

Gastrointestinal 
ulcera

Hepatobiliary 
disorders

Gallbladder 
perforationa,b

Skin and 
subcutaneous tissue 
disorders

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

Palmar-plantar 
erythro-
dysaesthesia 
syndrome

Musculoskeletal and 
connective tissue 
disorders

Arthralgia,
Myalgia

Fistulab,d, 
Muscular 
weakness, Back 
pain

Osteonecrosis of 
the jawa,b,
Non-mandibular 
osteonecrosisa,f

Renal and urinary 
disorders

Proteinuriab,d

Reproductive system 
and breast disorders

Ovarian 
failureb,c,d

Pelvic pain

Congenital, familial, 
and genetic disorder

Foetal 
abnormalitiesa,b

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 “Further information on selected serious adverse 
reactions.”

e Recto-vaginal fistulae are the most common fistulae in the GI-vaginal fistula category.
f Observed in pediatric population only



14

Table 2 Severe adverse reactions by frequency

System organ 
class

Very common Common Uncommon Rare Very rare Frequency not 
known

Infections and 
infestations

Sepsis, 
Cellulitis, 
Abscessa,b, 
Infection, 
Urinary tract 
infection

Necrotising 
fasciitisc

Blood and 
lymphatic 
system 
disorders

Febrile 
neutropenia, 
Leucopenia, 
Neutropeniaa, 
Thrombo-
cytopenia

Anaemia, 
Lymphopenia

Immune system 
disorders

Hypersensitivity, 
Infusion 
reactionsa,b,c

Metabolism and 
nutrition 
disorders

Dehydration,
Hyponatraemia

Nervous system 
disorders

Peripheral 
sensory 
neuropathya

Cerebrovascular 
accident, 
Syncope, 
Somnolence, 
Headache

Posterior 
reversible 
encephalopathy 
syndrome a,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

Aneurysms and 
artery 
dissections,
Renal thrombotic
microangiopathy
b,c

Respiratory, 
thoracic and 
mediastinal 
disorders

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

Pulmonary 
hypertensionc,
Nasal septum 
perforationc

Gastrointestinal 
disorders

Diarrhoea, 
Nausea, 
Vomiting, 
Abdominal pain

Intestinal 
perforation, 
Ileus, Intestinal 
obstruction, 
Recto-vaginal 
fistulaec,d,
Gastrointestinal 
disorder, 
Stomatitis, 
Proctalgia

Gastrointestinal 
perforationa,b,
Gastrointestinal 
ulcerc, Rectal 
haemorrhage

Hepatobiliary 
disorders

Gallbladder 
perforation b,c

Skin and 
subcutaneous 
tissue disorders

Wound healing 
complicationsa,b, 
Palmar-plantar 
erythrodysaesth
esia syndrome



15

System organ 
class

Very common Common Uncommon Rare Very rare Frequency not 
known

Musculoskeletal 
and connective 
tissue disorders

Fistulaa,b,
Myalgia, 
Arthralgia, 
Muscular 
weakness, Back 
pain

Osteonecrosis of 
the jawb,c

Renal and 
urinary 
disorders

Proteinuriaa,b

Reproductive 
system and 
breast disorders

Pelvic pain Ovarian failurea,b

Congenital, 
familial, and 
genetic disorder

Foetal 
abnormalitiesa,c

General 
disorders and 
administration 
site conditions

Asthenia, 
Fatigue,

Pain, Lethargy, 
Mucosal 
inflammation

Table 2 provides the frequency of severe adverse reactions. Severe reactions are defined as adverse reactions
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 postmarketing 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 “Further information on 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. 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.



16

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.

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 



17

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 
to 1.4% of treated patients. Testing for proteinuria is recommended prior to start of Zirabev therapy. 
In most clinical trials urine protein levels of ≥ 2 g/24 hrs led to the holding of bevacizumab until 
recovery to < 2 g/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 



18

treated with paclitaxel and topotecan.

The haemorrhagic reactions that have been observed in clinical trials were predominantly 
tumour-associated haemorrhage (see below) and minor mucocutaneous haemorrhage (e.g. epistaxis).

Tumour-associated haemorrhage (see section 4.4)

Major or massive pulmonary haemorrhage/haemoptysis has been observed primarily in trials in 
patients with non-small cell lung cancer (NSCLC). Possible risk factors include squamous cell 
histology, treatment with antirheumatic/anti-inflammatory substances, treatment with anticoagulants, 
prior radiotherapy, bevacizumab therapy, previous medical history of atherosclerosis, central tumour 
location and cavitation of tumours prior to or during therapy. The only variables that showed 
statistically significant correlations with bleeding were bevacizumab therapy and squamous cell 
histology. Patients with NSCLC of known squamous cell histology or mixed cell type with 
predominant squamous cell histology were excluded from subsequent phase III trials, while patients 
with unknown tumour histology were included.

In patients with NSCLC excluding predominant squamous histology, all Grade reactions were seen 
with a frequency of up to 9.3% when treated with bevacizumab plus chemotherapy compared with up 
to 5% in the patients treated with chemotherapy alone. Grade 3-5 reactions have been observed in up 
to 2.3% of patients treated with bevacizumab plus chemotherapy as compared with < 1% with 
chemotherapy alone (NCI-CTCAE v.3). Major or massive pulmonary haemorrhage/haemoptysis can 
occur suddenly and up to two thirds of the serious pulmonary haemorrhages resulted in a fatal 
outcome.

Gastrointestinal haemorrhages, including rectal bleeding and melaena have been reported in 
colorectal cancer patients, and have been assessed as tumour-associated haemorrhages.

Tumour-associated haemorrhage was also seen rarely in other tumour types and locations, including 
cases of central nervous system (CNS) bleeding in patients with CNS metastases (see section 4.4).

The incidence of CNS bleeding in patients with untreated CNS metastases receiving bevacizumab has 
not been prospectively evaluated in randomised clinical trials. In an exploratory retrospective analysis 
of data from 13 completed randomised trials in patients with various tumour types, 3 patients out of 
91 (3.3%) with brain metastases experienced CNS bleeding (all Grade 4) when treated with
bevacizumab, compared to 1 case (Grade 5) out of 96 patients (1%) that were not exposed to 
bevacizumab. In two subsequent studies in patients with treated brain metastases (which included 
around 800 patients), one case of Grade 2 CNS haemorrhage was reported in 83 subjects treated with 
bevacizumab (1.2%) at the time of interim safety analysis (NCI-CTCAE v.3).

Across all clinical trials, mucocutaneous haemorrhage has been seen in up to 50% of bevacizumab-
treated patients. These were most commonly NCI-CTCAE v.3 Grade 1 epistaxis that lasted less than
5 minutes, resolved without medical intervention and did not require any changes in the bevacizumab
treatment regimen. Clinical safety data suggest that the incidence of minor mucocutaneous 
haemorrhage (e.g. epistaxis) may be dose-dependent.

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 



19

receiving chemotherapy alone. Cerebrovascular accidents (including transient ischaemic attacks) 
were reported in up to 2.7% of patients treated with bevacizumab in combination with chemotherapy 
compared to up to 0.5% of patients treated with chemotherapy alone. Myocardial infarction was 
reported in up to 1.4% of patients treated with bevacizumab in combination with chemotherapy 
compared to up to 0.7% of patients treated with chemotherapy alone.

In one clinical trial evaluating bevacizumab in combination with 5-fluorouracil/folinic acid, 
AVF2192g, patients with metastatic colorectal cancer who were not candidates for treatment with 
irinotecan were included. In this trial arterial thromboembolic reactions were observed in 
11% (11/100) of patients compared to 5.8% (6/104) in the chemotherapy control group.

Venous thromboembolism
The incidence of venous thromboembolic reactions in clinical trials was similar in patients receiving 
bevacizumab in combination with chemotherapy compared to those receiving the control 
chemotherapy alone. Venous thromboembolic reactions include deep venous thrombosis, pulmonary 
embolism and thrombophlebitis.

In clinical trials across indications, the overall incidence of venous thromboembolic reactions ranged 
from 2.8% to 17.3% of bevacizumab-treated patients compared with 3.2% to 15.6% in the control 
arms.

Grade 3-5 (NCI-CTCAE v.3) venous thromboembolic reactions have been reported in up to 7.8% of 
patients treated with chemotherapy plus bevacizumab compared with up to 4.9% in patients treated 
with chemotherapy alone (across indications, excluding persistent, recurrent, or metastatic cervical 
cancer).

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study 
GOG-0240), grade 3-5 venous thromboembolic events have been reported in up to 15.6% of patients 
treated with bevacizumab in combination with paclitaxel and cisplatin compared with up to 7.0% of 
patients treated with paclitaxel and cisplatin.

Patients who have experienced a venous thromboembolic reaction may be at higher risk for a 
recurrence if they receive bevacizumab in combination with chemotherapy versus chemotherapy 
alone.

Congestive heart failure (CHF)

In clinical trials with bevacizumab, congestive heart failure (CHF) was observed in all cancer 
indications studied to date, but occurred predominantly in patients with metastatic breast cancer. In 
four phase III trials (AVF2119g, E2100, BO17708 and AVF3694g) in patients with metastatic breast 
cancer CHF Grade 3 (NCI-CTCAE v.3) or higher was reported in up to 3.5% of patients treated with 
bevacizumab in combination with chemotherapy compared with up to 0.9% in the control arms. For 
patients in study AVF3694g who received anthracyclines concomitantly with bevacizumab, the 
incidences of Grade 3 or higher CHF for the respective bevacizumab and control arms were similar 
to those in the other studies in metastatic breast cancer: 2.9% in the anthracycline + bevacizumab 
arm and 0% in the anthracycline + placebo arm. In addition, in study AVF3694g the incidences of all 
Grade CHF were similar between the anthracycline + bevacizumab (6.2%) and the 
anthracycline + placebo arms (6.0%).

Most patients who developed CHF during mBC trials showed improved symptoms and/or left 
ventricular function following appropriate medical therapy.

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.



20

An increased incidence of CHF has been observed in a clinical trial of patients with diffuse large 
B-cell lymphoma when receiving bevacizumab with a cumulative doxorubicin dose greater than
300 mg/m2. This phase III clinical trial compared
rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) plus bevacizumab to 
R-CHOP without bevacizumab. While the incidence of CHF was, in both arms, above that previously 
observed for doxorubicin therapy, the rate was higher in the R-CHOP plus bevacizumab arm. These 
results suggest that close clinical observation with appropriate cardiac assessments should be 
considered for patients exposed to cumulative doxorubicin doses greater than 300 mg/m2 when 
combined with bevacizumab.

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

In some clinical trials anaphylactic and anaphylactoid-type reactions were reported more frequently 
in patients receiving bevacizumab in combination with chemotherapy than with chemotherapy alone. 
The incidence of these reactions in some clinical trials of bevacizumab is common (up to 5% in 
bevacizumab- treated patients).

Infections

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study 
GOG-0240), grade 3-5 infections have been reported in up to 24% of patients treated with 
bevacizumab in combination with paclitaxel and topotecan compared with up to 13% of patients 
treated with paclitaxel and topotecan.

Ovarian failure/fertility (see sections 4.4 and 4.6)

In NSABP C-08, a phase III trial of bevacizumab in adjuvant treatment of patients with colon cancer, 
the incidence of new cases of ovarian failure, defined as amenorrhoea lasting 3 or more months, FSH 
level ≥ 30 mIU/mL and a negative serum β-HCG pregnancy test, has been evaluated in 
295 premenopausal women. New cases of ovarian failure were reported in 2.6% patients in the 
mFOLFOX-6 group compared to 39% in the mFOLFOX-6 + bevacizumab group. After 
discontinuation of bevacizumab treatment, ovarian function recovered in 86.2% of these evaluable 
women. Long term effects of the treatment with bevacizumab on fertility are unknown.

Laboratory abnormalities

Decreased neutrophil count, decreased white blood cell count and presence of urine protein may be 
associated with bevacizumab treatment.

Across clinical trials, the following Grade 3 and 4 (NCI-CTCAE v.3) laboratory abnormalities 
occurred in patients treated with bevacizumab with at least a 2% difference compared to the 
corresponding control groups: hyperglycaemia, decreased haemoglobin, hypokalaemia, 
hyponatraemia, decreased white blood cell count, increased international normalised ratio (INR).

Clinical trials have shown that transient increases in serum creatinine (ranging between 
1.5-1.9 times baseline level), both with and without proteinuria, are associated with the use of 
bevacizumab. The observed increase in serum creatinine was not associated with a higher incidence 
of clinical manifestations of renal impairment in patients treated with bevacizumab.

Other special populations

Elderly patients

In randomised clinical trials, age > 65 years was associated with an increased risk of developing 
arterial thromboembolic reactions, including cerebrovascular accidents (CVAs), transient ischaemic 
attacks (TIAs) and myocardial infarctions (MIs). Other reactions with a higher frequency seen in 
patients over 65 were 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, 



21

the incidence of hypertension of grade ≥ 3 was two fold higher in patients aged > 65 years than in the 
younger age group (<65 years). In a study of platinum-resistant recurrent ovarian cancer patients, 
alopecia, mucosal inflammation, peripheral sensory neuropathy, proteinuria and hypertension were
also reported and occurred at a rate at least 5% higher in the CT + BV arm for bevacizumab-treated 
patients ≥ 65 years of age compared with bevacizumab-treated patients aged < 65 years.

No increase in the incidence of other reactions, including gastrointestinal perforation, wound healing 
complications, congestive heart failure, and haemorrhage was observed in elderly patients 
(> 65 years) receiving bevacizumab as compared to those aged ≤ 65 years treated with bevacizumab.

Paediatric population

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

In study BO25041 of bevacizumab added to postoperative radiation therapy (RT) with concomitant 
and adjuvant temozolomide in paediatric patients with newly diagnosed supratentorial, infratentorial, 
cerebellar, or peduncular high-grade glioma, the safety profile was comparable with that observed in 
other tumour types in adults treated with bevacizumab.

In study BO20924 of bevacizumab with current standard of care in rhabdomyosarcoma and 
non-rhabdomyosarcoma soft tissue sarcoma, the safety profile of bevacizumab treated children was 
comparable with that observed in adults treated with bevacizumab.

Bevacizumab is not approved for use in patients under the age of 18 years. In published literature 
reports, cases of non-mandibular osteonecrosis have been observed in patients under the age of 
18 years treated with bevacizumab.

Post-marketing experience

Table 3 Adverse reactions reported in post-marketing setting

System organ class 
(SOC)

Reactions (frequency*)

Infections and 
Infestations

Necrotising fasciitis, usually secondary to wound healing 
complications, gastrointestinal perforation or fistula formation (rare) 
(see also section 4.4)

Immune system 
disorders

Hypersensitivity reactions and infusion reactions (not known); with the 
following possible co-manifestations: dyspnoea/difficulty breathing, 
flushing/redness/rash, hypotension or hypertension, oxygen 
desaturation, chest pain, rigors and nausea/vomiting (see also section
4.4 and Hypersensitivity reactions/infusion reactions above)

Nervous system 
disorders

Hypertensive encephalopathy (very rare) (see also section 4.4 and
Hypertension in section 4.8)
Posterior Reversible Encephalopathy Syndrome (PRES), (rare) (see 
also section 4.4)

Vascular disorders Renal thrombotic microangiopathy, which may be clinically 
manifested as proteinuria (not known) with or without concomitant 
sunitinib use. For further information on proteinuria see section 4.4 
and Proteinuria in section 4.8.

Respiratory, thoracic 
and mediastinal 
disorders

Nasal septum perforation (not known) 

Pulmonary hypertension (not known) 

Dysphonia (common)



22

System organ class 
(SOC)

Reactions (frequency*)

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

Zirabev is a biosimilar medicinal product. Detailed information is available on the website of the 
European Medicines Agency http://www.ema.europa.eu.

Mechanism of action

Bevacizumab binds to vascular endothelial growth factor (VEGF), the key driver of vasculogenesis 
and angiogenesis, and thereby inhibits the binding of VEGF to its receptors, Flt-1 (VEGFR-1) and 
KDR (VEGFR-2), on the surface of endothelial cells. Neutralising the biological activity of VEGF 
regresses the vascularisation of tumours, normalises remaining tumour vasculature, and inhibits the 
formation of new tumour vasculature, thereby inhibiting tumour growth.

Pharmacodynamic effects

Administration of bevacizumab or its parental murine antibody to xenotransplant models of cancer in 
nude mice resulted in extensive anti-tumour activity in human cancers, including colon, breast, 



23

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.

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



24

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 intravenous 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 intravenous 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 intravenous 2 
h

200 mg/m2 intravenous
2 h

400 mg/m2 intravenous
bolus, 
600 mg/m2 intravenous
22 h

Oxaliplatin on day 1 

Leucovorin on day 1 and 2

5-fluorouracil intravenous

bolus/infusion, each on days 1 

and 2

Placebo or 
bevacizumab

5 mg/kg 
intravenous 30-90 
min

Day 1, prior to FOLFOX-4, 
every 2 weeks

XELOX
or XELOX +
bevacizumab

Oxaliplatin 

Capecitabine

130 mg/m2 intravenous
2 h 

1000 mg/m2 oral bid

Oxaliplatin on day 1 

Capecitabine oral bid for 2 
weeks (followed by 1 week off
treatment)

Placebo or 
bevacizumab

7.5 mg/kg 
intravenous 30-90 
min

Day 1, prior to XELOX, q 
3 weeks

5-Fluorouracil: intravenous 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.



27

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

Endpoint (months) FOLFOX-4 or 
XELOX

+ placebo 
(n=701)

FOLFOX-4 or 
XELOX

+ bevacizumab 
(n=699)

P-value

Primary endpoint

Median PFS** 8.0 9.4 0.0023

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

Secondary endpoints

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

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

Overall response rate 
(invest. assessment)**

49.2% 46.5%

Median overall survival* 19.9 21.2 0.0769

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

*Overall survival analysis at clinical cut-off 31 January 2007
** Primary analysis at clinical cut-off 31 January 2006
a relative to control arm

In the FOLFOX treatment subgroup, the median PFS was 8.6 months in placebo and 9.4 months in 
bevacizumab treated patients, HR = 0.89, 97.5% CI = [0.73; 1.08]; p-value = 0.1871, the 
corresponding results in the XELOX treatment subgroup being 7.4 vs. 9.3 months, HR = 0.77, 
97.5% CI = [0.63; 0.94]; p-value = 0.0026.

The median overall survival was 20.3 months in placebo and 21.2 months in bevacizumab treated 
patients in the FOLFOX treatment subgroup, HR=0.94, 97.5% CI = [0.75; 1.16]; p-value = 0.4937, 
the corresponding results in the XELOX, treatment subgroup being 19.2 vs. 21.4 months, HR = 0.84, 
97.5% CI = [0.68; 1.04]; p-value = 0.0698.

ECOG E3200
This was a phase III randomised, active-controlled, open-label trial investigating bevacizumab
10 mg/kg in combination with leucovorin with 5-fluorouracil bolus and then 5-fluorouracil 
infusional, with intravenous 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).



28

Table 8 Efficacy results for trial E3200

E3200

FOLFOX-4 FOLFOX-4 + 
bevacizumaba

Number of patients 292 293

Overall survival

Median (months) 10.8 13.0

95% CI 10.12 – 11.86 12.09 – 14.03

Hazard ratiob 0.751
(p-value = 0.0012)

Progression-free survival

Median (months) 4.5 7.5

Hazard ratio 0.518
(p-value < 0.0001)

Objective response rate

Rate 8.6% 22.2%

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

No significant difference was observed in the duration of overall survival between patients who 
received bevacizumab monotherapy compared to patients treated with FOLFOX-4. 
Progression-free survival and objective response rate were inferior in the bevacizumab
monotherapy arm compared to the FOLFOX-4 arm.

ML18147
This was a Phase III randomised, controlled, open-label trial investigating bevacizumab 5.0 mg/kg 
every 2 weeks or 7.5 mg/kg every 3 weeks in combination with fluoropyrimidine-based 
chemotherapy versus fluoropyrimidine-based chemotherapy alone in patients with mCRC who have 
progressed on a first- line bevacizumab-containing regimen.

Patients with histologically confirmed mCRC and disease progression were randomised 1:1 within 
3 months after discontinuation of bevacizumab first-line therapy to receive 
fluoropyrimidine/oxaliplatin- or fluoropyrimidine/irinotecan-based chemotherapy (chemotherapy 
switched depending on first-line chemotherapy) with or without bevacizumab. Treatment was given 
until progressive disease or unacceptable toxicity. The primary outcome measure was overall survival 
defined as the time from randomisation until death from any cause.

A total of 820 patients were randomised. The addition of bevacizumab to fluoropyrimidine-based 
chemotherapy resulted in a statistically significant prolongation of survival in patients with mCRC 
who have progressed on a first-line bevacizumab-containing regimen (ITT = 819) (see Table 9).



29

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

 Study AVF3694g (capecitabine) 
o 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 



30

were randomised to paclitaxel alone (90 mg/m2 intravenous over 1 hour once weekly for three out of 
four weeks) or in combination with bevacizumab (10 mg/kg intravenous 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

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 



31

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.

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



32

Overall survivalb

HR

(95% CI)
0.88 (0.69; 1.13)

p-value (exploratory) 0.33

a1000 mg/m2 oral twice daily for 14 days administered every 3 weeks.
bStratified 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 intravenous 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 intravenous 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.

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



33

Table 12 Efficacy results for trial E4599

Arm 1

Carboplatin/ 
Paclitaxel

Arm 2

Carboplatin/ Paclitaxel 
+ bevacizumab

15 mg/kg q 3 weeks

Number of patients 444 434

Overall survival
Median (months) 10.3 12.3
Hazard ratio 0.80 (p=0.003)

95% CI (0.69; 0.93)
Progression-free survival
Median (months) 4.8 6.4
Hazard ratio 0.65 (p < 0.0001)

95% CI (0.56; 0.76)
Overall response rate
Rate (percent) 12.9 29.0 (p < 0.0001)

In an exploratory analysis, the extent of bevacizumab benefit on overall survival was less pronounced 
in the subgroup of patients who did not have adenocarcinoma histology.

BO17704
Trial BO17704 was a randomised, double-blind phase III trial of bevacizumab in addition to cisplatin 
and gemcitabine versus placebo, cisplatin and gemcitabine in patients with locally advanced (stage 
IIIb with supraclavicular lymph node metastases or with malignant pleural or pericardial effusion),
metastatic or recurrent non-squamous NSCLC, who had not received prior chemotherapy. The 
primary endpoint was progression free survival, secondary endpoints for the trial included the 
duration of overall survival.

Patients were randomised to platinum-based chemotherapy, cisplatin 80 mg/m2 intravenous infusion 
on day 1 and gemcitabine 1250 mg/m2 intravenous infusion on days 1 and 8 of every 3-week cycle for 
up to 6 cycles (CG) with placebo or CG with bevacizumab at a dose of 7.5 or 15 mg/kg intravenous
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.



34

The efficacy results are presented in Table 13.

Table 13 Efficacy results for trial BO17704

Cisplatin/Gemcitabine
+ placebo

Cisplatin/Gemcitabine
+ bevacizumab

7.5 mg/kg q 3 weeks

Cisplatin/Gemcitabine
+ bevacizumab

15 mg/kg q 3 weeks

Number of patients 347 345 351

Progression-free 
survival

Median (months) 6.1 6.7

(p=0.0026)

6.5 

(p=0.0301)

Hazard ratio 0.75

[0.62; 0.91]

0.82

[0.68; 0.98]

Best overall
response ratea

20.1% 34.1%
(p < 0.0001)

30.4% 
(p=0.0023)

a patients with measurable disease at baseline

Overall survival

Median (months) 13.1 13.6 

(p=0.4203)

13.4 

(p=0.7613)

Hazard ratio 0.93
[0.78; 1.11]

1.03
[0.86, 1.23]

Advanced and/or metastatic renal cell cancer (mRCC)

Bevacizumab in combination with interferon alfa-2a for the first-line treatment of advanced and/ or 
metastatic renal cell cancer (BO17705)
This was a phase III randomised double-blind trial conducted to evaluate the efficacy and safety of 
bevacizumab in combination with interferon (IFN) alfa-2a versus IFN alfa-2a alone as first-line 
treatment in mRCC. The 649 randomised patients (641 treated) had Karnofsky Performance Status 
(KPS) of ≥ 70%, no CNS metastases and adequate organ function. Patients were nephrectomised for 
primary renal cell carcinoma. Bevacizumab 10 mg/kg was given every 2 weeks until disease 
progression. IFN alfa-2a was given up to 52 weeks or until disease progression at a recommended 
starting dose of 9 MIU three times a week, allowing a dose reduction to 3 MIU three times a week in 
2 steps. Patients were stratified according to country and Motzer score and the treatment arms were
shown to be well balanced for the prognostic factors.

The primary endpoint was overall survival, with secondary endpoints for the trial including 
progression-free survival. The addition of bevacizumab to IFN-alpha-2a significantly increased PFS 
and objective tumour response rate. These results have been confirmed through an independent 
radiological review. However, the increase in the primary endpoint of overall survival by 2 months 
was not significant (HR= 0.91). A high proportion of patients (approximately 63% IFN/placebo; 
55% bevacizumab/IFN) received a variety of non-specified post-trial anti-cancer therapies, 
including antineoplastic agents, which may have impacted the analysis of overall survival.



35

The efficacy results are presented in Table 14

Table 14 Efficacy results for trial BO17705

BO17705

Placebo + IFNa Bvb + IFNa

Number of patients 322 327

Progression-free survival

Median (months) 

Hazard ratio

95% CI

5.4 10.2

0.63
0.52, 0.75

(p-value < 0.0001)

Objective response rate (%) in Patients with 
measurable disease

N
Response rate

289 306
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)

Hazard ratio

95% CI

21.3 23.3
0.91

0.76, 1.10
(p-value 0.3360)

An exploratory multivariate Cox regression model using backward selection indicated that the 
following baseline prognostic factors were strongly associated with survival independent of 
treatment: gender, white blood cell count, platelets, body weight loss in the 6 months prior to trial 
entry, number of metastatic sites, sum of longest diameter of target lesions, Motzer score. 
Adjustment for these baseline factors resulted in a treatment hazard ratio of 0.78 (95% CI [0.63; 
0.96], p=0.0219), indicating a 22% reduction in the risk of death for patients in the 
bevacizumab + IFN alfa-2a arm compared to IFN alfa-2a arm.

Ninety seven (97) patients in the IFN alfa-2a arm and 131 patients in the bevacizumab arm reduced 
the dose of IFN alfa-2a from 9 MIU to either 6 or 3 MIU three times a week as pre-specified in the 
protocol. Dose-reduction of IFN alfa-2a did not appear to affect the efficacy of the combination of 
bevacizumab and IFN alfa-2a based on PFS event free rates over time, as shown by a sub-group
analysis. The 131 patients in the bevacizumab + IFN alfa-2a arm who reduced and maintained the 
IFN alfa-2a dose at 6 or 3 MIU during the trial, exhibited at 6, 12 and 18 months PFS event free rates 
of 73, 52 and 21% respectively, as compared to 61, 43 and 17% in the total population of patients 
receiving bevacizumab + IFN alfa-2a.

AVF2938
This was a randomised, double-blind, phase II clinical trial investigating bevacizumab 10 mg/kg in a 
2 weekly schedule with the same dose of bevacizumab in combination with 150 mg daily erlotinib, in 
patients with metastatic clear cell RCC. A total of 104 patients were randomised to treatment in this 
trial, 53 to bevacizumab 10 mg/kg every 2 weeks plus placebo and 51 to bevacizumab 10 mg/kg every 
2 weeks plus erlotinib 150 mg daily. The analysis of the primary endpoint showed no difference 
between the bevacizumab + Placebo arm and the bevacizumab + Erlotinib arm (median PFS 8.5 
versus 9.9 months). Seven patients in each arm had an objective response. The addition of erlotinib to 
bevacizumab did not result in an improvement in OS (HR = 1.764; p=0.1789), duration of objective 
response (6.7 vs 9.1 months) or time to symptom progression (HR = 1.172; p=0.5076).



36

AVF0890
This was a randomised phase II trial conducted to compare the efficacy and safety of bevacizumab 
versus placebo. A total of 116 patients were randomised to receive bevacizumab 3 mg/kg every 
2 weeks (n=39), 10 mg/kg every 2 weeks; (n=37), or placebo (n=40). An interim analysis showed 
there was a significant prolongation of the time to progression of disease in the 10 mg/kg group as 
compared with the placebo group (hazard ratio, 2.55; p < 0.001). There was a small difference, of 
borderline significance, between the time to progression of disease in the 3 mg/kg group and that in
the placebo group (hazard ratio, 1.26; p=0.053). Four patients had objective (partial) response, and all 
of these had received the 10 mg/kg dose bevacizumab; the ORR for the 10 mg/kg dose was 10%.

Epithelial ovarian, fallopian tube and primary peritoneal cancer

Front-line treatment of ovarian cancer

The safety and efficacy of bevacizumab in the front-line treatment of patients with epithelial ovarian,
fallopian tube or primary peritoneal cancer were studied in two phase III trials (GOG-0218 and
BO17707) that evaluated the effect of the addition of bevacizumab to carboplatin and paclitaxel
compared to the chemotherapy regimen alone.

GOG-0218
The GOG-0218 study was a phase III multicentre, randomised, double-blind, placebo-controlled, three
arm study evaluating the effect of adding bevacizumab to an approved chemotherapy regimen
(carboplatin and paclitaxel) in patients with advanced (Stages IIIB, IIIC and IV according to FIGO
staging version dated 1988) epithelial ovarian, fallopian tube or primary peritoneal cancer.

Patients who had received prior therapy with bevacizumab or prior systemic anticancer therapy for
ovarian cancer (e.g. chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy, or
hormonal therapy) or previous radiotherapy to the abdomen or pelvis were excluded from the study.

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

 CPP arm: Five cycles of placebo (started cycle 2) in combination with carboplatin (AUC 
6) and paclitaxel (175 mg/m2) for 6 cycles followed by placebo alone, for a total of up to 
15 months of therapy

 CPB15 arm: Five cycles of bevacizumab (15 mg/kg q3w started cycle 2) in combination
with carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles followed by placebo
alone, for a total of up to 15 months of therapy

 CPB15+ arm: Five cycles of bevacizumab (15 mg/kg q3w started cycle 2) in combination
with carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles followed by continued
use of bevacizumab (15 mg/kg q3w) as single agent for a total of up to 15 months of
therapy.

The majority of patients included in the study were White (87% in all three arms); the median age was
60 years in CPP and CPB15 arms and 59 years in CPB15+ arm; and 29% of patients in CPP or CPB15
and 26% in CPB15+ were over 65 years of age. Overall approximately 50% of patients had a GOG PS
of 0 at baseline, 43% a GOG PS score of 1, and 7% a GOG PS score of 2. Most patients had EOC (82%
in CPP and CPB15, 85% in CPB15+) followed by PPC (16% in CPP, 15% in CPB15, 13% in CPB15+)
and FTC (1% in CPP, 3% in CPB15, 2% in CPB15+). The majority of patients had serous
adenocarcinoma histologic type (85% in CPP and CPB15, 86% in CPB15+). Overall approximately
34% of patients were FIGO Stage III optimally debulked with gross residual disease, 40% Stage III
sub-optimally debulked, and 26% were Stage IV patients.

The primary endpoint was PFS based on investigator’s assessment of disease progression based on
radiological scans or CA 125 levels, or symptomatic deterioration per protocol. In addition, a
prespecified analysis of the data censoring for CA-125 progression events was conducted, as well as
an independent review of PFS as determined by radiological scans.



37

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 15.

Table 15 Efficacy results from study GOG-0218

Progression-free survival 1

CPP CPB15 CPB15+
(n = 625) (n = 625) (n = 623)

Median PFS (months) 10.6 11.6 14.7
Hazard Ratio (95% CI) 2 0.89 0.70

(0.78, 1.02) (0.61, 0.81)
p-value 3,4 0.0437 < 0.0001
Objective response Rate 5

CPP CPB15 CPB15 +
(n = 396) (n = 393) (n = 403)

% pts with objective response 63.4 66.2 66.0
p-value 0.2341 0.2041
Overall survival 6

CPP CPB15 CPB15 +
(n = 625) (n = 625) (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-value 3 0.2197 0.0641

1 Investigator assessed GOG protocol-specified PFS analysis (neither censored for CA-125 progressions nor
censored for NPT prior to disease progression) with data cut-off date of 25 February, 2010.

2 Relative to the control arm; stratified hazard ratio.
3 One-sided log-rank p-value
4 Subject to a p-value boundary of 0.0116.
5 Patients with measurable disease at baseline.
6 Final overall survival analysis performed when 46.9% of the patients had died.

Prespecified PFS analyses were conducted, all with a cut-off date of 29 September 2009. The results
of these prespecified analyses are as follows:

 The protocol specified analysis of investigator-assessed PFS (without censoring for
CA-125 progression or non-protocol therapy [NPT]) shows a stratified hazard ratio of
0.71 (95% CI: 0.61-0.83, 1-sided log-rank p-value < 0.0001) when CPB15+ is compared
with CPP, with a median PFS of 10.4 months in the CPP arm and 14.1 months in the 
CPB15+ arm.

 The primary analysis of investigator-assessed PFS (censoring for CA-125 progressions and
NPT) shows a stratified hazard ratio of 0.62 (95% CI: 0.52-0.75, 1-sided log-rank p-value
< 0.0001) when CPB15+ is compared with CPP, with a median PFS of 12.0 months in the
CPP arm and 18.2 months in the CPB15+ arm.

 The analysis of PFS as determined by the independent review committee (censoring for
NPT) shows a stratified hazard ratio of 0.62 (95% CI: 0.50-0.77, 1-sided log-rank p-value
< 0.0001) when CPB15+ is compared with CPP, with a median PFS of 13.1 in the CPP
arm and 19.1 months in the CPB15+ arm.

PFS subgroup analyses by disease stage and debulking status are summarised in Table 16. These



38

results demonstrate robustness of the analysis of PFS as shown in Table 15.

Table 16 PFS1 results by disease stage and debulking status from study GOG-0218

Randomised patients stage III optimally debulked disease 2,3

CPP CPB15 CPB15+ 
(n = 219) (n = 204) (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 CPB15 CPB15+ 
(n = 253) (n = 256) (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 CPB15 CPB15+ 
(n = 153) (n = 165) (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 = 1386) epithelial ovarian, fallopian tube or primary peritoneal cancer
following surgery (NCI- CTCAE v.3). FIGO staging version dated 1988 was used in this trial.

Patients who had received prior therapy with bevacizumab or prior systemic anticancer therapy for
ovarian cancer (e.g. chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy, or
hormonal therapy) or previous radiotherapy to the abdomen or pelvis were excluded from the study.

A total of 1528 patients were randomised in equal proportions to the following two arms:

 CP arm: Carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles of 3 weeks duration
 CPB7.5+ arm: Carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles of 3 weeks

plus bevacizumab (7.5 mg/kg q3w) for up to 12 months (bevacizumab was started at cycle
2 of chemotherapy if treatment was initiated within 4 weeks of surgery or at cycle 1 if
treatment was initiated more than 4 weeks after surgery).

The majority of patients included in the study were White (96%), the median age was 57 years in
both treatment arms, 25% of patients in each treatment arm were 65 years of age or over, and
approximately 50% of patients had an ECOG PS of 1; 7% of patients in each treatment arm had an
ECOG PS of 2. The majority of patients had EOC (87.7%) followed by PPC (6.9%) and FTC (3.7%)
or a mixture of the three origins (1.7%). Most patients were FIGO Stage III (both 68%) followed by
FIGO Stage IV (13% and 14%), FIGO Stage II (10% and 11%) and FIGO Stage I (9% and 7%). The
majority of the patients in each treatment arm (74% and 71%) had poorly differentiated (Grade 3)
primary tumours at baseline. The incidence of each histologic sub-type of EOC was similar between
the treatment arms; 69% of patients in each treatment arm had serous adenocarcinoma histologic
type.



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 17.

Table 17 Efficacy results from study BO17707 (ICON7)

Progression-free survival 
CP CPB7.5+ 

(n = 764) (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 Rate 1

CP CPB7.5+ 
(n = 277) (n = 272) 

Response rate 54.9% 64.7%
(p-value = 0.0188) 

Overall Survival 3

CP CPB7.5+
(n = 764) (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 18. These results 
demonstrate robustness of the primary analysis of PFS as shown in Table 17.



40

Table 18 PFS1 results by disease stage and debulking status from study BO17707 (ICON7)

Randomised patients stage III optimally debulked disease 2,3

CP CPB7.5+ 
(n = 368) (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 disease 3

CP CPB7.5+ 
(n = 154) (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+ 
(n = 97) (n = 104) 

Median PFS (months) 10.1 13.5 
0.74 

Hazard Ratio (95% CI) 4 (0.55, 1.01) 
1 Investigator assessed PFS analysis with data cut-off date of 30 November 2010. 
2 With or without gross residual disease. 
3 5.8% of the overall randomised patient population had Stage IIIB disease. 
4 Relative to the control arm.

Recurrent ovarian cancer 

The safety and efficacy of bevacizumab in the treatment of recurrent epithelial ovarian, fallopian tube 
or primary peritoneal cancer was studied in three phase III trials (AVF4095g, MO22224 and 
GOG-0213) with different patient populations and chemotherapy regimens. 

 AVF4095g evaluated the efficacy and safety of bevacizumab in combination with carboplatin 
and gemcitabine, followed by bevacizumab as a single agent in patients with platinum-sensitive 
recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. 

 GOG-0213 evaluated the efficacy and safety of bevacizumab in combination with carboplatin
and paclitaxel, followed by bevacizumab as a single agent in patients with platinum-sensitive 
recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. 

 MO22224 evaluated the efficacy and safety of bevacizumab in combination with paclitaxel, 
topotecan, or pegylated liposomal doxorubicin in patients with platinum-resistant recurrent
epithelial ovarian, fallopian tube or primary peritoneal cancer.

AVF4095g 
The safety and efficacy of bevacizumab in the treatment of patients with platinum-sensitive, recurrent 
epithelial ovarian, fallopian tube or primary peritoneal cancer, who have not received prior 
chemotherapy in the recurrent setting or prior bevacizumab treatment, was studied in a phase III 
randomised, double-blind, placebo-controlled trial (AVF4095g). The study compared the effect of 
adding bevacizumab to carboplatin and gemcitabine chemotherapy and continuing bevacizumab as a 
single agent to progression, to carboplatin and gemcitabine alone. 

Only patients with histologically documented ovarian, primary peritoneal, or fallopian tube carcinoma 
that had recurred > 6 months after platinum-based chemotherapy and who had not received 
chemotherapy in the recurrent setting and who have not received prior therapy with bevacizumab or 
other VEGF inhibitors or VEGF receptor–targeted agents were included in the study.



41

A total of 484 patients with measurable disease were randomised 1:1 to either: 

 Carboplatin (AUC4, Day 1) and gemcitabine (1000 mg/m2 on Days 1 and 8) and concurrent 
placebo every 3 weeks for 6 and up to 10 cycles followed by placebo (every 3 weeks) alone 
until disease progression or unacceptable toxicity 

 Carboplatin (AUC4, Day 1) and gemcitabine (1000 mg/m2 on Days 1 and 8) and concurrent 
bevacizumab (15 mg/kg Day 1) every 3 weeks for 6 and up to 10 cycles followed by 
bevacizumab (15 mg/kg every 3 weeks) alone until disease progression or unacceptable toxicity 

The primary endpoint was progression-free survival based on investigator assessment using modified 
RECIST 1.0. Additional endpoints included objective response, duration of response, overall survival 
and safety. An independent review of the primary endpoint was also conducted. 

The results of this study are summarised in Table 19.

Table 19 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 20.



42

Table 20 Progression-free survival by time from last platinum therapy to recurrence

Investigator Assessment
Time from last platinum therapy
to recurrence

Placebo + C/G
(n = 242)

Bevacizumab
+ C/G

(n = 242)

6 - 12 months (n=202)
Median 8.0 11.9
Hazard ratio (95% CI) 0.41 (0.29 - 0.58)

> 12 months (n=282)
Median 9.7 12.4
Hazard ratio (95% CI) 0.55 (0.41 – 0.73)

GOG-0213 
GOG-0213, a phase III randomized controlled open label trial, studied the safety and efficacy of 
bevacizumab in the treatment of patients with platinum-sensitive, recurrent epithelial ovarian, fallopian 
tube or primary peritoneal cancer, who have not received prior chemotherapy in the recurrent setting.
There was no exclusion criterion for prior anti-angiogenic therapy. The study evaluated the effect of 
adding bevacizumab to carboplatin+paclitaxel and continuing bevacizumab as a single agent until
disease progression or unacceptable toxicity compared to carboplatin+paclitaxel alone. 

A total of 673 patients were randomized in equal proportions to the following two treatment arms: 
 CP arm: Carboplatin (AUC5) and paclitaxel (175 mg/m2 IV) every 3 weeks for 6 and up to 8 

cycles. 
 CPB arm: Carboplatin (AUC5) and paclitaxel (175 mg/m2 IV) and concurrent bevacizumab

(15 mg/kg) every 3 weeks for 6 and up to 8 cycles, followed by bevacizumab (15 mg/kg every 
3 weeks) alone until disease progression or unacceptable toxicity.

Most patients in both the CP arm (80.4%) and the CPB arm (78.9%) were White. The median age was 
60.0 years in the CP arm and 59.0 years in the CPB arm. The majority of patients (CP: 64.6%; CPB: 
68.8%) were in the age category < 65 years. At baseline, most patients in both treatment arms had a 
GOG PS of 0 (CP: 82.4%: CPB; 80.7%) or 1 (CP: 16.7%: CPB; 18.1%). A GOG PS of 2 at baseline 
was reported in 0.9% of patients in the CP arm and in 1.2% of patients in the CPB arm.

The primary efficacy endpoint was overall survival (OS). The main secondary efficacy endpoint was 
progression-free survival (PFS). Results are presented in Table 21.

Table 21 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 



43

status Yes/No (Yes=randomized to undergo cytoreduction or randomized to not undergo cytoreduction; No= not a 
candidate or did not consent to cytoreduction). 
b stratified by the duration of treatment free-interval prior to enrolling onto this study per the registration form, 
and secondary surgical debulking status Yes/No.

The trial met its primary objective of OS improvement. Treatment with bevacizumab at 15 mg/kg every 
3 weeks in combination with chemotherapy (carboplatin and paclitaxel) for 6 and up to 8 cycles, 
followed by bevacizumab until disease progression or unacceptable toxicity resulted, when data were 
derived from eCRF, in a clinically meaningful and statistically significant improvement in OS 
compared to treatment with carboplatin and paclitaxel alone.

MO22224 
Study MO22224 evaluated the efficacy and safety of bevacizumab in combination with chemotherapy 
for platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. This 
study was designed as an open-label, randomized, two-arm Phase III evaluation of bevacizumab plus 
chemotherapy (CT+BV) versus chemotherapy alone (CT). 

A total of 361 patients were enrolled into this study and administered either chemotherapy (paclitaxel,
topotecan, or pegylated liposomal doxorubicin (PLD) alone or in combination with bevacizumab: 

 CT Arm (chemotherapy alone): 
o Paclitaxel 80 mg/m2 as a 1-hour IV infusion on Days 1, 8, 15, and 22 every 4 weeks. 
o Topotecan 4 mg/m2 as a 30-minute IV infusion on Days 1, 8, and 15 every 4 weeks. 

Alternatively, a 1.25 mg/m2 dose could be administered over 30 minutes on Days 1–5 
every 3 weeks. 

o PLD 40 mg/m2 as a 1 mg/min IV infusion on Day 1 only every 4 weeks. After Cycle 1, 
the drug could be delivered as a 1-hour infusion.

 CT+BV Arm (chemotherapy plus bevacizumab): 
o The chosen chemotherapy was combined with bevacizumab 10 mg/kg IV every 

2 weeks (or bevacizumab 15 mg/kg every 3 weeks if used in combination with 
topotecan 1.25 mg/m2 on Days 1–5 every 3 weeks).

Eligible patients had epithelial ovarian, fallopian tube or primary peritoneal cancer that progressed 
within <6 months of previous platinum therapy consisting of a minimum of 4 platinum therapy cycles. 
Patients should have had a life expectancy of ≥ 12 weeks and no prior radiotherapy to the pelvis or 
abdomen. Most patients were FIGO Stage IIIC or Stage IV. The majority of patients in both arms had 
an ECOG Performance Status (PS) of 0 (CT: 56.4% vs. CT + BV: 61.2%). The percentage of patients 
with an ECOG PS of 1 or ≥ 2 was 38.7% and 5.0% in the CT arm, and 29.8% and 9.0% in the CT + BV 
arm. Information on race exists for 29.3% of patients and nearly all patients were white. The median 
age of patients was 61.0 (range: 25−84) years. A total of 16 patients (4.4%) were > 75 years old. The 
overall rates of discontinuation due to adverse events were 8.8% in the CT arm and 43.6% in the CT + 
BV arm (mostly due to Grade 2-3 adverse events) and the median time to discontinuation in the CT +
BV arm was 5.2 months compared with 2.4 months in the CT arm. The rates of discontinuation due to 
adverse events in the subgroup of patients > 65 years old were 8.8% in the CT arm and 50.0% in the CT 
+ BV arm. The HR for PFS was 0.47 (95% CI: 0.35, 0.62) and 0.45 (95% CI: 0.31, 0.67) for the < 65
and ≥ 65 subgroups, respectively. 

The primary endpoint was progression-free-survival, with secondary endpoints including objective 
response rate and overall survival. Results are presented in Table 22.



44

Table 22 Efficacy Results from Study MO22224

Primary Endpoint

Progression-Free Survival*

CT

(n=182)

CT+BV

(n=179)

Median (months) 3.4 6.7

Hazard ratio

(95% CI)
0.379 [0.296, 0.485]

p-value <0.0001

Secondary Endpoints

Objective Response Rate**

CT

(n=144)

CT+BV

(n=142)

% patients with objective response 18 (12.5%) 40 (28.2%)

p –value 0.0007

Overall Survival (final analysis)***

CT

(n=182)

CT+BV

(n=179)

Median OS (months) 13.3 16.6

Hazard Ratio

(95% CI)
0.870 [0.678, 1.116]

p-value 0.2711
All analyses presented in this table are stratified analyses.
* Primary analysis was performed with a data cut-off date of 14 November 2011.
**Randomized Patients with Measurable Disease at Baseline.
***The final analysis of overall survival was performed when 266 deaths, which account for 73.7 % of
enrolled patients, were observed.

The trial met its primary objective of PFS improvement. Compared to patients treated with
chemotherapy (paclitaxel, topotecan or PLD) alone in the recurrent platinum-resistant setting, patients
who received bevacizumab at a dose of 10 mg/kg every 2 weeks (or 15 mg/kg every 3 weeks if used
in combination with 1.25 mg/m2 topotecan on Days 1–5 every 3 weeks) in combination with
chemotherapy and continued to receive bevacizumab until disease progression or unacceptable
toxicity, had a statistically significant improvement in PFS. The exploratory PFS and OS analyses by
chemotherapy cohort (paclitaxel, topotecan and PLD) are summarized in Table 23.



45

Table 23 Exploratory PFS and OS analyses by chemotherapy cohort

CT CT+BV

Paclitaxel n=115

Median PFS (months) 3.9 9.2

Hazard ratio (95% CI) 0.47 [0.31, 0.72]

Median OS (months) 13.2 22.4
Hazard ratio (95% CI) 0.64 [0.41, 0.99]

Topotecan n=120

Median PFS (months) 2.1 6.2

Hazard ratio (95% CI) 0.28 [0.18, 0.44]

Median OS (months) 13.3 13.8

Hazard ratio (95% CI) 1.07 [0.70, 1.63]

PLD n=126

Median PFS (months) 3.5 5.1

Hazard ratio (95% CI) 0.53 [0.36, 0.77]

Median OS (months) 14.1 13.7
Hazard ratio (95% CI) 0.91 [0.61, 1.35]

Cervical cancer

GOG-0240
The efficacy and safety of bevacizumab in combination with chemotherapy (paclitaxel and cisplatin 
or paclitaxel and topotecan) in the treatment for patients with persistent, recurrent or metastatic 
carcinoma of the cervix was evaluated in study GOG-0240, a randomised, four-arm, open label, 
multi- centre phase III trial.

A total of 452 patients were randomised to receive either:

 Paclitaxel 135 mg/m2 intravenous over 24 hours on Day 1 and cisplatin 50 mg/m2

intravenous on Day 2, every 3 weeks (q3w); or
Paclitaxel 175 mg/m2 intravenous over 3 hours on Day 1 and cisplatin 50 mg/m2 intravenous
on Day 2 (q3w); or
Paclitaxel 175 mg/m2 intravenous over 3 hours on Day 1 and cisplatin 50 mg/m2 intravenous
on Day 1 (q3w)

 Paclitaxel 135 mg/m2 intravenous over 24 hours on Day 1 and cisplatin 50 mg/m2

intravenous on Day 2 plus bevacizumab 15 mg/kg intravenous on Day 2 (q3w); or
Paclitaxel 175 mg/m2 intravenous over 3 hours on Day 1 and cisplatin 50 mg/m2 intravenous
on Day 2 plus bevacizumab 15 mg/kg intravenous on Day 2 (q3w); or
Paclitaxel 175 mg/m2 intravenous over 3 hours on Day 1 and cisplatin 50 mg/m2 intravenous
on Day 1 plus bevacizumab 15 mg/kg intravenous on Day 1 (q3w)

 Paclitaxel 175 mg/m2 intravenous over 3 hours on Day 1 and topotecan 0.75 mg/m2

intravenous over 30 minutes on days 1-3 (q3w)

 Paclitaxel 175 mg/m2 intravenous over 3 hours on Day 1 and topotecan 0.75 mg/m2

intravenous over 30 minutes on Days 1-3 plus bevacizumab 15 mg/kg intravenous on Day 1 
(q3w)

Eligible patients had persistent, recurrent or metastatic squamous cell carcinoma, adenosquamous 
carcinoma, or adenocarcinoma of the cervix which was not amenable to curative treatment with 



46

surgery and/or radiation therapy and who have not received prior therapy with bevacizumab or other
VEGF inhibitors or VEGF receptor–targeted agents.

The median age was 46.0 years (range: 20-83) in the Chemo alone group and 48.0 years (range: 22-85) 
in the Chemo+bevacizumab group; with 9.3% of patients in the Chemo alone group and 7.5% of 
patients in the Chemo+bevacizumab group over the age of 65 years.

Of the 452 patients randomized at baseline, the majority of patients were white (80.0% in the Chemo 
alone group and 75.3% in the Chemo+bevacizumab group), had squamous cell carcinoma (67.1% in 
the Chemo alone group and 69.6% in the Chemo+bevacizumab group), had persistent/recurrent 
disease (83.6% in the Chemo alone group and 82.8% in the Chemo+bevacizumab group), had 
1-2 metastatic sites (72.0% in the Chemo alone group and 76.2% in the Chemo+bevacizumab group), 
had lymph node involvement (50.2% in the Chemo alone group and 56.4% in the 
Chemo+bevacizumab group), and had a platinum free interval ≥ 6 months (72.5% in the Chemo alone 
group and 64.4% in the Chemo+bevacizumab group).

The primary efficacy endpoint was overall survival. Secondary efficacy endpoints included 
progression-free survival and objective response rate. Results from the primary analysis and the 
follow-up analysis are presented by bevacizumab Treatment and by Trial Treatment in Table 24 and 
Table 25, respectively.

Table 24 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



47

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

Table 25 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+ 0.76 (0.55, 1.06) 0.79 (0.59, 1.07)

Paclitaxel (14.9 vs. 11.9 months; p = 0.1061) (16.2 vs. 12.0 months; p = 0.1342)

Topotecan+
Paclitaxel vs.

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)

Cisplatin+ 
Paclitaxel

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 



48

treated with bevacizumab (10 mg/kg) and irinotecan (125 mg/m2) every 2 weeks. There were 
no complete responses and 2 partial responses (MacDonald criteria).

In a randomized phase II study (BO25041) a total of 121 patients aged ≥ 3 years to <18 years with 
newly diagnosed supratentorial or infratentorial cerebellar or peduncular high-grade glioma (HGG) 
were treated with post operative radiation therapy (RT) and adjuvant temozolomide (T) with and 
without bevacizumab: 10 mg/kg every 2 weeks intravenously.

The study did not meet its primary endpoint of demonstrating a significant improvement of EFS 
(Central Radiology Review Committee (CRRC)-assessed) when bevacizumab was added to the RT/T 
arm compared with RT/T alone (HR = 1.44; 95% CI: 0.90, 2.30). These results were consistent with 
those from various sensitivity analyses and in clinically relevant subgroups. The results for all 
secondary endpoints (investigator assessed EFS, and ORR and OS) were consistent in showing no 
improvement associated with the addition of bevacizumab to the RT/T arm compared with the RT/T 
arm alone.

Addition of bevacizumab to RT/T did not demonstrate clinical benefit in study BO25041 in 
60 evaluable children patients with newly diagnosed supratentorial or infratentorial cerebellar or 
peduncular high- grade glioma (HGG) (see section 4.2 for information on paediatric use).

Soft tissue sarcoma

In a randomized phase II study (BO20924) a total of 154 patients aged ≥ 6 months to <18 years with 
newly diagnosed metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma 
were treated with standard of care (Induction IVADO/IVA+/- local therapy followed by Maintenance 
Vinorelbine and cyclophosphamide) with or without bevacizumab (2.5 mg/kg/week) for a total 
duration of treatment of approximately 18 months. At the time of the final primary analysis, the 
primary endpoint of EFS by independent central review did not show a statistically significant 
difference between the two treatment arms, with HR of 0.93 (95% CI: 0.61, 1.41; p-value = 0.72).

The difference in ORR per independent central review was 18% (CI: 0.6%, 35.3%) between the two 
treatment arms in the few patients who had evaluable tumor at baseline and had a confirmed response 
prior to receiving any local therapy: 27/75 patients (36.0%, 95% CI: 25.2%, 47.9%) in the Chemo arm 
and 34/63 patients (54.0%, 95% CI: 40.9%, 66.6%) in the Bv +Chemo arm. The secondary endpoint of 
Overall Survival (OS) was not mature. Until mature OS results and safety data are available no 
definitive conclusion can be drawn on the benefit/risk balance.

Addition of bevacizumab to standard of care did not demonstrate clinical benefit in clinical trial 
BO20924, in 71 evaluable children (from age 6 months to less than 18 years old) patients with 
metastatic Rhabdomyosarcoma and non-Rhabdomyosarcoma Soft Tissue Sarcoma.
(See section 4.2 for information on paediatric use).

The incidence of AEs, including Grade ≥3 AEs and SAEs, was similar between the two treatment 
arms. No AEs leading to death occurred in either treatment arm; all deaths were attributed to disease 
progression. Bevacizumab addition to multimodal standard of care treatment seemed to be tolerated in 
this paediatric population.

5.2 Pharmacokinetic properties

The pharmacokinetic data for bevacizumab are available from ten clinical trials in patients with solid 
tumours. In all clinical trials, bevacizumab was administered as an intravenous 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 



49

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

Assessment of bevacizumab metabolism in rabbits following a single intravenous dose of 
125 I-bevacizumab indicated that its metabolic profile was similar to that expected for a native IgG 
molecule which does not bind VEGF. The metabolism and elimination of bevacizumab is similar to 
endogenous IgG i.e. primarily via proteolytic catabolism throughout the body, including endothelial 
cells, and does not rely primarily on elimination through the kidneys and liver. Binding of the IgG to 
the FcRn receptor results in protection from cellular metabolism and the long terminal half-life.

Elimination

The value for clearance is, on average, equal to 0.188 and 0.220 L/day for female and male patients, 
respectively. After correcting for body weight, male patients had a higher bevacizumab clearance
(+ 17%) than females. According to the two-compartmental model, the elimination half-life is 
18 days for a typical female patient and 20 days for a typical male patient.

Low albumin and high tumour burden are generally indicative of disease severity. Bevacizumab 
clearance was approximately 30% faster in patients with low levels of serum albumin and 7% faster 
in subjects with higher tumour burden when compared with a typical patient with median values of 
albumin and tumour burden.

Pharmacokinetics in special populations

The population pharmacokinetics were analysed in adult and pediatric patients to evaluate the 
effects of demographic characteristics. In adults, the results showed no significant difference in the 
pharmacokinetics of bevacizumab in relation to age.

Renal impairment

No trials have been conducted to investigate the pharmacokinetics of bevacizumab in renally 
impaired patients since the kidneys are not a major organ for bevacizumab metabolism or excretion.

Hepatic impairment

No trials have been conducted to investigate the pharmacokinetics of bevacizumab in patients with 
hepatic impairment since the liver is not a major organ for bevacizumab metabolism or excretion.

Paediatric population

The pharmacokinetics of bevacizumab were evaluated in 152 children, adolescents and young adults 
(7 months to 21 years, 5.9 to 125 kg) across 4 clinical studies using a population pharmacokinetic 
model. The pharmacokinetic results show that the clearance and volume of distribution of 
bevacizumab were comparable between paediatric and young adult patients when normalised by 
body weight, with exposure trending lower as body weight decreased. Age was not associated with 
the pharmacokinetics of bevacizumab when body weight was taken into account.

The pharmacokinetics of bevacizumab was well characterized by the paediatric population PK 
model for 70 patients in Study BO20924 ((1.4 to 17.6 years; 11.6 to 77.5 kg) and 59 patients in 
Study BO25041 (1 to 17 years; 11.2 to 82.3 kg). In Study BO20924, bevacizumab exposure was 
generally lower compared to a typical adult patient at the same dose. In Study BO25041, 
bevacizumab exposure was similar compared to a typical adult at the same dose. In both studies, 
bevacizumb exposure trended lower as body weight decreased.



50

5.3 Preclinical safety data

In studies of up to 26 weeks duration in cynomolgus monkeys, physeal dysplasia was observed 
in young animals with open growth plates, at bevacizumab average serum concentrations below 
the expected human therapeutic average serum concentrations. In rabbits, bevacizumab was 
shown to inhibit wound healing at doses below the proposed clinical dose. Effects on wound 
healing were shown to be fully reversible.

Studies to evaluate the mutagenic and carcinogenic potential of bevacizumab have not been performed.

No specific studies in animals have been conducted to evaluate the effect on fertility. An adverse 
effect on female fertility can however be expected as repeat dose toxicity studies in animals have 
shown inhibition of the maturation of ovarian follicles and a decrease/absence of corpora lutea and 
associated decrease in ovarian and uterus weight as well as a decrease in the number of menstrual 
cycles.

Bevacizumab has been shown to be embryotoxic and teratogenic when administered to rabbits. 
Observed effects included decreases in maternal and foetal body weights, an increased number of 
foetal resorptions and an increased incidence of specific gross and skeletal foetal malformations. 
Adverse foetal outcomes were observed at all tested doses, of which the lowest dose resulted in 
average serum concentrations approximately 3 times larger than in humans receiving 5 mg/kg every 
2 weeks. Information on foetal malformations observed in the post marketing setting are provided 
in section 4.6 Fertility, Pregnancy and Lactation and 4.8 Undesirable Effects.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sucrose
Succinic acid
Disodium edetate 
Polysorbate 80
Sodium hydroxide (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

Vial (unopened)

3 years.

Diluted medicinal product

Chemical and physical in-use stability has been demonstrated for a period of up to 35 days at 2°C to 
8°C after dilution and a period of up to 48 hours at temperatures not exceeding 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.



51

6.4 Special precautions for storage

Store in a refrigerator (2°C-8°C). 
Do not freeze.
Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

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

Zirabev should be prepared by a healthcare professional using aseptic technique to ensure the sterility 
of the prepared solution.

Once the vial has been opened, the dilution must be performed immediately. 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 Zirabev 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 Zirabev and polyvinyl chloride or polyolefine bags or infusion sets 
have been observed.

Zirabev 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

Pfizer Europe MA EEIG
Boulevard de la Plaine 17 
1050 Bruxelles
Belgium

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/18/1344/001 100 mg/4 ml vial
EU/1/18/1344/002 400 mg/16 ml vial

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 14 February 2019



52

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



53

ANNEX II

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURERS 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



54

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

Name and address of the manufacturer of the biological active substance
Wyeth BioPharma Division of Wyeth Pharmaceuticals, LLC
1 Burtt Road
Andover
Massachusetts
01810
UNITED STATES

Name and address of the manufacturers responsible for batch release
Pfizer Ireland Pharmaceuticals
Grange Castle Business Park
Clondalkin
Dublin 22
IRELAND

Or

Pfizer Service Company BV
Hoge Wei 10
Zaventem
1930
BELGIUM

The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 Periodic safety update reports (PSURs)

The requirements for submission of 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 



55

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. 



56

ANNEX III

LABELLING AND PACKAGE LEAFLET



57

A. LABELLING



58

Zirabev 25 mg/ml concentrate for solution for infusion
bevacizumab

Each vial contains 100 mg bevacizumab.

Sucrose, succinic acid, disodium edetate, polysorbate 80, sodium hydroxide, water for injections.

Concentrate for solution for infusion 
1 vial of 4 ml
100 mg/4 ml

For intravenous use after dilution 
Read the package leaflet before use

Keep out of the sight and reach of children

EXP

Store in a refrigerator.
Do not freeze.
Keep the vial in the outer carton in order to protect from light.

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON

1. NAME OF THE MEDICINAL PRODUCT

2. STATEMENT OF ACTIVE SUBSTANCE(S)

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

5. METHOD AND ROUTE(S) OF ADMINISTRATION

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

9. SPECIAL STORAGE CONDITIONS



59

Pfizer Europe MA EEIG
Boulevard de la Plaine 17 
1050 Bruxelles
Belgium

EU/1/18/1344/001

Lot

Justification for not including Braille accepted.

2D barcode carrying the unique identifier included.

PC
SN
NN

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

12. MARKETING AUTHORISATION NUMBER(S)

13. BATCH NUMBER

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA



60

Zirabev 25 mg/ml sterile concentrate
bevacizumab
IV after dilution

EXP

Lot

100 mg/4 ml

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

4. BATCH NUMBER

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER



61

Zirabev 25 mg/ml concentrate for solution for infusion 
bevacizumab

Each vial contains 400 mg bevacizumab.

Sucrose, succinic acid, disodium edetate, polysorbate 80, sodium hydroxide, water for injections.

Concentrate for solution for 
infusion 
1 vial of 16 ml
400 mg/16 ml

For intravenous use after dilution 
Read the package leaflet before use

Keep out of the sight and reach of children

EXP

Store in a refrigerator.
Do not freeze.
Keep the vial in the outer carton in order to protect from light.

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON

1. NAME OF THE MEDICINAL PRODUCT

2. STATEMENT OF ACTIVE SUBSTANCE(S)

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

5. METHOD AND ROUTE(S) OF ADMINISTRATION

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

9. SPECIAL STORAGE CONDITIONS



62

Pfizer Europe MA EEIG
Boulevard de la Plaine 17 
1050 Bruxelles
Belgium

EU/1/18/1344/002

Lot

Justification for not including Braille accepted.

2D barcode carrying the unique identifier included.

PC
SN
NN

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

12. MARKETING AUTHORISATION NUMBER(S)

13. BATCH NUMBER

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA



63

Zirabev 25 mg/ml sterile concentrate
bevacizumab
IV after dilution

EXP

Lot

400 mg/16 ml

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

4. BATCH NUMBER

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER



64

B. PACKAGE LEAFLET



65

Package leaflet: Information for the user

Zirabev 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 Zirabev is and what it is used for
2. What you need to know before you use Zirabev
3. How to use Zirabev
4. Possible side effects
5. How to store Zirabev
6. Contents of the pack and other information

1. What Zirabev is and what it is used for

Zirabev 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.

Zirabev is a medicine used for the treatment of adult patients with advanced cancer in the large bowel, 
i.e., in the colon or rectum. Zirabev will be administered in combination with chemotherapy treatment 
containing a fluoropyrimidine medicine.

Zirabev 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.

Zirabev is also used for the treatment of adult patients with advanced non-small cell lung cancer. 
Zirabev will be administered together with a chemotherapy regimen containing platinum.

Zirabev 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.

Zirabev 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, Zirabev will be administered in 
combination with carboplatin and gemcitabine or with carboplatin and paclitaxel. 



66

When used for those adult patients with advanced epithelial ovarian, fallopian tube, or primary 
peritoneal cancer whose disease has come back before 6 months after the last time they were treated 
with a chemotherapy regimen containing a platinum agent, Zirabev will be administered in 
combination with topotecan or pegylated liposomal doxorubicin.

Zirabev is also used for the treatment of adult patients with persistent, recurrent or metastatic cervical 
cancer. Zirabev 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 Zirabev

Do not use Zirabev
● if you are allergic (hypersensitive) to bevacizumab or to any of the other ingredients of 

this medicine (listed in section 6).
● if you are allergic (hypersensitive) to Chinese hamster ovary (CHO) cell products or to 

other recombinant human or humanised antibodies.
● if you are pregnant.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before using Zirabev:

● Your doctor should record the brand name and batch number of your medication.

● It is possible that Zirabev 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.

● Zirabev may increase the risk of developing an abnormal connection or passageway 
between two organs or vessels. The risk of developing connections between the vagina and 
any parts of the gut can increase if you have persistent, recurrent or metastatic cervical 
cancer.

● This medicine can increase the risk of bleeding or increase the risk of problems with wound 
healing after surgery. If you are going to have an operation, if you have had major surgery 
within the last 28 days or if you still have an unhealed wound following surgery, you should 
not receive this medicine.

● Zirabev 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.

● Zirabev 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 Zirabev
treatment.

● If you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) 
or a tear in a blood vessel wall.

● This medicine increases the risk of having protein in your urine especially if you already 
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.



67

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

● Zirabev 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 Zirabev 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 bevacizumab 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 Zirabev or while you are being treated with Zirabev:
● 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 Zirabev, 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 Zirabev.

Children and adolescents
Zirabev use is not recommended in children and adolescents under the age of 18 years because the 
safety and benefit have not been established in these patient populations.

Death of bone tissue (osteonecrosis) in bones other than the jaw have been reported in patients under 
18 years old when treated with bevacizumab.

Other medicines and Zirabev
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines.

Combinations of Zirabev 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 Zirabev may increase the risk of severe side effects.



68

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. Zirabev 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 Zirabev and for at least 6 months after the last dose of Zirabev.

Tell your doctor straightaway if you are pregnant, become pregnant during treatment with this 
medicine, or plan to become pregnant in the near future.

You must not breast-feed your baby during treatment with Zirabev and for at least 6 months after the 
last dose of Zirabev, as this medicine may interfere with the growth and development of your baby.

Zirabev 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
Bevacizumab 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 bevacizumab use. If you experience 
symptoms that affect your vision or concentration, or your ability to react, do not drive and use
machines until symptoms disappear.

3. How to use Zirabev

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

Method and route of administration
Zirabev is a concentrate for solution for infusion. Depending on the dose prescribed for you, some or
all of the contents of the Zirabev vial will be diluted with sodium chloride solution before use. A 
doctor or nurse will give you this diluted Zirabev 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 Zirabev 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 Zirabev 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,



69

● any severe bleeding.

If too much Zirabev 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 Zirabev is missed
● your doctor will decide when you should be given your next dose of Zirabev. You should 

discuss this with your doctor.

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

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet.

The side effects listed below were seen when bevacizumab was given together with chemotherapy. 
This does not necessarily mean that these side effects were strictly caused by bevacizumab.

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, 



70

and urinary tracts,
• sores in the mouth and the tube from the mouth to the stomach, which may be painful and 

cause difficulty swallowing,
• pain, including headache, back pain and pain in the pelvis and anal regions,
• localised pus collection,
• infection, and in particular infection in the blood or bladder,
• reduced blood supply to the brain or stroke,
• sleepiness,
• nose bleed,
• increase in heart rate (pulse),
• blockage in the gut or bowel,
• abnormal urine test (protein in the urine),
• shortness of breath or low levels of oxygen in the blood,
• infections of the skin or deeper layers under the skin,
• fistula: abnormal tube-like connection between internal organs and skin or other tissues that 

are not normally connected, including connections between vagina and the gut in patients 
with cervical cancer.

Severe side effects of unknown frequency (frequency cannot be estimated from the available data), 
include:
• serious infections of the skin or deeper layers under the skin, especially if you had holes in the 

gut wall or problems with wound healing,
• allergic reactions (the signs may include difficulty breathing, facial redness, rash, low 

blood pressure or high blood pressure, low oxygen in your blood, chest pain, or 
nausea/vomiting),

• a negative effect on a woman’s ability to have children (see the paragraphs below the list of 
side effects for further recommendations),

• a brain condition with symptoms including seizures (fits), headache, confusion, and changes 
in vision (Posterior Reversible Encephalopathy Syndrome or PRES),

• symptoms that suggest changes in normal brain function (headaches, vision changes, 
confusion, or seizures), and high blood pressure,

• an enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall 
(aneurysms and artery dissections),

• clogging of a very small blood vessel(s) in the kidney,
• abnormally high blood pressure in the blood vessels of the lungs which makes the right side of 

the heart work harder than normal,
• a hole in the cartilage wall separating the nostrils of the nose,
• a hole in the stomach or intestines,
• 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,



71

• 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.

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.

Zirabev 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.

Zirabev 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 Zirabev 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 Zirabev

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.



72

Infusion solutions should be used immediately after dilution. Do not use Zirabev 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 Zirabev contains

• The active substance is bevacizumab. Each ml of concentrate contains 25 mg of 
bevacizumab.
Each 4 ml vial contains 100 mg of bevacizumab.
Each 16 ml vial contains 400 mg of bevacizumab.

• The other ingredients are sucrose, succinic acid, disodium edetate, polysorbate 80, sodium 
hydroxide (for pH adjustment), and water for injections.

What Zirabev looks like and contents of the pack
Zirabev is a concentrate for solution for infusion. The concentrate is a clear to slightly opalescent, 
colourless to pale brown liquid in a glass vial with a rubber stopper. Each vial contains 100 mg 
bevacizumab in 4 ml of solution or 400 mg bevacizumab in 16 ml of solution. Each pack of Zirabev
contains one vial.

Marketing Authorisation Holder
Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium

Manufacturer
Pfizer Ireland Pharmaceuticals, Grange Castle Business Park, Clondalkin, Dublin 22, Ireland

Or

Pfizer Service Company BV, Hoge Wei 10, Zaventem, 1930, Belgium

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder.

België/Belgique/Belgien
Luxembourg/Luxemburg
Pfizer NV/SA
Tél/Tel: +32 (0)2 554 62 11

Kύπρος
PFIZER EΛΛAΣ A.E. (CYPRUS BRANCH)
T: +357 22 817690

Česká Republika
Pfizer, spol. s r.o.
Tel: +420-283-004-111

Magyarország
Pfizer Kft.
Tel: +36 1 488 3700

Danmark
Pfizer ApS
Tlf: +45 44 201 100

Malta
Drugsales Ltd
Tel: +356 21 419 070/1/2

Deutschland
Pfizer Pharma PFE GmbH
Tel: +49 (0)800 8535555

Nederland
Pfizer bv
Tel: +31 (0)10 406 43 01

България
Пфайзер Люксембург САРЛ,
Клон България
Teл: +359 2 970 4333

Norge
Pfizer AS
Tlf: +47 67 52 61 00



73

Eesti
Pfizer Luxembourg SARL Eesti filiaal
Tel: +372 666 7500

Österreich
Pfizer Corporation Austria Ges.m.b.H.
Tel: +43 (0)1 521 15-0

Ελλάδα
PFIZER EΛΛAΣ A.E.
Τηλ.: +30 210 67 85 800

Polska
Pfizer Polska Sp. z o.o.
Tel.: +48 22 335 61 00

España
Pfizer, S.L.
Tel: +34 91 490 99 00

Portugal
Laboratórios Pfizer, Lda.
Tel: +351 21 423 5500

France
Pfizer
Tél: +33 (0)1 58 07 34 40

România
Pfizer România S.R.L
Tel: +40 (0) 21 207 28 00

Hrvatska
Pfizer Croatia d.o.o.
Tel: +385 1 3908 777

Slovenija
Pfizer Luxembourg SARL, Pfizer, podružnica
za svetovanje s področja farmacevtske
dejavnosti, Ljubljana
Tel: +386 (0)1 52 11 400

Ireland
Pfizer Healthcare Ireland
Tel: +1800 633 363 (toll free)
Tel: +44 (0)1304 616161

Slovenská Republika
Pfizer Luxembourg SARL, organizačná zložka
Tel: +421 2 3355 5500

Ísland
Icepharma hf.
Tel: +354 540 8000

Suomi/Finland
Pfizer PFE Finland Oy
Puh/Tel: +358 (0)9 430 040

Italia
Pfizer S.r.l.
Tel: +39 06 33 18 21

Sverige
Pfizer AB
Tel: +46 (0)8 550 520 00

Latvija
Pfizer Luxembourg SARL filiāle Latvijā
Tel. +371 67035775

United Kingdom
Pfizer Limited
Tel: +44 (0)1304 616161

Lietuva
Pfizer Luxembourg SARL filialas Lietuvoje
Tel. +3705 2514000

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency (EMA) web site: 
http://www.ema.europa.eu


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