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 erlotinib is indicated for first-line treatment of adult patients with
unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer with
Epidermal Growth Factor Receptor (EGFR) activating mutations (see section 5.1).

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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).

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.

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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.

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

EGFR mutation testing should be performed prior to initiation of treatment with the combination of
Zirabev and erlotinib. It is important that a well-validated and robust methodology is chosen to avoid
false negative or false positive determinations.

The recommended dose of Zirabev when used in addition to erlotinib is 15 mg/kg of body weight
given once every 3 weeks as an intravenous infusion.

It is recommended that the treatment with Zirabev in addition to erlotinib is continued until disease
progression.

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

Advanced and/or metastatic renal cell cancer (mRCC)

The recommended dose of 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.

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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 patients ≥ 65 years of age.

Patients with renal impairment

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

Patients with hepatic impairment

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

Paediatric population

The safety and efficacy of bevacizumab in children aged less than 18 years old have not been
established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation
on a posology can be made.

There is no relevant use of bevacizumab in the paediatric population in the indications for treatment of
cancers of the colon, rectum, breast, lung, ovarian, fallopian tube, peritoneum, cervix and kidney.

Method of administration

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.

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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 (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

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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
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).

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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.

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.

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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
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).

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Effect of bevacizumab on the pharmacokinetics of other antineoplastic agents

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

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

Combination of bevacizumab and sunitinib malate

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

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

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

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

Radiotherapy

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

EGFR monoclonal antibodies in combination with bevacizumab chemotherapy regimens

No interaction studies have been performed. EGFR monoclonal antibodies should not be administered
for the treatment of mCRC in combination with bevacizumab-containing chemotherapy. Results from
the randomised phase III studies, PACCE and CAIRO-2, in patients with mCRC suggest that the use
of anti-EGFR monoclonal antibodies panitumumab and cetuximab, respectively, in combination with
bevacizumab plus chemotherapy, is associated with decreased PFS and/or OS, and with increased
toxicity compared with bevacizumab plus chemotherapy alone.

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).

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Breast-feeding

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

Fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

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

The most serious adverse reactions were:

• Gastrointestinal perforations (see section 4.4).

• Haemorrhage, including pulmonary haemorrhage/haemoptysis, which is more common in
non-small cell lung cancer patients (see section 4.4).
• Arterial thromboembolism (see section 4.4).

The most frequently observed adverse reactions across clinical trials in patients receiving bevacizumab
were hypertension, fatigue or asthenia, diarrhoea and abdominal pain.

Analyses of the clinical safety data suggest that the occurrence of hypertension and proteinuria with
bevacizumab therapy are likely to be dose-dependent.

Tabulated list of adverse reactions

The adverse reactions listed in this section fall into the following frequency categories: Very common
(≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to
< 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Tables 1 and 2 list adverse reactions associated with the use of bevacizumab in combination with
different chemotherapy regimens in multiple indications, by MedDRA system organ class.

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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.

Table 1 Adverse reactions by frequency

System organ Very common Common Uncommon Rare Very rare Frequency not
class known
Infections and Sepsis, Necrotisi
infestations Abscessb,d, ng
Cellulitis, fasciitisa
Infection,
Urinary
tract
infection
Blood and Febrile Anaemia,
lymphatic system neutropenia, Lymphopen
disorders Leucopenia, ia
Neutropeniab,
Thrombo-
cytopenia
Immune system Hypersensiti
disorders vity,
Infusion
reactionsa,b,d
Metabolism and Anorexia, Dehydration
nutrition disorders Hypomagnesae
mia,Hyponatrae
mia

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 System organ Very common Common Uncommon Rare Very rare Frequency not
class known
Nervous system Peripheral Cerebrovasc Posterior Hyperten
disorders sensory ular reversible sive
neuropathyb, accident, encephal encephalo
Dysarthria, Syncope, o- pathy - pathya
Headache, Somnolence syndrome
a,b,d
Dysguesia
Eye disorders Eye disorder,
Lacrimation
increased
Cardiac disorders Congestive
heart
failureb,d,
Supraventri
cular
tachycardia
Vascular disorders Hypertensionb,d, Thrombo- Aneurysms and
Thrombo- embolism artery
embolism (arterial)b,d, dissections,
(venous)b,d Haemorrhag Renal
eb,d, Deep thrombotic
vein microangiopath
thrombosis ya,b
Respiratory, Dyspnoea, Pulmonary Pulmonary
thoracic and Rhinitis, haemorrhag hypertensiona,
mediastinal Epistaxis, e/Haemopty Nasal septum
disorders Cough sisb,d, perforationa
Pulmonary
embolism,
Hypoxia,
Dysphoniaa
Gastrointestinal Rectal Gastrointest Gastrointestinal
disorders haemorrhage, inal ulcera
Stomatitis, perforationb,
d
Constipation, , Intestinal
Diarrhoea, perforation,
Nausea, Ileus,
Vomiting, Intestinal
Abdominal pain obstruction,
Recto-
vaginal
fistulaed,e,
Gastrointest
inal
disorder,
Proctalgia
Hepatobiliary Gallbladder
disorders perforationa,b
Skin and Wound healing Palmar-
subcutaneous complicationsb,d plantar
tissue disorders , Exfoliative erythro-
dermatitis, Dry dysaesthesia
skin, Skin syndrome
discoloration
Musculoskeletal Arthralgia, Fistulab,d, Osteonecrosis
and connective Myalgia Muscular of the jawa,b,
tissue disorders weakness, Non-
Back pain mandibular
osteonecrosisa,f
Renal and urinary Proteinuriab,d
disorders

13
 System organ Very common Common Uncommon Rare Very rare Frequency not
class known
Reproductive Ovarian Pelvic pain
system and breast failureb,c,d
disorders
Congenital, Foetal
familial, and abnormalitiesa,b
genetic disorder
General disorders Asthenia, Lethargy
and Fatigue,
administration Pyrexia, Pain,
site conditions Mucosal
inflammation
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 paediatric population only.

Table 2 Severe adverse reactions by frequency

System Very Common Uncommon Rare Very rare Frequency

organ class common not known
Infections Sepsis, Necrotising
and Cellulitis, fasciitisc
infestations Abscessa,b,
Infection,
Urinary tract
infection
Blood and Febrile Anaemia,
lymphatic neutropenia, Lymphopeni
system Leucopenia, a
disorders Neutropeniaa
, Thrombo-
cytopenia
Immune Hypersensitivi
system ty, Infusion
disorders reactionsa,b,c
Metabolism Dehydration,
and nutrition Hyponatraem
disorders ia

14
 System Very Common Uncommon Rare Very rare Frequency
organ class common not known
Nervous Peripheral Cerebrovascu Posterior
system sensory lar accident, reversible
disorders neuropathya Syncope, encephalopath
Somnolence, y syndrome
a,b,c
Headache ,
Hypertensive
encephalopath
yc
Cardiac Congestive
disorders heart
failurea,b,
Supraventricu
lar
tachycardia
Vascular Hypertension Thromboemb Aneurysms
a,b
disorders olism and artery
arteriala,b, dissections,
Haemorrhage Renal
a,b
, thrombotic
Thromboemb microangiopat
olism hyb,c
(venous)a,b,
Deep vein
thrombosis
Respiratory, Pulmonary Pulmonary
thoracic and haemorrhage/ hypertensionc,
mediastinal Haemoptysisa Nasal septum
,b
disorders , Pulmonary perforationc
embolism,
Epistaxis,
Dyspnoea,
Hypoxia
Gastrointesti Diarrhoea, Intestinal Gastrointestin
nal disorders Nausea, perforation, al
Vomiting, Ileus, perforationa,b,
Abdominal Intestinal Gastrointestin
pain obstruction, al ulcerc,
Recto-vaginal Rectal
fistulaec,d, haemorrhage
Gastrointestin
al disorder,
Stomatitis,
Proctalgia
Hepatobiliary Gallbladder
disorders perforationb,c

Skin and Wound

subcutaneous healing
tissue complications
a,b
disorders , Palmar-
plantar
erythrodysaes
-thesia
syndrome
Musculoskel Fistulaa,b, Osteonecrosis
etal and Myalgia, of the jawb,c
connective Arthralgia,
tissue Muscular
disorders weakness,
Back pain

15
 System Very Common Uncommon Rare Very rare Frequency
organ class common not known
Renal and Proteinuriaa,b
urinary
disorders
Reproductive Pelvic pain Ovarian
system and failurea,b
breast
disorders
Congenital, Foetal
familial, and abnormalitiesa,
c
genetic
disorder
General Asthenia, Pain,
disorders and Fatigue Lethargy,
administratio Mucosal
n site inflammation
conditions

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 post-marketing setting, therefore, the
frequency and NCI-CTCAE grade is not known. These clinically significant reactions have therefore been
included in Table 2 within the column entitled “Frequency Not Known.”
a
Terms represent a group of events that describe a medical concept rather than a single condition or MedDRA
(Medical Dictionary for Regulatory Activities) preferred term. This group of medical terms may involve the
same underlying pathophysiology (e.g. arterial thromboembolic reactions include cerebrovascular accident,
myocardial infarction, transient ischaemic attack and other arterial thromboembolic reactions).
b
For additional information refer below within section “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-0240),
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).

17
Hypertension (see section 4.4)

In clinical trials, with the exception of study JO25567, the overall incidence of hypertension (all
grades) ranged up to 42.1% in the bevacizumab containing arms compared with up to 14% in the
control arms. The overall incidence of NCI-CTC Grade 3 and 4 hypertension in patients receiving
bevacizumab ranged from 0.4% to 17.9%. Grade 4 hypertension (hypertensive crisis) occurred in up to
1.0% of patients treated with bevacizumab and chemotherapy compared to up to 0.2% of patients
treated with the same chemotherapy alone.

In study JO25567, all grade hypertension was observed in 77.3% of the patients who received
bevacizumab in combination with erlotinib as first-line treatment for non-squamous NSCLC with
EGFR activating mutations, compared to 14.3% of patients treated with erlotinib alone. Grade 3
hypertension was 60.0% in patients treated with bevacizumab in combination with erlotinib compared
to 11.7% in patients treated with erlotinib alone. There were no grade 4 or 5 hypertension events.

Hypertension was generally adequately controlled with oral antihypertensives 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.

18
Haemorrhage (see section 4.4)

In clinical trials across all indications the overall incidence of NCI-CTCAE v.3 Grade 3-5 bleeding
reactions ranged from 0.4% to 6.9% in bevacizumab-treated patients, compared with up to 4.5% of
patients in the chemotherapy control group.

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study
GOG-0240), grade 3-5 bleeding reactions have been reported in up to 8.3% of patients treated with
bevacizumab in combination with paclitaxel and topotecan compared with up to 4.6% of patients
treated with paclitaxel and topotecan.

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

Tumour-associated haemorrhage (see section 4.4)

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

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

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

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

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

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

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

There have also been less common reactions of minor mucocutaneous haemorrhage in other locations,
such as gingival bleeding or vaginal bleeding.

19
Thromboembolism (see section 4.4)

Arterial thromboembolism
An increased incidence of arterial thromboembolic reactions was observed in patients treated with
bevacizumab across indications, including cerebrovascular accidents, myocardial infarction, transient
ischaemic attacks, and other arterial thromboembolic reactions.

In clinical trials, the overall incidence of arterial thromboembolic reactions ranged up to 3.8% in the
bevacizumab containing arms compared with up to 2.1% in the chemotherapy control arms. Fatal
outcome was reported in 0.8% of patients receiving bevacizumab compared to 0.5% in patients
receiving chemotherapy alone. Cerebrovascular accidents (including transient ischaemic attacks) were
reported in up to 2.7% of patients treated with bevacizumab in combination with chemotherapy
compared to up to 0.5% of patients treated with chemotherapy alone. Myocardial infarction was
reported in up to 1.4% of patients treated with bevacizumab in combination with chemotherapy
compared to up to 0.7% of patients treated with chemotherapy alone.

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

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

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

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

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

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

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

Congestive heart failure (CHF)

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

20
Grade CHF were similar between the anthracycline + bevacizumab (6.2%) and the
anthracycline + placebo arms (6.0%).

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

In most clinical trials of bevacizumab, patients with pre-existing CHF of NYHA (New York Heart
Association) II-IV were excluded, therefore, no information is available on the risk of CHF in this
population.

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

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

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

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

Infections

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

Ovarian failure/fertility (see sections 4.4 and 4.6)

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

Laboratory abnormalities

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

21
Clinical trials have shown that transient increases in serum creatinine (ranging between 1.5-1.9 times
baseline level), both with and without proteinuria, are associated with the use of bevacizumab. The
observed increase in serum creatinine was not associated with a higher incidence of clinical
manifestations of renal impairment in patients treated with bevacizumab.

Other special populations

Elderly patients

In randomised clinical trials, age > 65 years was associated with an increased risk of developing
arterial thromboembolic reactions, including cerebrovascular accidents (CVAs), transient ischaemic
attacks (TIAs) and myocardial infarctions (MIs). Other reactions with a higher frequency seen in
patients over 65 were Grade 3-4 leucopenia and thrombocytopenia (NCI-CTCAE v.3); and all Grade
neutropenia, diarrhoea, nausea, headache and fatigue as compared to those aged ≤ 65 years when
treated with bevacizumab (see sections 4.4 and 4.8 under Thromboembolism). In one clinical trial, the
incidence of hypertension of grade ≥ 3 was two fold higher in patients aged > 65 years than in the
younger age group (< 65 years). In a study of platinum-resistant recurrent ovarian cancer patients,
alopecia, mucosal inflammation, peripheral sensory neuropathy, proteinuria and hypertension were
also reported and occurred at a rate at least 5% higher in the CT + BV arm for bevacizumab-treated
patients ≥ 65 years of age compared with bevacizumab-treated patients aged < 65 years.

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

Paediatric population

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

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

In study BO20924 of bevacizumab with current standard of care in 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 Reactions (frequency*)

(SOC)
Infections and Necrotising fasciitis, usually secondary to wound healing
infestations complications, gastrointestinal perforation or fistula formation (rare)
(see also section 4.4)
Immune system Hypersensitivity reactions and infusion reactions (not known); with the
disorders 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)

22
 System organ class Reactions (frequency*)
(SOC)
Nervous system Hypertensive encephalopathy (very rare) (see also section 4.4 and
disorders 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 Nasal septum perforation (not known)
and mediastinal
disorders Pulmonary hypertension (not known)
Dysphonia (common)
Gastrointestinal Gastrointestinal ulcer (not known)
disorders
Hepatobiliary Gall bladder perforation (not known)
disorders
Musculoskeletal and Cases of Osteonecrosis of the Jaw (ONJ) have been reported in patients
connective tissue treated with bevacizumab, most of which occurred in patients who had
disorders 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, Cases of foetal abnormalities in women treated with bevacizumab alone
and genetic disorder 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 [Link]

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

23
KDR (VEGFR-2), on the surface of endothelial cells. Neutralising the biological activity of VEGF
regresses the vascularisation of tumours, normalises remaining tumour vasculature, and inhibits the
formation of new tumour vasculature, thereby inhibiting tumour growth.

Pharmacodynamic effects

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

nude mice resulted in extensive anti-tumour activity in human cancers, including colon, breast,
pancreas and prostate. Metastatic disease progression was inhibited and microvascular permeability
was reduced.

Clinical efficacy

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

24
continued until disease progression. The overall mean age was 59.4 years; 56.6% of patients had an
ECOG performance status of 0, 43% had a value of 1 and 0.4% had a value of 2. 15.5% had received
prior radiotherapy and 28.4% prior chemotherapy.

The primary efficacy variable of the trial was overall survival. The addition of bevacizumab to IFL
resulted in statistically significant increases in overall survival, progression-free survival and overall
response rate (see Table 4). The clinical benefit, as measured by overall survival, was seen in all
pre-specified patient subgroups, including those defined by age, sex, performance status, location of
primary tumour, number of organs involved and duration of metastatic disease.

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

Table 4 Efficacy results for trial AVF2107g

AVF2107g
Arm 1 Arm 2
IFL + placebo 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

25
rates, longer progression-free survival, and a trend in longer survival, compared with 5-FU/FA
chemotherapy alone (see Table 5). These efficacy data are consistent with the results from trial
AVF2107g.

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

Table 5 Efficacy results for trials AVF0780g and AVF2192g

AVF0780g AVF2192g
5-FU/FA + 5-FU/FA + 5-FU/FA +
5-FU/FA +
5-FU/FA bevacizuma bevacizuma bevacizuma
placebo
ba bb b
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 - 13.63 -
16.95 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 Oxaliplatin 85 mg/m2 intravenous 2 h Oxaliplatin on day 1
FOLFOX-4 + Leucovorin 200 mg/m2 intravenous 2 h Leucovorin on day 1 and 2
bevacizumab 5-Fluorouracil 400 mg/m2 intravenous bolus, 5-fluorouracil intravenous
600 mg/m2 intravenous 22 h bolus/infusion, each on days 1
and 2
Placebo or 5 mg/kg intravenous 30-90 Day 1, prior to FOLFOX-4, every
bevacizumab min 2 weeks
XELOX Oxaliplatin 130 mg/m2 intravenous 2 h Oxaliplatin on day 1
or XELOX + Capecitabine 1000 mg/m2 oral bid Capecitabine oral bid for 2 weeks
bevacizumab (followed by 1 week off
treatment)
Placebo or 7.5 mg/kg intravenous 30-90 Day 1, prior to XELOX, q 3
bevacizumab min 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.

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

Endpoint (months) FOLFOX-4 or FOLFOX-4 or P-value

XELOX XELOX
+ placebo (n=701) + bevacizumab
(n=699)
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. 49.2% 46.5%
assessment)**
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

27
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 bevacizumabtreated
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).

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.

28
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).

Table 9 Efficacy results for study ML18147 (ITT population)

ML18147
Fluoropyrimidine/irinoteca
Fluoropyrimidine/irinotecan
n or
or
fluoropyrimidine/oxaliplati
fluoropyrimidine/oxaliplatin
n based chemotherapy
based chemotherapy
+ bevacizumaba
Number of patients 410 409
Overall survival
Median (months) 9.8 11.2
0.81 (0.69, 0.94)
Hazard ratio (95% confidence interval)
(p-value = 0.0062)
Progression-free survival
Median (months) 4.1 5.7
0.68 (0.59, 0.78)
Hazard ratio (95% confidence interval)
(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:

29
• 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
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 Paclitaxel/bevaciz Paclitaxel Paclitaxel/bevaciz
umab (n=368) umab (n=368)
(n=354) (n=354)
Median PFS (months) 5.8 11.4 5.8 11.3
Hazard ratio 0.421 0.483
(95% CI) (0.343; 0.516) (0.385; 0.607)
p-value < 0.0001 < 0.0001
Response rates (for patients with measurable disease)
Investigator assessment IRF assessment
Paclitaxel Paclitaxel/bevaciz Paclitaxel Paclitaxel/bev
umab (n=252) acizumab
(n=273) (n=243) (n=229)
% pts with objective 23.4 48.0 22.2 49.8
response
p-value < 0.0001 < 0.0001
* primary analysis

Overall survival
Paclitaxel Paclitaxel/bevacizumab
(n=354) (n=368)
Median OS (months) 24.8 26.5
Hazard ratio 0.869
(95% CI) (0.722; 1.046)
p-value 0.1374

30
The clinical benefit of bevacizumab as measured by PFS was seen in all pre-specified subgroups tested
(including disease-free interval, number of metastatic sites, prior receipt of adjuvant chemotherapy and
oestrogen receptor (ER) status).

AVF3694g
Study AVF3694g was a Phase III, multicentre, randomised, placebo-controlled trial designed to
evaluate the efficacy and safety of bevacizumab in combination with chemotherapy compared to
chemotherapy plus placebo as first-line treatment for patients with HER2-negative metastatic or
locally recurrent breast cancer.

Chemotherapy was chosen at the investigator's discretion prior to randomisation in a 2:1 ratio to
receive either chemotherapy plus bevacizumab or chemotherapy plus placebo. The choices of
chemotherapy included capecitabine, taxane (protein-bound paclitaxel, docetaxel), and
anthracycline-based agents (doxorubicin/cyclophosphamide, epirubicin/cyclophosphamide,
5-fluorouracil/doxorubicin/cyclophosphamide, 5-fluorouracil/epirubicin/cyclophosphamide) given
every three weeks (q3w). Bevacizumab or placebo was administered at a dose of 15 mg/kg q3w.

This study included a blinded treatment phase, an optional open-label post-progression phase, and a
survival follow-up phase. During the blinded treatment phase, patients received chemotherapy and
medicinal product (bevacizumab or placebo) every 3 weeks until disease progression,
treatment-limiting toxicity, or death. On documented disease progression, patients who entered the
optional open-label phase could receive open-label bevacizumab together with a wide-range of second
line therapies.

Statistical analyses were performed independently for 1) patients who received capecitabine in
combination with bevacizumab or placebo; 2) patients who received taxane-based or
anthracycline-based chemotherapy in combination with bevacizumab or placebo. The primary
endpoint of the study was PFS by investigator assessment. In addition, the primary endpoint was also
assessed by an independent review committee (IRC).

The results of this study from the final protocol defined analyses for progression free survival and
response rates for the independently powered capecitabine cohort of Study AVF3694g are presented in
Table 11. Results from an exploratory overall survival analysis which include an additional 7 months
of follow-up (approximately 46% of patients had died) are also presented. The percentage of patients
who received bevacizumab in the open-label phase was 62.1% in the capecitabine + placebo arm and
49.9% in the capecitabine + bevacizumab arm.

Table 11 Efficacy results for study AVF3694g: – Capecitabinea and Bevacizumab/Placebo

(Cap + Bevacizumab/Pl)

Progression-free survivalb
Investigator Assessment IRC Assessment
Cap + Pl Cap + Cap + Pl Cap +
(n=206) Bevacizumab (n=206) Bevacizumab
(n=409) (n=409)
Median PFS (months) 5.7 8.6 6.2 9.8
Hazard ratio vs 0.69 (0.56; 0.84) 0.68 (0.54; 0.86)
placebo arm (95% CI)
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 23.6 35.4
response
p-value 0.0097
Overall survivalb

31
Progression-free survivalb
Investigator Assessment IRC Assessment
Cap + Pl Cap + Cap + Pl Cap +
(n=206) Bevacizumab (n=206) Bevacizumab
(n=409) (n=409)
Hazard ratio (95% CI) 0.88 (0.69; 1.13)
p-value (exploratory) 0.33
a 2
1000 mg/m oral twice daily for 14 days administered every 3 weeks.
b
Stratified analysis included all progression and death events except those where non-protocol therapy (NPT)
was initiated prior to documented progression; data from those patients were censored at the last tumour
assessment prior to starting NPT.

An unstratified analysis of PFS (investigator assessed) was performed that did not censor for
non-protocol therapy prior to disease progression. The results of these analyses were very similar to
the primary PFS results.

Non-small cell lung cancer (NSCLC)

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

The safety and efficacy of bevacizumab, in addition to platinum-based chemotherapy, in the first-line
treatment of patients with non-squamous non-small cell lung cancer (NSCLC), was investigated in
trials E4599 and BO17704. An overall survival benefit has been demonstrated in trial E4599 with a
15 mg/kg/q3wk dose of bevacizumab. Trial BO17704 has demonstrated that both 7.5 mg/kg/q3wk and
15 mg/kg/q3wk bevacizumab doses increase progression free survival and response rate.

E4599
E4599 was an open-label, randomised, active-controlled, multicentre clinical trial evaluating
bevacizumab as first-line treatment of patients with locally advanced (stage IIIb with malignant pleural
effusion), metastatic or recurrent NSCLC other than predominantly squamous cell histology.

Patients were randomised to platinum-based chemotherapy (paclitaxel 200 mg/m2) and carboplatin
AUC = 6.0, both by 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.

Table 12 Efficacy results for trial E4599

Arm 1 Arm 2

Carboplatin/Paclitaxel Carboplatin/Paclitaxel +
bevacizumab
15 mg/kg q 3 weeks
Number of patients 444 434
Overall survival
Median (months) 10.3 12.3

32
 Arm 1 Arm 2

Carboplatin/Paclitaxel Carboplatin/Paclitaxel +
bevacizumab
15 mg/kg q 3 weeks
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.

33
The efficacy results are presented in Table 13.

Table 13 Efficacy results for trial BO17704

Cisplatin/Gemcitabine + Cisplatin/Gemcitabine +
Cisplatin/Gemcitabine + bevacizumab 7.5 mg/kg bevacizumab 15 mg/kg
placebo q 3 weeks q 3 weeks
Number of patients 347 345 351
Progression-free
survival
Median (months) 6.1 6.7 6.5
(p = 0.0026) (p = 0.0301)
Hazard ratio 0.75 0.82
[0.62; 0.91] [0.68; 0.98]
Best overall 20.1% 34.1% 30.4%
response ratea (p < 0.0001) (p = 0.0023)
a
patients with measurable disease at baseline

Overall survival
Median (months) 13.1 13.6 13.4
(p = 0.4203) (p = 0.7613)
Hazard ratio 0.93 1.03
[0.78; 1.11] [0.86, 1.23]

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

JO25567
Study JO25567 was a randomised, open-label, multicentre Phase II study conducted in Japan to
evaluate the efficacy and safety of bevacizumab used in addition to erlotinib in patients with
non-squamous NSCLC with EGFR activating mutations (exon 19 deletion or exon 21 L858R
mutation) who had not received prior systemic therapy for Stage IIIB/IV or recurrent disease.

The primary endpoint was progression-free survival (PFS) based on independent review assessment.
Secondary endpoints included overall survival, response rate, disease control rate, duration of
response, and safety.

EGFR mutation status was determined for each patient prior to patient screening and 154 patients were
randomised to receive either erlotinib + bevacizumab (erlotinib 150 mg oral daily + bevacizumab
[15 mg/kg intravenous every 3 weeks]) or erlotinib monotherapy (150 mg oral daily) until disease
progression (PD) or unacceptable toxicity. In the absence of PD, discontinuation of one component of
study treatment in the erlotinib + bevacizumab arm did not lead to discontinuation of the other
component of study treatment as specified in the study protocol.

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

34
Table 14 Efficacy results for study JO25567

Erlotinib Erlotinib + Bevacizumab

N = 77# N = 75#
PFS^ (months)
Median 9.7 16.0
HR (95% CI) 0.54 (0.36; 0.79)
p-value 0.0015
Overall Response Rate
Rate (n) 63.6% (49) 69.3% (52)
p-value 0.4951
Overall Survival* (months)
Median 47.4 47.0
HR (95% CI) 0.81 (0.53; 1.23)
p-value 0.3267
#
A total of 154 patients (ECOG Performance Status 0 or 1) were randomised. However two of the randomised
patients discontinued the study before receiving any study treatment.
^ Blinded independent review (protocol-defined primary analysis).
* Exploratory analysis: final OS analysis at clinical cut off on 31 October 2017, approx. 59% of patients had
died.

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

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.

The efficacy results are presented in Table 15.

35
Table 15 Efficacy results for trial BO17705

BO17705
Placebo + IFNa Bvb + IFNa
Number of patients 322 327
Progression-free survival
Median (months) 5.4 10.2
Hazard ratio 0.63
95% CI 0.52, 0.75
(p-value < 0.0001)
Objective response rate (%) in patients with
measurable disease
N 289 306
Response rate 12.8% 31.4%
(p-value < 0.0001)
a
Interferon alfa-2a 9 MIU 3x/week
b
Bevacizumab 10 mg/kg q 2 wk

Overall survival
Median (months) 21.3 23.3
Hazard ratio 0.91
95% CI 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).

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

36
there was a significant prolongation of the time to progression of disease in the 10 mg/kg group as
compared with the placebo group (hazard ratio, 2.55; p < 0.001). There was a small difference, of
borderline significance, between the time to progression of disease in the 3 mg/kg group and that in the
placebo group (hazard ratio, 1.26; p = 0.053). Four patients had objective (partial) response, and all of
these had received the 10 mg/kg dose bevacizumab; the ORR for the 10 mg/kg dose was 10%.

Epithelial ovarian, fallopian tube and primary peritoneal cancer

Front-line treatment of ovarian cancer

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

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

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

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

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

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

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

The trial met its primary objective of PFS improvement. Compared to patients treated with
chemotherapy (carboplatin and paclitaxel) alone in the front-line setting, patients who received
bevacizumab at a dose of 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.

37
In patients who only received bevacizumab in combination with chemotherapy and did not continue to
receive bevacizumab alone (CPB15), no clinically meaningful benefit in PFS was observed.

The results of this study are summarised in Table 16.

Table 16 Efficacy results from study GOG-0218

Progression-free 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 17. These
results demonstrate robustness of the analysis of PFS as shown in Table 16.

38
 Table 17 PFS1 results by disease stage and debulking status from study GOG-0218

Randomised patients stage III optimally debulked disease 2,3

CPP 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.

The primary endpoint was PFS as assessed by the investigator using RECIST.

39
The trial met its primary objective of PFS improvement. Compared to patients treated with
chemotherapy (carboplatin and paclitaxel) alone in the front-line setting, patients who received
bevacizumab at a dose of 7.5 mg/kg q3w in combination with chemotherapy and continued to receive
bevacizumab for up to 18 cycles had a statistically significant improvement in PFS.

The results of this study are summarised in Table 18.

Table 18 Efficacy results from study BO17707 (ICON7)

Progression-free survival
CP 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 19. These
results demonstrate robustness of the primary analysis of PFS as shown in Table 18.

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

Randomised patients stage III optimally debulked 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)

40
Randomised patients with stage IV disease
CP CPB7.5+
(n=97) (n=104)
Median PFS (months) 10.1 13.5
Hazard ratio (95% CI) 4 0.74
(0.55, 1.01)
1
Investigator assessed PFS analysis with data cut-off date of 30 November 2010.
2
With or without gross residual disease.
3
5.8% of the overall randomised patient population had Stage IIIB disease.
4
Relative to the control arm.

Recurrent ovarian cancer

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

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

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

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

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

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

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

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

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

The results of this study are summarised in Table 20.

41
Table 20 Efficacy results from study AVF4095g

Progression-free survival
Investigator Assessment IRC Assessment
Placebo + Bevacizumab Placebo + Bevacizumab
C/G + C/G C/G + C/G
(n=242) (n=242) (n=242) (n=242)
Not censored for NPT
Median PFS (months) 8.4 12.4 8.6 12.3
Hazard ratio
0.524 [0.425, 0.645] 0.480 [0.377, 0.613]
(95% CI)
p–value <0.0001 <0.0001
Censored for NPT
Median PFS (months) 8.4 12.4 8.6 12.3
Hazard ratio
0.484 [0.388, 0.605] 0.451 [0.351, 0.580]
(95% CI)
p –value <0.0001 <0.0001
Objective response rate
Investigator Assessment IRC Assessment
Placebo + Bevacizumab Placebo + Bevacizumab
C/G + C/G C/G + C/G
(n=242) (n = 242) (n=242) (n=242)
% pts with objective
57.4% 78.5% 53.7% 74.8%
response
p –value < 0.0001 < 0.0001
Overall survival
Placebo+ Bevacizumab
C/G + C/G
(n=242) (n=242)
Median OS (months) 32.9 33.6
Hazard ratio
0.952 [0.771, 1.176]
(95% CI)
p-value 0.6479

PFS subgroup analyses depending on recurrence since last platinum therapy are summarised in Table
21.

Table 21 Progression-free survival by time from last platinum therapy to recurrence

Investigator Assessment
Time from last platinum Placebo + Bevacizum
therapy to recurrence C/G ab+ C/G
(n=242) (n=242)
6 - 12 months (n=202)
Median 8.0 11.9
Hazard ratio (95% CI) 0.41 (0.29 - 0.58)
> 12 months (n=282)
Median 9.7 12.4
Hazard ratio (95% CI) 0.55 (0.41 – 0.73)
GOG-0213
GOG-0213, a phase III randomised controlled open-label trial, studied the safety and efficacy of
bevacizumab in the treatment of patients with platinum-sensitive, recurrent epithelial ovarian, fallopian
tube or primary peritoneal cancer, who have not received prior chemotherapy in the recurrent setting.
There was no exclusion criterion for prior anti-angiogenic therapy. The study evaluated the effect of

42
adding bevacizumab to carboplatin + paclitaxel and continuing bevacizumab as a single agent until
disease progression or unacceptable toxicity compared to carboplatin + paclitaxel alone.

A total of 673 patients were randomised in equal proportions to the following two treatment arms:
• CP arm: Carboplatin (AUC5) and paclitaxel (175 mg/m2 intravenous) every 3 weeks for 6 and
up to 8 cycles.
• CPB arm: Carboplatin (AUC5) and paclitaxel (175 mg/m2 intravenous) and concurrent
bevacizumab (15 mg/kg) every 3 weeks for 6 and up to 8 cycles, followed by bevacizumab
(15 mg/kg every 3 weeks) alone until disease progression or unacceptable toxicity.

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

The primary efficacy endpoint was overall survival (OS). The main secondary efficacy endpoint was
progression-free survival (PFS). Results are presented in Table 22.

Table 22 Efficacy results1,2 from study GOG-0213

Primary Endpoint
Overall survival (OS) CP CPB
(n=336) (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 CPB
(n=336) (n=337)
Median PFS (months) 10.2 13.8
Hazard ratio (95% CI) 0.613 [CI: 0.521, 0.721]
p-value < 0.0001
1
Final Analysis
2
Tumour assessments and response evaluations were determined by the investigators using the GOG RECIST
criteria (Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228Y247).
a
Hazard ratio was estimated from Cox proportional hazards models stratified by the duration of platinum
free-interval prior to enrolling onto this study per eCRF (electronic case report form) and secondary surgical
debulking status Yes/No (Yes = randomised to undergo cytoreduction or randomised to not undergo
cytoreduction; No = not a candidate or did not consent to cytoreduction).
b
Stratified by the duration of treatment free-interval prior to enrolling onto this study per the registration form,
and secondary surgical debulking status Yes/No.

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, randomised, two-arm Phase III evaluation of bevacizumab plus
chemotherapy (CT + BV) versus chemotherapy alone (CT).

43
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 intravenous infusion on Days 1, 8, 15, and 22 every 4
weeks.
o Topotecan 4 mg/m2 as a 30-minute intravenous 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 intravenous 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 intravenous 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 23.

Table 23 Efficacy Results from Study MO22224

Primary Endpoint
Progression-Free Survival*
CT CT + BV
(n=182) (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 CT + BV
(n=144) (n=142)
% patients with objective response 18 (12.5%) 40 (28.2%)
p-value 0.0007
Overall Survival (final analysis)***
CT CT + BV
(n=182) (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.

44
* Primary analysis was performed with a data cut-off date of 14 November 2011.
** Randomised Patients with Measurable Disease at Baseline.
***The final analysis of overall survival was performed when 266 deaths, which account for 73.7 % of enrolled
patients, were observed.

The trial met its primary objective of PFS improvement. Compared to patients treated with
chemotherapy (paclitaxel, topotecan or PLD) alone in the recurrent platinum-resistant setting, patients
who received bevacizumab at a dose of 10 mg/kg every 2 weeks (or 15 mg/kg every 3 weeks if used in
combination with 1.25 mg/m2 topotecan on Days 1–5 every 3 weeks) in combination with
chemotherapy and continued to receive bevacizumab until disease progression or unacceptable
toxicity, had a statistically significant improvement in PFS. The exploratory PFS and OS analyses by
chemotherapy cohort (paclitaxel, topotecan and PLD) are summarized in Table 24.

Table 24 Exploratory PFS and OS analyses by chemotherapy cohort

CT CT + BV
Paclitaxel n=115
Median PFS (months) 3.9 9.2
Hazard ratio (95% CI) 0.47 [0.31, 0.72]
Median OS (months) 13.2 22.4
Hazard ratio (95% CI) 0.64 [0.41, 0.99]
Topotecan n=120
Median PFS (months) 2.1 6.2
Hazard ratio (95% CI) 0.28 [0.18, 0.44]
Median OS (months) 13.3 13.8
Hazard ratio (95% CI) 1.07 [0.70, 1.63]
PLD n=126
Median PFS (months) 3.5 5.1
Hazard ratio (95% CI) 0.53 [0.36, 0.77]
Median OS (months) 14.1 13.7
Hazard ratio (95% CI) 0.91 [0.61, 1.35]

Cervical cancer

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

A total of 452 patients were randomised to receive either:

• Paclitaxel 135 mg/m2 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)

45
• 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
surgery and/or radiation therapy and who have not received prior therapy with bevacizumab or other
VEGF inhibitors or VEGF receptor–targeted agents.

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

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

The primary efficacy endpoint was overall survival. Secondary efficacy endpoints included
progression-free survival and objective response rate. Results from the primary analysis and the
follow-up analysis are presented by bevacizumab Treatment and by Trial Treatment in Table 25 and
Table 26, respectively.

Table 25 Efficacy results from study GOG-0240 by bevacizumab treatment

Chemotherapy Chemotherapy + bevacizumab

(n=225) (n=227)
Primary endpoint
Overall survival – Primary analysis6
Median (months)1 12.9 16.8
Hazard ratio [95% CI] 0.74 [0.58, 0.94]
(p-value5 = 0.0132)
Overall survival – Follow-up analysis7
Median (months)1 13.3 16.8
Hazard ratio [95% CI] 0.76 [0.62, 0.94]
(p-value5,8 = 0.0126)
Secondary endpoints
Progression-free survival – Primary analysis6
Median PFS (months)1 6.0 8.3
Hazard ratio [95% CI] 0.66 [0.54, 0.81]
(p-value5 <0.0001)
Best overall response – Primary analysis6
Responders (Response rate2) 76 (33.8%) 103 (45.4%)
95% CI for response rates3 [27.6%, 40.4%] [38.8%, 52.1%]
Difference in response rates 11.60%
95% CI for difference in response rates4 [2.4%, 20.8%]
p-value (Chi-squared test) 0.0117
1
Kaplan-Meier estimates
2
Patients and percentage of patients with best overall response of confirmed CR or PR; percentage calculated
on patients with measurable disease at baseline
3
95% CI for one sample binomial using Pearson-Clopper method
4
Approximate 95% CI for difference of two rates using Hauck-Anderson method
5
Log-rank test (stratified)

46
6
Primary analysis was performed with a data cut-off date of 12 December 2012 and is considered the final
analysis
7
Follow-up analysis was performed with a data cut-off date of 07 March 2014
8
p-value displayed for descriptive purpose only

Table 26 Overall survival results from study GOG-0240 by trial treatment

Treatment Overall survival – primary Overall survival - follow-up analysis2

comparison Other factor analysis1 Hazard ratio (95% CI) Hazard ratio (95% CI)
Bevacizumab Cisplatin + 0.72 (0.51, 1.02) 0.75 (0.55, 1.01)
vs. No Paclitaxel (17.5 vs.14.3 months; p = 0.0609) (17.5 vs.15.0 months; p = 0.0584)
Bevacizumab
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 + Bevacizumab 1.15 (0.82, 1.61) 1.15 (0.85, 1.56)

Paclitaxel vs. (14.9 vs. 17.5 months; p = 0.4146) (16.2 vs 17.5 months; p = 0.3769)
Cisplatin + No 1.13 (0.81, 1.57) 1.08 (0.80, 1.45)
Paclitaxel Bevacizumab (11.9 vs.14.3 months; p = 0.4825) (12.0 vs 15.0 months; p = 0.6267)
1
Primary analysis was performed with a data cut-off date of 12 December 2012 and is considered the final
analysis
2
Follow-up analysis was performed with a data cut-off date of 07 March 2014; all p-values are displayed for
descriptive purpose only

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies, in all
subsets of the paediatric population, in breast carcinoma, adenocarcinoma of the colon and rectum,
lung carcinoma (small cell and non-small cell carcinoma), kidney and renal pelvis carcinoma
(excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal
medullary carcinoma and rhabdoid tumour of the kidney), ovarian carcinoma (excluding
rhabdomyosarcoma and germ cell tumours), fallopian tube carcinoma (excluding rhabdomyosarcoma
and germ cell tumours), peritoneal carcinoma (excluding blastomas and sarcomas) and cervix and
corpus uteri carcinoma.

High-grade glioma

Anti-tumour activity was not observed in two earlier studies among a total of 30 children aged
> 3 years old with relapsed or progressive high-grade glioma when treated with bevacizumab and
irinotecan (CPT-11). There is insufficient information to determine the safety and efficacy of
bevacizumab in children with newly-diagnosed high-grade glioma.

• In a single-arm study (PBTC-022), 18 children with recurrent or progressive non-pontine

high-grade glioma (including 8 with glioblastoma [WHO Grade IV], 9 with anaplastic
astrocytoma [Grade III] and 1 with anaplastic oligodendroglioma [Grade III]) were treated with
bevacizumab (10 mg/kg) two weeks apart and then with bevacizumab in combination with
CPT-11 (125-350 mg/m2) once every two weeks until progression. There were no objective
(partial or complete) radiological responses (MacDonald criteria). Toxicity and adverse
reactions included arterial hypertension and fatigue as well as CNS ischaemia with acute
neurological deficit.

• In a retrospective single institution series, 12 consecutive (2005 to 2008) children with relapsed
or progressive high-grade glioma (3 with WHO Grade IV, 9 with Grade III) were treated with
bevacizumab (10 mg/kg) and irinotecan (125 mg/m2) every 2 weeks. There were no complete
responses and 2 partial responses (MacDonald criteria).

In a randomised phase II study (BO25041) a total of 121 patients aged ≥ 3 years to < 18 years with
newly diagnosed supratentorial or infratentorial cerebellar or peduncular high-grade glioma (HGG)

47
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 randomised phase II study (BO20924) a total of 154 patients aged ≥ 6 months to < 18 years with
newly diagnosed metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma were
treated with standard of care (Induction IVADO/IVA +/- local therapy followed by Maintenance
Vinorelbine and cyclophosphamide) with or without bevacizumab (2.5 mg/kg/week) for a total
duration of treatment of approximately 18 months. At the time of the final primary analysis, the
primary endpoint of EFS by independent central review did not show a statistically significant
difference between the two treatment arms, with HR of 0.93 (95% CI: 0.61, 1.41; p-value = 0.72).

The difference in ORR per independent central review was 18% (CI: 0.6%, 35.3%) between the two
treatment arms in the few patients who had evaluable tumour at baseline and had a confirmed response
prior to receiving any local therapy: 27/75 patients (36.0%, 95% CI: 25.2%, 47.9%) in the Chemo arm
and 34/63 patients (54.0%, 95% CI: 40.9%, 66.6%) in the Bv + Chemo arm. The secondary endpoint
of Overall Survival (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
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.

48
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 paediatric patients to evaluate the effects
of demographic characteristics. In adults, the results showed no significant difference in the
pharmacokinetics of bevacizumab in relation to age.

Renal impairment

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

Hepatic impairment

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

Paediatric population

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

The pharmacokinetics of bevacizumab was well 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.

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

49
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.

50
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.

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

51
10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency [Link]

52
 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

53
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.

54
An updated RMP should be submitted:
• At the request of the European Medicines Agency;
• Whenever the risk management system is modified, especially as the result of new
information being received that may lead to a significant change to the benefit/risk profile or
as the result of an important (pharmacovigilance or risk minimisation) milestone being
reached.

55
 ANNEX III

LABELLING AND PACKAGE LEAFLET

56
A. LABELLING

57
 PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON

1. NAME OF THE MEDICINAL PRODUCT

Zirabev 25 mg/ml concentrate for solution for infusion

bevacizumab

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial contains 100 mg bevacizumab.

3. LIST OF EXCIPIENTS

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

4. PHARMACEUTICAL FORM AND CONTENTS

Concentrate for solution for

infusion
1 vial of 4 ml
100 mg/4 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

For intravenous use after dilution

Read the package leaflet before
use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

58
 9. SPECIAL STORAGE CONDITIONS

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

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Pfizer Europe MA EEIG

Boulevard de la Plaine 17
1050 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/18/1344/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted.

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

59
 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL

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

Zirabev 25 mg/ml sterile concentrate

bevacizumab
IV after dilution

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

100 mg/4 ml

6. OTHER

60
 PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON

1. NAME OF THE MEDICINAL PRODUCT

Zirabev 25 mg/ml concentrate for solution for infusion

bevacizumab

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial contains 400 mg bevacizumab.

3. LIST OF EXCIPIENTS

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

4. PHARMACEUTICAL FORM AND CONTENTS

Concentrate for solution for

infusion
1 vial of 16 ml
400 mg/16 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

For intravenous use after dilution

Read the package leaflet before
use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

61
 9. SPECIAL STORAGE CONDITIONS

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

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Pfizer Europe MA EEIG

Boulevard de la Plaine 17
1050 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/18/1344/002

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted.

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

62
 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL

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

Zirabev 25 mg/ml sterile concentrate

bevacizumab
IV after dilution

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

400 mg/16 ml

6. OTHER

63
B. PACKAGE LEAFLET

64
 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 the treatment of adult patients with advanced non-small cell lung cancer when
cancer cells have specific mutations of a protein called epidermal growth factor receptor (EGFR).
Zirabev will be administered in combination with erlotinib.

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.

65
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.

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.

66
● 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.

● 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.

67
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.

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,

68
● a hole in your gut wall,
● an abnormal tube-like connection or passage between the windpipe and the gullet, between
internal organs and skin, between the vagina and any parts of the gut or between other tissues
that are not normally connected (fistula), and are judged by your doctor to be severe,
● serious infections of the skin or deeper layers under the skin,
● a blood clot in your arteries,
● a blood clot in the blood vessels of your lungs,
● any severe bleeding.

If too much 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,

69
● heart failure,
● problems with wound healing after surgery,
● redness, peeling, tenderness, pain, or blistering on the fingers or feet,
● decreased number of red cells in the blood,
● lack of energy,
● stomach and intestinal disorder,
● muscle and joint pain, muscular weakness,
● dry mouth in combination with thirst and/or reduced or darkened urine,
● inflammation of the moist lining of mouth and gut, lungs and air passages, reproductive, and
urinary tracts,
● sores in the mouth and the tube from the mouth to the stomach, which may be painful and cause
difficulty swallowing,
● pain, including headache, back pain and pain in the pelvis and anal regions,
● localised pus collection,
● infection, and in particular infection in the blood or bladder,
● reduced blood supply to the brain or stroke,
● sleepiness,
● nose bleed,
● increase in heart rate (pulse),
● blockage in the gut or bowel,
● abnormal urine test (protein in the urine),
● shortness of breath or low levels of oxygen in the blood,
● infections of the skin or deeper layers under the skin,
● fistula: abnormal tube-like connection between internal organs and skin or other tissues that are
not normally connected, including connections between vagina and the gut in patients with
cervical cancer.

Severe side effects of unknown frequency (frequency cannot be estimated from the available data),
include:
● serious infections of the skin or deeper layers under the skin, especially if you had holes in the
gut wall or problems with wound healing,
● allergic reactions (the signs may include difficulty breathing, facial redness, rash, low blood
pressure or high blood pressure, low oxygen in your blood, chest pain, or nausea/vomiting),
● a negative effect on a woman’s ability to have children (see the paragraphs below the list of side
effects for further recommendations),
● a brain condition with symptoms including seizures (fits), headache, confusion, and changes in
vision (Posterior Reversible Encephalopathy Syndrome or PRES),
● symptoms that suggest changes in normal brain function (headaches, vision changes, confusion,
or seizures), and high blood pressure,
● an enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms
and artery dissections),
● clogging of a very small blood vessel(s) in the kidney,
● abnormally high blood pressure in the blood vessels of the lungs which makes the right side of
the heart work harder than normal,
● a hole in the cartilage wall separating the nostrils of the nose,
● a hole in the stomach or intestines,
● 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).

70
You should seek help as soon as possible if you suffer from any of the below mentioned side
effects.

Very common (may affect more than 1 in 10 people) side effects, which were not severe, include:
● constipation,
● loss of appetite,
● fever,
● problems with the eyes (including increased production of tears),
● changes in speech,
● change in the sense of taste,
● runny nose,
● dry skin, flaking and inflammation of the skin, change in skin colour,
● loss of body weight,
● nose bleeds.

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

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

71
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.

Infusion solutions should be used immediately after dilution. If not used immediately, in-use
storage times and conditions are the responsibility of the user and would normally not be longer
than 24 hours at 2°C to 8°C, unless the infusion solutions have been prepared in a sterile
environment. When dilution has taken place in a sterile environment, Zirabev is stable 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.

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.

72
België/Belgique/Belgien Kύπρος
Luxembourg/Luxemburg PFIZER EΛΛAΣ A.E. (CYPRUS BRANCH)
Pfizer NV/SA Tηλ: +357 22 817690
Tél/Tel: +32 (0)2 554 62 11

Česká Republika Magyarország

Pfizer, spol. s r.o. Pfizer Kft.
Tel: +420-283-004-111 Tel: +36 1 488 3700

Danmark Malta
Pfizer ApS Drugsales Ltd
Tlf: +45 44 201 100 Tel: +356 21 419 070/1/2

Deutschland Nederland
Pfizer Pharma PFE GmbH Pfizer bv
Tel: +49 (0)800 8535555 Tel: +31 (0)10 406 43 01

България Norge
Пфайзер Люксембург САРЛ, Pfizer AS
Клон България Tlf: +47 67 52 61 00
Teл: +359 2 970 4333

Eesti Österreich
Pfizer Luxembourg SARL Eesti filiaal Pfizer Corporation Austria Ges.m.b.H.
Tel: +372 666 7500 Tel: +43 (0)1 521 15-0

Ελλάδα Polska
PFIZER EΛΛAΣ A.E. Pfizer Polska Sp. z o.o.
Τηλ.: +30 210 67 85 800 Tel.: +48 22 335 61 00

España Portugal
Pfizer, S.L. Laboratórios Pfizer, Lda.
Tel: +34 91 490 99 00 Tel: +351 21 423 5500

France România
Pfizer Pfizer România S.R.L
Tél: +33 (0)1 58 07 34 40 Tel: +40 (0) 21 207 28 00

Hrvatska Slovenija
Pfizer Croatia d.o.o. Pfizer Luxembourg SARL, Pfizer, podružnica
Tel: +385 1 3908 777 za svetovanje s področja farmacevtske
dejavnosti, Ljubljana
Tel: +386 (0)1 52 11 400

Ireland Slovenská Republika

Pfizer Healthcare Ireland Pfizer Luxembourg SARL, organizačná zložka
Tel: +1800 633 363 (toll free) Tel: +421 2 3355 5500
Tel: +44 (0)1304 616161

Ísland Suomi/Finland
Icepharma hf. Pfizer PFE Finland Oy
Tel: +354 540 8000 Puh/Tel: +358 (0)9 430 040

Italia Sverige
Pfizer S.r.l. Pfizer AB
Tel: +39 06 33 18 21 Tel: +46 (0)8 550 520 00

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Latvija United Kingdom
Pfizer Luxembourg SARL filiāle Latvijā Pfizer Limited
Tel. +371 67035775 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 web site:
[Link]

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