AVASTIN adalah obat baru yang terdaftar tahun 2006.

Informasi di bawah ini merupakan informasi update tahun 2009.

Avastin
Bevacizumab
Anti-neoplastic agent
COMPOSITION
Active ingredient : Bevacizumab (humanised anti-VEGF monoclonal antibody).
Avastin is supplied in 100 mg and 400 mg preservative-free, single-use vials containing 4 ml or
16 ml of Avastin (25 mg/ml)
Each Avastin 100 mg vial contains 100 mg of bevacizumab.
Each Avastin 400 mg vial contains 400 mg of bevacizumab.
PHARMACOLOGICAL PROPERTIES & EFFECTS
Pharmacodynamic properties
Mechanism of Action
Bevacizumab binds to vascular endothelial growth factor (VEGF), the key driver of
vasculogenesis and angiogenesis and thereby inhibits the binding of VEGF to its receptors, Flt-1
(VEGFR-1) and KDR (VEGFR-2), on the surface of endothelial cells.
Neutralising the biological activity of VEGF reduces 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 parenteral 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
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. Avastin was
combined with two chemotherapy regimens:
AVF2107g: A weekly schedule of irinotecan/bolus 5-fluorouracil/folinic acid (IFL) for 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.
All three trials evaluated Avastin at a dose of 5 mg/kg of body weight every two weeks and
enrolled patients with previously untreated metastatic carcinoma of the colon or rectum.

Avastin in Combination with IFL Chemotherapy for First-Line Treatment of Metastatic

Carcinoma of the Colon or Rectum (AVF2107g): This was a phase III randomised, doubleblind, active-controlled clinical trial evaluating Avastin in combination with IFL as first-line
treatment for metastatic carcinoma of the colon or rectum. Eight hundred-thirteen patients were
randomised to receive IFL + placebo (Arm 1) or IFL + Avastin (5 mg/kg every 2 weeks, Arm 2)
(see Table 1). A third group of 110 patients received bolus 5-FU/FA + Avastin (Arm3). Enrollment
in Arm 3 was discontinued, as pre-specified, once safety of Avastin with the IFL regimen was
established and considered acceptable. All treatments were continued until disease progression.
The overall mean age was 59.4 years; 56.6% of patients had an ECOG performance status of
0.43% had a value of 1 and 0.4% had a value 2. 15.5% had received prior radiotherapy and
28.4% prior chemotherapy.
Table 1 Treatment Regimens in Study AVF2107g

Arm 1

Arm 2

Arm 3

Treatment

Starting Dose

Schedule

Placebo

IV

Every 2 weeks

Irinotecan
5-Fluorouracil
Folinic acid

125 mg/m2 i.v

Placebo

i.v

Irinotecan
5-Fluorouracil1
Folinic acid

125 mg/m2 i.v

Avastin

5 mg/kg i.v

Every 2 weeks

5-Fluorouracil
Folinic acid

500 mg/m2 i.v

500 mg/m2 i.v

Given once weekly for 6 weeks every 8

weeks

Avastin

5 mg/kg i.v

Every 2 weeks

500 mg/m2 i.v

20 mg/m2 i.v

500 mg/m2 i.v

20 mg/m2 i.v

Given once weekly for 4 weeks every 6

weeks
Every 2 weeks
Given once weekly for 4 weeks every 6
weeks

5-Fluorouracil : i.v bolus injection immediately after leucovorin

Folinic acid : i.v. bolus injection (over 1 2 minutes) immediately after each irinotecan
dose
The primary efficacy variable of the trial was duration of survival. The addition of Avastin to IFL
resulted in a statistically significant increase in overall survival (see Table 2). 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 Avastin in combination with IFL-chemotherapy are displayed in Table 2.
Table 2 Efficacy Results for Study AVF2107g
AVF2107g
Arm 2
Arm 1
IFL +
IFL +
Placebo Avastina

Number of Patients
Overall Survival
Median (months)
95 % confidence interval

411

402

15.6
14.29
16.99

20.3
18.46
24.18
0.660
0.00004

6.2

10.6
0.54
<0.00001

34.8
30.2
39.6

44.8
39.9
49.8
0.0036

Hazard ratiob
p-value
Progression-Free Survival
Median (months)
Hazard ratio
p-value
Overall Response Rate
Rate (percent)
95% confidence interval
p-value
Duration of Response
Median (months)
25-75 percentile (months)

7.1
10.4
4.7 11.8 6.7 15.0

a5 mg/kg every 2 weeks

bRelative to control arm

Among the 110 patients randomized to Arm 3 (5-FU/FA + Avastin), the median overall survival
was 18.3 months, median progression free survival was 8.8 months, overall response rate was
39% and median duration of response was 8.5 months.
Avastin in Combination with 5-FU/FA Chemotherapy for the First-Line Treatment of
Metastatic Carcinoma of the Colon or Rectum in patients who were not optimal candidates
for first-line irinotecan treatment (AVF2192g): This was a phase II randomized, double blind,
active controlled clinical trial evaluating the efficacy and safety of Avastin in combination with 5FU/FA as first-line treatment for metastatic colorectal cancer in patients who were not optimal
candidates for first-line irinotecan treatment. Patients had to be either more susceptible to
irinotecan toxicity ( 65 years, prior radiotherapy to pelvis or abdomen) or less likely to benefit
from irinotecan treatment (PS 1, baseline albumin < 3.5 g/dl) in order to be eligible for
enrolment. One hundred and five patients were randomised to 5-FU/FA + placebo arm and 104
patients to 5-FU/FA + Avastin (5 mg/kg every 2 weeks) arm. All treatments were continued until
disease progression. The overall mean age was 71 years; 28.2% of patients had a ECOG
performance status of 0, 65.1% had a value of 1 and 6.7% had a value of 2. The addition of
Avastin 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, compared to 5FU/FA chemotherapy alone (see Table 3). These efficacy data were consistent with the results
observed in studies AVF2107g and AVF0780g.
Avastin in Combination with 5-FU/FA Chemotherapy for the First-Line Treatment of
Metastatic Carcinoma of the Colon or Rectum (AVF0780g): This was a phase II randomized,
active-controlled, open-labelled clinical trial investigating Avastin 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 randomized to receive bolus 5-FU/FA or 5-FU/FA Avastin (5 mg/kg every 2 weeks). A third
group of 33 patients received bolus 5-FU/FA Avastin (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 Avastin 5 mg/kg every two weeks to 5-FU/FA
resulted in higher objective response rates, longer progression-free survival, and a trend in
longer survival, compared with 5-FU/FA chemotherapy alone (see Table 3). These efficacy data
are consistent with the result from study AVF2107g.
The efficacy data from studies AVF0780g and AVF2192g investigating Avastin in combination
with 5-FU/FA-chemotherapy are summarized in Table 3.
Table 3 Efficacy Results from Studies AVF0780g and AVF2192g
AVF0780g
AVF2192g
5-FU/FA 5-FU/FA 5-FU/FA
55-FU/FA +
+
+
+
FU/FA
Avastin
Avastina Avastinb placebo
Number of Patients
Overall Survival
Median (months)
95% Confidence
Interval
Hazard ratioc
p-value
Progression-Free
Survival
Median (months)
Hazard ratio
p-value
Overall Response
Rate
Rate (percent)
95% confidence
interval
p-value
Duration of
Response
Median (months)
25-75 percentile
(months)
a5

36

35

33

105

104

13.6

17.7

15.2

12.9
10.35
16.95

0.52

1.01

16.6
13.63
19.32
0.79

0.073

0.978

0.16

5.2

9.0

7.2

0.44
0.0049

0.69
0.217

16.7

40.0

24.2

15.2

26

7.0
33.5
-

24.4
57.8
0.029

11.7
42.6
0.43

9.2
23.9

18.1 35.6

NR

9.3

5.0

6.8

9.2

5.59
9.17

5.88
13.01

5.5 NR

mg/kg every 2 weeks

b 10

mg/kg every 2 weeks

Relative to control arm
NR = Not reached
c

Pharmacokinetic Properties

6.1 - NR 3.8 7.8

5.5

9.2
0.5
0.0002

0.055

The pharmacokinetic data for bevacizumab are available from eight clinical trials in patients with
solid tumours. In all clinical trials, bevacizumab was administered as an IV infusion. The rate of
infusion was based on tolerability, with an initial infusion duration of 90 minutes. The
pharmacokinetics of bevacizumab was linear at doses ranging from 1 to 10 mg/kg.
Absorption
Not applicable.
Distribution
Based on a population pharmacokinetic analysis of 491 subjects receiving Avastin weekly, every
2 weeks, or every 3 weeks, in doses ranging from 1 to 20 mg/kg, the volume of the central
compartment (Vc) was 2.921. Results also indicated that, after correcting for body weight, male
subjects had a larger Vc (+ 22%) than females.
Metabolism
Assessment of bevacizumab metabolism in rabbits following a single IV dose of 125Ibevacizumab 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
result in protection from cellular metabolism and the long terminal half-life.
Elimination
Bevacizumab clearance was 0.231 1/day. The volume of the central compartment (Vc) and
clearance correspond to an initial half-life of 1.4 days and a terminal half-life of about 20 days.
This half-life is consistent with the terminal elimination half-life for human endogenous IgG, which
is 18 to 23 days.
In patients with low albumin (29 g/l) and high alkaline phosphatase ( 484U/l) (both markers of
disease severity), clearance was approximately 20% higher than in patients with median
laboratory values.
Pharmacokinetics in Special Populations
The population pharmacokinetics were analyzed to evaluate the effects of demographic
characteristics. The results showed no significant difference in the pharmacokinetics of
bevacizumab in relation to age.
Children and adolescents: The pharmacokinetics of bevacizumab have been studied in a limited
number of paediatric patients. The resulting pharmacokinetic data suggest that the volume of
distribution and clearance of bevacizumab were comparable to that in adults with solid tumours.
Renal impairment: No studies have been conducted to investigate the pharmacokinetics of
bevacizumab in renally impaired patients.
Hepatic impairment: No studies have been conducted to investigate the pharmacokinetics of
bevacizumab in patients with hepatic impairment.
Preclinical Safety Data

In studies of up to 26 weeks duration in cynomolgus monkeys, physeal dysplasia was observed

in young animals with open growth plates, at bevacizumab average serum concentrations below
the expected human therapeutic average serum concentrations. In rabbits, bevacizumab was
shown to inhibit wound healing at doses below the proposed clinical dose. Effects on wound
healing were shown to be fully reversible
Studies to evaluate the mutagenic and carcinogenic potential of bevacizumab have not been
performed.
No specific studies in animals have been conducted to evaluate the effect on fertility. An adverse
effect on female fertility can however be expected as repeat dose toxicity studies in animals have
shown inhibition of the maturation of ovarian follicles and a decrease/absence of corpora lutea
and associated decrease in ovarian and uterus weight as well as a decrease in the number of
menstrual cycles.
Bevacizumab has been shown to be embryotoxic and teratogenic when administered to rabbits.
Observed effects included decrease 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.
CLINICAL PARTICULARS
Therapeutic Indications
Avastin (bevacizumab) in combination with intravenous 5-fluorouracil/folinic acid or intravenous
5-fluorouracil/folinic acid/irinotecan is indicated for treatment of patients with metastatic
carcinoma of the colon or rectum.
Metastatic colorectal cancer (mCRC)
Avastin in combination with fluoropyridine - based chemotherapy is indicated for treatment of
patients with metastatic carcinoma of the colon or rectum
Locally recurrent or metastatic triple negative Breast Cancer (mBC)
Avastatin in combination with paclitaxel is indicated for the treatment of patients with locally
recurrent or metastatic breast cancer, which is HER-2, estrogen receptor and progesterone
receptor negative.
Posology and Method of Administration
General
Avastin should be prepared by a healthcare professional using aseptic technique (see section
4.2 Special Instructions for Use, Handling and Disposal). Experienced in the use of
antineoplastic medicinal products.
It is recommended that treatment be continued until progression of the underlying disease.
Do not administer as an intravenous push or bolus.
The initial Avastin 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 60minutes infusion is well tolerated, all subsequent infusion may be administered over 30 minutes.
Instruction for the preparations of Avastin infusion are described in section instructions for Use,
Handling and Disposal. Avastin infusion should not be administered with glucose solutions.
Metastatic Colorectal Cancer (mCRC)
The recommended dose of Avastin, administered as an intravenous infusion, is either 5 mg/kg or
10mg/kg of body weight given once every 2 weeks or 7.5mg/kg or 15mg/kg of body weight given
once every 3 weeks. Dose reduction for adverse events is not recommended. If indicated,
therapy should either be permanently discontinued or temporarely suspended as described in
Special Warnings and Special Precautions for Use.
Locally recurrent or metastatic triple negative Breast cancer (mBC)
The recommended dose of Avastin 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 Avastin treatment be continued until progression of the underlying
malignant disease.
Special Dosage Instructions
Children and Adolescents: The safety and efficacy of Avastin in children and adolescents has
not been studied. Avastin is not recommended for use in children and adolescents due to a lack
of data on safety and efficacy (see section Preclinical safety data).
Elderly: No dose adjustment is required in the elderly.
Renal impairment: The safety and efficacy of Avastin has not been studied in patients with renal
impairment.
Hepatic impairment: The safety and efficacy of Avastin has not been studied in patients with
hepatic impairment.
Contraindications
Avastin is contraindicated in patients with known hypersensitivity to:
Any components of the product.
Chinese hamster ovary cell products or other recombinant human or humanized antibodies.
Pregnancy (see section Pregnancy and Lactation)
Avastin is contraindicated in patients with untreated Central Nervous System (CNS) metastases
(see also Special Warnings and Special Precautions for Use, and Undesirable Effects).
Special Warnings and Special Precautions for Use
General
Gastrointestinal Perforations
Patients may be at increased risk for the development of gastrointestinal perforation when treated

with Avastin (see also section 2.6.1 Clinical Trials (Undesirable Effects). Avastin should be
permanently discontinued in patients who develop gastrointestinal perforation. Intra-abdominal
inflammatory process may be at 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.
Haemorrhage (see also section 2.6.1 Clinical Trials (Undesirable Effects)
Patients treated with Avastin have an increased risk of haemorrhage, especially tumourassociated haemorrhage (see section 2.6.1 Haemorrhage). Avastin should be permanently
discontinued in patients who experience Grade 3 or 4 bleeding during Avastin therapy.
The risk of CNS haemorrhage in patients with CNS metastases receiving Avastin could not be
fully evaluated, as these patients were excluded from clinical trials. Thus, Avastin should not be
used in these patients (see sections Contraindication and Undesirable Effects).
There is no information on the safety profile of Avastin in patients with congenital bleeding
diathesis, acquired coagulopathy or in patients receiving full dose of anticoagulants for the
treatment of thromboembolism prior to starting Avastin 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 Avastin therapy
did not appear to have an increased rate of Grade 3 or above bleeding when treated with full
dose of warfarin and Avastin concomitantly.
Pulmonary Haemorrhage/Haemoptysis (see section 2.6 Undesirable Effects)
Patients with non-small cell lung cancer treated with Avastin may be at risk for serious, and in
some cases fatal, pulmonary haemorrhage/haemoptysis (see section 2.6.1 Haemorrhage).
Patients with recent pulmonary haemorrhage/haemoptysis (> 1/2 teaspoon red blood) should not
be treated with Avastin.
Hypertension
An increased incidence of hypertension was observed in patients treated with Avastin. Clinical
safety data suggest that the incidence of hypertension is likely to be dose-dependent. Pre
existing hypertension should be adequately controlled before starting Avastin treatment. There is
no information on the effect of Avastin in patients with uncontrolled hypertension at the time of
initiating therapy. Monitoring of blood pressure is recommended during Avistatin therapy (see
also section 2.6.1 Clinical Trials (Undesirable Effects)
In most cases hypertension was controlled adequately using standard antihypertensive treatment
appropriate for the individual situation of the affected patient. The use of diuretic to manage
hypertension is not advised in patients who receive a clispatin -based chemotherapy regiment.
Avastin should be permanently discontinued if medically significant hypertension can not be
adequately controlled with antihypertensive therapy, or if, the patient develops hypertensive
crisis or hypertensive encephalopathy (see also section 3.8.1 Experience from Clinical Trials and
3.8.2 Post-Marketing Experience)
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
There have been rare reports of Avastin-treated patients developing signs and symptoms that are

consistent with Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a rare

neurological 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 RPLS requires confirmation by brain imaging. In
patients developing RPLS, treatment of specific symptoms including control of hypertension is
recommended along with discontinuation of Avastin. The safety of reinitiating Avastin therapy in
patients previously experiencing RPLS is not known (see also section 2.6.2 Post-Marketing
Experience).
Arterial Thromboembolism
In clinical trials, the incidence of arterial thromboembolism events including cerebrovascular
accidents, transients ischaemic attact (TIA) and myocardial infarction (MI) was higher in patients
receiving Avastin in combination with chemotherapy compared to those who received
chemotherapy alone.
Avastin should be permanently discontinued in patients who develop arterial thromboembolic
events.
Patients receiving Avastin plus chemotherapy with a history of arterial thromboembolism or age
greater than 65 years have an increased risk of developing arterial thromboembolic events
during Avastin therapy. Caution should be taken when treating such patients with Avastin.
Venous Thromboembolism Patients may be at risk of developing venous thromboembolic
events, including pulmonary embolism under Avastin treatment. Avastin should be discontinued
in patients with life-threatening (Grade 4) pulmonary embolism, patients with Grade 3 need to
be closely monitored.
Congestive Heart Failure (see section 2.6 Undesirable Effects)
Events consistent with congestive heart failure (CHF) were reported in clinical trials. The
symptoms ranged from asymptomatic declines in left ventricular ejection fraction to symptomatic
CHF, requiring treatment or hospitalisation. Most of the patient 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, such as pre-existing coronary
heart disease or concomitant cardiotoxic therapy.
Caution should be exercised when treating patients with clinically significant cardiovascular
disease or pre-existing congestive heart failure with Avastin
Neutropenia
Increased rates of severe neutropenia, febrile neutropenia, or infection with severe neutropenia
(including some fatalities) have been observed in patients treated with some myelotoxic
chemotherapy regimens plus Avastin in comparison to chemotherapy alone.
Wound Healing
Avastin may adversely affect the wound healing process. Avastin 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 Avastin treatment, Avastin should be

withheld until the wound is fully healed. Avastin therapy should be withheld for elective surgery
(see also section 2.6.1 Clinical Trials (Undesirable Effects).
Proteinuria (see also section 2.6.1 Clinical Trials (Undesirable Effects)
In clinical trials, the incidence of proteinurea was higher in patients receiving Avastin in
combination with chemotherapy compared to those received chemotherapy alone. Grade 4
proteinurea (nephrotic syndrome) was uncommon in patients with Avastin. In the events of Grade
4 proteinurea Avastin treatment should be permanently discontinued.
Patients with history of hypertension may be at increased risk for the development of proteinurea
when treated with Avastin. There is evidence suggesting that grade 1 [US National Cancer
Intitute-Common Toxicity Criteria (NCI-CTC) version 2.0] proteinurea may be related to the dose.
Monitoring of proteinurea by dipstick urinalysis is recommended prior to starting and during
therapy
Fistulae
Patients may be at increased risk for the development of fistulae when treated with Avastin.
Permanently discontinue Avastin in patients with TE (Tracheoesopageal) fistula or any grade 4
fistula. In cases of internal fistula not arising in the GI tract, discontinuation of Avastin should be
considered.
Pregnancy and Lactation
Pregnancy
There are no data on the use of Avastin in pregnant women. Studies in animals have shown
reproductive toxicity including malformations (see section Preclinical safety data). IgGs are
known to cross the placenta, and Avastin is anticipated to inhibit angiogenesis in the foetus and
thus is suspected to cause serious birth defect when administered during pregnancy. Avastin is
contraindicated in pregnancy. In women of childbearing potential, appropriate contraceptive
measures must be used during therapy, and for at least 6 months following the last dose of
Avastin.
Lactation
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 Preclinical Safety
Data), women must discontinue breast-feeding during therapy and not breast feed for at least six
months following the last dose of Avastin.
Effects on Ability to Drive and Use Machines
No studies on the effects on the ability to drive and use machine have been performed. However,
there is no evidence that Avastin treatment results in an increase in adverse events that might
lead to impairment of the ability to drive or operate machinery or impairment of mental ability.
Interactions with other Medicinal Products and other Forms of Interaction
No formal drug interaction studies with other antineoplastic agents have been conducted.
However, the existing data suggest that bevacizumab does not affect the pharmacokinetics of 5fluorouracil (5-FU), carboplatin, paclitaxel, and doxorubicin to a clinically relevant extent.
In one study, irinotecan concentrations were similar in patients receiving Irinotecan/5-FU/folinic

acid (IFL) alone and in combination with bevacizumab. Concentrations of SN38, the active
metabolite of irinotecan, were analysed in a subset of patients (approximately 30 per treatment
arm). Concentrations of SN38 were on average 33% higher in patients receiving IFL in
combination with bevacizumab compared with IFL alone. Due to high inter-patient variability and
limited sampling, it is uncertain if the increase in SN38 levels observed was due to bevacizumab.
There was a small increase in diarrhoea and leukopenia adverse events (known adverse drug
reactions of irinotecan), and also more dose reductions of irinotecan were reported in the IFL +
bevacizumab treated patients.
Patients who develop severe diarrhoea, leukopenia or neutropenia with bevacizumab and
irinotecan combination should have irinotecan dose modifications as specified in the Summary of
Product Characteristics for the medicinal product containing irinotecan).
Effect of antineoplastic agents on befacizumab pharmacokinetics
No clinically relevant pharmacokinetics interaction of co-administered chemotherapy on Avastin
disposition has been observed based on the results of a population PK analysis. There was no
different in clearance of Avastin in patients treated with single-agent Avastin compared to
patients receiving Avastin in combination with the bolus-IFL regimen. The effect of other coadministered chemotherapies on Avastin clearance is considered not clinically significant.
Result from one study in metastatic colorectal cancer patients demonstrated no significant effect
of befacizumab on the pharmacokinetic of capecitabine and its metabolites, and on the
pharmacokinetics of oxaliplatin, as determined by measurement of free and total platinum. Result
from one study in renal cancer patients demonstrated no significant effect of bevacizumab on the
pharmacokinetics of interferon alfa-2a.
The safety and efficacy of concomitant administration of radiotherapy and Avastin has not been
established.
Undesirable Effects
The overall safety profile of Avastin is based on data from over 3,500 patients with various
malignancies, predominantly treated with Avastin in combination with chemotherapy in clinical
trials.
The most serious adverse drug reactions were:
Gastrointestinal perforations (see section Special Warnings and Special Precautions for Use)
Hemorrhage, including pulmonary haemorrhage/haemoptysis (see section Special Warnings
and Special Precautions for Use)
Arterial thromboembolism (see section Special Warnings and Special Precautions for Use)
The most frequently observed adverse drug reactions across clinical trials in patients receiving
Avastin were hypertension, fatigue or asthenia, diarrhoea and abdominal pain.
Analyses of the clinical safety data suggest that the occurrence of hypertension and proteinuria
with Avastin therapy are likely to be dose-dependent.
Table 1 lists adverse drug reactions associated with the use of Avastin in combination with
different chemotherapy regimens in multiple indications. These reactions had occurred either
with at least a 2% difference compared to the control arm (NCI-CTC grade 3-5 reactions), or with

at least a 10% difference compared to the control arm (NCI-CTC grade 1-5 reactions), in at least
one of the major clinical trials.
The adverse drug reactions listed in this table fall into the following categories: Very common
(=10%) and common (=1%-<10%). Adverse drug reactions are added to the appropriate category
in the table below according to the highest incidence seen in any of the major clinical trials.
Within each frequency grouping adverse drug reactions are presented in the order of decreasing
seriousness. Some of the adverse drug reactions are reactions commonly seen with
chemotherapy, (e.g palmar-plantar erythrodysaesthesia syndrome with capecitabine and
peripheral sensory neuropathy with paxlitaxel or oxaliplatin); however, an exacerbation by
Avastin therapy can not be excluded.
Table 1. Very common and common Adverse Drug Reactions
System organ Class NCI-CTC Grade 3-5 reactions (2%
All Grade Reactions (10%
(SOC)
difference between the study arms in at
difference between the study
least one clinical trials)
arms in at least one clinical trials)
Very common
Infections and
infestations
Blood and the
lymphatic systems

Common

Very common

Sepsis Abses
Infection
Leucopenia

Febrile Neutropenia

Thrombocytopenia

Anaemia

Neutropenia
Metabolism and
nutritions disorders
Nervous system
disorders

Peripheral
sensory
neurophaty

Dehydration

Anorexia

Cerebrovascular
accident

Dysgeusia
Headache

Syncope
Somnolence
Headache

Eye disorders

Eye disorders

Cardiac Disorders

Cardiac failure
Congestive
Supraventricular
tachicardia

Vascular disorders

Hypertension

Thromboembolism
(arterial)*
Deep vein
thrombosis
haemorrhage

Hypertension

Respiratory, thoratic
and mediastinal
disorders

Pulmonary
embolism
dyspnoea

Dyspnoea
Epistaxis
Rhynitis

Hypoxia
Epistaxis
Gastrointestinal
disorders

Diarrhoea
Nausea
Vomiting

Intestinal perforation
Ileus
Intestinal
obstruction

Constipation
Stomatitis
Rectal Haemorrhage

Abdominal pain
Gastrointestinal
disorder
Skin and
subcutaneous tissue
disorders

Palmar-Plantar

Exfoliative dermatitis

Erythrodysaesthesia
syndrome

Dry Skin

Musculoskeletal,
connective tissue
and bone disorders

Muscular weakness

Renal and urinary

disorders

Proteinurea

General disorders
and administration
site conditions

Skin discoloration

Proteinurea

Urinary Tract
Asthenia

Pain

Pyrexia

Fatigue

Lethargy

Asthenia
Pain

* Pooled arterial thromboembolic events including cerebrovascular accident, myocardial

infarction, transient ischaemic attack and other arterial thromboembolic events. Data are
unadjusted for the differential time on treatment
The following adverse events have been observed in patients treated with Avastin, and may be
potentially related to Avastin therapy:
Gastrointestinal perforation (see Special Warnings and Special Precautions for Use)
Avastin has been associated with serious cases of gastrointestinal perforation in patients with
metastatic carcinoma of the colon or rectum.
In clinical trials in metastatic carcinoma of the colon or rectum, gastrointestinal perforation was
observed in 1.4% - 2.0% of the Avastin-treated patients. Of these, 0.4% - 1% had fatal outcome.
The presentation of these events varied in type and severity, ranging from free air seen on the

plain abdominal X-ray, which resolved without treatment, to a colonic perforation with abdominal
abscess and fatal outcome. The common feature among these cases was intra-abdominal
inflammation, either from gastric ulcer disease, tumour necrosis, diverticulitis, or chemotherapyassociated colitis.
Gastrointestinal perforation have been reported in clinical trials with an incidence of less 1% in
patients with metastatic breast cancer or non-squamous non-small cell lung cancer, an in up to
2.0% in metastatic colorectal cancer patients. Fatal outcomes was reported in approximately a
third of serious cases of gastrointestinal perforations, which represents between 0.2%-1% of all
Avastin treated patients.
Wound healing (see Special Warnings and Special Precautions for Use)
As Avastin may adversely impact wound healing, patients who had major surgery within the last
28 days were excluded from participation in clinical trials for metastatic cancer of the colon or
rectum.
In clinical trials of metastatic carcinoma of the colon or rectum, patients who underwent cancerrelated surgery between 28 and 60 days prior to starting therapy did not have increased risk of
post-operative bleeding or wound healing complications during treatment compared to the
controlled groups.
Adverse events consistent with post-operative bleeding or wound healing complication were
observed in 10% - 20% of Avastin-treated patients who underwent major surgery while receiving
treatment.
An increased incidence of post-operative bleeding or wound healing complication occurring
within 60 days of major surgery was observed if the patients was being treated with Avastin at the
time of surgery. The incidence varied between 10% (4/40) and 20% (3/15).
In locally recurrent and metastatic breast cancer, Grade 3-5 wound healing complications were
observed in 1.1% of patients receiving Avastin + paclitaxel and in none of the patients receiving
paclitaxel alone.
Hypertension (see Special Warnings and Special Precautions for Use)
An increased incidence of hypertension has been observed in Avastin-treated patients.
Hypertension was generally treated with oral anti-hypertensives such as angiotensin-converting
enzyme inhibitors, diuretics and calcium-channel blockers. It rarely resulted in discontinuation
(0.7% of all Avastin treated patients) or hospitalization, and resulted in hypertensive
encephalopathy in one case (0.1%).
The risk of Avastin-associated hypertension did not correlate with the patients baseline
characteristic, underlying disease or concomitant therapy.
In clinical trials of metastatic carcinoma of the colon or rectum, hypertension of any grade
occurred in 22.4% - 32% of Avastin-treated patients. Grade 3 hypertension (requiring oral antihypertensive medication) was reported in 11.0% - 16.0% of Avastin-treated patients. No
hypertensive crisis (Grade 4) was reported. At week 24 of treatment, the mean change of blood
pressure (BP) from baseline was diastolic BP +4.1 to +5.4 mmHg and systolic BP +5.5 to +8.4
mmHg in the treated patients.

Hypertension was generally adequately controlled with oral-hypertensive such as angiotensinconverting enzyme inhibitors, diuretics and calcium-channel blockers. It rarely resulted in
discontinuation of Avastin treatment or hospitalisation.
Very rare cases of hypertension encephalopathy have been reported, some of which were fatal.
Fistulae:
Avastin use has been associated with serious cases of fistulae including events resulting in
death. In clinical trial, gastrointestinal fistulae have been reported with an incidence of up to 2%
in patients with metastatic colorectal cancer, but were also reported less commonly in patients
with other types of cancer.
Uncommon (=0.1% < 1%) reports of other types of fistulae that involve areas of the body other
than the gastrointestinal tract (e.g. bronchopleural, urogenital and biliary fistulae) were observes
across various indications. Fistulae have also been reported in post-marketing experience.
Event were reported at various time points during treatment ranging from one week to greater
than 1 year from initation of Avastin, with most events occurring within the first 6 months of
therapy.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
There have been rare reports of Avastin - treated patients developing signs and symptoms that
are consistent with Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a rare
neurological 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.
Proteinuria (see Special Warnings and Special Precautions for Use)
Proteinuria, reported as adverse event, was observed in 23.3% of all Avastin-treated patients. It
ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic
syndrome, with the great majority as Grade 1 proteinuria. The proteinuria seen in clinical trials
was not associated with renal dysfunction and rarely required permanent discontinuation of
therapy.
In clinical trials of metastatic carcinoma of the colon or rectum, proteinuria was reported as an
adverse event in 21.7% - 38.0% of Avastin-treated patients. No Grade 4 proteinuria was reported.
Haemorrhage (see Special Warnings and Special Precautions for Use)
Overall, 4.0% of NCI-CTC Grade 3 and 4 bleeding events were observed in all Avastin treated
patients. In clinical trials of metastatic carcinoma of the colon or rectum, there was no significant
difference in the incidence of grade 3 and 4 bleeding events observed between Avastin-treated
patients (3.1% - 5.1%) compared to that observed in the controls (2.5% - 2.9%). The
haemorrhagic events that have been observed in clinical studies were predominantly tumour
associated haemorrhage (see below) and minor mucocutaneous haemorrhage.
Tumour-associated haemorrhage was observed in phase I and phase II studies. In patients
with non-small cell lung cancer receiving Avastin, serious haemorrhage was observed in 9% (6%

fatal) of treated patients. These events occurred suddenly and presented as major or massive
haemoptysis in patients with either squamous cell histology and/or tumours located in the centre
of the chest in close proximity to major blood vessels. In some cases, these haemorrhages were
preceded by cavitation and/or necrosis of the tumour.
Tumour-associated haemorrhage was also seen rarely in other tumour types and locations,
including central nervous system (CNS) bleeding in a patient with hepatoma with occult CNS
metastases (see Contraindications) and continuous oozing of blood from a thigh sarcoma with
necrosis.
In clinical trials of metastatic carcinoma of the colon or rectum, tumour-associated haemorrhagic
events were observed in 1% - 3% of the Avastin-treated patients. The addition of Avastin did not
result in significant increase in the incidence or severity of Grade 3 or 4 haemorrhagic events.
Across all clinical trials, mucocutaneous haemorrhage has been seen in 20% - 40% of Avastin
treated patients. These were most commonly NCI-CTC Grade 1 epistaxis that lasted less than 5
minutes, resolved without medical intervention and did not require any changes in treatment
regimen. In clinical trials of metastatic carcinoma of the colon or rectum, epistaxis was reported in
22.0% - 34.3% of Avastin-treated patients.
There have also been less common events of minor mucocutaneous haemorrhage in other
locations, such as gingival bleeding and vaginal bleeding.
Thromboembolism (see Special Warnings and Special Precautions for Use)
In clinical trials of metastatic carcinoma of the colon or rectum, the overall incidence of
thromboembolic events was similar between Avastin-treated patients (18.0% - 19.4%) and the
controls (16.2% - 18.3%).
Arterial thromboembolism
In clinical trials of metastatic carcinoma of the colon or rectum, the incidence of arterial
thromboembolic events including CVAs, MIs, TIAs, and other arterial thromboembolic events was
higher in Avastin-treated patients (3.3% - 10.0%) compared to the controls (1.3% - 4.8%).
In five randomized trials including metastatic carcinoma of the colon or rectum trials (N=1745),
arterial thromboembolic events including CVAs, MIs, TIAs, and other thromboembolic events
occurred in 4.5% (45/1004) of patients treated with Avastin in combination with chemotherapy
compared to 2.0% (15/741) of patients treated with chemotherapy alone. In patients treated with
Avastin plus chemotherapy, arterial thromboembolic events led to a fatal outcome in 0.8%
(8/1004).
In patients treated with chemotherapy alone, a fatal outcome from arterial thromboembolic events
was reported in 0.4% (3/741). CVAs (including TIAs) occurred in 2.2% of patients treated with
Avastin in combination with chemotherapy and 0.5% of patients treated with chemotherapy
alone. MI occurred in 1.9% of patients treated with Avastin in combination with chemotherapy
compared to 1.1% of patients treated with chemotherapy alone.
Venous thromboembolism
In clinical trials of metastatic carcinoma of the colon or rectum, venous thromboembolic events,

including deep venous thrombosis, pulmonary embolism and thrombophlebitis occurred in 9.0%16.6% of Avastin-treated patients compared to that of 13.5% - 15.2% in the controls. It could not
be determined if these events were due to the patients underlying cancer, their cytotoxic
chemotherapy, Avastin or other risk factors.
Congestive Heart Failure (CHF)/Cardiomyopathy
In the phase III controlled clinical trial of metastatic breast cancer, CHF/cardiomyopathy was
reported in 3% of the avastin-treated patients compared with 1% in the controlled group. These
events varied in severity from asymptomatic declines in left ventricular ejection fraction to
symptomatic CHF requiring hospitalization and treatment. All the Avastin-treated patients were
previously treated with anthracyclines (doxorubicin cumulative dose range 240-360 mg/m2).
Many of these patients also had prior radiotherapy to the left chest wall. Most of these patients
showed improved symptoms and/or left ventricular function following appropriate medical
therapy.
There was no information on patients with pre-existing CHF (NYHA II-IV) at the time of initiating
the therapy, as these patients were excluded from studies. In patients with metastatic cancer of
the colon or rectum, there was no increased incidence of CHF in Avastin-treated patients.
Elderly Patients
Data from 5 randomised clinical trials showed that age > 65 years was associated with an
increased risk of developing arterial thromboembolic events including cerebrovascular accident
(CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs) when treated with
Avastin (see Special Warning and Special Precautions for Use and undesirable effects under
Thromboembolism). No increased incidence of Avastin-related events including gastrointestinal
perforation, wound healing complications, hypertension, proteinuria, haemorrhage and
congestive heart failure/cardiomyopathy was observed in elderly patients (> 65 years) with
metastatic cancer of the colon or rectum receiving Avastin compared to those patients aged 65
years treated with Avastin.
In the phase III study in metastatic carcinoma of colon or rectum trial (AVF2107g), 114 out of the
392 patients who received Avastin were older than 65 years. Only Grade 3/4 leucopenia
occurred at an incidence of 5% in the elderly patients (> 65 years) compared to those patients
aged 65 years.
In the phase II study in metastatic carcinoma of colon or rectum trial (AVF2192g), the majority of
the Avastin-treated patients was older than 65 years (83%). The overall safety profile of Avastin
from this study was comparable to the overall safety profile observed in Study AVF2107g.
Laboratory Abnormalities
Decreased neutrophil count, decreased white blood cell count and presence of urine protein may
be associated with Avastin.
Across clinical trials, the following Grade 3 and 4 laboratory abnormalities occurred in patients
treated with Avastin with at least a 2% difference compared to the corresponding control groups :
hyperglycaemia, decreased haemoglobin, hyperkalaemia, hyponatraemia, decreased white
blood cell count, increased international normalised ratio (INR).

The higher incidence of decreased neutrophil count and decreased white blood cell count
observed in the IFL + Avastin arm possibly correlated to the increased concentrations of SN38,
the active metabolite of irinotecan (see Interaction with other medicinal products and other forms
of interaction).
Overdose
The highest dose tested in humans (20 mg/kg of body weight, intravenous) was associated with
severe migraine in several patients.
Incompatibilities
No incompatibilities between Avastin and polyvinyl chloride or polyolefin bags have been
observed. A concentration-dependent degradation profile of Avastin was observed when diluted
with dextrose solutions (5%).
Stability
Avastin should not be used after the expiry date (EXP) shown on the pack.
Special Remarks
Special Precautions for Storage
Store vials in a refrigerator at 2oC - 8oC. Keep vial in the outer carton due to light sensitivity.
DO NOT FREEZE. DO NOT SHAKE.
Avastin does not contain any antimicrobial preservative; therefore, care must be taken to ensure
the sterility of the prepared solution.
Chemical and physical in-use stability has been demonstrated for 48 hours at 2oC-30oC in 0.9%
sodium chloride solution. 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 2oC to 8oC, unless dilution has taken
place in controlled and validated aseptic conditions
Instruction for Use, Handling and Disposal
Avastin should be prepared by healthcare professional using aseptic technique. Withdraw the
necessary amount of Avastin for a dose of 5 mg/kg of body weight and dilute in a total volume of
100 ml of 0.9% sodium chloride injection. Discard any unused portion left in a vial, as the product
contains no preservatives. Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to administration.
Packs
Vial 400mg/16ml
Box, 1 vial @ 16 ml
Vial 100 mg/4 ml
Box, 1 vial @ 4 ml

Reg No.:
Reg No.:

Medicine: keep out of reach of

children
Harus dengan resep dokter
On medical prescriptions only
Made for F.Hoffmann La Roche Ltd, Basel, Switzerland
By Genentech Inc., South San Francisco, California, USA
Imported by
PT Roche Indonesia
Jakarta, Indonesia