ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Avastin 25 mg/ml concentrate for solution for infusion.
2.
Each ml contains 25 mg of bevacizumab.
Each vial contains 100 mg of bevacizumab in 4 ml and 400 mg in 16 ml respectively, corresponding to
1.4 to 16.5 mg/ml when diluted as recommended.
Bevacizumab is a recombinant humanised monoclonal antibody produced by DNA technology in
Chinese Hamster ovary cells.
For a full list of excipients, see section 6.1.
3.
Concentrate for solution for infusion.
Clear to slightly opalescent, colourless to pale brown liquid.
4.
Avastin (bevacizumab) in combination with fluoropyrimidine-based chemotherapy is indicated for
treatment of patients with metastatic carcinoma of the colon or rectum.
Avastin in combination with paclitaxel is indicated for first-line treatment of patients with metastatic
breast cancer. For further information as to HER2 status, please refer to section 5.1.
Avastin, in addition to platinum-based chemotherapy, is indicated for first-line treatment of patients
with unresectable advanced, metastatic or recurrent non-small cell lung cancer other than
predominantly squamous cell histology.
Avastin in combination with interferon alfa-2a is indicated for first line treatment of patients with
advanced and/or metastatic renal cell cancer.
Avastin must be administered under the supervision of a physician experienced in the use of
antineoplastic medicinal products.
It is recommended that treatment be continued until progression of the underlying disease.
Dose reduction for adverse events is not recommended. If indicated, therapy should either be
permanently discontinued or temporarily suspended as described in section 4.4.
Metastatic carcinoma of the colon or rectum (mCRC)
The recommended dose of Avastin, 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.
2
Metastatic 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.
Non-small cell lung cancer (NSCLC)
Avastin is administered in addition to platinum-based chemotherapy for up to 6 cycles of treatment
followed by Avastin as a single agent until disease progression.
The recommended dose of Avastin is 7.5 mg/kg or 15 mg/kg of body weight given once every 3
weeks as an intravenous infusion.
Clinical benefit in NSCLC patients has been demonstrated with both 7.5 mg/kg and 15 mg/kg doses.
For details refer to section 5.1
Pharmacodynamic Properties,
Non-small cell lung cancer (NSCLC)
.
Advanced and/or metastatic Renal Cell Cancer (mRCC)
The recommended dose of Avastin is 10 mg/kg of body weight given once every 2 weeks as an
intravenous infusion.
Special populations
Elderly:
No dose adjustment is required in the elderly.
Renal impairment
: The safety and efficacy have not been studied in patients with renal impairment.
Hepatic impairment
: The safety and efficacy have not been studied in patients with hepatic
impairment.
Paediatric population
The safety and efficacy of bevacizumab in children and adolescents have not been established. There
is no relevant use of bevacizumab in the paediatric population in the granted indications. Currently
available data are described in section 5.2 and section 5.3 but no recommendation on a posology can
be made.
Method of administration
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.
Do not administer as an intravenous push or bolus.
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. Avastin
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.
•
Hypersensitivity to the active substance or to any of the excipients.
•
Hypersensitivity to Chinese hamster ovary (CHO) cell products or other recombinant human or
humanised antibodies.
•
Pregnancy (see section 4.6).
3
Gastrointestinal perforations
(see section 4.8)
Patients may be at an increased risk for the development of gastrointestinal perforation when treated
with Avastin. 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. Therapy should be permanently discontinued in patients who
develop gastrointestinal perforation.
Fistulae
(see section 4.8)
Patients may be at increased risk for the development of fistulae when treated with Avastin.
Permanently discontinue Avastin in patients with TE (tracheoesophageal) fistula or any grade 4 fistula.
Limited information is available on the continued use of Avastin in patients with other fistulae.
In cases of internal fistula not arising in the GI tract, discontinuation of Avastin should be considered.
Wound healing complications
(see section 4.8)
Avastin may adversely affect the wound healing process. 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.
Hypertension
(see section 4.8)
An increased incidence of hypertension was observed in Avastin-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 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 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. Avastin
should be permanently discontinued if medically significant hypertension cannot be adequately
controlled with antihypertensive therapy, or if the patient develops hypertensive crisis or hypertensive
encephalopathy.
Reversible posterior leukoencephalopathy syndrome (RPLS)
(see section 4.8)
There have been rare reports of Avastin-treated patients developing signs and symptoms that are
consistent with Reversible Posterior Leukoencephalopathy Syndrome (RPLS), 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 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.
Proteinuria
(see section 4.8)
Patients with a history of hypertension may be at increased risk for the development of proteinuria
when treated with Avastin. There is evidence suggesting that all Grade [US National Cancer Institute-
Common Toxicity Criteria (NCI-CTC) version 3.0] proteinuria may be related to the dose. Monitoring
of proteinuria by dipstick urinalysis is recommended prior to starting and during therapy. Therapy
should be permanently discontinued in patients who develop Grade 4 proteinuria (nephrotic syndrome).
Arterial thromboembolism
(see section 4.8)
In clinical trials, the incidence of arterial thromboembolic events including cerebrovascular accidents
(CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs) was higher in patients
4
receiving Avastin in combination with chemotherapy compared to those who received chemotherapy
alone.
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
therapy. Caution should be taken when treating these patients with Avastin.
Therapy should be permanently discontinued in patients who develop arterial thromboembolic events.
Venous thromboembolism
(see section 4.8)
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.
Haemorrhage
Patients treated with Avastin have an increased risk of haemorrhage, especially tumour-associated
haemorrhage. Avastin should be discontinued permanently in patients who experience Grade 3 or 4
bleeding during Avastin therapy (see section 4.8).
Patients with untreated CNS metastases were routinely excluded from clinical trials with Avastin,
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 Avastin treatment discontinued in
cases of intracranial bleeding.
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 therapy did not appear to have an
increased rate of grade 3 or above bleeding when treated with a full dose of warfarin and Avastin
concomitantly.
Pulmonary haemorrhage/haemoptysis
Patients with non-small cell lung cancer treated with Avastin 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 Avastin.
Congestive heart failure (CHF)
(see section 4.8)
Events consistent with 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 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, 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 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 Avastin in comparison to chemotherapy alone. This has mainly been seen
in combination with platinum- or taxane-based therapies in the treatment of NSCLC and mBC.
Hypersensitivity reactions/infusion reactions
(see section 4.8)
Patients may be at risk of developing infusion/hypersensitivity reaction. Close observation of the
patient during and following the administration of bevacizumab is recommended as expected for any
5
infusion of a therapeutic humanized 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 (see section 4.8)
Cases of ONJ have been reported in cancer patients treated with Avastin, the majority of whom had
received prior or concomitant treatment with i.v. bisphosphonates, for which ONJ is an identified risk.
Caution should be exercised when Avastin and i.v. 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 Avastin. In patients who
have previously received or are receiving i.v. bisphosphonates invasive dental procedures should be
avoided, if possible.
Eye disorders
Adverse reactions have been reported from unapproved intravitreal use. 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 appeared as serious adverse reactions.
Effect of antineoplastic agents on bevacizumab pharmacokinetics
No clinically relevant pharmacokinetic interaction of co-administered chemotherapy on Avastin
pharmacokinetics has been observed based on the results of a population PK analysis. There was
neither statistical significance nor clinically relevant difference in clearance of Avastin in patients
receiving Avastin monotherapy compared to patients receiving Avastin in combination with interferon
alfa-2a or other chemotherapies (IFL, 5-FU/LV, carboplatin/paclitaxel, capecitabine, doxorubicin or
cisplatin/gemcitabine).
Effect of bevacizumab on the pharmacokinetics of other antineoplastic agents
Results from a dedicated drug-drug interaction trial demonstrated no significant effect of bevacizumab
on the pharmacokinetics of irinotecan and its active metabolite SN38.
Results from one trial in metastatic colorectal cancer patients demonstrated no significant effect of
bevacizumab on the pharmacokinetics of capecitabine and its metabolites, and on the
pharmacokinetics of oxaliplatin, as determined by measurement of free and total platinum.
Results from one trial in renal cancer patients demonstrated no significant effect of bevacizumab on
the pharmacokinetics of interferon alfa-2a.
The potential effect of bevacizumab on the pharmacokinetics of cisplatin and gemcitabine was
investigated in non-squamous NSCLC patients. Trial results demonstrated no significant effect of
bevacizumab on the pharmacokinetics of cisplatin. Due to high inter-patient variability and limited
sampling, the results from that trial do not allow firm conclusions to be drawn on the impact of
bevacizumab on gemcitabine pharmacokinetics.
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
6
upon discontinuation of bevacizumab and sunitinib malate (see
Hypertension, Proteinuria, RPLS
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 Avastin has not been
established.
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 data on the use of Avastin in pregnant women. Studies in animals have shown
reproductive toxicity including malformations (see section 5.3). 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 defects when administered during pregnancy. Avastin is contraindicated in pregnancy (see
section 4.3).
Breastfeeding
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 Avastin.
Fertility
No specific trials in human or animals have been conducted to study the effect of bevacizumab on
fertility. However, repeat dose toxicity studies in animals have shown that bevacizumab may have an
adverse effect on female fertility (see section 5.3).
No studies on the effects on the ability to drive and use machines 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.
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 reactions were:
•
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 Avastin
were hypertension, fatigue or asthenia, diarrhoea and abdominal pain.
7
•
Gastrointestinal perforations (see section 4.4).
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 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 reactions listed in this table fall into the following categories: Very Common (≥ 1/10) and
Common (≥ 1/100 - < 1/10). Adverse 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 reactions are presented in the order of decreasing seriousness.
Some of the adverse reactions are reactions commonly seen with chemotherapy, (e.g. palmar-plantar
erythrodysaesthesia syndrome with capecitabine and peripheral sensory neuropathy with paclitaxel or
oxaliplatin); however, an exacerbation by Avastin therapy can not be excluded.
Table 1
Very common and common adverse reactions
System organ class
(SOC)
NCI-CTC grade 3-5 reactions
(
≥
2% difference between the trial arms in at
least one clinical trial)
All grade reactions
(
≥
10% difference
between the trial arms in
at least one clinical trial)
Very common
Common
Very common
Infections and
infestations
Sepsis
Abscess
Infection
Blood and the
lymphatic systems
disorders
Febrile neutropenia
Leucopenia
Thrombocytopenia
Neutropenia
Anaemia
Metabolism and
nutrition disorders
Dehydration
Anorexia
Nervous system
disorders
Peripheral sensory
neuropathy
Cerebrovascular
accident
Syncope
Somnolence
Headache
Dysgeusia
Headache
Eye disorders
Eye disorder
Lacrimation increased
Cardiac disorders
Cardiac failure
congestive
Supraventricular
tachycardia
Vascular disorders
Hypertension
Thromboembolism
(arterial)*
Deep vein thrombosis
Haemorrhage
Hypertension
Respiratory, thoracic
and mediastinal
disorders
Pulmonary embolism
Dyspnoea
Hypoxia
Epistaxis
Dyspnoea
Epistaxis
Rhinitis
8
System organ class
(SOC)
NCI-CTC grade 3-5 reactions
(
≥
2% difference between the trial arms in at
least one clinical trial)
All grade reactions
(
≥
10% difference
between the trial arms in
at least one clinical trial)
Very common
Common
Very common
Gastrointestinal
disorders
Diarrhoea
Nausea
Vomiting
Intestinal Perforation
Ileus
Intestinal obstruction
Abdominal pain
Gastrointestinal
disorder
Stomatitis
Constipation
Stomatitis
Rectal haemorrhage
Skin and subcutaneous
tissue disorders
Palmar-plantar
erythrodysaesthesia
syndrome
Exfoliative dermatitis
Dry skin
Skin discolouration
Musculoskeletal,
connective tissue and
bone disorders
Muscular weakness
Myalgia
Arthralgia
Renal and urinary
disorders
Proteinuria
Urinary Tract
Infection
Proteinuria
General disorders and
administration site
conditions
Asthenia
Fatigue
Pain
Lethargy
Mucosal inflammation
Pyrexia
Asthenia
Pain
Mucosal inflammation
* 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.
Further information on selected serious adverse reactions
Gastrointestinal perforations
(see section 4.4)
Avastin 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 metastatic breast cancer or non-squamous non-small cell lung cancer, and up to 2.0% in
metastatic colorectal cancer patients. Fatal outcome was reported in approximately a third of serious
cases of gastrointestinal perforations, which represents between 0.2%-1% of all Avastin treated
patients.
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 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.
Fistulae
(see section 4.4)
Avastin use has been associated with serious cases of fistulae including events resulting in death.
In clinical trials, 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
cancers. Uncommon (≥ 0.1% to < 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 observed
across various indications. Fistulae have also been reported in post-marketing experience.
9
Events were reported at various time points during treatment ranging from one week to greater than
1 year from initiation of Avastin, with most events occurring within the first 6 months of therapy.
Wound healing
(see section 4.4)
As Avastin 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 Avastin. 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 Avastin at the time of surgery. The incidence varied between 10% (4/40) and 20% (3/15).
In locally recurrent and metastatic breast cancer trials, Grade 3-5 wound healing complications were
observed in up to 1.1% of patients receiving Avastin compared with up to 0.9% of patients in the
control arms.
Hypertension
(see section 4.4)
An increased incidence of hypertension (all grades) of up to 34% has been observed in Avastin-treated
patients in clinical trials compared with up to 14% in those treated with comparator. Grade 3 and 4
hypertension (requiring oral anti-hypertensive medicines) in patients receiving Avastin ranged from
0.4% to 17.9%. Grade 4 hypertension (hypertensive crisis) occurred in up to 1.0% of patients treated
with Avastin and chemotherapy compared to up to 0.2% of patients treated with the same
chemotherapy alone.
Hypertension was generally adequately controlled with oral anti-hypertensives such as
angiotensin-converting enzyme inhibitors, diuretics and calcium-channel blockers. It rarely resulted in
discontinuation of Avastin treatment or hospitalisation.
Very rare cases of hypertensive encephalopathy have been reported, some of which were fatal.
The risk of Avastin-associated hypertension did not correlate with the patients’ baseline characteristics,
underlying disease or concomitant therapy.
Proteinuria
(see section 4.4)
In clinical trials, proteinuria has been reported within the range of 0.7% to 38% of patients receiving
Avastin.
Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic
syndrome, with the great majority as Grade 1 proteinuria. Grade 3 proteinuria was reported in < 3% of
treated patients: however, in patients treated for advanced and/or metastatic renal cell carcinoma this
was up to 7% in patients having minimal to no proteinuria at baseline. Grade 4 proteinuria (nephrotic
syndrome) was seen in up to 1.4% of treated patients. The proteinuria seen in clinical trials was not
associated with renal dysfunction and rarely required permanent discontinuation of therapy. Testing
for proteinuria is recommended prior to start of Avastin therapy. In most clinical trials urine protein
levels of ≥ 2g/24 hrs led to the holding of Avastin until recovery to < 2g/24 hrs.
Haemorrhage
(see section 4.4)
In clinical trials across all indications the overall incidence of NCI-CTC Grade 3-5 bleeding events
ranged from 0.4% to 5% in Avastin treated patients, compared with up to 2.9% of patients in the
chemotherapy control group.
The haemorrhagic events that have been observed in clinical trials were predominantly tumour-
associated haemorrhage (see below) and minor mucocutaneous haemorrhage (e.g. epistaxis).
10
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, Avastin 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 Avastin 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 events were seen with a
frequency of up to 9% when treated with Avastin plus chemotherapy compared with 5% in the patients
treated with chemotherapy alone. Grade 3-5 events have been observed in up to 2.3% of patients
treated with Avastin plus chemotherapy as compared with < 1% with chemotherapy alone. 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
ongoing trials in patients with treated brain metastases, one case of Grade 2 CNS haemorrhage was
reported in 83 subjects treated with bevacizumab (1.2%) at the time of interim safety analysis.
Across all clinical trials, mucocutaneous haemorrhage has been seen in up to 50% 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 the Avastin 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 events of minor mucocutaneous haemorrhage in other locations,
such as gingival bleeding or vaginal bleeding.
Thromboembolism
(see section 4.4)
Arterial thromboembolism:
An increased incidence of arterial thromboembolic events was observed in
patients treated with Avastin across indications, including cerebrovascular accidents, myocardial
infarction, transient ischemic attacks, and other arterial thromboembolic events.
In clinical trials, the overall incidence of arterial thromboembolic events ranged up to 3.8% in the
Avastin containing arms compared with up to 1.7% in the chemotherapy control arms. Fatal outcome
was reported in 0.8% of patients receiving Avastin compared to 0.5% in patients receiving
chemotherapy alone. Cerebrovascular accidents (including transient ischemic attacks) were reported in
up to 2.3% of patients treated with Avastin in combination with chemotherapy compared to 0.5% of
patients treated with chemotherapy alone. Myocardial infarction was reported in 1.4% of patients
treated with Avastin in combination with chemotherapy compared to 0.7% of patients treated with
chemotherapy alone.
11
In one clinical trial evaluating Avastin 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 events 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 events in clinical trials was
similar in patients receiving Avastin in combination with chemotherapy compared to those receiving
the control chemotherapy alone. Venous thromboembolic events include deep venous thrombosis,
pulmonary embolism and thrombophlebitis.
In clinical trials across indications, the overall incidence of venous thromboembolic events ranged
from 2.8% to 17.3% of Avastin-treated patients compared with 3.2% to 15.6% in the control arms.
Grade 3-5 venous thromboembolic events 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.
Patients who have experienced a venous thromboembolic event may be at higher risk for a recurrence
if they receive Avastin in combination with chemotherapy versus chemotherapy alone.
Congestive heart failure (CHF)
In clinical trials with Avastin, congestive heart failure (CHF) was observed in all cancer indications
studied to date, but occurred predominantly in patients with metastatic breast cancer. In two phase III
trials (AVF2119g and E2100) in patients with metastatic breast cancer an increase of CHF Grade 3 or
more with Avastin was seen. CHF was reported in up to 3.5% of patients treated with Avastin
compared with up to 0.9% in the control arms. Most of these patients showed improved symptoms
and/or left ventricular function following appropriate medical therapy.
In most clinical trials of Avastin, 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.
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 Avastin in combination with chemotherapy than with chemotherapy alone. The
incidence of these reactions in some clinical trials of Avastin is common (up to 5% in bevacizumab-
treated patients).
Elderly patients
In randomised clinical trials, age > 65 years was associated with an increased risk of developing
arterial thromboembolic events, 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; and all grade neutropenia,
diarrhoea, nausea, headache and fatigue as compared to those aged ≤ 65 years when treated with
Avastin (see sections 4.4 and 4.8 under
Thromboembolism
).
No increase in the incidence of other reactions, including gastrointestinal perforation, wound healing
complications, hypertension, proteinuria, congestive heart failure, and haemorrhage was observed in
elderly patients (> 65 years) receiving Avastin as compared to those aged ≤ 65 years treated with
Avastin.
Paediatric population
The safety of Avastin in children and adolescents has not been established.
12
Laboratory abnormalities
Decreased neutrophil count, decreased white blood cell count and presence of urine protein may be
associated with Avastin treatment.
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, hypokalaemia, hyponatraemia, decreased white blood cell
count, increased international normalised ratio (INR).
Post-marketing experience
Table 2
Adverse reactions reported in post-marketing setting
System organ class
(SOC)
Reactions (frequency*)
Nervous system
disorders
Hypertensive encephalopathy (very rare) (see also section 4.4 and
Hypertension
in section 4.8)
Reversible posterior leukoencephalopathy syndrome (rare) (see also
section 4.4)
Vascular disorders
Renal thrombotic microangiopathy, clinically manifested as
proteinuria (not known). For further information on proteinuria see
section 4.4 and
Proteinuria
in section 4.8.
Respiratory, thoracic
and mediastinal
disorders
Nasal septum perforation (not known)
Pulmonary hypertension (not known)
Dysphonia (common)
Gastrointestinal
disorders
Gastrointestinal ulcer (not known)
Immune system
disorders
Hypersensitivity reactions and infusion reactions (not known); with
the following possible co-manifestations: dyspnoea/difficulty
breathing, flushing/redness/rash, hypotension or hypertension, oxygen
desaturation, chest pain, rigors and nausea/vomiting (see also section
4.4 and
Hypersensitivity reactions/infusion reactions
above)
Osteonecrosis of the
jaw
Cases of osteonecrosis of the jaw (ONJ) have been reported in patients
treated with Avastin, most of which occurred in patients who had
identified risk factors for ONJ, in particular exposure to i.v.
bisphosphonates and/or a history of dental disease requiring invasive
dental procedures (see also section 4.4)
* if specified, the frequency has been derived from clinical trial data
The highest dose tested in humans (20 mg/kg of body weight, intravenous every 2 weeks) was
associated with severe migraine in several patients.
13
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: monoclonal antibody, ATC code: L01X C07
Mechanism of action
Bevacizumab binds to vascular endothelial growth factor (VEGF), the key driver of vasculogenesis
and angiogenesis, and thereby inhibits the binding of VEGF to its receptors, Flt-1 (VEGFR-1) and
KDR (VEGFR-2), on the surface of endothelial cells. Neutralising the biological activity of VEGF
regresses the vascularisation of tumours, normalises remaining tumour vasculature, and inhibits the
formation of new tumour vasculature, thereby inhibiting tumour growth.
Pharmacodynamic effects
Administration of bevacizumab or its parental murine antibody to xenotransplant models of cancer in
nude mice resulted in extensive anti-tumour activity in human cancers, including colon, breast,
pancreas and prostate. Metastatic disease progression was inhibited and microvascular permeability
was reduced.
Clinical efficacy
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. Avastin 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.
Two additional trials were conducted in first (NO16966) and second line (E3200) treatment of
metastatic carcinoma of the colon or rectum, with Avastin administered in the following dosing
regimens, in combination with FOLFOX-4 (5FU/LV/Oxaliplatin) and XELOX
(Capecitabine/Oxaliplatin):
•
NO16966:
Avastin 7.5 mg/kg of body weight every 3 weeks in combination with oral
capecitabine and intravenous oxaliplatin (XELOX) or Avastin 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:
Avastin 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).
AVF2107g
This was a phase III randomised, double-blind, active-controlled clinical trial evaluating Avastin 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 + Avastin (5 mg/kg every 2 weeks, Arm 2). A third group of 110 patients received bolus
5-FU/FA+Avastin (Arm 3). Enrolment in Arm 3 was discontinued, as pre-specified, once safety of
Avastin with the IFL regimen was established and considered acceptable. All treatments were
14
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 Avastin to IFL resulted
in statistically significant increases in overall survival, progression-free survival and overall response
rate (see Table 3). 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 3.
Table 3
Efficacy results for trial AVF2107g
AVF2107g
Arm 1
IFL
+
placebo
Arm 2
IFL
+
Avastin
a
Number of patients
411
402
Overall survival
Median time (months)
15.6
20.3
95% Confidence interval
14.29 – 16.99
18.46 – 24.18
Hazard ratio
b
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)
Among the 110 patients randomised to Arm 3 (5-FU/FA + Avastin) prior to discontinuation of this
arm, the median overall survival was 18.3 months and the median progression free survival was
8.8 months.
a
5 mg/kg every 2 weeks.
b
Relative to control arm.
AVF2192g
This
was a phase II randomised, double-blind, active-controlled clinical trial evaluating the efficacy
and safety of Avastin 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 + Avastin
(5 mg/kg every 2 weeks) arm. All treatments were continued until disease progression. 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 as compared to 5-FU/FA chemotherapy
alone.
AVF0780g
This was a phase II randomised, 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 randomised to receive bolus 5-FU/FA or 5-FU/FA + Avastin (5 mg/kg
15
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 4). These efficacy
data are consistent with the results from trial AVF2107g.
The efficacy data from trials AVF0780g and AVF2192g investigating Avastin in combination with
5-FU/FA-chemotherapy are summarised in Table 4.
Table 4
Efficacy results for trials AVF0780g and AVF2192g
AVF0780g
AVF2192g
5-FU/FA
5-FU/FA
+
Avastin
a
5-FU/FA
+
Avastin
b
5-FU/FA +
placebo
5-FU/FA +
Avastin
Number of patients
36
35
33
105
104
Overall survival
Median time (months)
13.6
17.7
15.2
12.9
16.6
95% Confidence
interval
10.35 -
16.95
13.63 -
19.32
Hazard ratio
c
-
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 Avastin
7.5 mg/kg in combination with oral capecitabine and IV oxaliplatin (XELOX), administered on a 3-
weekly schedule; or Avastin 5 mg/kg in combination with leucovorin with 5-fluorouracil bolus,
followed by 5-fluorouracil infusional, with IV oxaliplatin (FOLFOX-4), administered on a 2-weekly
schedule. The trial contained two parts: an initial unblinded 2-arm part (Part I) in which patients were
randomised to two different treatment groups (XELOX and FOLFOX-4) and a subsequent 2 x 2
factorial 4-arm part (Part II) in which patients were randomised to four treatment groups (XELOX +
placebo, FOLFOX-4 + placebo, XELOX + Avastin, FOLFOX-4 + Avastin). In Part II, treatment
assignment was double-blind with respect to Avastin.
Approximately 350 patients were randomised into each of the 4 trial arms in the Part II of the trial.
16
Table 5
Treatment regimens in trial N016966 (mCRC)
Treatment
Starting dose
Schedule
FOLFOX-4
or
FOLFOX-4 +
Avastin
Oxaliplatin
85 mg/m
2
IV 2 h
Oxaliplatin on day 1
Leucovorin on day 1 and 2
5-fluorouracil IV bolus/infusion,
each on days 1 and 2
Leucovorin
200 mg/m
2
IV 2 h
5-Fluorouracil
400 mg/m
2
IV bolus,
600 mg/ m
2
IV 22 h
Placebo or
Avastin
5 mg/kg IV 30-90
min
Day 1, prior to FOLFOX-4,
every 2 weeks
XELOX
or
XELOX+
Avastin
Oxaliplatin
130 mg/m
2
IV 2 h
Oxaliplatin on day 1
Capecitabine oral bid for 2
weeks (followed by 1 week off
treatment)
Capecitabine
1000 mg/m
2
oral bid
Day 1, prior to XELOX, q
3 weeks
5-Fluorouracil: IV bolus injection immediately after leucovorin
Placebo or
Avastin
7.5 mg/kg IV 30-90
min
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 Avastin 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 Avastin-containing arms versus the chemotherapy alone arms in the overall
comparison was demonstrated in terms of progression-free survival in the ITT population
(Table 6).
Secondary PFS analyses, based on ‘on-treatment’-based response assessments, confirmed the
significantly superior clinical benefit for patients treated with Avastin (analyses shown in Table 6),
consistent with the statistically significant benefit observed in the pooled analysis.
17
Table 6 Key efficacy results for the superiority analysis (ITT population, trial NO16966)
Endpoint (months)
FOLFOX-4
or XELOX
+ placebo
(n=701)
FOLFOX-4
or XELOX
+ bevacizumab
(n=699)
P value
Primary endpoint
Median PFS**
8.0
9.4
0.0023
Hazard ratio (97.5% CI)a
0.83 (0.72–0.95)
Secondary endpoints
Median PFS (on treatment)**
7.9
10.4
<0.0001
Hazard ratio (97.5% CI)
0.63 (0.52-0.75)
Overall response rate
(invest. assessment)**
49.2%,
46.5%
Median overall survival*
19.9
21.2
0.0769
Hazard ratio (97.5% CI)
0.89 (0.76-1.03)
* Overall survival analysis at clinical cut-off 31 January 2007
** Primary analysis at clinical cut-off 31 January 2006
a
relative to control arm
In the FOLFOX treatment subgroup, the median PFS was 8.6 months in placebo and 9.4 months in
bevacizumab treated patients, HR = 0.89, 97.5% CI
= [
0.73
;
1.08
]
; p-value
=
0.1871, the
corresponding results in the XELOX treatment subgroup being 7.4 vs. 9.3 months, HR = 0.77, 97.5%
CI =
[
0.63
;
0.94
]
; p-value
=
0.0026.
The median overall survival was 20.3 months in placebo and 21.2 months in bevacizumab treated
patients in the FOLFOX treatment subgroup, HR=0.94, 97.5% CI
= [
0.75
;
1.16
]
; p-value
=
0.4937, the
corresponding results in the XELOX, treatment subgroup being 19.2 vs. 21.4 months, HR = 0.84,
97.5% CI
= [
0.68
;
1.04
]
; p-value
=
0.0698.
ECOG E3200
This was a phase III randomised, active-controlled, open-label trial investigating Avastin 10 mg/kg in
combination with leucovorin with 5-fluorouracil bolus and then 5-fluorouracil infusional, with IV
oxaliplatin (FOLFOX-4), administered on a 2-weekly schedule in previously-treated patients (second
line) with advanced colorectal cancer. In the chemotherapy arms, the FOLFOX-4 regimen used the
same doses and schedule as shown in Table 5 for trial NO16966.
The primary efficacy parameter of the trial was overall survival, defined as the time from
randomization to death from any cause. Eight hundred and twenty-nine patients were randomised (292
FOLFOX-4, 293 Avastin + FOLFOX-4 and 244 Avastin monotherapy). The addition of Avastin 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 7).
18
Table 7
Efficacy results for trial E3200
E3200
FOLFOX-4
FOLFOX-4 + Avastin
a
Number of patients
292
293
Overall survival
Median (months)
10.8
13.0
95% confidence interval
10.12 – 11.86
12.09 – 14.03
Hazard ratio
b
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 Avastin monotherapy compared to patients treated with FOLFOX-4. Progression-free
survival and objective response rate were inferior in the Avastin monotherapy arm compared to the
FOLFOX-4 arm.
The benefit of Avastin re-treatment in metastatic colorectal cancer patients who were exposed to
Avastin in previous therapies has not been addressed in randomized clinical trials.
Metastatic breast cancer (mBC)
ECOG E2100
Trial E2100 was an open-label, randomised, active controlled, multicentre clinical trial evaluating
Avastin 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/m
2
IV over 1 hour once weekly for three out of four weeks) or
in combination with Avastin (10 mg/kg IV infusion every two weeks). Prior hormonal therapy for the
treatment of metastatic disease was allowed. Adjuvant taxane therapy was allowed only if it was
completed at least 12 months prior to trial entry. Of the 722 patients in the trial, the majority of
patients had HER2-negative disease (90%), with a small number of patients with unknown (8%) or
confirmed HER2-positive status (2%), who had previously been treated with or were considered
unsuitable for trastuzumab therapy. Furthermore, 65% of patients had received adjuvant chemotherapy
including 19% prior taxanes and 49% prior anthracyclines. Patients with central nervous system
metastasis, 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 Avastin 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 8.
19
Table 8
Trial E2100 efficacy results
Progression-free survival
Investigator assessment*
IRF assessment
Paclitaxel
(n=354)
Paclitaxel/
Avastin
(n=368)
Paclitaxel
(n=354)
Paclitaxel/
Avastin
(n=368)
Median PFS (months)
5.8
11.4
5.8
11.3
HR
(95% CI)
0.421
(0.343 ; 0.516)
0.483
(0.385 ; 0.607)
p-value
<0.0001
<0.0001
Response rates
(for patients with measurable disease)
Investigator assessment
IRF assessment
Paclitaxel
(n=273)
Paclitaxel/
Avastin
(n=252)
Paclitaxel
(n=243)
Paclitaxel/
Avastin
(n=229)
% pts with objective
response
23.4
48.0
22.2
49.8
p-value
<0.0001
<0.0001
* primary analysis
Overall survival
Paclitaxel
(n=354)
Paclitaxel/
Avastin
(n=368)
Median OS (months)
24.8
26.5
HR
(95% CI)
0.869
(0.722 ; 1.046)
p-value
0.1374
The clinical benefit of Avastin 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 estrogen receptor (ER) status).
Non-small cell lung cancer (NSCLC)
The safety and efficacy of Avastin, 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 Avastin
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 randomized to platinum-based chemotherapy (paclitaxel 200 mg/m2 and carboplatin
AUC = 6.0, both by IV infusion) (PC) on day 1 of every 3-week cycle for up to 6 cycles or PC in
combination with Avastin at a dose of 15 mg/kg IV infusion day 1 of every 3-week cycle. After
completion of six cycles of carboplatin-paclitaxel chemotherapy or upon premature discontinuation of
chemotherapy, patients on the Avastin + carboplatin–paclitaxel arm continued to receive Avastin as a
single agent every 3 weeks until disease progression. 878 patients were randomised to the two arms.
20
During the trial, of the patients who received trial treatment, 32.2% (136/422) of patients received
7-12 administrations of Avastin and 21.1% (89/422) of patients received 13 or more administrations of
Avastin.
The primary endpoint was duration of survival. Results are presented in Table 9.
Table 9
Efficacy results for trial E4599
Arm 1
Carboplatin/
Paclitaxel
Arm 2
Carboplatin/
Paclitaxel +
Avastin
15 mg/kg q 3 weeks
Number of patients
444
434
Overall survival
Median (months)
10.3
12.3
Hazard ratio
0.80 (p=0.003)
95% CI (0.69, 0.93)
Progression-free survival
Median (months)
4.8
6.4
Hazard ratio
0.65 (p<0.0001)
95% CI (0.56, 0.76)
Overall response rate
Rate (percent)
12.9
29.0 (p<0.0001)
In an exploratory analysis, the extent of Avastin 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 Avastin 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 i.v. infusion on day 1
and gemcitabine 1250 mg/m2 i.v. infusion on days 1 and 8 of every 3-week cycle for up to 6 cycles
(CG) with placebo or CG with Avastin at a dose of 7.5 or 15 mg/kg IV infusion day 1 of every 3-week
cycle. In the Avastin-containing arms, patients could receive Avastin as a single-agent every 3 weeks
until disease progression or unacceptable toxicity. Trial results show that 94% (277 / 296) of eligible
patients went on to receive single agent bevacizumab at cycle 7
.
A high proportion of patients
(approximately 62%) went on to receive a variety of non-protocol specified anti-cancer therapies,
which may have impacted the analysis of overall survival.
The efficacy results are presented in Table 10.
21
Table 10 Efficacy results for trial BO17704
Cisplatin/Gemcitabine
+ placebo
Cisplatin/Gemcitabine
+ Avastin
7.5 mg/kg q 3 weeks
Cisplatin/Gemcitabine
+ Avastin
15 mg/kg q 3 weeks
Number of
patients
347
345
351
Progression-free
survival
Median (months)
6.1
6.7
(p = 0.0026)
6.5
(p = 0.0301)
Hazard ratio
0.75
[0.62;0.91]
0.82
[0.68;0.98]
Best overall
response rate
a
20.1%
34.1%
(p< 0.0001)
30.4%
(p=0.0023)
a
patients with measurable disease at baseline
Overall survival
Median (months)
13.1
13.6
(p = 0.4203)
13.4
(p = 0.7613)
Hazard ratio
0.93
[0.78; 1.11]
1.03
[0.86, 1.23]
Advanced and/or metastatic Renal Cell Cancer (mRCC)
Avastin in Combination with Interferon alfa-2a for the First-Line Treatment of Advance and/ or
Metastatic Renal Cell Cancer (BO17705)
This was a phase III randomised double-blind trial conducted to evaluate the efficacy and safety of
Avastin in combination with interferon (IFN) alfa-2a (Roferon
®
) versus IFN alfa-2a alone as first-line
treatment in mRCC. The 649 randomized 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. Avastin 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 recommend 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 Avastin 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%
Avastin/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 11.
22
Table 11 Efficacy results for trial BO17705
BO17705
Placebo+ IFN
a
Bv
b
+ IFN
a
Number of patients
322
327
Progression-free survival
Median (months)
5.4
10.2
Hazard ratio
95% CI
0.63
0.52, 0.75
(p-value < 0.0001)
Objective response rate
(%) in
Patients with measurable disease
289
306
n
Response rate
12.8%
31.4%
(p-value < 0.0001)
a
Interferon alfa-2a 9 MIU 3x/week
b
Bevacizumab 10 mg/kg q 2 wk
Overall survival
Median (months)
21.3
23.3
Hazard ratio
95% CI
0.91
0.76, 1.10
(p-value 0.3360)
An exploratory multivariate Cox regression model using backward selection indicated that the
following baseline prognostic factors were strongly associated with survival independent of treatment:
gender, white blood cell count, platelets, body weight loss in the 6 months prior to trial entry, number
of metastatic sites, sum of longest diameter of target lesions, Motzer score. Adjustment for these
baseline factors resulted in a treatment hazard ratio of 0.78 (95% CI [0.63;0.96], p = 0.0219),
indicating a 22% reduction in the risk of death for patients in the Avastin+ 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 Avastin 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 Avastin and
IFN alfa-2a based on PFS event free rates over time, as shown by a sub-group analysis. The 131
patients in the Avastin + 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 Avastin +
IFN alfa-2a.
AVF2938
This was a randomised, double-blind, phase II clinical trial investigating Avastin 10 mg/kg in a 2
weekly schedule with the same dose of Avastin 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
Avastin 10 mg/kg every 2 weeks plus placebo and 51 to Avastin 10 mg/kg every 2 weeks plus
erlotinib 150 mg daily. The analysis of the primary endpoint showed no difference between the
Avastin + Placebo arm and the Avastin + 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).
23
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 randomized to receive bevacizumab 3 mg/kg every 2
weeks (n=39), 10 mg/kg every 2 weeks; (n=37), or placebo (n=40). An interim analysis showed there
was a significant prolongation of the time to progression of disease in the 10 mg/kg group as
compared with the placebo group (hazard ratio, 2.55; p<0.001). There was a small difference, of
borderline significance, between the time to progression of disease in the 3 mg/kg group and that in
the placebo group (hazard ratio, 1.26; p=0.053). Four patients had objective (partial) response, and all
of these had received the 10 mg/kg dose bevacizumab; the ORR for the 10 mg/kg dose was 10%.
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) and kidney and renal pelvis carcinoma
(excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal
medullary carcinoma and rhabdoid tumour of the kidney).
5.2 Pharmacokinetic properties
The pharmacokinetic data for bevacizumab are available from ten clinical trials in patients with solid
tumours. In all clinical trials, bevacizumab was administered as an IV infusion. The rate of infusion
was based on tolerability, with an initial infusion duration of 90 minutes. The pharmacokinetics of
bevacizumab was linear at doses ranging from 1 to 10 mg/kg.
Distribution
The typical value for central volume (V
c
) 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 (V
p
) was 1.69 L and 2.35 L for female and male patients
respectively, when bevacizumab is coadministered with anti-neoaplastic agents. After correcting for
body weight, male patients had a larger Vc (+ 20%) than female patients.
Metabolism
Assessment of bevacizumab metabolism in rabbits following a single IV 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 result
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 to evaluate the effects of demographic characteristics.
The results showed no significant difference in the pharmacokinetics of bevacizumab in relation to age.
24
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 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.
5.3 Preclinical safety data
In studies of up to 26 weeks duration in cynomolgus monkeys, physeal dysplasia was observed in
young animals with open growth plates, at bevacizumab average serum concentrations below the
expected human therapeutic average serum concentrations. In rabbits, bevacizumab was shown to
inhibit wound healing at doses below the proposed clinical dose. Effects on wound healing were
shown to be fully reversible.
Studies to evaluate the mutagenic and carcinogenic potential of bevacizumab have not been performed.
No specific studies in animals have been conducted to evaluate the effect on fertility. An adverse
effect on female fertility can however be expected as repeat dose toxicity studies in animals have
shown inhibition of the maturation of ovarian follicles and a decrease/absence of corpora lutea and
associated decrease in ovarian and uterus weight as well as a decrease in the number of menstrual
cycles.
Bevacizumab has been shown to be embryotoxic and teratogenic when administered to rabbits.
Observed effects included decreases in maternal and foetal body weights, an increased number of
foetal resorptions and an increased incidence of specific gross and skeletal foetal malformations.
Adverse foetal outcomes were observed at all tested doses, of which the lowest dose resulted in
average serum concentrations approximately 3 times larger than in humans receiving 5 mg/kg every 2
weeks.
6.
6.1 List of excipients
Trehalose dihydrate
Sodium phosphate
Polysorbate 20
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
A concentration dependent degradation profile of bevacizumab was observed when diluted with
glucose solutions (5%).
25
6.3 Shelf life
2 years.
Chemical and physical in-use stability has been demonstrated for 48 hours at 2°C to 30°C in sodium
chloride 9 mg/ml (0.9%) solution for injection. From a microbiological point of view, the product
should be used immediately. If not used immediately, in-use storage times and conditions are the
responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless
dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store in a refrigerator (2°C-8°C).
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
For storage conditions of the diluted 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
Avastin 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 1.4-16.5 mg/ml.
Parenteral medicinal products should be inspected visually for particulate matter and discolouration
prior to administration.
Avastin is for single-use only, as the product contains no preservatives. Any unused product or waste
material should be disposed of in accordance with local requirements.
No incompatibilities between Avastin and polyvinyl chloride or polyolefine bags or infusion sets have
been observed.
7.
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
26
8.
EU/1/04/300/001 – 100 mg/4 ml vial
EU/1/04/300/002 – 400 mg/16 ml vial
9.
Date of first authorisation: 12 January 2005
Date of latest renewal: 14 January 2010
Detailed information on this product is available on the website of the European Medicines Agency
(EMA):
http://www.ema.europa.eu
27
ANNEX II
A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER(S) RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
28
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers of the biological active substance
Genentech, Inc.
1 DNA Way
South San Francisco, CA 94080-4990
USA
Genentech, Inc.
1 Antibody Way
Oceanside, CA 92056
USA
F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124
CH-4070 Basel
Switzerland
Name and address of the manufacturer responsible for batch release
Roche Pharma AG
Emil-Barrell-Str. 1,
D-79639 Grenzach-Wyhlen
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
●
Medicinal product subject to restricted medical prescription (see Annex: Summary of Product
Characteristics, section 4.2).
●
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
●
OTHER CONDITIONS
Risk Management Plan
The MAH commits to performing the trials and additional pharmacovigilance activities detailed in the
Pharmacovigilance Plan, as agreed in version 7.0 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report (PSUR).
29
In addition, an updated RMP should be submitted
●
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
●
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
●
At the request of the EMA
The MAH will continue to submit yearly PSURs, unless otherwise specified by the CHMP.
Biomarker
The MAH should investigate suitable biomarkers (including VEGF-A) to allow identification and
selection of a more targeted population of patients most likely to benefit from the combination of
Avastin and paclitaxel in the treatment of first-line metastatic breast cancer. A report on the research
programme should be submitted within 3 months of the Commission Decision. Progress reports should
be submitted on a yearly basis.
30
ANNEX III
LABELLING AND PACKAGE LEAFLET
31
A. LABELLING
32
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Avastin 25 mg/ml concentrate for solution for infusion
Bevacizumab
100 mg/4 ml
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 100 mg bevacizumab.
3.
LIST OF EXCIPIENTS
Trehalose dihydrate, sodium phosphate, polysorbate 20, water for injections.
4.
Concentrate for solution for infusion
1 vial of 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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
This medicinal product does not contain any preservative
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Keep the vial in the outer carton
33
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
EU/1/04/300/001
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
<Justification for not including Braille accepted>
34
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
Avastin 25 mg/ml concentrate for solution for infusion
Bevacizumab
100 mg/4 ml
2.
METHOD OF ADMINISTRATION
For intravenous use after dilution
IV
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
100 mg/4 ml
6.
OTHER
35
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Avastin 25 mg/ml concentrate for solution for infusion
Bevacizumab
400 mg/16 ml
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 400 mg bevacizumab.
3.
LIST OF EXCIPIENTS
Trehalose dihydrate, sodium phosphate, polysorbate 20, water for injections.
4.
Concentrate for solution for infusion
1 vial of 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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
This medicinal product does not contain any preservative
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Keep the vial in the outer carton
36
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
EU/1/04/300/002
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
<Justification for not including Braille accepted>
37
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
Avastin 25 mg/ml concentrate for solution for infusion
Bevacizumab
400 mg/16 ml
2.
METHOD OF ADMINISTRATION
For intravenous use after dilution
IV
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
400 mg/16 ml
6.
OTHER
38
B. PACKAGE LEAFLET
39
PACKAGE LEAFLET: INFORMATION FOR THE USER
Avastin 25 mg/ml concentrate for solution for infusion
Bevacizumab
Read all of this leaflet carefully before you start using this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the
side
effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Avastin is and what it is used for
2.
Before you use Avastin
3.
Possible side effects
5.
How to store Avastin
6.
Further information
1.
WHAT AVASTIN IS AND WHAT IT IS USED FOR
Avastin contains the active substance bevacizumab, which is a humanised monoclonal antibody.
Monoclonal antibodies are proteins which specifically recognise and bind to other unique proteins in
the body. 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. VEGF causes blood
vessels to grow within tumours, these blood vessels provide the tumour with nutrients and oxygen.
Once bevacizumab is bound to VEGF, it stops VEGF working properly. This has the effect of
preventing tumour growth by blocking the growth of the blood vessels providing the nutrients and
oxygen to the tumour.
Avastin is a medicine used for the treatment of advanced cancer in the large bowel, i.e., in the colon or
rectum. Avastin will be administered in combination with chemotherapy treatment containing a
fluoropyrimidine medicine.
Avastin is also used for the treatment of metastatic breast cancer. When used for patients with breast
cancer, it will be administered with a chemotherapy drug called paclitaxel.
Avastin is also used for the treatment of advanced non-small cell lung cancer. Avastin will be
administered together with a chemotherapy regimen containing platinum.
Avastin is also used for treatment of advanced kidney cancer. When used for patients with kidney
cancer, it will be administered with another type of medicine called interferon.
2.
BEFORE YOU USE AVASTIN
Do not use Avastin
if:
-
you are allergic (hypersensitive) to Chinese hamster ovary (CHO) cell products or to other
recombinant human or humanised antibodies.
-
you are pregnant.
40
-
Keep this leaflet. You may need to read it again.
4.
How to use Avastin
-
you are allergic (hypersensitive) to bevacizumab or to any of the other ingredients of Avastin.
Take special care with Avastin:
-
if you have conditions causing inflammation inside the abdomen (e.g. diverticulitis, stomach
ulcers, colitis associated with chemotherapy), as it is possible that Avastin may increase the risk
of developing holes in the gut wall.
-
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 as
Avastin can increase the risk of bleeding or increase the risk of problems with wound healing
after surgery.
-
if you have high blood pressure which is not well controlled with blood pressure medicines as
Avastin can increase the incidence of high blood pressure. Your doctor should make sure that
your blood pressure is under control before starting Avastin treatment.
-
if you have high blood pressure, as you may have a higher risk of having protein in your urine.
-
if you are over 65 years old and also have had blood clots in your arteries (a type of blood
vessel) in the past, as these factors can increase the risk of further blood clots in the arteries.
-
if you or your family tend to suffer from bleeding problems or you are taking medicines to thin
the blood for the treatment of blood clots.
-
if you have been coughing or spitting blood or had any bleeding in your lungs.
-
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 as Avastin can increase the risk of developing a weak heart.
-
if you have headache, vision changes, confusion or seizure with or without high blood pressure,
you should contact your doctor. This could be a rare neurological side effect named reversible
posterior leukoencephalopathy syndrome.
Please consult your doctor, even if these statements were applicable to you at any time in the past.
Before you are given Avastin or while you are being treated with Avastin:
−
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 Avastin, in particular when you are also receiving or have received an iv
bisphosphonate.
You may be advised to have a dental check-up before you start treatment with Avastin.
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Please tell your doctor if you have recently received, or are receiving, radiotherapy.
Pregnancy and breast feeding
You must not use this medicine if you are pregnant. Avastin 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 Avastin and for at least 6 months after the last dose of Avastin.
41
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 Avastin and for at least 6 months after the
last dose of Avastin, as this medicine may interfere with the growth and development of your baby.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Avastin has not been shown to impair your ability to drive or to use any tools or machines.
3.
HOW TO USE AVASTIN
Dosage and frequency of administration
The dose of Avastin 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 Avastin that is right for you. You will be treated with Avastin 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 Avastin fails to stop your tumour
growing. Your doctor will discuss this with you.
Method and route of administration
Avastin is a concentrate for solution for infusion. Depending on the dose prescribed for you, some or
all of the contents of the Avastin vial will be diluted with sodium chloride solution before use. A
doctor or nurse will give you this diluted Avastin solution by intravenous infusion. 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 Avastin 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 Avastin 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,
-
an abnormal tube-like connection or passage between the windpipe and the gullet, or between
internal organs and skin or other tissues that are not normally connected, and are judged by your
doctor to be severe,
-
a blood clot in your arteries,
-
a blood clot in the veins of your lungs,
If too much Avastin is given
-
you may develop a severe migraine. If this happens you should talk to your doctor or pharmacist
immediately.
If a dose of Avastin is missed
-
your doctor will decide when you should be given your next dose of Avastin. You should
discuss this with your doctor.
42
-
a hole in your gut wall,
-
any severe bleeding.
If you stop treatment with Avastin
Stopping your treatment with Avastin may stop the effect on tumour growth. Do not stop treatment
with Avastin unless you have discussed this with your doctor.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Avastin can cause side effects, although not everybody gets them.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
The side effects listed below were seen when Avastin was given together with chemotherapy. This
does not necessarily mean that these side effects were strictly caused by Avastin.
These side effects may occur with certain frequencies, which are defined as follows:
-
very common: affects more than 1 user in 10
-
uncommon: affects 1 to 10 users in 1,000
-
rare: affects 1 to 10 users in 10,000
-
very rare: affects less than 1 user in 10,000
-
not known: frequency cannot be estimated from the available data.
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, increased muscle tension, feeling sick (nausea) or being sick (vomiting).
You should seek help immediately if you suffer from any of the below mentioned side effects.
The
common
side effects are:
-
perforation of the gut,
-
bleeding, including bleeding in the lungs in patients with non-small cell lung cancer,
-
blocking of the veins in the lungs by a blood clot.
The severe side effects, which may be
very common,
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,
-
lack of energy or tiredness,
-
diarrhoea, nausea and vomiting.
The severe side effects, which may be
common,
include:
-
allergic reactions,
-
decreased number of red cells in the blood,
-
lack of energy,
-
abdominal pain,
-
muscle pain,
-
dry mouth in combination with thirst and/or reduced or darkened urine,
-
inflammation of the lining of the mouth,
-
pain, including headache,
43
-
common: affects 1 to 10 users in 100
-
blocking of the arteries by a blood clot,
-
problems with wound healing after surgery,
-
bleeding associated with the tumour,
-
blood clots in the veins of the legs or difficulties in getting the blood to clot,
-
infection, and in particular infection in the blood or bladder,
-
reduced blood supply to the brain or stroke,
-
blood clots in the arteries, which can lead to a stroke and a heart attack,
-
falling asleep or fainting,
-
problems with the heart with breathing difficulties,
-
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.
The severe side effects, which may be
rare
, include:
-
seizures (fits),
-
confusion,
-
changes in vision,
-
an abnormal tube-like connection between the windpipe and the passage to the stomach (gullet).
You should seek help as soon as possible if you suffer from any of the below mentioned side effects
The
very common
side effects, which were not severe, include:
-
pain, including joint pain,
-
lack of energy,
-
constipation, bleeding from the lower part of the large bowel, inflammation of the mouth,
-
loss of appetite,
-
protein in the urine,
-
nose bleed,
-
fever,
-
headache,
-
problems with the eyes (including increased production of tears).
The
common
side effects, which were not severe, include:
-
shortness of breath,
-
runny nose,
-
dry skin, flaking and inflammation of the skin, change in skin colour,
-
change in the sense of taste,
-
voice changes, hoarseness.
Other
less common
side effects of any severity which have been reported are heart failure, bleeding
from the lining of the mouth or vagina, abnormal tube-like connection between internal organs and
skin or other tissues that are not normally connected and ulcers in the digestive system (the signs may
include abdominal pain, feeling bloated, black tarry stools or blood in your stools (faeces) or blood in
your vomit).
There have been
very rare
reports of patients developing a hole in the septum of the nose – the
structure, which separates the nostrils.
Some side effects are more common in elderly patients. These side effects include blood clot in the
arteries which can lead to a stroke or a heart attack. In addition, elderly patients have a higher risk of a
reduction in the number of white cells in the blood, and cells that help the blood clot. Other side effects
reported with a higher frequency in elderly patients were diarrhoea, sickness, headache and fatigue.
44
-
localised pus collection,
-
headache,
-
high blood pressure,
-
nose bleed,
Avastin 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); 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.
Outside of the approved use of Avastin for cancer treatment, the following side effects may occur
when Avastin is injected directly into the eye (unapproved use):
- 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.
5.
HOW TO STORE AVASTIN
Keep out of the reach and sight of children.
Do not use after the expiry date which is stated on the outer carton and on the vial label after the
abbreviation EXP. The expiry date refers to the last day of that month.
Store in a refrigerator (2°C–8°C).
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
Infusion solutions should be used immediately after dilution. Do not use Avastin if you notice any
particulate matter or discoloration prior to administration.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Avastin contains
Each pack of Avastin concentrate for solution for infusion contains one vial. This vial contains either
4 ml or 16 ml of a slightly opaque, colourless to pale brown sterile liquid concentrate. The concentrate
must be diluted before use to make a solution for intravenous infusion.
-
Each ml contains 25 mg of bevacizumab, corresponding to 1.4 to 16.5 mg/ml when diluted as
recommended.
-
The other ingredients are trehalose dihydrate, sodium phosphate, polysorbate 20 and water for
injections.
What Avastin looks like and contents of the pack
Avastin is a clear, colourless to pale brown liquid in a glass vial with a rubber stopper. Each vial
contains 100 mg bevacizumab in 4 ml of solution or 400 mg bevacizumab in 16 ml of solution.
45
Marketing Authorisation Holder
Roche Registration Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW,
United Kingdom.
Manufacturer
Roche Pharma AG, Emil-Barell-Str. 1, 79639 Grenzach-Wyhlen, Germany.
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
N.V. Roche S.A.
Tél/Tel: +32 (0) 2 525 82 11
Luxembourg/Luxemburg
(Voir/siehe Belgique/Belgien)
България
Рош България ЕООД
Тел: +359 2 818 44 44
Magyarország
Roche (Magyarország) Kft.
Tel: +36 - 23 446 800
Česká republika
Roche s. r. o.
Tel: +420 - 2 20382111
Malta
(See United Kingdom)
Danmark
Roche a/s
Tlf: +45 - 36 39 99 99
Nederland
Roche Nederland B.V.
Tel: +31 (0) 348 438050
Deutschland
Roche Pharma AG
Tel: +49 (0) 7624 140
Norge
Roche Norge AS
Tlf: +47 - 22 78 90 00
Eesti
Roche Eesti OÜ
Tel: + 372 - 6 177 380
Österreich
Roche Austria GmbH
Tel: +43 (0) 1 27739
Ελλάδα
Roche (Hellas) A.E.
Τηλ: +30 210 61 66 100
Polska
Roche Polska Sp.z o.o.
Tel: +48 - 22 345 18 88
España
Roche Farma S.A.
Tel: +34 - 91 324 81 00
Portugal
Roche Farmacêutica Química, Lda
Tel: +351 - 21 425 70 00
France
Roche
Tél: +33 (0) 1 46 40 50 00
România
Roche România S.R.L.
Tel: +40 21 206 47 01
Ireland
Roche Products (Ireland) Ltd.
Tel: +353 (0) 1 469 0700
Slovenija
Roche farmacevtska družba d.o.o.
Tel: +386 - 1 360 26 00
Ísland
Roche a/s
c/o Icepharma hf
Sími:+354 540 8000
Slovenská republika
Roche Slovensko, s.r.o.
Tel: +421 - 2 52638201
46
Italia
Roche S.p.A.
Tel: +39 - 039 2471
Suomi/Finland
Roche Oy
Puh/Tel: +358 (0) 10 554 500
Kύπρος
Γ.Α.Σταμάτης & Σια Λτδ.
Τηλ: +357 - 22 76 62 76
Sverige
Roche AB
Tel: +46 (0) 8 726 1200
Latvija
Roche Latvija SIA
Tel: +371 - 6 7039831
United Kingdom
Roche Products Ltd.
Tel: +44 (0) 1707 366000
Lietuva
UAB “Roche Lietuva”
Tel: +370 5 2546799
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site:
http://www.ema.europa.eu
47
Source: European Medicines Agency
- Please bookmark this page (add it to your favorites).
- If you wish to link to this page, you can do so by referring to the URL address below this line.
https://theodora.com/drugs/eu/avastin.html
Copyright © 1995-2021 ITA all rights reserved.