1. Name Of The Medicinal Product
Avastin
2. Qualitative And Quantitative Composition
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. Pharmaceutical Form
Concentrate for solution for infusion.
Clear to slightly opalescent, colourless to pale brown liquid.
4. Clinical Particulars
4.1 Therapeutic Indications
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 combination with capecitabine is indicated for first-line treatment of patients with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline-containing regimens in the adjuvant setting within the last 12 months should be excluded from treatment with Avastin in combination with capecitabine. 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.
4.2 Posology And Method Of Administration
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.
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.
4.3 Contraindications
• 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).
4.4 Special Warnings And Precautions For Use
Gastrointestinal perforations (see section 4.8)
Patients may be at an increased risk for the development of gastrointestinal perforation and gall bladder 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 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) thromboembolic events, including pulmonary embolism. Patients with thromboembolic events
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 findings ranged from asymptomatic declines in left ventricular ejection fraction to symptomatic CHF, requiring treatment or hospitalisation. Caution should be exercised when treating patients with clinically significant cardiovascular disease such as pre-existing coronary artery disease, or congestive heart failure with Avastin.
Most of the patients who experienced CHF had metastatic breast cancer and had received previous treatment with anthracyclines, prior radiotherapy to the left chest wall or other risk factors for CHF were present.
In patients in AVF3694g who received treatment with anthracyclines and who had not received anthracyclines before, no increased incidence of all grade CHF was observed in the anthracycline + bevacizumab group compared to the treatment with anthracyclines only. CHF grade 3 or higher events were somewhat more frequent among patients receiving bevacizumab in combination with chemotherapy than in patients receiving chemotherapy alone. This is consistent with results in patients in other studies of metastatic breast cancer who did not receive concurrent anthracycline treatment (see section 4.8).
Neutropenia and infections (see section 4.8)
Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia (including some fatalities) have been observed in patients treated with some myelotoxic chemotherapy regimens plus 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 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.
Ovarian failure/fertility
Avastin may impair female fertility (see sections 4.6 and 4.8). Therefore fertility preservation strategies should be discussed with women of child-bearing potential prior to starting treatment with Avastin.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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 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.
4.6 Pregnancy And Lactation
Women of childbearing potential
Women of childbearing potential have to use effective contraception during (and up to 6 months after) treatment.
Pregnancy
There are no 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
Repeat dose toxicity studies in animals have shown that bevacizumab may have an adverse effect on female fertility (see section 5.3). In a phase III trial in the adjuvant treatment of patients with colon cancer, a substudy with premenopausal women has shown a higher incidence of new cases of ovarian failure in the bevacizumab group compared to the control group. After discontinuation of bevacizumab treatment, ovarian function recovered in the majority of patients. Long term effects of the treatment with bevacizumab on fertility are unknown.
4.7 Effects On Ability To Drive And Use Machines
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.
4.8 Undesirable Effects
The overall safety profile of Avastin is based on data from over 3,500 patients with various malignancies, predominantly treated with Avastin in combination with chemotherapy in clinical trials.
The most serious adverse reactions were:
• Gastrointestinal perforations (see section 4.4).
• Haemorrhage, including pulmonary haemorrhage/haemoptysis, which is more common in non-small cell lung cancer patients (see section 4.4).
• Arterial thromboembolism (see section 4.4).
The most frequently observed adverse reactions across clinical trials in patients receiving Avastin were hypertension, fatigue or asthenia, diarrhoea and abdominal pain.
Analyses of the clinical safety data suggest that the occurrence of hypertension and proteinuria with Avastin therapy are likely to be dose-dependent.
Table 1 lists adverse 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 (
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
(
|
All grade reactions
(
|
|
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
|
Gastrointestinal disorders
|
Diarrhoea
Nausea
Vomiting
|
Intestinal Perforation
Ileus
Intestinal obstruction
Abdominal pain
Gastrointestinal disorder
Stomatitis
|
Constipation
Stomatitis
Rectal haemorrhage
|
Endocrine disorders
|
|
|
Ovarian failure**
|
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.
** Based on a substudy from NSABP C-08 with 295 patients
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 (
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
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).
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 subsequent studies in patients with treated brain metastases (which included around 800 patients), one case of Grade 2 CNS haemorrhage was reported in 83 subjects treated with bevacizumab (1.2%) at the time of interim safety analysis.
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.
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 four phase III trials (AVF2119g, E2100, BO17708 and AVF3694g) in patients with metastatic breast cancer CHF Grade 3 or higher was reported in up to 3.5% of patients treated with Avastin in combination with chemotherapy compared with up to 0.9% in the control arms. For patients in study AVF3694g who received anthracyclines concomitantly with bevacizumab, the incidences of grade 3 or higher CHF for the respective bevacizumab and control arms were similar to those in the other studies in metastatic breast cancer: 2.9% in the anthracycline + bevacizumab arm and 0% in the anthracycline + placebo arm. In addition, in study AVF3694g the incidences of all grade CHF were similar between the anthracycline + Avastin (6.2%) and the anthracycline + placebo arms (6.0%).
Most patients who developed CHF during mBC trials showed improved symptoms and/or left ventricular function following appropriate medical therapy.
In most clinical trials of 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.
An increased incidence of CHF has been observed in a clinical trial of patients with diffuse large B-cell lymphoma when receiving bevacizumab with a cumulative doxorubicin dose greater than 300 mg/m2. This phase III clinical trial compared rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) plus bevacizumab to R-CHOP without bevacizumab. While the incidence of CHF was, in both arms, above that previously observed for doxorubicin therapy, the rate was higher in the R-CHOP plus bevacizumab arm. These results suggest that close clinical observation with appropriate cardiac assessments should be considered for patients exposed to cumulative doxorubicin doses greater than 300 mg/m2 when combined with bevacizumab.
Hypersensitivity reactions/infusion reactions (see section 4.4 and Post-marketing experience below)
In some clinical trials anaphylactic and anaphylactoid-type reactions were reported more frequently in patients receiving 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 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
Paediatric population
The safety of Avastin in children and adolescents has not been established.
Ovarian failure/fertility (see sections 4.4 and 4.6)
In NSABP C-08, a phase III trial of Avastin in adjuvant treatment of patients with colon cancer, the incidence of new cases of ovarian failure, defined as amenorrhoea lasting 3 or more months, FSH level
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
