Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The overall safety profile of Avastin is based on data from over 5,700 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.

Tabulated list of adverse reactions

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

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

Table 1 provides all adverse reactions by frequency that were determined to have a causal relationship with Avastin through:
• comparative incidences noted between clinical trial treatment arms (with at least a 10% difference compared to the control arm for NCI-CTCAE Grade 1-5 reactions or at least a 2% difference compared to the control arm for NCI-CTCAE Grade 3-5 reactions,
• post-authorisation safety studies,
• spontaneous reporting,
• epidemiological studies\non-interventional or observational studies,
• or through an evaluation of individual case reports.

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

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

Adverse reactions are added to the appropriate frequency category in the tables below according to the highest incidence seen in any indication.
Within each frequency category, adverse reactions are presented in the order of decreasing seriousness.

Some of the adverse reactions are reactions commonly seen with chemotherapy; however, Avastin may exacerbate these reactions when combined with chemotherapeutic agents.

Examples include palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine, peripheral sensory neuropathy with paclitaxel or oxaliplatin, nail disorders or alopecia with paclitaxel, and paronychia with erlotinib.

Table 1:         Adverse Reactions by Frequency
System          Very Common           Common            Uncommon       Rare          Very Rare     Frequency Not organ class                                                                                             Known 

Infections                               Sepsis,                      Necrotising and                                 Abscessb,d,                     fasciitis a infestations                            Cellulitis,
Infection,
Urinary tract infection
Blood and             Febrile           Anaemia,
lymphatic           neutropenia,       Lymphopenia system            Leucopenia,
disorders         Neutropeniab,
Thrombo-cytopenia


Immune                               Hypersensitivity,                Anaphylactic system                                  infusion                        shock disorders                              reactionsa,b,d
Metabolism            Anorexia          Dehydration and nutrition     Hypomagnesaemia disorders        Hyponatraemia

Nervous         Peripheral sensory   Cerebrovascular                    Posterior     Hypertensive system           neuropathyb,          accident,                       reversible     encephalo- disorders          Dysarthria,          Syncope,                       encephalo-        pathya Headache,         Somnolence                          pathy
Dysguesia                                         syndromea,b,d
Eye disorders       Eye disorder,
Lacrimation increased
Cardiac                             Congestive heart disorders                               failureb,d,
Supraventricular tachycardia
Vascular         Hypertensionb,d,       Thrombo-                                                          Renal disorders       Thrombo-embolism        embolism                                                       thrombotic (venous)b,d        (arterial)b,d,                                                    micro- Haemorrhageb,d,                                                  angiopathya,b Deep vein                                                    Aneurysms and thrombosis                                                         artery dissections
Respiratory,         Dyspnoea,           Pulmonary                                                       Pulmonary thoracic and          Rhinitis          haemorrhage/                                                   hypertensiona, mediastinal         Epistaxis         Haemoptysisb,d,                                                  Nasal septum disorders           Cough              Pulmonary                                                       perforationa embolism,
Hypoxia,
Dysphoniaa
Gastrointestin         Rectal          Gastrointestinal                                                Gastrointestinal al disorders       haemorrhage,        perforationb,d,                                                     ulcera Stomatitis,           Intestinal
Constipation,        perforation,
Diarrhoea,              Ileus,
Nausea,              Intestinal
Vomiting,           obstruction,
Abdominal pain       Recto-vaginal fistulaed,e,
Gastrointestinal
Disorder,
Proctalgia

System         Very Common           Common             Uncommon      Rare          Very Rare       Frequency Not organ class                                                                                              Known 

Hepatobiliary                                                                                               Gallbladder disorders                                                                                                perforationa,b Skin and            Wound healing       Palmar-plantar subcutaneous          complicationsb,d       erythro- tissue              Exfoliative        dysaesthesia disorders             dermatitis,         syndrome
Dry skin,
Skin discoloration


Musculoskele            Arthralgia          Fistulab,d,                                                    Osteonecrosis tal and              Myalgia            Muscular                                                        of the jawa,b connective                                 weakness,                                                     Non - tissue                                 Back pain                                                     mandibular disorders                                                                                               osteonecrosisa,f Renal and            Proteinuriab,d urinary disorders
Reproductive              Ovarian          Pelvic Pain system and              failureb,c,d breast disorders
Congenital,                                                                                                  Foetal familial, and                                                                                             abnormalitiesa,b genetic disorder
General              Asthenia,           Lethargy disorders and            Fatigue,
administratio            Pyrexia,
n site                Pain,
conditions              Mucosal inflammation
Investigations       Weight decreased

When events were noted as both all grade and grade 3-5 adverse drug reactions in clinical trials, the highest frequency observed in patients has been reported. Data are unadjusted for the differential time on treatment.
a For further information please refer to Table 3 'Adverse reactions reported in post-marketing setting.' b Terms represent a group of events that describe a medical concept rather than a single condition or MedDRA (Medical Dictionary for Regulatory Activities) preferred term. This group of medical terms may involve the same underlying pathophysiology (e.g. arterial thromboembolic reactions include cerebrovascular accident, myocardial infarction, transient ischaemic attack and other arterial thromboembolic reactions).
c Based on a substudy from NSABP C-08 with 295 patients d For additional information refer below within section "Further information on selected serious adverse reactions." e Recto-vaginal fistulae are the most common fistulae in the GI-vaginal fistula category.
f Observed in pediatric population only


Table 2: Severe Adverse Reactions by Frequency

System organ        Very Common           Common              Uncommon     Rare        Very        Frequency Not class                                                                              Rare            Known Infections and                            Sepsis,                                                   Necrotising infestations                           Cellulitis,                                                   fasciitisc Abscessa,b,
Infection,
Urinary tract infection
Blood and            Febrile           Anaemia,
lymphatic          neutropenia,       Lymphopenia system           Leucopenia,
disorders         Neutropeniaa,
Thrombo- cytopenia

System organ       Very Common            Common            Uncommon      Rare        Very    Frequency Not class                                                                             Rare       Known Immune system                         Hypersensitivity,                Anaphylactic disorders                          infusion reactions                   shock a,b,c

Metabolism and                          Dehydration nutrition                           Hyponatraemia disorders
Nervous system       Peripheral       Cerebrovascular                                             Posterior disorders          sensory            accident,                                               reversible neuropathya          Syncope,                                               encephalo- Somnolence,                                                 pathy
Headache                                              syndrome a,b,c, Hypertensive encephalo- pathyc
Cardiac                           Congestive heart disorders                             failurea,b,
Supraventricular tachycardia

Vascular        Hypertensiona,b   Thromboembolism                                                Renal disorders                             arteriala,b,                                            thrombotic Haemorrhagea,b,                                        microangiopathyb,c Thromboembolism                                          ,Aneurysms and (venous)a,b                                          artery dissections Deep vein thrombosis
Respiratory,                           Pulmonary                                               Pulmonary thoracic and                          haemorrhage/                                            hypertensionc, mediastinal                         Haemoptysisa,b,                                          Nasal septum disorders                            Pulmonary                                               perforationc embolism,
Epistaxis,
Dyspnoea,
Hypoxia
Gastrointestinal     Diarrhoea,           Intestinal                                          Gastrointestinal disorders           Nausea,           perforation,                                           perforationa,b, Vomiting,              Ileus,                                            Gastrointestinal Abdominal            Intestinal                                               ulcerc, pain            obstruction,                                               Rectal Recto-vaginal                                          haemorrhage fistulaec,d,
Gastrointestinal disorder,
Stomatitis,
Proctalgia
Hepatobiliary                                                                                  Gallbladder disorders                                                                                  perforation b,c Skin and                            Wound healing subcutaneous                          complicationsa,b,
tissue disorders                        Palmar-plantar erythrodysaesthesia syndrome
Musculoskeletal                            Fistulaa,b,                                        Osteonecrosis of and connective                             Myalgia,                                              the jawb,c tissue disorders                          Arthralgia,
Muscular weakness,
Back Pain
Renal and                             Proteinuriaa,b urinary

System organ       Very Common             Common            Uncommon           Rare         Very      Frequency Not class                                                                                    Rare         Known disorders
Reproductive                              Pelvic pain                                                 Ovarian failurea,b system and breast disorders

Congenital,                                                                                             Foetal familial, and                                                                                        abnormalitiesa,c genetic disorder
General          Asthenia,               Pain,
disorders and       Fatigue,             Lethargy,
administration                             Mucosal site conditions                         Inflammation

Table 2 provides the frequency of severe adverse reactions. Severe reactions are defined as adverse events with at least a 2% difference compared to the control arm in clinical studies for NCI-CTCAE Grade 3-5 reactions. Table 2 also includes adverse reactions which are considered by the MAH to be clinically significant or severe.
These clinically significant adverse reactions were reported in clinical trials but the grade 3-5 reactions did not meet the threshold of at least a 2% difference compared to the control arm. Table 2 also includes clinically significant adverse reactions that were observed only in the postmarketing setting, therefore, the frequency and NCI-CTCAE grade is not known. These clinically significant reactions have therefore been included in Table 2 within the column entitled “Frequency Not Known.” a Terms represent a group of events that describe a medical concept rather than a single condition or MedDRA 
(Medical Dictionary for Regulatory Activities) preferred term. This group of medical terms may involve the same underlying pathophysiology (e.g. arterial thromboembolic reactions include cerebrovascular accident, myocardial infarction, transient ischaemic attack and other arterial thromboembolic reactions).
b For additional information refer below within section "Further information on selected serious adverse reactions" c For further information please refer to Table 3 'Adverse reactions reported in post-marketing setting'.
d
Recto-vaginal fistulae are the most common fistulae in the GI-vaginal fistula category.

Description of selected serious adverse reactions

Gastrointestinal (GI) perforations and Fistulae (see section 4.4)
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 non-squamous non-small cell lung cancer, up to 1.3% in patients with metastatic breast cancer, up to 2.0% in patients with metastatic renal cell cancer or in patients with ovarian cancer, and up to 2.7% (including gastrointestinal fistula and abscess) in patients with metastatic colorectal cancer. Cases of GI perforations have also been observed in patients with relapsed glioblastoma. From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), GI perforations (all grade) were reported in 3.2% of patients, all of whom had a history of prior pelvic radiation.

The occurrence of those events varied in type and severity, ranging from free air seen on the plain abdominal X-ray, which resolved without treatment, to intestinal perforation with abdominal abscess and fatal outcome. In some cases underlying intra-abdominal inflammation was present, either from gastric ulcer disease, tumour necrosis, diverticulitis, or chemotherapy- associated colitis.

Fatal outcome was reported in approximately a third of serious cases of gastrointestinal perforations, which represents between 0.2%-1% of all Avastin treated patients.

In Avastin clinical trials, gastrointestinal fistulae (all grade) have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer and ovarian cancer, but were also reported less commonly in patients with other types of cancer.

GI-vaginal Fistulae in study GOG-0240

In a trial of patients with persistent, recurrent or metastatic cervical cancer, the incidence of GI- vaginal fistulae was 8.3% in Avastin-treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. The frequency of GI-vaginal fistulae in the group treated with Avastin + chemotherapy was higher in patients with recurrence within the field of prior radiation (16.7%) compared with patients with no prior radiation and/ or no recurrence inside the field of prior radiation (3.6%). The corresponding frequencies in the control group receiving chemotherapy alone were 1.1% vs. 0.8%, respectively. Patients who develop GI-vaginal fistulae may also have bowel obstructions and require surgical intervention as well as diverting ostomies.

Non-GI Fistulae (see section 4.4)
Avastin use has been associated with serious cases of fistulae including reactions resulting in death.

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (GOG- 240), 1.8% of Avastin-treated patients and 1.4% of control patients were reported to have had non-gastrointestinal vaginal, vesical, or female genital tract fistulae.

Uncommon ( 0.1% to < 1%) reports of fistulae that involve areas of the body other than the gastrointestinal tract (e.g. bronchopleural and biliary fistulae) were observed across various indications. Fistulae have also been reported in post-marketing experience.

Reactions were reported at various time points during treatment ranging from one week to greater than 1 year from initiation of Avastin, with most reactions 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 a study of patients with relapsed glioblastoma (study AVF3708g), the incidence of post- operative wound healing complications (including craniotomy site wound dehiscence and cerebrospinal fluid leak) was 3.6% in patients treated with single-agent Avastin and 1.3% in patients treated with Avastin plus irinotecan.

Serious wound healing complications, including anastomotic complications, have been reported, some of which had a fatal outcome.

In locally recurrent and metastatic breast cancer trials, Grade 3-5 wound healing complications were observed in up to 1.1% of patients receiving Avastin compared with up to 0.9% of patients in the control arms (NCI-CTCAE v.3).

In clinical trials of ovarian cancer, Grade 3-5 wound healing complications were observed in up to 1.8% of patients in the bevacizumab arm versus 0.1% in the control arm (NCI-CTCAE v.3).

Hypertension (see section 4.4)
In clinical trials, with the exception of study JO25567, the overall incidence of hypertension (all grades) ranged up to 42.1% in the Avastin containing arms compared with up to 14% in the control arms. The overall incidence of NCI-CTC Grade 3 and 4 hypertension in patients receiving 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.

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

Hypertension was generally adequately controlled with oral anti-hypertensives such as angiotensin-converting enzyme inhibitors, diuretics and calcium-channel blockers. It rarely resulted in discontinuation of 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.

Posterior Reversible Encephalopathy Syndrome (see section 4.4)
There have been rare reports of Avastin-treated patients developing signs and symptoms that are consistent with PRES, a rare neurological disorder. Presentation may include seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. The clinical presentation of PRES is often nonspecific, and therefore the diagnosis of PRES requires confirmation by brain imaging, preferably MRI.

In patients developing PRES, early recognition of symptoms with prompt treatment of specific symptoms including control of hypertension (if associated with severe uncontrolled hypertension) is recommended in addition to discontinuation of bevacizumab therapy. Symptoms usually resolve or improve within days after treatment discontinuation, although some patients have experienced some neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing PRES is not known.

Across clinical trials, 8 cases of PRES have been reported. Two of the eight cases did not have radiological confirmation via MRI.

Proteinuria (see section 4.4)
In clinical trials, proteinuria has been reported within the range of 0.7% to 54.7% of patients receiving Avastin.

Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic syndrome, with the great majority as Grade 1 proteinuria (NCI-CTCAE v.3). Grade 3 proteinuria was reported in up to 10.9% of treated patients. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of treated patients. Testing for proteinuria is recommended prior to start of 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-CTCAE v.3 Grade 3-5 bleeding reactions ranged from 0.4% to 6.9% in Avastin treated patients, compared with up to 4.5% of patients in the chemotherapy control group.

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

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

Tumour-associated haemorrhage (see section 4.4)
Major or massive pulmonary haemorrhage/haemoptysis has been observed primarily in trials in patients with non-small cell lung cancer (NSCLC). Possible risk factors include squamous cell histology, treatment with antirheumatic/anti-inflammatory substances, treatment with anticoagulants, prior radiotherapy, 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 reactions were seen with a frequency of up to 9.3% when treated with Avastin plus chemotherapy compared with up to 5% in the patients treated with chemotherapy alone. Grade 3-5 reactions have been observed in up to 2.3% of patients treated with Avastin plus chemotherapy as compared with < 1% with chemotherapy alone (NCI-CTCAE v.3). Major or massive pulmonary haemorrhage/haemoptysis can occur suddenly and up to two thirds of the serious pulmonary haemorrhages resulted in a fatal outcome.

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

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

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

Intracranial haemorrhage can occur in patients with relapsed glioblastoma. In study AVF3708g, CNS haemorrhage was reported in 2.4% (2/84) of patients in the Avastin alone arm (Grade 1); and in 3.8% (3/79) of patients treated with Avastin and irinotecan (Grades 1, 2 and 4).

Across all clinical trials, mucocutaneous haemorrhage has been seen in up to 50% of Avastin- treated patients. These were most commonly NCI-CTCAE v.3 Grade 1 epistaxis that lasted less than 5 minutes, resolved without medical intervention and did not require any changes in the 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 reactions of minor mucocutaneous haemorrhage in other locations, such as gingival bleeding or vaginal bleeding.

Thromboembolism (see section 4.4)

Arterial thromboembolism:

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

In clinical trials, the overall incidence of arterial thromboembolic reactions ranged up to 3.8% in the Avastin containing arms compared with up to 2.1% 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 ischaemic attacks) were reported in up to 2.7% of patients treated with Avastin in combination with chemotherapy compared to up to 0.5% of patients treated with chemotherapy alone. Myocardial infarction was reported in up to 1.4% of patients treated with Avastin in combination with chemotherapy compared to up 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 reactions were observed in 11% (11/100) of patients compared to 5.8% (6/104) in the chemotherapy control group. In an uncontrolled clinical trial, AVF3708g, in patients with relapsed glioblastoma, arterial thromboembolic events were observed in up to 6.3% (5/79) of patients who received Avastin in combination with irinotecan compared to up to 4.8% (4/84) of patients who received Avastin alone.

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

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

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

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

Patients who have experienced a venous thromboembolic reaction may be at higher risk for a recurrence if they receive 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 (NCI-CTCAE v.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 (including anaphylactic shock) /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).

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

Ovarian failure/fertility (see sections 4.4 and 4.6)
In NSABP C-08, a phase III trial of 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 ≥ 30 mIU/mL and a negative serum β-HCG pregnancy test, has been evaluated in 295 premenopausal women. New cases of ovarian failure were reported in 2.6% patients in the mFOLFOX-6 group compared to 39% in the mFOLFOX-6 + bevacizumab group. After discontinuation of bevacizumab treatment, ovarian function recovered in 86.2% of these evaluable women. Long term effects of the treatment with bevacizumab on fertility are unknown.

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

Across clinical trials, the following Grade 3 and 4 (NCI-CTCAE v.3) 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).

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


Other special populations
Elderly patients
In randomised clinical trials, age > 65 years was associated with an increased risk of developing arterial thromboembolic reactions, including cerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs). Other reactions with a higher frequency seen in patients over 65 were Grade 3-4 leucopenia and thrombocytopenia (NCI- CTCAE v.3); and all Grade neutropenia, diarrhoea, nausea, headache and fatigue as compared to those aged ≤ 65 years when treated with Avastin (see sections 4.4 and 4.8 under Thromboembolism).
In one clinical trial, the incidence of hypertension of grade ≥ 3 was two fold higher in patients aged > 65 years than in the younger age group (<65 years). In a study of platinum-resistant recurrent ovarian cancer patients, alopecia, mucosal inflammation, peripheral sensory neuropathy, proteinuria and hypertension were also reported and occurred at a rate at least 5% higher in the CT + BV arm for bevacizumab-treated patients ≥ 65 years of age compared with bevacizumab-treated patients aged < 65 years.
No increase in the incidence of other reactions, including gastrointestinal perforation, wound healing complications, congestive heart failure, and haemorrhage was observed in elderly patients (> 65 years) receiving Avastin as compared to those aged ≤ 65 years treated with Avastin.

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

In study BO25041 of Avastin added to postoperative radiation therapy (RT) with concomitant and adjuvant temozolomide in paediatric patients with newly diagnosed supratentorial, infratentorial, cerebellar, or peduncular high-grade glioma, the safety profile was comparable with that observed in other tumour types in adults treated with Avastin.
In study BO20924 of Avastin with current standard of care in rhabdomyosarcoma and non- rhabdomyosarcoma soft tissue sarcoma, the safety profile of Avastin treated children was comparable with that observed in adults treated with Avastin.

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

Post-marketing experience

Table 3      Adverse reactions reported in post-marketing setting
System organ class                                  Reactions (frequency*) (SOC)

Infections and                Necrotising fasciitis, usually secondary to wound healing Infestations                  complications, gastrointestinal perforation or fistula formation (rare) (see also section 4.4)
Immune system                 Hypersensitivity reactions and infusion reactions (common); disorders                     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).
Anaphylactic shock (rare) (see also section 4.4).



System organ class                               Reactions (frequency*) (SOC)

Nervous system                Hypertensive encephalopathy (very rare) (see also section 4.4 disorders                     and Hypertension in section 4.8)
Posterior Reversible Encephalopathy Syndrome (PRES),
(rare) (see also section 4.4)
Vascular disorders            Renal thrombotic microangiopathy, which may be clinically manifested as proteinuria (not known) with or without concomitant sunitinib use. For further information on proteinuria see section 4.4 and Proteinuria in section 4.8.
Respiratory, thoracic         Nasal septum perforation (not known) and mediastinal               Pulmonary hypertension (not known) disorders                     Dysphonia (common)
Gastrointestinal              Gastrointestinal ulcer (not known) disorders
Hepatobiliary disorders       Gall bladder perforation (not known)
Musculoskeletal and           Cases of Osteonecrosis of the Jaw (ONJ) have been reported connective tissue             in patients treated with Avastin, most of which occurred in disorders                     patients who had identified risk factors for ONJ, in particular exposure to intravenous bisphosphonates and/or a history of dental disease requiring invasive dental procedures (see also section 4.4)
Cases of non-mandibular osteonecrosis have been observed in Avastin treated paediatric patients (see section 4.8,
Paediatric population).
Congenital, familial,         Cases of foetal abnormalities in women treated with and genetic disorder          bevacizumab alone or in combination with known embryotoxic chemotherapeutics have been observed (see section 4.6).
* if specified, the frequency has been derived from clinical trial data 
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form :https://sideeffects.health.gov.il