Adverse reactions : תופעות לוואי

4.8 Undesirable effects

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

The most serious adverse reactions were:
• Gastrointestinal perforations (see section 4.4).
• Haemorrhage, including pulmonary haemorrhage/haemoptysis, which is more common in non-small cell lung cancer patients (see section 4.4).
• Arterial thromboembolism (see section 4.4).

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

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

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

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

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

Table 2 provides the frequency of severe adverse reactions. Severe reactions are defined as adverse 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, bevacizumab may exacerbate these reactions when combined with chemotherapeutic agents.
Examples include palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine, peripheral sensory neuropathy with paclitaxel or oxaliplatin, nail disorders or alopecia with paclitaxel, and paronychia with erlotinib.
Table 1:         Adverse Reactions by Frequency
System organ         Very Common                 Common               Uncommon       Rare         Very Rare        Frequency class                                                                                                          Not Known 
Infections and                                    Sepsis,                         Necrotising infestations                                   Abscessb,d,                        fasciitisa Cellulitis,
Infection,
Urinary tract infection

Blood and         Febrile neutropenia,   Anaemia, Lymphopenia lymphatic system        Leucopenia,
disorders           Neutropeniab,
Thrombo-cytopenia
Immune system                                 Hypersensitivity,                   Anaphylactic disorders                                 infusion reactionsa,b,d                  shock Metabolism and           Anorexia,               Dehydration nutrition          Hypomagnesaemia,
disorders           Hyponatraemia
Nervous system      Peripheral sensory        Cerebrovascular                       Posterior     Hypertensive disorders           neuropathyb,               accident,                          reversible     encephalo- Dysarthria,              Syncope,                          encephalo-        pathya Headache,              Somnolence                             pathy
Dysguesia                                                 syndromea,b,d Eye disorders         Eye disorder,
Lacrimation increased
Cardiac disorders                              Congestive heart failureb,d,
Supraventricular tachycardia
Vascular          Hypertensionb,d,       Thrombo-embolism                                                     Renal thrombotic disorders        Thrombo-embolism            (arterial)b,d,                                                         micro- (venous)b,d          Haemorrhageb,d,                                                       angiopathya,b Deep vein thrombosis                                                   Aneurysms and artery dissections
Respiratory,          Dyspnoea,               Pulmonary                                                           Pulmonary thoracic and           Rhinitis,             haemorrhage/                                                        hypertensiona, mediastinal        Epistaxis Cough         Haemoptysisb,d,                                                      Nasal septum disorders                               Pulmonary embolism,                                                     perforationa Hypoxia,
Dysphoniaa
Gastrointestinal    Rectal haemorrhage,        Gastrointestinal                                                   Gastrointestinal disorders             Stomatitis,             perforationb,d,,                                                       ulcera Constipation,        Intestinal perforation,
Diarrhoea,
Ileus,
Nausea,
Intestinal obstruction,
Vomiting,
Recto-vaginal
Abdominal pain               fistulaed,e,
Gastrointestinal
Disorder,

Proctalgia

System organ       Very Common             Common                Uncommon    Rare       Very Rare     Frequency Not class                                                                                                Known Hepatobiliary                                                                                           Gallbladder disorders                                                                                              perforationa,b Skin and         Wound healing        Palmar-plantar subcutaneous       complicationsb,d,        erythro- tissue disorders      Exfoliative          dysaesthesia dermatitis,           syndrome
Dry skin,
Skin discoloration
Musculoskeletal     Arthralgia Myalgia       Fistulab,d,                                                Osteonecrosis and                                Muscular weakness,                                              of the jawa,b, connective tissue                            Back pain                                                       Non - disorders mandibular osteonecrosisa,f
Renal and         Proteinuriab,d urinary disorders

Reproductive           Ovarian            Pelvic Pain system and breast       failureb,c,d disorders

Congenital,                                                                                              Foetal familial, and                                                                                         abnormalitiesa,b genetic disorder

General disorders       Asthenia,            Lethargy and               Fatigue,
administration          Pyrexia,
site conditions           Pain,
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 system    neutropenia,         Lymphopenia disorders        Leucopenia,
Neutropeniaa,
Thrombo- cytopenia
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,                                               encephalopathy Somnolence,                                               syndromea,b,c, Headache                                               Hypertensive encephalopathyc


Cardiac                            Congestive heart disorders                               failurea,b,
Supraventricular tachycardia
Vascular        Hypertensiona,b    Thromboembolism                                            Renal thrombotic disorders                              arteriala,b,                                          microangiopathyb,c, Haemorrhagea,b,                                            Aneurysms and Thromboembolism                                            artery dissections (venous)a,b,
Deep vein thrombosis

Respiratory,                           Pulmonary                                                 Pulmonary thoracic and                          haemorrhage/                                              hypertensionc, mediastinal                         Haemoptysisa,b,                                            Nasal septum disorders                        Pulmonary embolism,                                           perforationc Epistaxis,
Dyspnoea,
Hypoxia

Gastrointestinal     Diarrhoea,      Intestinal perforation,                                      Gastrointestinal disorders           Nausea,                  Ileus,                                              perforationa,b, Vomiting,       Intestinal obstruction,                                      Gastrointestinal Abdominal pain        Recto-vaginal                                                 ulcerc, fistulaec,d,
Rectal haemorrhage
Gastrointestinal disorder,
Stomatitis,
Proctalgia


System organ       Very Common          Common            Uncommon        Rare         Very     Frequency Not class                                                                              Rare        Known Hepatobiliary                                                                                  Gallbladder disorders                                                                                     perforationb,c Skin and                            Wound healing subcutaneous                          complicationsa,b,
tissue disorders                        Palmar-plantar erythrodysaesthesia syndrome
Musculoskeletal                           Fistulaa,b,                                          Osteonecrosis of the and connective                           Myalgia,                                                    jawb,c tissue disorders                        Arthralgia,
Muscular weakness,
Back Pain
Renal and                          Proteinuriaa,b urinary 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)
Bevacizumab has been associated with serious cases of gastrointestinal perforation.
Gastrointestinal perforations have been reported in clinical trials with an incidence of less than 1% in patients with non-squamous non-small cell lung cancer, up to 1.3% in patients with metastatic breast cancer, up to 2.0% in patients with metastatic renal cell cancer or in patients with ovarian cancer, and up to 2.7% (including gastrointestinal fistula and abscess) in patients with metastatic colorectal cancer. 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 bevacizumab treated patients.

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

GI-vaginal Fistulae in study GOG-0240
In a trial of patients with persistent, recurrent or metastatic cervical cancer, the incidence of GI-vaginal fistulae was 8.3% in bevacizumab-treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. The frequency of GI-vaginal fistulae in the group treated with bevacizumab + chemotherapy was higher in patients with recurrence within the field of prior radiation (16.7%) compared with patients with no prior radiation and/ or no recurrence inside the field of prior radiation (3.6%). The corresponding frequencies in the control group receiving chemotherapy alone were 1.1% vs. 0.8%, respectively. Patients who develop GI-vaginal fistulae may also have bowel obstructions and require surgical intervention as well as diverting ostomies.

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

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (GOG-0240), 1.8% of bevacizumab-treated patients and 1.4% of control patients were reported to have had non- gastrointestinal vaginal, vesical, or female genital tract fistulae.

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

Reactions were reported at various time points during treatment ranging from one week to greater than 1 year from initiation of bevacizumab, with most reactions occurring within the first 6 months of therapy.

Wound healing (see section 4.4)
As bevacizumab may adversely impact wound healing, patients who had major surgery within the last 28 days were excluded from participation in phase III clinical trials.

In clinical trials of metastatic carcinoma of the colon or rectum, there was no increased risk of post- operative bleeding or wound healing complications observed in patients who underwent major surgery 28- 60 days prior to starting bevacizumab. An increased incidence of postoperative bleeding or wound healing complication occurring within 60 days of major surgery was observed if the patient was being treated with bevacizumab at the time of surgery. The incidence varied between 10% (4/40) and 20% (3/15).

In a study of patients with relapsed glioblastoma (study AVF3708g), the incidence of postoperative wound healing complications (including craniotomy site wound dehiscence and cerebrospinal fluid leak) was 3.6% in patients treated with single-agent bevacizumab and 1.3% in patients treated with bevacizumab 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 bevacizumab compared with up to 0.9% of patients in the control arms (NCI-CTCAE v.3).

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

Hypertension (see section 4.4)
In clinical trials, with the exception of study JO25567, the overall incidence of hypertension (all grades) ranged up to 42.1% in the bevacizumab containing arms compared with up to 14% in the control arms.
The overall incidence of NCI-CTC Grade 3 and 4 hypertension in patients receiving Bevacizumab ranged from 0.4% to 17.9%. Grade 4 hypertension (hypertensive crisis) occurred in up to 1.0% of patients treated with bevacizumab and chemotherapy compared to up to 0.2% of patients treated with the same chemotherapy alone.

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

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

Very rare cases of hypertensive encephalopathy have been reported, some of which were fatal.

The risk of bevacizumab-associated hypertension did not correlate with the patients’ baseline characteristics, underlying disease or concomitant therapy.

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

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

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

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

Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic syndrome, with the great majority as Grade 1 proteinuria (NCI-CTCAE v.3). Grade 3 proteinuria was reported in up to 10.9% of treated patients. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of treated patients. Testing for proteinuria is recommended prior to start of bevacizumab therapy. In most clinical trials urine protein levels of ≥ 2g/24 hrs led to the holding of bevacizumab 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 bevacizumab treated patients, compared with up to 4.5% of patients in the chemotherapy control group.

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

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

Tumour-associated haemorrhage (see section 4.4)
Major or massive pulmonary haemorrhage/haemoptysis has been observed primarily in trials in patients with non-small cell lung cancer (NSCLC). Possible risk factors include squamous cell histology, treatment with antirheumatic/anti-inflammatory substances, treatment with anticoagulants, prior radiotherapy, bevacizumab therapy, previous medical history of atherosclerosis, central tumour location and cavitation of tumours prior to or during therapy. The only variables that showed statistically significant correlations with bleeding were bevacizumab therapy and squamous cell histology. Patients with NSCLC of known squamous cell histology or mixed cell type with predominant squamous cell histology were excluded from subsequent phase III trials, while patients with unknown tumour histology were included.

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

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

Tumour-associated haemorrhage was also seen rarely in other tumour types and locations, including cases of central nervous system (CNS) bleeding in patients with CNS metastases 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 bevacizumab alone arm (Grade 1); and in 3.8% (3/79) of patients treated with bevacizumab and irinotecan (Grades 1, 2 and 4).

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

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

Thromboembolism (see section 4.4)

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

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

In one clinical trial evaluating bevacizumab in combination with 5-fluorouracil/folinic acid, AVF2192g, patients with metastatic colorectal cancer who were not candidates for treatment with irinotecan were included. In this trial arterial thromboembolic reactions were observed in 11% (11/100) of patients compared to 5.8% (6/104) in the chemotherapy control group. 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 bevacizumab in combination with irinotecan compared to up to 4.8% (4/84) of patients who received bevacizumab alone.

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

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

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

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

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


Congestive heart failure (CHF)
In clinical trials with bevacizumab, congestive heart failure (CHF) was observed in all cancer indications studied to date, but occurred predominantly in patients with metastatic breast cancer. In four phase III trials (AVF2119g, E2100, BO17708 and AVF3694g) in patients with metastatic breast cancer CHF Grade 3 (NCI-CTCAE v.3) or higher was reported in up to 3.5% of patients treated with bevacizumab in combination with chemotherapy compared with up to 0.9% in the control arms. For patients in study AVF3694g who received anthracyclines concomitantly with bevacizumab, the incidences of Grade 3 or higher CHF for the respective bevacizumab and control arms were similar to those in the other studies in metastatic breast cancer: 2.9% in the anthracycline + bevacizumab arm and 0% in the anthracycline + placebo arm. In addition, in study AVF3694g the incidences of all Grade CHF were similar between the anthracycline + bevacizumab (6.2%) and the anthracycline + placebo arms (6.0%).

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

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

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

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

Hypersensitivity reactions (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 bevacizumab in combination with chemotherapy than with chemotherapy alone. The incidence of these reactions in some clinical trials of bevacizumab is common (up to 5% in bevacizumab- treated patients).

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

Ovarian failure/fertility (see sections 4.4 and 4.6)
In NSABP C-08, a phase III trial of bevacizumab in adjuvant treatment of patients with colon cancer, the incidence of new cases of ovarian failure, defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β-HCG pregnancy test, has been evaluated in 295 premenopausal women. New cases of ovarian failure were reported in 2.6% patients in the mFOLFOX-6 group compared to 39% in the mFOLFOX-6 + bevacizumab group. After discontinuation of bevacizumab treatment, ovarian function recovered in 86.2% of these evaluable women. Long term effects of the treatment with bevacizumab on fertility are unknown.


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

Across clinical trials, the following Grade 3 and 4 (NCI-CTCAE v.3) laboratory abnormalities occurred in patients treated with bevacizumab with at least a 2% difference compared to the corresponding control groups: hyperglycaemia, decreased haemoglobin, hypokalaemia, hyponatraemia, decreased white blood cell count, increased international normalised ratio (INR).

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

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

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

In study BO25041 of bevacizumab added to 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 bevacizumab.

In study BO20924 of bevacizumab with current standard of care in rhabdomyosarcoma and non- rhabdomyosarcoma soft tissue sarcoma, the safety profile of bevacizumab treated children was comparable with that observed in adults treated with bevacizumab.

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


Post-marketing experience

Table 3          Adverse reactions reported in post-marketing setting 
System organ class                                     Reactions (frequency*) (SOC)
Infections and                   Necrotising fasciitis, usually secondary to wound healing Infestations                     complications, gastrointestinal perforation or fistula formation (rare) (see also section 4.4)

Immune system                    Hypersensitivity reactions and infusion reactions (common); with disorders                        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).
Nervous system                   Hypertensive encephalopathy (very rare) (see also section 4.4 and disorders                        Hypertension in section 4.8)
Posterior Reversible Encephalopathy Syndrome (PRES), (rare)
(see also section 4.4)

Vascular disorders               Renal thrombotic microangiopathy, which may be clinically manifested as proteinuria (not known) with or without concomitant sunitinib use. For further information on proteinuria see section 4.4 and Proteinuria in section 4.8.
Respiratory, thoracic            Nasal septum perforation (not known) and mediastinal                  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 in connective tissue                patients treated with bevacizumab, 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 bevacizumab treated paediatric patients (see section 4.8, Paediatric population).
Congenital, familial,            Cases of foetal abnormalities in women treated with bevacizumab and genetic disorder             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