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).

•     Hemorrhage, including pulmonary hemorrhage/hemoptysis, 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, diarrhea 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-authorization 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 erythrodysesthesia 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                 Uncom   Rare            Very rare    Frequency not class                                                      mon                                  known 
Infections and                      Sepsis,                        Necrotizing infestations                                                       fasciitisa Abscessb,d,

Cellulitis,

Infection,
Urinary tract infection

Blood and        Febrile            Anemia,
lymphatic        neutropenia,
Lymphopenia system
Leukopenia,
disorders
Neutropeniab,

Thrombocytopeni a
Immune                              Hypersensitivity               Anaphylactic system                              ,                              shock disorders
Infusion reactionsa,b,d

Metabolism       Anorexia,          Dehydration and nutrition
Hypomagnesemia disorders
,
Hyponatremia

Nervous          Peripheral         Cerebrovascular                Posterior       Hypertensi system           sensory            accident,                      reversible      ve disorders        neuropathyb,                                      encephalopa     encephalo- Syncope,
thy             pathya
Dysarthria,
Somnolence                     syndromea,b,d
Headache,

Dysgeusia

Eye disorders    Eye disorder,
Lacrimation increased



System organ     Very common        Common                Uncom   Rare   Very rare   Frequency not class                                                     mon                        known 
Cardiac                             Congestive disorders                           heart failureb,d,

Supraventricular tachycardia
Vascular         Hypertensionb,d,   Thromboemboli                                    Renal disorders                           sm (arterial)b,d,                                thrombotic Thromboembolis microangiopath m (venous)b,d      Hemorrhageb,d,
ya,b,
Deep vein
Aneurysms and thrombosis artery dissections

Respiratory,     Dyspnea,           Pulmonary                                        Pulmonary thoracic and                        hemorrhage/                                      hypertensiona, Rhinitis,
mediastinal                         Hemoptysisb,d,
Nasal septum disorders        Epistaxis,
Pulmonary                                        perforationa
Cough embolism,

Hypoxia,

Dysphoniaa
Gastrointestin   Rectal             Gastrointestinal                                 Gastrointestinal al disorders     hemorrhage,        perforationb,d,                                  ulcera 
Stomatitis,        Intestinal perforation,
Constipation,
Ileus,
Diarrhea,
Intestinal
Nausea,
obstruction,
Vomiting,
Recto-vaginal
Abdominal pain     fistulaed,e,

Gastrointestinal disorder,
Proctalgia

Hepatobiliary                                                                        Gallbladder disorders                                                                            perforationa,b 


System organ      Very common            Common                 Uncom     Rare             Very rare       Frequency not class                                                           mon                                        known 
Skin and          Wound healing          Palmar-plantar subcutaneous      complicationsb,d,      erythrodysesthe tissue                                   sia syndrome
Exfoliative disorders dermatitis,

Dry skin,
Skin discoloration

Musculoskelet     Arthralgia,            Fistulab,d,                                                       Osteonecrosis al and                                                                                                     of the jawa,b, Myalgia                Muscular connective weakness,                                                         Non-mandibular tissue osteonecrosisa,f disorders                                Back pain

Renal and         Proteinuriab,d urinary disorders

Reproductive      Ovarian failureb,c,d   Pelvic pain system and breast disorders
Congenital,                                                                                                Fetal familial, and                                                                                              abnormalitiesa,b genetic disorders

General           Asthenia,              Lethargy disorders and
Fatigue,
administratio n site            Pyrexia,
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 ischemic 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          Very common          Common                    Uncomm       Rare         Very rare    Frequency not organ class                                                    on                                     known 
Infections                           Sepsis,                                                          Necrotizing and                                                                                                   fasciitisc Cellulitis,
infestations
Abscessa,b,

Infection,

Urinary tract infection
Blood and       Febrile              Anemia,
lymphatic       neutropenia,
Lymphopenia system
Leukopenia,
disorders
Neutropeniaa,

Thrombocytope nia

Immune                               Hypersensitivity,                      Anaphyl system                                                                      actic Infusion                               shock disorders reactionsa,b,c

Metabolism                           Dehydration,
and nutrition
Hyponatremia disorders

Nervous         Peripheral           Cerebrovascular                                                  Posterior system          sensory              accident,                                                        reversible disorders       neuropathya                                                                           encephalopathy Syncope,
syndromea,b,c,
Somnolence,
Hypertensive
Headache                                                         encephalopathyc 

System         Very common       Common                  Uncomm   Rare   Very rare   Frequency not organ class                                              on                          known 
Cardiac                          Congestive heart disorders                        failurea,b,

Supraventricular tachycardia
Vascular       Hypertensiona,b   Thromboembolism                                     Renal thrombotic disorders                        arteriala,b,                                        microangiopathyb, c
,
Hemorrhagea,b,
Aneurysms and
Thromboembolism artery dissections
(venous)a,b,

Deep vein thrombosis

Respiratory,                     Pulmonary                                           Pulmonary thoracic and                     hemorrhage/                                         hypertensionc, mediastinal                      Hemoptysisa,b,
Nasal septum disorders
Pulmonary                                           perforationc embolism,

Epistaxis,

Dyspnea,
Hypoxia

Gastro-        Diarrhea,         Intestinal                                          Gastrointestinal intestinal                       perforation,                                        perforationa,b, Nausea,
disorders
Ileus,                                              Gastrointestinal
Vomiting,
ulcerc,
Intestinal
Abdominal pain obstruction,                                        Rectal hemorrhage
Recto-vaginal fistulaec,d,

Gastrointestinal disorder,

Stomatitis,
Proctalgia

Hepatobiliar                                                                         Gallbladder y disorders                                                                          perforationb,c 


System          Very common         Common                  Uncomm       Rare        Very rare      Frequency not organ class                                                 on                                      known 
Skin and                            Wound healing subcutaneou                         complicationsa,b,
s tissue
Palmar-plantar disorders erythrodysesthesia syndrome

Musculoskel                         Fistulaa,b,                                                     Osteonecrosis of etal and                                                                                            the jawb,c Myalgia,
connective tissue                              Arthralgia,
disorders
Muscular weakness,

Back pain

Renal and                           Proteinuriaa,b urinary disorders
Reproductive                        Pelvic pain                                                     Ovarian failurea,b system and breast disorders

Congenital,                                                                                         Fetal familial, and                                                                                       abnormalitiesa,c genetic disorders

General         Asthenia,           Pain,
disorders
Fatigue             Lethargy,
and administratio                       Mucosal n site                              inflammation conditions


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 post-marketing 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 ischemic 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, tumor 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 post-operative 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 post-operative 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 hospitalization.


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 MVASI therapy. In most clinical trials urine protein levels of ≥ 2 g/24 hrs led to the holding of bevacizumab until recovery to < 2 g/24 hrs.


Hemorrhage (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 hemorrhagic reactions that have been observed in clinical trials were predominantly tumor- associated hemorrhage (see below) and minor mucocutaneous hemorrhage (e.g. epistaxis).


Tumor-associated hemorrhage (see section 4.4)


Major or massive pulmonary hemorrhage/hemoptysis 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 tumor location and cavitation of tumors 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 tumor 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 hemorrhage/hemoptysis can occur suddenly and up to two thirds of the serious pulmonary hemorrhages resulted in a fatal outcome.


Gastrointestinal hemorrhages, including rectal bleeding and melena have been reported in colorectal cancer patients, and have been assessed as tumor-associated hemorrhages.


Tumor-associated hemorrhage was also seen rarely in other tumor 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 randomized clinical trials. In an exploratory retrospective analysis of data from 13 completed randomized trials in patients with various tumor 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 hemorrhage was reported in 83 subjects treated with bevacizumab (1.2%) at the time of interim safety analysis (NCI-CTCAE v.3).


Intracranial hemorrhage can occur in patients with relapsed glioblastoma. In study AVF3708g, CNS hemorrhage 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 hemorrhage 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 hemorrhage (e.g. epistaxis) may be dose-dependent.


There have also been less common reactions of minor mucocutaneous hemorrhage 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 ischemic 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 ischemic 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 amenorrhea 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 MVASI 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: hyperglycemia, decreased hemoglobin, hypokalemia, hyponatremia, decreased white blood cell count, increased international normalized 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 randomized clinical trials, age > 65 years was associated with an increased risk of developing arterial thromboembolic reactions, including cerebrovascular accidents (CVAs), transient ischemic attacks (TIAs) and myocardial infarctions (MIs). Other reactions with a higher frequency seen in patients over 65 were grade 3-4 leukopenia and thrombocytopenia (NCI-CTCAE v.3); and all grade neutropenia, diarrhea, 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 hemorrhage was observed in elderly patients (> 65 years) receiving bevacizumab as compared to those aged ≤ 65 years treated with bevacizumab.


Pediatric 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 post-operative radiation therapy (RT) with concomitant and adjuvant temozolomide in pediatric patients with newly diagnosed supratentorial, infratentorial, cerebellar, or peduncular high-grade glioma, the safety profile was comparable with that observed in other tumor 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.

MVASI 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 infestations   Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation (rare) (see also section 4.4)

Immune system disorders       Hypersensitivity reactions and infusion reactions (common); with the following possible co-manifestations: dyspnea/difficulty breathing,
flushing/redness/rash, hypotension or hypertension, oxygen desaturation, chest pain, rigors and nausea/vomiting (see also section 4.4 and Hypersensitivity reactions (including anaphylactic shock)/infusion reactions above). Anaphylactic shock (rare) (see also section 4.4).

Nervous system disorders      Hypertensive encephalopathy (very rare) (see also section 4.4 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



System organ class
Reactions (frequency*)
(SOC)

Respiratory, thoracic and       Nasal septum perforation (not known) mediastinal disorders
Pulmonary hypertension (not known)
Dysphonia (common)

Gastrointestinal disorders      Gastrointestinal ulcer (not known)

Hepatobiliary disorders         Gall bladder perforation (not known)
Musculoskeletal and             Cases of osteonecrosis of the jaw (ONJ) have been reported in connective tissue disorders     patients treated with bevacizumab, most of which occurred in 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 pediatric patients (see section 4.8, Pediatric population)

Congenital, familial, and       Cases of fetal abnormalities in women treated with bevacizumab genetic disorders               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 authorization 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/