SIDE EFFECTS
The following serious adverse reactions are discussed in
greater detail in other sections of the label:
- Gastrointestinal Perforations and Fistulae [see BOXED
WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
- Non-Gastrointestinal Fistulae [see DOSAGE AND
ADMINISTRATION, WARNINGS AND PRECAUTIONS].
- Surgery and Wound Healing Complications [see BOXED
WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
- Hemorrhage [see BOXED WARNING, DOSAGE AND
ADMINISTRATION, WARNINGS AND PRECAUTIONS].
- Arterial Thromboembolic Events [see DOSAGE AND
ADMINISTRATION, WARNINGS AND PRECAUTIONS].
- Venous Thromboembolic Events [see DOSAGE AND
ADMINISTRATION, WARNINGS AND PRECAUTIONS].
- Hypertensive Crisis [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
- Posterior Reversible Encephalopathy Syndrome [see DOSAGE
AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
- Proteinuria [see DOSAGE AND ADMINISTRATION, WARNINGS
AND PRECAUTIONS].
- Infusion Reactions [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
- Ovarian Failure [see WARNINGS AND PRECAUTIONS, Use
In Specific Populations].
The most common adverse reactions observed in bevacizumab
patients at a rate >10% and at least twice the control arm rate, are
epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry
skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative
dermatitis. Some of the adverse reactions are commonly seen with chemotherapy;
however, bevacizumab products may exacerbate these reactions when combined with
chemotherapeutic agents. Examples include palmar-plantar erythrodysesthesia
syndrome with capecitabine, peripheral sensory neuropathy with paclitaxel or
oxaliplatin, and nail disorders or alopecia with paclitaxel.
Across all studies, bevacizumab was discontinued in 8.4
to 21% of patients because of adverse reactions.
Clinical Trial Experience
Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.
The data below reflect exposure to bevacizumab in more
than 5500 patients with CRC, non-squamous NSCLC, glioblastoma, mRCC, or
cervical cancer, including controlled (Studies 1, 2, 4, 5, 8 and 9), or uncontrolled,
single arm trials (Study 6), or other cancers treated at the recommended dose
and schedule for a median of 6 to 23 doses of bevacizumab [see Clinical
Studies]. The population was aged 18-89 years (median 60 years), 42% male
and 86% White. The population included 2184 first-and second-line mCRC patients
who received a median of 10 doses of bevacizumab, 480 first-line metastatic
NSCLC patients who received a median of 8 doses of bevacizumab, 163
glioblastoma patients who received a median of 9 doses of bevacizumab, 337 mRCC
patients who received a median of 16 doses of bevacizumab, 218 cervical cancer
patients who received a median of 6 doses of bevacizumab. These data also
reflect exposure to bevacizumab in 363 patients with metastatic breast cancer
(MBC) who received a median of 9.5 doses of bevacizumab, 1338 adjuvant CRC
patients, including 669 female patients, who received a median of 23 doses of
bevacizumab, 403 previously untreated patients with diffuse large B-cell
lymphoma (DLBCL) who received a median of 8 doses of bevacizumab and 572
patients with other cancers. Bevacizumab products are not approved for use in
MBC, adjuvant CRC, or DLBCL.
Surgery And Wound Healing Complications
The incidence of post-operative wound healing and/or bleeding
complications was increased in patients with mCRC receiving bevacizumab as
compared to patients receiving only chemotherapy.
Among patients requiring surgery on or within 60 days of
receiving study treatment, wound healing and/or bleeding complications occurred
in 15% (6/39) of patients receiving bolus-IFL plus bevacizumab as compared to
4% (1/25) of patients who received bolus-IFL alone.
In Study 6, events of post-operative wound healing
complications (craniotomy site wound dehiscence and cerebrospinal fluid leak)
occurred in patients with previously treated glioblastoma: 3/84 patients in the
bevacizumab alone arm and 1/79 patients in the bevacizumab plus irinotecan arm [see
BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND
PRECAUTIONS].
Hemorrhage
The incidence of epistaxis was higher (35% vs. 10%) in
patients with mCRC receiving bolus-IFL plus bevacizumab compared with patients
receiving bolus-IFL plus placebo. All but one of these events were Grade 1 in
severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic
events were more frequent in patients receiving bolus-IFL plus bevacizumab when
compared to those receiving bolus-IFL plus placebo and included
gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and
vaginal hemorrhage (4% vs. 2%) [see BOXED WARNING, DOSAGE AND
ADMINISTRATION, WARNINGS AND PRECAUTIONS].
Venous Thromboembolic Events
The overall incidence of Grade 3-4 venous thromboembolic
events in Study 1 was 15.1% in patients receiving bolus-IFL plus bevacizumab
and 13.6% in patients receiving bolus-IFL plus placebo. In Study 1, more
patients in the bevacizumab containing arm experienced deep venous thrombosis
(34 vs. 19 patients) and intra-abdominal venous thrombosis (10 vs. 5 patients).
The risk of developing a second thromboembolic event
while on bevacizumab and oral anticoagulants was evaluated in two randomized
studies. In Study 1, 53 patients (14%) on the bolus-IFL plus bevacizumab arm
and 30 patients (8%) on the bolus-IFL plus placebo arm received full dose
warfarin following a venous thromboembolic event (VTE). Among these patients,
an additional thromboembolic event occurred in 21% (11/53) of patients
receiving bolus-IFL plus bevacizumab and 3% (1/30) of patients receiving
bolus-IFL alone.
In a second, randomized, 4-arm study in 1401 patients
with mCRC, prospectively evaluating the incidence of VTE (all grades), the
overall incidence of first VTE was higher in the bevacizumab containing arms
(13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated
with anticoagulants following an initial VTE event (73 in the bevacizumab plus
chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence
of subsequent VTEs was also higher among the bevacizumab treated patients
(31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants,
the overall incidence of bleeding, the majority of which were Grade 1, was
higher in the bevacizumab treated arms than the chemotherapy arms (27.4% vs.
20.9%).
From a clinical trial in patients with persistent,
recurrent, or metastatic cervical cancer (Study 9), Grade 3 or 4 VTE have been
reported in 10.6% of patients treated with chemotherapy and bevacizumab
compared with 5.4% in patients receiving chemotherapy alone. There were no
patients with Grade 5 VTE. [see DOSAGE AND ADMINISTRATION, WARNINGS AND
PRECAUTIONS].
Neutropenia And Infection
The incidences of neutropenia and febrile neutropenia are
increased in patients receiving bevacizumab products plus chemotherapy compared
to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia
was increased in mCRC patients receiving IFL plus bevacizumab (21%) compared to
patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4
neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin
(PC) plus bevacizumab (26.2%) compared with patients receiving PC alone
(17.2%). Febrile neutropenia was also increased (5.4% for PC plus bevacizumab
vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4
neutropenia in the PC plus bevacizumab arm of which 3 were fatal compared to 9
(2%) neutropenic infections in patients receiving PC alone, of which none were
fatal. During the first 6 cycles of treatment, the incidence of serious
infections including pneumonia, febrile neutropenia, catheter infections and
wound infections was increased in the PC plus bevacizumab arm [58 patients
(13.6%)] compared to the PC alone arm [29 patients (6.6%)].
In Study 6, one fatal event of neutropenic infection
occurred in a patient with previously treated glioblastoma receiving
bevacizumab alone. The incidence of any grade of infection in patients
receiving bevacizumab alone was 55% and the incidence of Grade 3-5 infection
was 10%.
Proteinuria
Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies
1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only
adequately assessed in Study 8, in which the incidence was 20%. Median onset of
proteinuria was 5.6 months (range 15 days to 37 months) after initiation of
bevacizumab. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3
months). Proteinuria did not resolve in 40% of patients after median follow up
of 11.2 months and required permanent discontinuation of bevacizumab in 30% of
the patients who developed proteinuria (Study 8).
In an exploratory, pooled analysis of 8273 patients
treated in 7 randomized clinical trials, 5.4% (271 of 5037) of patients
receiving bevacizumab in combination with chemotherapy experienced Grade
≥2 proteinuria. The Grade ≥ 2 proteinuria resolved in 74.2% (201 of
271) of patients. Bevacizumab was re-initiated in 41.7% (113 of 271) of patients.
Of the 113 patients who re-initiated bevacizumab, 47.8% (54 of 113) experienced
a second episode of Grade ≥ 2 proteinuria [see WARNINGS AND PRECAUTIONS].
Renal Injury
A retrospective analysis across clinical trials where
5805 patients had received bevacizumab and chemotherapy and 3713 had received
chemotherapy alone has shown higher rates of elevated serum creatinine levels
(ranging between 1.5 – 1.9 times baseline levels) in patients who had received bevacizumab.
Creatinine levels did not return to baseline in approximately one-third of
patients who received bevacizumab.
Congestive Heart Failure (CHF)
The incidence of Grade ≥ 3 left ventricular
dysfunction was 1.0% in patients receiving bevacizumab compared to 0.6% in the control
arm across indications. In patients with metastatic breast cancer (MBC), an
indication for which bevacizumab products are not approved, the incidence of
Grade 3-4 CHF was increased in patients in the bevacizumab plus paclitaxel arm
(2.2%) as compared to the control arm (0.3%). Among patients receiving prior
anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving
bevacizumab as compared to 0.6% for patients receiving paclitaxel alone. The
safety of continuation or resumption of bevacizumab products in patients with
cardiac dysfunction has not been studied.
In previously untreated patients with diffuse large
B-cell lymphoma (DLBCL), an indication for which bevacizumab products are not
approved, the incidence of CHF and decline in left-ventricular ejection
fraction (LVEF) were significantly increased in the bevacizumab plus R-CHOP
(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n
= 403) compared to the placebo plus R-CHOP arm (n = 379); both regimens were given
for 6 to 8 cycles. At the completion of R-CHOP therapy, the incidence of CHF
was 10.9% in the bevacizumab plus R-CHOP arm compared to 5.0% in the R-CHOP
alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF
event, defined as a decline from baseline of 20% or more in LVEF or a decline
from baseline of 10% or more to a LVEF value of less than 50%, was also
increased in the bevacizumab plus R-CHOP arm (10.4%) compared to the R-CHOP
alone arm (5.0%). Time to onset of left-ventricular dysfunction or CHF was 1-6
months after initiation of therapy in at least 85% of the patients and was
resolved in 62% of the patients experiencing CHF in the bevacizumab arm
compared to 82% in the control arm.
Ovarian Failure
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) was prospectively evaluated in a subset of 179
women receiving mFOLFOX chemotherapy alone (n = 84) or with bevacizumab (n = 95).
New cases of ovarian failure were identified in 34% (32/95) of women receiving
bevacizumab in combination with chemotherapy compared with 2% (2/84) of women
receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After
discontinuation of bevacizumab treatment, recovery of ovarian function at all
time points during the post-treatment period was demonstrated in 22% (7/32) of
the bevacizumab-treated women. Recovery of ovarian function is defined as
resumption of menses, a positive serum β-HCG pregnancy test, or a FSH
level <30 mIU/mL during the post-treatment period. Long term effects of
bevacizumab product exposure on fertility are unknown [see WARNINGS AND
PRECAUTIONS, Use In Specific Populations].
Post-Treatment Vascular Events
In an open-label, randomized, controlled trial of
bevacizumab in adjuvant colorectal cancer, an indication for which bevacizumab
products are not approved, the overall incidence rate of post-treatment Grade
≥ 3 vascular events was 3.1% (41 of 1338) among patients receiving
mFOLFOX6 plus bevacizumab, compared to 1.6% (21 of 1349) among patients
receiving mFOLFOX6 alone. Post-treatment vascular events included arterial and
venous thromboembolic events, ischemic events, and vascular aneurysms.
Metastatic Colorectal Cancer (mCRC)
The data in Table 1 and Table 2 were obtained in Study 1,
a randomized, double-blind, controlled trial comparing chemotherapy plus
bevacizumab with chemotherapy plus placebo. Bevacizumab was administered at 5
mg/kg every 2 weeks.
All Grade 3-4 adverse events and selected Grade 1-2
adverse events (hypertension, proteinuria, thromboembolic events) were
collected in the entire study population. Severe and life-threatening (Grade
3-4) adverse events, which occurred at a higher incidence (≥ 2%) in
patients receiving bolus-IFL plus bevacizumab as compared to bolus-IFL plus
placebo, are presented in Table 1.
Table 1: NCI-CTC Grade 3-4 Adverse Events in Study 1
(Occurring at Higher Incidence [≥ 2%] Bevacizumab vs. Control)
|
Arm 1 IFL + Placebo
(n = 396) |
Arm 2 IFL + Bevacizumab
(n = 392) |
NCI-CTC Grade 3-4 Events |
74% |
87% |
Body as a Whole |
Asthenia |
7% |
10% |
Abdominal Pain |
5% |
8% |
Pain |
5% |
8% |
Cardiovascular |
Hypertension |
2% |
12% |
Deep Vein Thrombosis |
5% |
9% |
Intra-Abdominal Thrombosis |
1% |
3% |
Syncope |
1% |
3% |
Digestive |
Diarrhea |
25% |
34% |
Constipation |
2% |
4% |
Hemic/Lymphatic |
Leukopenia |
31% |
37% |
Neutropeniaa |
14% |
21% |
a Central laboratories were collected on Days
1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm
1 and 276 in Arm 2. |
Grade 1-4 adverse events which occurred at a higher
incidence (≥ 5%) in patients receiving bolus-IFL plus bevacizumab as
compared to the bolus-IFL plus placebo arm are presented in Table 2.
Grade 1-4 adverse events were collected for the first
approximately 100 patients in each of the three treatment arms who were
enrolled until enrollment in Arm 3 (5-FU/LV + bevacizumab) was discontinued.
Table 2: NCI-CTC Grade 1-4 Adverse Events in Study 1
(Occurring at Higher Incidence [≥ 5%] in IFL + Bevacizumab
vs. IFL)
|
Arm 1 IFL+ Placebo
(n = 98) |
Arm 2 IFL+ Bevacizumab
(n = 102) |
Arm 3 5-FU/LV + Bevacizumab
(n = 109) |
Body as a Whole |
Pain |
55% |
61% |
62% |
Abdominal Pain |
55% |
61% |
50% |
Headache |
19% |
26% |
26% |
Cardiovascular |
Hypertension |
14% |
23% |
34% |
Hypotension |
7% |
15% |
7% |
Deep Vein Thrombosis |
3% |
9% |
6% |
Digestive |
Vomiting |
47% |
52% |
47% |
Anorexia |
30% |
43% |
35% |
Constipation |
29% |
40% |
29% |
Stomatitis |
18% |
32% |
30% |
Dyspepsia |
15% |
24% |
17% |
GI Hemorrhage |
6% |
24% |
19% |
Weight Loss |
10% |
15% |
16% |
Dry Mouth |
2% |
7% |
4% |
Colitis |
1% |
6% |
1% |
Hemic/Lymphatic |
Thrombocytopenia |
0% |
5% |
5% |
Nervous |
Dizziness |
20% |
26% |
19% |
Respiratory |
Upper Respiratory Infection |
39% |
47% |
40% |
Epistaxis |
10% |
35% |
32% |
Dyspnea |
15% |
26% |
25% |
Voice Alteration |
2% |
9% |
6% |
Skin/Appendages |
Alopecia |
26% |
32% |
6% |
Skin Ulcer |
1% |
6% |
6% |
Special Senses |
Taste Disorder |
9% |
14% |
21% |
Urogenital |
Proteinuria |
24% |
36% |
36% |
Bevacizumab In Combination With FOLFOX4 In Second-line mCRC
Only Grade 3-5 non-hematologic and Grade 4-5 hematologic
adverse events related to treatment were collected in Study 2. The most
frequent adverse events (selected Grade 3-5 non-hematologic and Grade 4-5
hematologic adverse events) occurring at a higher incidence (≥ 2%) in 287
patients receiving FOLFOX4 plus bevacizumab compared to 285 patients receiving
FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory
neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%),
dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%),
hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and
headache (3% vs. 0%). These data are likely to under-estimate the true adverse
event rates due to the reporting mechanisms used in Study 2.
Bevacizumab In Combination With Fluoropyrimidine-Irinotecan
Or Fluoropyrimidine-Oxaliplatin Based Chemotherapy In Second-line mCRC Patients
Who Have Progressed On A Bevacizumab Containing Regimen In First-line mCRC:
No new safety signals were observed in Study 4 when
bevacizumab was administered in second line mCRC patients who progressed on a
bevacizumab containing regimen in first line mCRC. The safety data was
consistent with the known safety profile established in first and second line
mCRC.
Unresectable Non-Squamous Non-Small Cell Lung Cancer
(NSCLC)
Only Grade 3-5 non-hematologic and Grade 4-5 hematologic
adverse events were collected in Study 5. Grade 3-5 non-hematologic and Grade
4-5 hematologic adverse events (occurring at a higher incidence (≥ 2%) in
427 patients receiving PC plus bevacizumab compared with 441 patients receiving
PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension
(8% vs.0.7%), infection without neutropenia (7% vs. 3%), venous
thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary
infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%),
hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).
Glioblastoma
All adverse events were collected in 163 patients
enrolled in Study 6 who either received bevacizumab alone or bevacizumab plus
irinotecan. All patients received prior radiotherapy and temozolomide.
Bevacizumab was administered at 10 mg/kg every 2 weeks
alone or in combination with irinotecan. Bevacizumab was discontinued due to
adverse events in 4.8% of patients treated with bevacizumab alone.
In patients receiving bevacizumab alone (N = 84), the
most frequently reported adverse events of any grade were infection (55%),
fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea
(21%). Of these, the incidence of Grade ≥ 3 adverse events was infection
(10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two
deaths on study were possibly related to bevacizumab: one retroperitoneal
hemorrhage and one neutropenic infection.
In patients receiving bevacizumab alone or bevacizumab
plus irinotecan (N = 163), the incidence of bevacizumab-related adverse events
(Grade 1-4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage
(5%), hypertension (32%), venous thromboembolic event (8%), arterial
thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%),
gastrointestinal perforation (2%), and PRES (1%). The incidence of Grade 3-5
events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage
(1%), hypertension (5%), venous thromboembolic event (7%), arterial
thromboembolic event (3%), wound-healing complications (3%), proteinuria  (1%),
and gastrointestinal perforation (2%).
Metastatic Renal Cell Carcinoma (mRCC)
All grade adverse events were collected in Study 8. Grade
3-5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients
receiving interferon alfa (IFN-α) plus bevacizumab compared to 304
patients receiving IFN-α plus placebo arm were fatigue (13% vs. 8%),
asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%;
including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%;
including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric
ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial,
large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic
hematoma).
Grade 1-5 adverse events occurring at a higher incidence
(≥ 5%) in patients receiving IFN-α plus bevacizumab compared to the
IFN-α plus placebo arm are presented in Table 3.
Table 3: NCI-CTC Grades 1-5 Adverse Events in Study 8
(Occurring at Higher Incidence [≥ 5%] in IFN-α + Bevacizumab
vs. IFN-α + Placebo)
System Organ Class/Preferred terma |
IFN-α + Placebo
(n = 304) |
IFN-α + Bevacizumab
(n = 337) |
Gastrointestinal disorders |
Diarrhea |
16% |
21% |
General disorders and administration site conditions |
Fatigue |
27% |
33% |
Investigations |
Weight decreased |
15% |
20% |
Metabolism and nutrition disorders |
Anorexia |
31% |
36% |
Musculoskeletal and connective tissue disorders |
Myalgia |
14% |
19% |
Back pain |
6% |
12% |
Nervous system disorders |
Headache |
16% |
24% |
Renal and urinary disorders |
Proteinuria |
3% |
20% |
Respiratory, thoracic and mediastinal disorders |
Epistaxis |
4% |
27% |
Dysphonia |
0% |
5% |
Vascular disorders |
Hypertension |
9% |
28% |
aAdverse events were encoded using MedDRA,
Version 10.1. |
The following adverse events were reported at a 5-fold
greater incidence in the IFN-α plus bevacizumab arm compared to IFN-α
alone and not represented in Table 3: gingival bleeding (13 patients vs. 1
patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1);
gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7
vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0);
gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).
Persistent, Recurrent, Or Metastatic Carcinoma Of The Cervix
All grade adverse reactions were collected in Study 9.
Grade 1-4 adverse reactions occurring where the incidence
difference is ≥ 5% in patients receiving bevacizumab plus chemotherapy
compared to chemotherapy alone are presented in Table 4.
Table 4: NCI-CTC Grades 1-4 and 3-4 Adverse Reactions
in Study 9 (Incidence Difference of ≥ 5% Between Treatment Arms in Chemo +
bevacizumab vs. Chemo Alone)
|
Grade 1-4 reactions |
Grade 3-4 reactions |
Chemo Alone
(n = 222) |
Chemo + bevacizumab
(n = 218) |
Chemo Alone
(n = 222) |
Chemo + bevacizumab
(n = 218) |
Metabolism and Nutrition Disorders |
Decreased Appetite |
26% |
34% |
|
|
Hyperglycemia |
19% |
26% |
|
|
Hypomagnesemia |
15% |
24% |
|
|
Hyponatremia |
10% |
19% |
|
|
Hypoalbuminemia |
11% |
16% |
|
|
General Disorders and Administration Site Conditions |
Fatigue |
75% |
80% |
|
|
Edema Peripheral |
22% |
15% |
|
|
Investigations |
Weight Decreased |
7% |
21% |
|
|
Blood Creatinine Increased |
10% |
16% |
|
|
Infections and Infestations |
Urinary Tract Infection |
14% |
22% |
|
|
Infection |
5% |
10% |
|
|
Vascular Disorders |
Hypertension |
6% |
29% |
0.5% |
11.5% |
Thrombosis |
3% |
10% |
2.7% |
8.3% |
Nervous System Disorders |
Headache |
13% |
22% |
|
|
Dysarthria |
1% |
8% |
|
|
Gastrointestinal Disorders |
Stomatitis |
10% |
15% |
|
|
Proctalgia |
1% |
6% |
|
|
Anal Fistula |
— |
6% |
|
|
Blood and Lymphatic System Disorders |
Neutropenia |
6% |
12% |
|
|
Lymphopenia |
5% |
12% |
|
|
Psychiatric Disorders |
Anxiety |
10% |
17% |
|
|
Reproductive System and Breast Disorders |
Pelvic Pain |
8% |
14% |
|
|
Respiratory, Thoracic and Mediastinal Disorders |
Epistaxis |
1% |
17% |
|
|
Renal and Urinary Disorders |
Proteinuria |
3% |
10% |
|
|
Grade 3 or 4 adverse reactions occurring at a higher
incidence (≥ 2%) in 218 patients receiving chemotherapy plus bevacizumab
compared to 222 patients receiving chemotherapy alone were abdominal pain
(11.9% vs. 9.9%), diarrhea (5.5% vs. 2.7%), anal fistula (3.7% vs. 0%),
proctalgia (2.8% vs.0%), urinary tract infection (8.3% vs. 6.3%), cellulitis
(3.2% vs. 0.5%), fatigue (14.2% vs. 9.9%), hypokalemia (7.3% vs. 4.5%),
hyponatremia (3.7% vs. 1.4%), dehydration (4.1% vs. 0.5%), neutropenia (7.8%
vs. 4.1%), lymphopenia (6.0% vs. 3.2%), back pain (5.5% vs. 3.2%), and pelvic
pain (5.5% vs. 1.4%).
There were no Grade 5 adverse reactions occurring at a
higher incidence (≥ 2%) in patients receiving chemotherapy plus
bevacizumab compared to patients receiving chemotherapy alone.
Immunogenicity
As with all therapeutic proteins, there is a potential
for immunogenicity. The detection of antibody formation is highly dependent on
the sensitivity and the specificity of the assay. Additionally, the observed
incidence of antibody (including neutralizing antibody) positivity in an assay
may be influenced by several factors, including assay methodology, sample
handling, timing of sample collection, concomitant medications, and underlying
disease. For these reasons, comparison of the incidence of antibodies in the
studies described below with the incidence of antibodies in other studies or to
other bevacizumab products may be misleading.
In clinical trials of adjuvant colon carcinoma, 14 of
2233 evaluable patients (0.63%) tested positive for treatment-emergent
anti-bevacizumab antibodies detected by an electrochemiluminescent (ECL) based
assay. Among these 14 patients, three tested positive for neutralizing
antibodies against bevacizumab using an enzyme-linked immunosorbent assay
(ELISA). The clinical significance of these anti-product antibody responses to
bevacizumab products is unknown.
Postmarketing Experience
The following adverse reactions have been identified
during post-approval use of bevacizumab products. Because these reactions are
reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Body as a Whole: Polyserositis
Cardiovascular: Pulmonary hypertension, PRES,
Mesenteric venous occlusion
Eye disorders (from unapproved intravitreal use for treatment
of various ocular disorders):
Permanent loss of vision; Endophthalmitis (infectious and
sterile); Intraocular inflammation; Retinal detachment; Increased intraocular
pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal
hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort
Gastrointestinal: Gastrointestinal ulcer,
Intestinal necrosis, Anastomotic ulceration
Hemic and lymphatic: Pancytopenia
Hepatobiliary disorders: Gallbladder perforation
Infections and infestations: Necrotizing
fasciitis, usually secondary to wound healing complications, gastrointestinal
perforation or fistula formation
Musculoskeletal and Connective Tissue Disorders: Osteonecrosis
of the jaw; Non-mandibular osteonecrosis (cases have been observed in pediatric
patients who have received bevacizumab products)
Neurological: Posterior Reversible Encephalopathy
Syndrome (PRES)
Renal: Renal thrombotic microangiopathy
(manifested as severe proteinuria)
Respiratory: Nasal septum perforation, dysphonia
Systemic Events (from unapproved intravitreal use for
treatment of various ocular disorders): Arterial thromboembolic events,
Hypertension, Gastrointestinal perforation, Hemorrhage