JOBEVNE can cause serious side effects, including:
Gastrointestinal (GI) perforations and fistulae: Serious, and
sometimes fatal, gastrointestinal perforation occurred at a higher
incidence in patients receiving bevacizumab products compared to
patients receiving chemotherapy. The incidence ranged from 0.3% to 3%
across clinical studies, with the highest incidence in patients with a
history of prior pelvic radiation. Serious fistulae ranged from < 1%
to 1.8% across clinical studies, with the highest incidence in
patients with cervical cancer. Avoid JOBEVNE in patients with ovarian
cancer who have evidence of recto-sigmoid involvement by pelvic
examination or bowel involvement on CT scan or clinical symptoms of
bowel obstruction. Discontinue in patients who develop
gastrointestinal perforation, tracheoesophageal fistula, or any Grade
4 fistula. Discontinue in patients with fistula formation involving
any internal organ.
Surgery and Wound Healing Complications: The incidence of
surgery and wound healing complications, including serious and fatal
complications, was increased in patients receiving bevacizumab
products. In patients who experience wound healing complications
during treatment, withhold JOBEVNE until adequate wound healing. Do
not use JOBEVNE for at least 28 days following major surgery, to allow
time for the wound to heal. Discontinue JOBEVNE in patients who
develop necrotizing fasciitis.
Hemorrhage: Severe or fatal hemorrhage including hemoptysis,
gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and
vaginal bleeding, occurred up to 5-fold more frequently in patients
receiving bevacizumab products vs chemotherapy alone. Discontinue
JOBEVNE in patients who develop a Grades 3-4 hemorrhage.
Arterial Thromboembolic Events: Serious, sometimes fatal,
arterial thromboembolic events (ATE) including cerebral infarction,
transient ischemic attacks, myocardial infarction, and angina,
occurred at a higher incidence in patients receiving bevacizumab vs
chemotherapy. Discontinue JOBEVNE in patients who develop severe ATE.
The safety of reinitiating bevacizumab products after an ATE is
resolved is not known.
Venous Thromboembolic Events: An increased risk of venous
thromboembolic events (VTE) was observed across clinical studies.
Discontinue JOBEVNE in patients with a Grade 4 VTE, including
pulmonary embolism.
Hypertension: Severe hypertension occurred at a higher
incidence in patients receiving bevacizumab products as compared to
chemotherapy alone. Monitor blood pressure every two to three weeks
during treatment with JOBEVNE. Treat with appropriate
anti-hypertensive therapy and monitor blood pressure regularly.
Discontinue in patients who develop hypertensive crisis or
hypertensive encephalopathy.
Posterior Reversible Encephalopathy Syndrome (PRES): PRES was
reported in < 0.5% of patients across clinical studies. Discontinue
JOBEVNE in patients who develop PRES.
Renal Injury and Proteinuria: The incidence and severity of
proteinuria was higher in patients receiving bevacizumab as compared
to patients receiving chemotherapy. Nephrotic syndrome occurred in <
1% of patients receiving bevacizumab products across clinical studies,
in some instances with fatal outcome. Discontinue JOBEVNE in patients
who develop nephrotic syndrome.
Infusion-related reactions: Infusion-related reactions reported
across clinical studies and post marketing experience include
hypertension, hypertensive crises associated with neurologic signs and
symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity,
anaphylactoid/anaphylactic reactions, chest pain, headaches, rigors,
and diaphoresis. In clinical studies, infusion-related reactions with
the first dose of bevacizumab products occurred in < 3% of patients
and severe reactions occurred in 0.4% of patients. Decrease the rate
of infusion for mild, clinically insignificant infusion-related
reactions. Interrupt the infusion in patients with clinically
significant infusion-related reactions and consider resuming at a
slower rate following resolution. Discontinue JOBEVNE in patients who
develop a severe infusion-related reaction and administer appropriate
medical therapy.
Embryo-Fetal Toxicity: Bevacizumab products may cause fetal
harm when administered to pregnant women. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive potential to
use effective contraception during treatment with JOBEVNE and for 6
months after the last dose.
Ovarian Failure: The incidence of ovarian failure was 34% vs 2%
in premenopausal women receiving bevacizumab with chemotherapy vs
chemotherapy alone for adjuvant treatment of a solid tumor. Inform
females of reproductive potential of the risk of ovarian failure prior
to initiating JOBEVNE.
Congestive Heart Failure (CHF): JOBEVNE is not indicated for
use with anthracycline-based chemotherapy. Discontinue JOBEVNE in
patients who develop CHF.
Most common adverse reactions incidence (incidence >10%):
epistaxis, headache, hypertension, rhinitis, proteinuria, taste
alteration, dry skin, hemorrhage, lacrimation disorder, back pain and
exfoliative dermatitis.
Across clinical studies, bevacizumab was discontinued in 8% to 22% of
patients because of adverse reactions.
Most Common Adverse Reactions by Indication
Metastatic Colorectal Cancer:
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in combination with intravenous fluorouracil-based chemotherapy
for first- or second-line treatment (Study AVF2107g):
Grades 3-4 adverse reactions occurring at higher incidence (≥2%) in
patients receiving bevacizumab with IFL (N=392) vs placebo with IFL
(N=396) were leukopenia (37% vs 31%), neutropenia (21% vs 14%),
diarrhea (34% vs 25%), abdominal pain (8% vs 5%), constipation (4%
vs 2%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%),
intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), asthenia
(10% vs 7%), and pain (8% vs 5%).
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Metastatic colorectal cancer, in combination with
fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based
chemotherapy for second-line treatment in patients who have
progressed on a first-line bevacizumab product-containing regimen
(Study E3200):
Selected Grades 3–5 (non-hematologic) and Grades 4–5 (hematologic)
occurring at a higher incidence (≥ 2%) in patients (N=521) receiving
bevacizumab with FOLFOX4 compared to 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%).
First-Line Non-Squamous Non–Small Cell Lung Cancer (NSCLC)
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Study E4599: Grades 3–5 (non-hematologic) and Grade 4–5
(hematologic) adverse reactions in a clinical study occurred at ≥ 2%
higher incidence in patients (N=422) receiving bevacizumab with
paclitaxel and carboplatin vs. patients receiving chemotherapy alone
were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension
(8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous
thromboembolism (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%).
Recurrent Glioblastoma
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Study EORTC 26101: In patients (N=278) with recurrent GBM
following radiotherapy and temozolomide, patients received
bevacizumab with lomustine or lomustine alone, 22% of patients
discontinued treatment in the bevacizumab with the lomustine arm
compared with 10% of patients in the lomustine arm. In patients
receiving bevacizumab with lomustine, the adverse reaction profile
was similar to that observed in other approved indications.
Metastatic Renal Cell Carcinoma
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Study BO17705: Grades 3-5 adverse reactions occurring at a
>2% higher incidence in bevacizumab with interferon alfa (N=337)
compared to placebo with interferon alfa (N=304), 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, hemoptysis, hemorrhage intracranial, large
intestinal hemorrhage, respiratory tract hemorrhage, and traumatic
hematoma).
Persistent, Recurrent, or Metastatic Cervical Cancer
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Study GOG-0240: Grades 3 or 4 adverse reactions occurred at a
higher incidence of ≥ 2% in patients receiving bevacizumab with
chemotherapy (N = 218) compared to patients receiving chemotherapy
alone (N = 222), were abdominal pain (12% vs. 10%), hypertension
(11% vs. 0.5%), thrombosis (8% vs. 3%), diarrhea (6% vs. 3%), anal
fistula (4% vs. 0%), proctalgia (3% vs. 0%), urinary tract infection
(8% vs. 6%), cellulitis (3% vs. 0.5%), fatigue (14% vs. 10%),
hypokalemia (7% vs. 4%), hyponatremia (4% vs. 1%), dehydration (4%
vs. 0.5%), neutropenia (8% vs. 4%), lymphopenia (6% vs. 3%), back
pain (6% vs. 3%), and pelvic pain (6% vs. 1%).
Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer
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Combination with carboplatin and paclitaxel, followed by
Bevacizumab as a single agent, for stage III or IV disease
following initial surgical resection (Study BO17705):
Grades 3-4 adverse reactions occurring at a higher incidence (≥2%)
in either of the bevacizumab arms vs. the control arm were fatigue
(CPB15+ -9%, CPB15 -6%, CPP -6%), hypertension (CPB15+ -10%, CPB15
-6%, CPP -2%), thrombocytopenia (CPB15+ -21%, CPB15 -20%, CPP -15%)
and leukopenia (CPB15+ -51%, CPB15 -53%, CPP -50%).
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Combination with paclitaxel, pegylated liposomal doxorubicin, or
topotecan for platinum-resistant recurrent disease who received no
more than 2 prior chemotherapy regimens (Study MO22224):
Grades 3-4 adverse reactions occurring at a higher incidence (≥ 2%)
in patients receiving bevacizumab with chemotherapy (N = 179) vs.
patients receiving chemotherapy alone (N = 181) were hypertension
(6.7% vs. 1.1%) and palmar-plantar erythrodysaesthesia syndrome
(4.5% vs. 1.7%).
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Combination with carboplatin and paclitaxel or carboplatin and
gemcitabine, followed by Bevacizumab as a single agent for
platinum-sensitive recurrent disease (Study AVF4095g):
Grades 3-4 adverse reactions occurring at a higher incidence (≥ 2%)
in patients receiving bevacizumab with chemotherapy (N=247) compared
to placebo with chemotherapy (N=233) were thrombocytopenia (40% vs.
34%), nausea (4% vs. 1.3%), fatigue (6% vs. 4%), headache (4% vs.
0.9%), proteinuria (10% vs. 0.4%), dyspnea (4% vs. 1.7%), epistaxis
(5% vs. 0.4%), and hypertension (17% vs. 0.9%).
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Patients with platinum-sensitive recurrent epithelial ovarian,
fallopian tube, or primary peritoneal cancer, who have not
received more than one previous regimen of chemotherapy (Study
GOG-0213):
Grades 3-4 adverse reactions occurring at a higher incidence (≥ 2%)
in patients receiving bevacizumab with chemotherapy compared to
chemotherapy alone were hypertension (11% vs. 0.6%), fatigue (8% vs.
3%), febrile neutropenia (6% vs. 3%), proteinuria (8% vs. 0%),
abdominal pain (6% vs. 0.9%), hyponatremia (4% vs. 0.9%), headache
(3% vs. 0.9%), and pain in extremity (3% vs. 0%).
