Note: This document contains side effect information about bevacizumab. Some dosage forms listed on this page may not apply to the brand name Zirabev.

Applies to bevacizumab: intravenous solution.

Serious side effects of Zirabev

Along with its needed effects, bevacizumab (the active ingredient contained in Zirabev) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking bevacizumab:

More common

• Black, tarry stools
• bleeding gums
• body aches or pain
• burning, tingling, numbness, or pain in the hands, arms, feet, or legs
• chest pain or discomfort
• chills
• cloudy urine
• cough
• cracks in the skin
• decreased urine output
• difficult or labored breathing
• dilated neck veins
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• ear congestion
• extreme tiredness or weakness
• fever
• irregular breathing
• irregular heartbeat
• lack or loss of strength
• lightheadedness
• loss of appetite
• loss of heat from the body
• loss of voice
• mood changes
• nervousness
• pain, redness, or swelling in the arm or leg
• painful or difficult urination
• pinpoint red spots on the skin
• pounding in the ears
• rapid breathing
• redness
• runny or stuffy nose
• seizures
• sensation of pins and needles
• slow or fast heartbeat
• sore throat
• sores on the skin
• sores, ulcers, or white spots on the lips or in the mouth
• stabbing pain
• sunken eyes
• sweating
• swelling of the face, fingers, feet, or lower legs
• swelling or inflammation of the mouth
• swollen glands
• thirst
• tightness in the chest
• trouble breathing
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting of blood or material that looks like coffee grounds
• watery or bloody diarrhea
• weight gain
• wrinkled skin
• yellow skin

Less common

• Bone pain
• difficulty with swallowing
• fainting
• severe constipation
• severe vomiting
• stomach pain or tenderness

Rare

• Back pain
• blisters
• blurred vision
• confusion
• dizziness
• drowsiness
• headache
• increased thirst
• loss of consciousness
• muscle pain or cramps
• open sores
• pale skin

Incidence not known

• Bloody mucus or unexplained nosebleeds
• constipation
• diarrhea
• heartburn
• heavy jaw feeling
• high fever
• hoarseness
• indigestion
• loosening of a tooth
• nausea
• pain, swelling, or numbness in the mouth or jaw
• severe stomach pain
• stomach cramping or burning
• stomach pain, usually after eating a meal
• sudden weakness in the arms or legs
• sudden, severe chest pain
• unexplained bleeding or bruising
• unusual tiredness or weakness
• voice changes

Other side effects of Zirabev

Some side effects of bevacizumab may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Belching
• change in taste or bad unusual or unpleasant (after) taste
• change in walking and balance
• clumsiness or unsteadiness
• dry mouth
• excess flow of tears
• hair loss or thinning of hair
• stomach discomfort or upset
• weight loss

For Healthcare Professionals

Applies to bevacizumab: intravenous solution.

Gastrointestinal

All three TE fistulas occurred during the bevacizumab (the active ingredient contained in Zirabev) maintenance phase of the study in the context of persistent esophagitis. Additionally, six other cases of TE fistula have been reported in other lung and esophageal cancer studies using bevacizumab and chemotherapy alone or with concurrent radiation treatment.

The incidence of gastrointestinal perforation (gastrointestinal perforation, fistula formation, and/or intraabdominal abscess) in patients with colorectal cancer and in patients with non-small cell lung cancer (NSCLC) receiving bevacizumab was 2.4% and 0.9%, respectively.^[Ref]

Very common (10% or more): Abdominal pain (up to 61%), vomiting (up to 52%), anorexia (up to 43%), constipation (up to 40%), diarrhea (up to 34%), stomatitis (up to 32%), dyspepsia (up to 24%), gastrointestinal hemorrhage (up to 24%), flatulence (up to 19%)

Common (1% to 10%): Dry mouth, colitis, constipation, nausea

Very rare (less than 0.01%): TE fistula, upper aerodigestive tract hemorrhage

Frequency not reported: Intestinal obstruction, intestinal necrosis, mesenteric venous occlusion, ileus, anastomotic ulceration, gastrointestinal perforation and wound dehiscence (complicated by intra-abdominal abscesses), tracheoesophageal fistulae^[Ref]

Cardiovascular

Risk factors for the development of arterial thromboembolic events have included a history of arterial thromboembolism prior to bevacizumab (the active ingredient contained in Zirabev) exposure, age 65 years and above, and bevacizumab therapy. These events have occurred at a higher rate in these high-risk groups.

In one study, the rate of congestive heart failure (defined as NCI-CTC grade 3 and 4) in the bevacizumab plus paclitaxel arm was 2.2% versus 0.3% in the control arm. Among patients receiving anthracyclines, the rate of CHF was 3.8% for bevacizumab treated patients and 0.6% for patients receiving paclitaxel alone. Congestive heart failure occurred in six of 44 (14%) patients with relapsed acute leukemia (a non-FDA approved indication) receiving bevacizumab and concurrent anthracyclines in a single arm study. The safety of continuation or resumption of bevacizumab in patients with cardiac dysfunction has not been studied.^[Ref]

Very common (10% or more): Hypertension (up to 34%), hypotension (up to 15%)

Common (1% to 10%): Deep vein thrombosis, congestive heart failure

Frequency not reported: Arterial thromboembolic events (including cerebrovascular accident (stroke), myocardial infarction, transient ischemic attack, angina), fatal arterial thrombotic events, cerebral ischemia, supraventricular tachycardia, both serious and non-serious hemorrhagic events^[Ref]

Nervous system

Very common (10% or more): Dizziness (up to 26%), sensory neuropathy (24%)

Common (1% to 10%): Confusion, abnormal gait, CNS hemorrhage, cerebrovascular ischemia

Rare (less than 0.1%): Brain-capillary leak syndrome (reversible posterior hyponatremia

hypertensive encephalopathy

Frequency not reported: Dysgeusia^[Ref]

RPLS is a neurological disorder associated with hypertension, fluid retention, and cytotoxic effects of immunosuppressive drugs on the vascular endothelium. The syndrome can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present, but is not necessary for diagnosis. The onset of symptoms has been reported to occur from sixteen hours to one year after initiation of bevacizumab. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS.^[Ref]

Hematologic

Very common (10% or more): Leukopenia (37%), neutropenia (21%)

Common (1% to 10%): Thrombocytopenia

Frequency not reported: Hemorrhagic events, pancytopenia, febrile neutropenia, decreased hemoglobin, anemia, prothrombin time prolongations, infection with severe neutropenia^[Ref]

Hepatic

Postmarketing reports: Gallbladder perforation

Metabolic

Very common (10% or more): Hyperglycemia (up to 26%), hypomagnesemia (up to 24%), hyponatremia (up to 19%), hypoalbuminemia (16%), weight loss (up to 16%), hypokalemia (up to 16%)

Common (1% to 10%): Bilirubinemia

Frequency not reported: Increased blood potassium, decreased blood phosphorus, increased blood alkaline phosphatase^[Ref]

Musculoskeletal

Very common (10% or more): Myalgia (up to 15%)

Common (1% to 10%): Bone pain, back pain

Postmarketing reports: Osteonecrosis of the jaw^[Ref]

Genitourinary

Frequency not reported: Ureteral stricture^[Ref]

Respiratory

Very common (10% or more): Upper respiratory infection (up to 47%), severe or fatal hemoptysis (up to 31%), epistaxis (up to 35%), dyspnea (up to 26%)

Frequency not reported: Pulmonary hypertension, fatal pulmonary hemorrhage, nasal septum perforation

Common (1% to 10%): Voice alteration^[Ref]

Patients with recent hemoptysis (greater than or equal to 1/2 tsp of red blood) should not receive bevacizumab.

In study 6, four of 13 (31%) bevacizumab-treated patients with squamous cell histology and two of 53 (4%) bevacizumab-treated patients with histology other than squamous cell, experienced serious or fatal pulmonary hemorrhage as compared to none of the 32 (0%) patients receiving chemotherapy alone. In study 5, the rate of pulmonary hemorrhage requiring medical intervention for the paclitaxel, carboplatin, plus bevacizumab arm was 2.3% (10 of 427) compared to 0.5% (2 of 441) for the paclitaxel plus carboplatin alone arm. There were seven deaths due to pulmonary hemorrhage reported by investigators in the paclitaxel, carboplatin, plus bevacizumab arm as compared to one in the paclitaxel plus carboplatin alone arm. Generally, these serious hemorrhagic events presented as major or massive hemoptysis without a history of minor hemoptysis during bevacizumab therapy.^[Ref]

Renal

Kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

In study 5, patients age 65 and older receiving carboplatin, paclitaxel, and bevacizumab (the active ingredient contained in Zirabev) had a greater relative risk for proteinuria as compared to younger patients.^[Ref]

Very common (10% or more): Proteinuria (up to 36%)

Uncommon (0.1% to 1%): Nephrotic syndrome^[Ref]

Ocular

Very common (10% or more): Lacrimation increased

Postmarketing reports: Cases of serious ocular adverse reactions have been reported following unapproved intravitreal use of this drug compounded from vials approved for IV administration. These reactions included infectious endophthalmitis, intraocular inflammation such as sterile endophthalmitis, uveitis and vitreitis, retinal detachment, retinal pigment epithelial tear, intraocular pressure increased, intraocular hemorrhage (such as vitreous hemorrhage or retinal hemorrhage and conjunctival hemorrhage). Some of these reactions have resulted in various degrees of visual loss, including permanent blindness.^[Ref]

It has been suggested that reduction in macular edema after treatment may have resulted in anatomic changes at the fovea and may have triggered the visual hallucinations.^[Ref]

Dermatologic

Very common (10% or more): Alopecia (up to 32%)

Common (1% to 10%): Rash/desquamation, skin ulcer

Frequency not reported: Exfoliative dermatitis, skin discoloration

Postmarketing reports: Necrotizing fasciitis^[Ref]

Other

Very common (10% or more): Asthenia (up to 74%), pain (up to 62%), fatigue (up to 80%), headache (up to 37%), peripheral edema (up to 22%), taste disorder (up to 9%)

Common (1% to 10%): Infection with an unknown ANC

Uncommon (0.1% to 1%): Nongastrointestinal fistula formation, infection without neutropenia

Frequency not reported: Mesenteric venous occlusion, syncope, dehydration, somnolence, polyserositis, polyserositis^[Ref]

Immunologic

Frequency not reported: Sepsis, wound healing complications, urinary tract infection, positive assays for treatment-emergent anti-bevacizumab^[Ref]