Bevacizumab

GI perforation, (sometimes fatal) in patients receiving bevacizumab products ranges from 0.3% to 3%; discontinue bevacizumab products in patients with GI perforation. A higher incidence of GI perforation is associated with a history of prior pelvic radiation. Most cases of GI perforation occurred within 50 days of the first bevacizumab dose. Perforation may be complicated by intra-abdominal abscess, fistula formation, and/or diverting ostomy requirement. Serious fistulae (including tracheoesophageal, bronchopleural, biliary, vaginal, renal, and bladder fistulas) have been reported at a higher incidence in patients receiving bevacizumab products (compared to patients receiving chemotherapy), with the highest incidence occurring in patients with cervical cancer. Most fistulae occurred within 6 months of the first bevacizumab dose. Patients who develop gastrointestinal vaginal fistula may also have bowel obstruction which requires surgical intervention and diverting ostomy. Avoid bevacizumab products in patients with ovarian cancer with 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, any grade 4 fistula, or fistula formation involving any internal organ.

In a scientific statement from the American Heart Association, bevacizumab has been determined to be an agent that may either cause reversible direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: moderate/major) (AHA [Page 2016]). Bevacizumab is not indicated for use in combination with anthracycline-based chemotherapy. The incidence of grade ≥3 left ventricular dysfunction was higher in patients receiving bevacizumab with chemotherapy compared to patients who received chemotherapy alone (1% vs 0.6%). Among patients who received prior anthracycline therapy, the incidence of HF was higher in patients receiving bevacizumab with chemotherapy, compared to patients who received chemotherapy alone (4% vs 0.6%). In previously untreated patients with hematologic malignancy, the incidence of HF and left ventricular ejection fraction (LVEF) decline were increased in patients receiving bevacizumab with anthracycline-based chemotherapy (compared to patients receiving anthracycline-based chemotherapy alone). The proportion of patients with a LVEF decline (from baseline) of ≥20% or a decline from baseline of 10% to • Hemorrhage: [US Boxed Warning]: Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding occur up to 5-fold more frequently in patients receiving bevacizumab products. Do not administer bevacizumab products to patients with a recent history of h

Bevacizumab may cause and/or worsen hypertension. The incidence of severe hypertension in increased with bevacizumab products. Manage hypertension with antihypertensive therapy. Monitor BP every 2 to 3 weeks during bevacizumab treatment and regularly after discontinuation if bevacizumab-induced hypertension occurs or worsens. Withhold bevacizumab treatment in patients with severe hypertension that is uncontrolled with medical management (resume bevacizumab after blood pressure is controlled). Discontinue bevacizumab products in patients who experience a hypertensive crisis or hypertensive encephalopathy.

Infusion reactions (eg, hypertension, hypertensive crisis [associated with neurologic signs/symptoms], wheezing, oxygen desaturation, hypersensitivity [grade 3], chest pain, rigors, headache, diaphoresis) may occur with the first infusion (uncommon); severe reactions were rare. Decrease the infusion rate for mild/clinically insignificant infusion reactions. Interrupt infusion for clinically significant infusion reactions and consider resuming at a slower rate following resolution. Discontinue bevacizumab for severe infusion reaction and administer appropriate medical therapy (eg, epinephrine, corticosteroids, IV antihistamines, bronchodilators, and/or oxygen).

Bevacizumab, in combination with chemotherapy (or biologic therapy), is associated with an increased risk of treatment-related mortality; a higher risk of fatal adverse events was identified in a meta-analysis of 16 trials in which bevacizumab was used for the treatment of various cancers (breast cancer, colorectal cancer, NSCLC, pancreatic cancer, prostate cancer, and renal cell cancer) and compared to chemotherapy alone (Ranpura 2011).

Cases of necrotizing fasciitis, including fatalities, have been reported in patients receiving bevacizumab, usually secondary to wound healing complications, GI perforation or fistula formation. Discontinue in patients who develop necrotizing fasciitis.

Serious eye infections and vision loss due to endophthalmitis have been reported from intravitreal administration (off-label use/route).

According to a position paper by the American Association of Maxillofacial Surgeons (AAOMS), medication-related osteonecrosis of the jaw (MRONJ) has been associated with bisphosphonates and other antiresorptive agents (denosumab), and antiangiogenic agents (eg, bevacizumab, sunitinib) used for the treatment of osteoporosis or malignancy. Antiangiogenic agents, when given concomitantly with antiresorptive agents, are associated with an increased risk of ONJ. Other risk factors for MRONJ include dentoalveolar surgery (eg, tooth extraction, dental implants), preexisting inflammatory dental disease, and concomitant corticosteroid use. The AAOMS suggests that if medically permissible, initiation of antiangiogenic agents for cancer therapy should be delayed until optimal dental health is attained (if extractions are required, antiangiogenesis therapy should delayed until the extraction site has mucosalized or until after adequate osseous healing). Once antiangiogenic therapy for oncologic disease is initiated, procedures that involve direct osseous injury and placement of dental implants should be avoided. Patients developing ONJ during therapy should receive care by an oral surgeon (AAOMS [Ruggiero 2014]). Cases of non-mandibular ONJ has also been reported in pediatric patients who have received bevacizumab (bevacizumab is not approved for use in pediatric patients).

In premenopausal women with solid tumors receiving adjuvant therapy, the incidence of ovarian failure was 34% for bevacizumab with chemotherapy versus 2% for chemotherapy alone. Recovery of ovarian function (resumption of menses, positive serum β-HCG pregnancy test, or FSH level • Posterior reversible encephalopathy syndrome: Cases of posterior reversible encephalopathy syndrome (PRES) have been reported. Symptoms (which include headache, seizure, confusion, lethargy, blindness and/or other vision, or neurologic disturbances) may occur from 16 hours to 1 year after treatment initiation. PRES may also be associated with mild to severe hypertension. MRI is necessary for confirmation of PRES diagnosis. Discontinue bevacizumab products in patients who develop PRES. Resolution of symptoms usually occurs within days after discontinuation; however, neurologic sequelae may remain. The safety of treatment reinitiation after PRES is not known.

Bevacizumab products are associated with an increased incidence and severity of proteinuria. Grade 3 (urine dipstick 4+ or >3.5 g protein/24 hours) and grade 4 (nephrotic syndrome) proteinuria have occurred in clinical studies. The overall incidence of all grades of proteinuria in one study was 20%. The median onset of proteinuria was 5.6 months (range: 0.5 to 37 months) after bevacizumab initiation and the median time to resolution was ~6 months. Proteinuria remained unresolved in 40% of patients after median follow-up of 11.2 months and required bevacizumab discontinuation in nearly one-third of patients. A pooled analysis from 7 studies found that 5% of patients receiving bevacizumab products in combination with chemotherapy experienced grades 2 to 4 proteinuria (urine dipstick 2+ or >1 g protein/24 hours or nephrotic syndrome), which resolved in nearly three-fourths of patients; bevacizumab was reinitiated in 42% of patients, although nearly half of patients who reinitiated experienced recurrent grades 2 to 4 proteinuria. Nephrotic syndrome has occurred (rarely) in patients receiving bevacizumab, sometimes with fatal outcome. In some cases, kidney biopsy of patients with proteinuria demonstrated findings consistent with thrombotic microangiopathy. A large retrospective analysis comparing bevacizumab with chemotherapy to chemotherapy alone found higher rates of serum creatinine elevations (1.5 to 1.9 times baseline) in patients who received bevacizumab; serum creatinine di

The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in patients receiving bevacizumab products; discontinue in patients who develop wound healing complications that require medical intervention. Withhold bevacizumab products at least 28 days prior to elective surgery. Do not administer bevacizumab products for at least 28 days after surgery and until the surgical wound is fully healed. In a controlled study in which bevacizumab was not administered within 28 days of major surgical procedures, the incidence of wound healing complications (including serious/fatal complications) was higher in patients with mCRC who underwent surgery while receiving bevacizumab compared to patients who did not receive bevacizumab. In a controlled clinical study in patients with relapsed or recurrent glioblastoma, the incidence of wound healing events was higher in patients who received bevacizumab compared to patients who did not receive bevacizumab. In a retrospective review of central venous access device placements (a minor procedure), a greater risk of wound dehiscence was observed when port placement and bevacizumab administration were separated by Disease-related concerns:

An increase in diastolic and systolic blood pressures were noted in a retrospective review of patients with renal insufficiency (CrCl ≤60 mL/minute) who received bevacizumab for renal cell cancer (Gupta 2011). Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Patients ≥65 years of age have an increased incidence of arterial thrombotic events.