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  • CLASSES

    Monoclonal Antibodies that Target VEGF
    Wet AMD Treatment Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Humanized monoclonal antibody against vascular endothelial growth factor
    Used for metastatic colorectal cancer, hepatocellular cancer, renal cell cancer, non-small cell lung cancer, cervical cancer, recurrent glioblastoma, and epithelial ovarian, fallopian tube, or primary peritoneal cancer
    May cause infusion-related reactions that require a reduced infusion rate or discontinuation of therapy; also associated with wound healing complications requiring treatment interruption for 28 days before and after surgery

    COMMON BRAND NAMES

    Avastin, MVASI

    HOW SUPPLIED

    Avastin/Bevacizumab (Hamster)/MVASI Ophthalmic Sol: 1mL, 25mg
    Avastin/MVASI Intravenous Inj Sol: 1mL, 25mg

    DOSAGE & INDICATIONS

    For the treatment of metastatic colorectal cancer.
    NOTE: Bevacizumab is not indicated for the adjuvant treatment of colorectal cancer due to lack of efficacy in 2 randomized, open-label clinical trials.
    For the first-line treatment of metastatic colorectal cancer in combination with capecitabine and oxaliplatin†.
    Intravenous dosage
    Adults

    7.5 mg/kg IV over 90 minutes on day 1 in combination with oxaliplatin (130 mg/m2 IV on day 1) and capecitabine (1,000 mg/m2 PO twice daily on days 1 to 14), repeated every 3 weeks. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. In a phase 3 clinical trial (n = 1,401), the addition of bevacizumab to oxaliplatin-based therapy (CapeOx or FOLFOX4) provided a significant increase in the primary endpoint of progression-free survival (9.4 months vs. 8 months). Overall survival and response rate were not significantly improved in the bevacizumab containing arms.[41609] The primary endpoint of treatment-related grade 3 or 4 adverse reactions in the first 12 weeks occurred in 67% of patients with previously untreated metastatic or recurrent colorectal cancer treated with CapeOx compared to 56% of those who received CapeOx plus bevacizumab in 2 sequentially conducted, open-label cohorts (TREE-1 and TREE-2). The addition of bevacizumab to CapeOx improved the overall response rate (ORR) (46% vs. 27%), the median time to progression (TTP) (10.3 months vs. 5.9 months), and median overall survival (OS) (24.6 months vs. 17.2 months) compared to CapeOx without bevacizumab.[47464]

    For the first-line or second-line treatment of metastatic colorectal cancer in combination with fluorouracil, leucovorin, and irinotecan (IFL plus bevacizumab).
    Intravenous dosage
    Adults

    5 mg/kg IV over 90 minutes every 2 weeks. On days 1, 8, 15, and 22, give irinotecan 125 mg/m2 IV over 90 minutes, followed by leucovorin 20 mg/m2 IV bolus and then fluorouracil 500 mg/m2 IV bolus; repeat every 6 weeks (IFL). On bevacizumab treatment days, administer bevacizumab concomitantly (but in separate bags) with or without irinotecan. The sequence of administration is irinotecan, concomitantly with or without bevacizumab, followed by leucovorin, then fluorouracil. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. Treatment with bevacizumab plus IFL significantly improved overall survival (20.3 months vs. 15.6 months) and progression-free survival (10.6 months vs. 6.2 months) compared with IFL plus placebo in a randomized, double-blind phase 3 trial of patients with previously untreated metastatic colorectal cancer. The overall response rate (45% vs. 35%) for a duration of 10.4 months versus 7.1 months, respectively, was also significantly improved in the bevacizumab arm.[11459] [60402] [62350] [64400] [59718] [30469] In a single-arm study of patients with mCRC and progression following both irinotecan- and oxaliplatin-based chemotherapy, the objective response rate of patients treated with bevacizumab plus fluorouracil (infusional or bolus) and leucovorin was 1%.[60402] [62350] [64400] Mortality was increased in patients who received IFL compared with FOLFIRI in one trial and was inferior to FOLFOX in another.[41656] [41658] [60896]

    For the second-line treatment of metastatic colorectal cancer in patients who progressed on a first-line bevacizumab-containing regimen, in combination with fluoropyrimidine and irinotecan- or fluoropyrimidine and oxaliplatin-based chemotherapy.
    Intravenous dosage
    Adults

    5 mg/kg IV over 90 minutes every 2 weeks OR 7.5 mg/kg IV over 90 minutes every 3 weeks in combination with fluoropyrimidine and irinotecan- or fluoropyrimidine and oxaliplatin-based chemotherapy until disease progression or unacceptable toxicity. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. Second-line treatment with bevacizumab plus either fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy significantly improved overall survival (11.2 months vs. 9.8 months) and progression-free survival (5.7 months vs. 4 months) compared with chemotherapy alone in a randomized, open-label study in patients with metastatic colorectal cancer that progressed on a first-line regimen containing bevacizumab.

    For the treatment of advanced colorectal cancer, in combination with leucovorin, fluorouracil, and oxaliplatin (FOLFOX4 plus bevacizumab).
    Intravenous dosage
    Adults

    10 mg/kg IV over 90 minutes on day 1, followed by oxaliplatin 85 mg/m2 IV, administered concurrently over 2 hours in separate bags via Y-site with leucovorin 200 mg/m2 IV; following completion of the leucovorin and oxaliplatin infusions, give fluorouracil 400 mg/m2 IV bolus over 2 to 4 minutes, followed by fluorouracil 600 mg/m2 continuous IV infusion (CIV) over 22 hours on day 1. On day 2, repeat leucovorin 200 mg/m2 IV over 2 hours followed by fluorouracil 400 mg/m2 IV bolus, then fluorouracil 600 mg/m2 CIV over 22 hours. The order of administration is (bevacizumab) followed by oxaliplatin and leucovorin, followed by fluorouracil. This 2-day regimen (FOLFOX4-bevacizumab) is repeated every 2 weeks until disease progression or unacceptable toxicity. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. Prolongation of the oxaliplatin infusion to 6 hours may mitigate acute toxicities; the infusion time for fluorouracil and leucovorin need not be changed. Treatment with FOLFOX4 plus bevacizumab significantly improved overall survival (12.9 months vs. 10.8 months) and progression-free survival (7.3 months vs. 4.7 months) compared with FOLFOX4 alone in patients with previously treated metastatic colorectal cancer in a randomized, open-label, placebo-controlled phase 3 trial. The overall response rate was also significantly improved in the bevacizumab/FOLFOX4 arm (22.7% vs. 8.6%). The significance of the effect of bevacizumab on overall survival is not consistent across clinical trials.

    For the treatment of metastatic colorectal cancer, in combination with irinotecan, leucovorin, and fluorouracil (FOLFIRI plus bevacizumab).
    Intravenous dosage
    Adults

    5 mg/kg IV over 90 minutes, concurrently but in separate bags (via y-site) with irinotecan 180 mg/m2 IV over 90 minutes and leucovorin 400 mg/m2 IV over 2 hours on day 1; when the leucovorin infusion is complete, administer fluorouracil 400 mg/m2 IV bolus, followed by fluorouracil 1,200 mg/m2 per day on days 1 and 2 by continuous IV infusion (CIV) (total infusional dose, 2,400 mg/m2 over 46 hours) for cycles 1 and 2. If there is no toxicity greater than grade 1, the fluorouracil infusion dose may be increased to 3,000 mg/m2 for all subsequent cycles. Repeat this 2-day regimen (FOLFIRI with bevacizumab) every 2 weeks until disease progression or unacceptable toxicity. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. Treatment with bevacizumab plus FOLFIRI significantly improved overall survival (OS) compared with bevacizumab plus modified IFL (mIFL) (28 months vs. 19.2 months) in a cohort of a randomized phase 3 trial of patients with previously untreated metastatic colorectal cancer (mCRC); progression-free survival (PFS) was numerically improved in the bevacizumab arm, but this was not statistically significant (11.2 months vs. 8.3 months).[41656] Median PFS (10.3 months) and OS (25 months) were similar to bevacizumab plus FOLFIRI treatment in another randomized clinical trial of patients with KRAS wild-type metastatic colorectal cancer.[62811] FOLFIRI has alternatively been dosed as irinotecan 180 mg/m2 IV over 90 minutes followed by leucovorin 200 mg/m2 IV over 2 hours, and then fluorouracil 400 mg/m2 IV bolus and 600 mg/m2 CIV over 22 hours; leucovorin and fluorouracil (bolus and CIV) are repeated on day 2. Repeat every 2 weeks until disease progression or unacceptable toxicity.[30469]

    For the treatment of metastatic colorectal cancer in combination with leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6 with bevacizumab).
    Intravenous dosage
    Adults

    5 mg/kg IV over 90 minutes on day 1, followed by oxaliplatin 85 mg/m2 IV and leucovorin 400 mg/m2 IV concurrently in separate bags via y-site over 2 hours. After completion of the leucovorin infusion on day 1, administer fluorouracil 400 mg/m2 IV bolus, followed by fluorouracil 1,200 mg/m2 per day on days 1 and 2 by continuous IV infusion (CIV) (total infusional dose, 2,400 mg/m2 over 46 to 48 hours). The order of administration is bevacizumab, followed by oxaliplatin and leucovorin, followed by fluorouracil. This 2-day regimen is repeated every 2 weeks until disease progression or unacceptable toxicity.[47464] [59895] If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes, and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes.[60402] [62350] [64400] Prolongation of the oxaliplatin infusion to 6 hours may mitigate acute toxicities;[41958] the infusion time for fluorouracil and leucovorin need not be changed. The primary endpoint of treatment-related grade 3 or 4 adverse reactions in the first 12 weeks occurred with a similar frequency in patients with previously untreated metastatic or recurrent colorectal cancer treated with mFOLFOX6 compared to mFOLFOX6 plus bevacizumab (59% vs. 59%) in 2 sequentially conducted, open-label cohorts (TREE-1 and TREE-2). The addition of bevacizumab to mFOLFOX6 improved the overall response rate (ORR) (41% vs. 52%), the median time to progression (TTP) (8.7 months vs. 9.9 months), and median overall survival (OS) (19.2 months vs. 26.1 months) compared to mFOLFOX6 without bevacizumab.[47464] [59895] For patients with initially unresectable RAS mutant colorectal liver metastases, treatment with bevacizumab plus mFOLFOX6 significantly increased resectability of liver metastases and also significantly improved response rates, progression-free survival, and overall survival compared with mFOLFOX6 alone.

    For the treatment of non-small cell lung cancer (NSCLC).
    For the first-line treatment of unresectable, locally advanced, recurrent, or metastatic nonsquamous non-small cell lung cancer (NSCLC), in combination with carboplatin and paclitaxel.
    Intravenous dosage
    Adults

    15 mg/kg IV over 90 minutes on day 1, followed by paclitaxel (200 mg/m2 IV over 3 hours) and carboplatin (AUC 6 IV), every 3 weeks for 6 cycles of chemotherapy. After completion of chemotherapy, continue bevacizumab (15 mg/kg IV), on day 1 of each 21-day cycle until disease progression or unacceptable toxicity. To prevent hypersensitivity reactions, all patients should be premedicated with dexamethasone 20 mg PO approximately 12 and 6 hours before paclitaxel, diphenhydramine (or equivalent) 50 mg IV 30 to 60 minutes before paclitaxel, and an IV H2-blocker 30 to 60 minutes before paclitaxel. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. In a randomized, open-label clinical trial (n = 878), median overall survival was significantly longer in chemotherapy-naive patients with locally advanced, metastatic, or recurrent nonsquamous NSCLC treated with bevacizumab/paclitaxel/carboplatin (BCP) compared with paclitaxel/carboplatin (CP) alone (12.3 months vs. 10.3 months); investigator-assessed progression-free survival (PFS) was also longer in the bevacizumab arm. In an exploratory analysis, the impact of bevacizumab was not significant in women, patients age 65 years and older, or in patients with weight loss of 5% or more at study entry.[60402] [62350] [64400]

    For the first-line treatment of metastatic nonsquamous non-small cell lung cancer (NSCLC) without EGFR or ALK mutations, in combination with atezolizumab, paclitaxel, and carboplatin.
    NOTE: Atezolizumab is FDA-approved in combination with bevacizumab, paclitaxel, and carboplatin for this indication.
    Intravenous dosage
    Adults

    15 mg/kg IV over 90 minutes on day 1, preceded by atezolizumab 1,200 mg IV over 60 minutes, and followed by paclitaxel (200 mg/m2 IV over 3 hours, or 175 mg/m2 IV in Asian patients), and carboplatin (AUC 6 IV), every 21 days for a maximum of 4 to 6 cycles of chemotherapy. The sequence of administration is atezolizumab followed by bevacizumab, paclitaxel, and then carboplatin. After completion of chemotherapy, continue atezolizumab 1,200 mg IV, followed by bevacizumab (15 mg/kg IV), on day 1 of each 21-day cycle until disease progression or unacceptable toxicity. If bevacizumab is discontinued, atezolizumab may be continued as monotherapy at a dose of 840 mg IV every 2 weeks; 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks. To prevent hypersensitivity reactions, all patients should be premedicated with dexamethasone 20 mg PO approximately 12 and 6 hours before paclitaxel, diphenhydramine (or equivalent) 50 mg IV 30 to 60 minutes before paclitaxel, and an IV H2-blocker 30 to 60 minutes before paclitaxel. If the first atezolizumab infusion is tolerated, subsequent doses may be given over 30 minutes. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. In a multicenter, randomized, open-label, phase 3 clinical trial, treatment with atezolizumab/bevacizumab/paclitaxel/carboplatin (ABCP) significantly improved overall survival in patients with metastatic nonsquamous NSCLC compared with bevacizumab/paclitaxel/carboplatin (BCP) (19.2 months vs. 14.7 months); overall survival with atezolizumab/paclitaxel/carboplatin was not significantly different from BCP. Progression-free survival was also significantly improved in the ABCP arm compared with BCP (8.5 months vs. 7 months). The objective response rate was 55% (complete response [CR], 4%) versus 42% (CR, 1%), respectively, for a median duration of 10.8 months and 6.5 months, respectively.[60793] [63819]

    For the treatment of renal cell cancer.
    NOTE: The FDA has designated bevacizumab as an orphan drug for the treatment of renal cell carcinoma.
    For the treatment of metastatic renal cell cancer, in combination with interferon alfa.
    Intravenous dosage
    Adults

    10 mg/kg IV over 90 minutes every 2 weeks in combination with interferon alfa (9 million units subcutaneously 3 times weekly for up to 52 weeks) until disease progression or unacceptable toxicity. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. Median progression-free survival (PFS) was significantly longer in patients with previously untreated metastatic renal cell cancer treated with bevacizumab plus interferon alfa compared with interferon alfa plus placebo in a randomized, double-blind clinical trial; the objective response rate was also significantly higher in the bevacizumab arm (30% vs. 12%). Overall survival, the primary endpoint, was not significantly different in the final analysis, which may have been confounded by crossover to bevacizumab after the interim analysis in patients originally in the interferon monotherapy arm.[34479] [36107] [60402] [62350] [64400] Another trial of 732 patients had similar findings.[34478] [36109]

    For the first-line treatment of advanced or metastatic renal cell cancer, in combination with atezolizumab†.
    Intravenous dosage
    Adults

    15 mg/kg IV over 90 minutes plus atezolizumab (1,200 mg IV over 60 minutes), repeated every 3 weeks until disease progression or unacceptable toxicity. If the first atezolizumab infusion is tolerated over 60 minutes, all subsequent infusions may be infused over 30 minutes. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. In a randomized, phase 3 clinical trial, first-line treatment with atezolizumab plus bevacizumab significantly improved median investigator-assessed PFS in patients with advanced or metastatic RCC compared with sunitinib; however, these results were not supported by an independent review committee (IRC) which found a nonsignificant trend toward improved PFS. An exploratory analysis found that treatment with atezolizumab plus bevacizumab significantly improved investigator-assessed PFS in intent-to-treat patients with sarcamoid histology, which has a particularly poor prognosis. Treatment with atezolizumab plus bevacizumab did not significantly improve overall survival compared with sunitinib in this patient population, but patients who received combination therapy experienced a longer time to clinically relevant decline.

    For the treatment of glioblastoma multiforme.
    NOTE: The FDA has designated bevacizumab as an orphan drug for the treatment of malignant gliomas.
    For the treatment of recurrent or relapsed glioblastoma in combination with irinotecan†.
    Intravenous dosage
    Adults

    10 mg/kg IV over 90 minutes once every 14 days in combination with irinotecan 125 mg/m2 (non-EIAED) OR 340 mg/m2 (EIAED) IV once every 14 days; treatment cycles were defined as a 6-week period. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. Progression-free survival (PFS) at 6 months (50.3%,) and objective response rate (ORR) (37.8%) were significantly higher compared with the assumed 15% 6-month PFS with salvage therapy or irinotecan monotherapy and the 10% ORR with irinotecan monotherapy in a phase 2 trial. Toxicities grade 3 and higher occurred in 65.8% of patients, and 17.7% had to discontinue bevacizumab and irinotecan.[35142] In another phase 2 trial, the primary endpoint of 6-month PFS was 46% and 6-month overall survival (OS) was 77% in 2 cohorts of patients with recurrent grade III and IV malignant gliomas (n = 35) treated with either bevacizumab 10 mg/kg IV every 14 days plus irinotecan 125 mg/m2 (non-EIAED) or 340 mg/m2 (EIAED) IV on days 1 and 8 (every 21 days) OR bevacizumab 15 mg/kg IV every 21 days, in combination with irinotecan 125 mg/m2 (non-EIAED) or 350 mg/m2 (EIAED) IV on days 1, 8, 22 and 29 (every 42 days).[35027] Extended follow-up data revealed 6-month PFS and 6-month OS for grade III disease was 59% and 79% and for grade IV disease was 43% and 77% respectively.[35026] Of note, no objective radiographic responses were observed in patients who progressed on bevacizumab for the treatment of relapsed glioblastoma and then received bevacizumab 10 mg/kg IV and irinotecan 125 mg/m2 (non-EIAED) or 340 mg/m2 (EIAED) IV every 14 days in a small phase 2 companion trial (n = 19); 95% of patients showed evidence of progression by the second cycle.[35028]

    For the first-line treatment of glioblastoma multiforme, in combination with temozolomide and radiation therapy†.
    Intravenous dosage
    Adults

    10 mg/kg IV over 30 to 90 minutes repeated every 2 weeks concurrently with or starting on week 4 of standard chemoradiation therapy (CRT) with radiation plus oral temozolomide did not result in improved overall survival compared to standard CRT alone in 2 multinational, randomized, double-blind, placebo-controlled clinical trials.[55356] [55357] Starting 4 weeks after CRT, bevacizumab 10 mg/kg IV was given every 2 weeks in combination with temozolomide for 6 months; then bevacizumab 15 mg/kg IV every 3 weeks was continued as monotherapy until progressive disease in the AVAglio trial. Investigator-assessed progression-free survival (PFS) was significantly improved with the addition of bevacizumab in this trial.[55356] Bevacizumab 10 mg/kg IV was continued every 2 weeks in combination with adjuvant temozolomide for up to 12 months in the RTOG 0825 trial. The PFS was not significantly improved with the addition of bevacizumab in this trial.[55357]

    For the treatment of recurrent glioblastoma.
    Intravenous dosage
    Adults

    10 mg/kg IV over 90 minutes every 2 weeks until disease progression. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. Treatment may need to be discontinued or temporarily withheld in patients who experience toxicity.   In a randomized, open-label, phase 3 trial (the EORTC 26101 trial), the primary endpoint of median overall survival (OS) time was not significantly improved following treatment with bevacizumab plus lomustine (n = 288) compared with lomustine alone (n = 149) in patients with progressive glioblastoma after first-line standard chemotherapy plus radiotherapy (9.1 months vs. 8.6 months); however, the centrally reviewed progression-free survival (PFS) time was significantly higher in the bevacizumab-containing arm (3.8 months vs. 1.5 months). Approximately 50% of patients were receiving corticosteroid therapy at study entry. Grade 3 to 5 adverse events occurred more often in the bevacizumab plus lomustine arm compared with the lomustine only arm (63.6% vs. 38.1%). In a clinical trial of 48 patients with recurrent glioblastoma, bevacizumab was administered as a single agent, with subsequent enrollment into a companion study of irinotecan and bevacizumab at disease progression. The primary endpoint of the single-agent bevacizumab trial, 6-month PFS, was 29% with a 6-month OS of 57%. Additionally, treatment with single-agent bevacizumab led to an estimated 6-month PFS rate of 42.6%, a median PFS time of 4.2 months, and a median OS time of 9.2 months in patients with recurrent glioblastoma (n = 85) in a randomized, noncomparative study.

    For the treatment of ovarian cancer.
    NOTE: The FDA has designated bevacizumab as an orphan drug for the treatment of ovarian, fallopian tube, and primary peritoneal cancer.
    As adjuvant therapy of stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection, in combination with carboplatin and paclitaxel.
    Intravenous dosage
    Adults

    15 mg/kg IV over 90 minutes, in combination with paclitaxel (175 mg/m2 IV over 3 hours) and carboplatin (AUC 6 IV over 30 minutes), all given on day 1 and repeated every 3 weeks for up to 6 cycles; in the clinical trial (GOG-0218), bevacizumab was administered on cycles 2 through 6 (and omitted in cycle 1) to limit wound healing complications. To prevent hypersensitivity reactions, all patients should be premedicated with dexamethasone 20 mg PO approximately 12 and 6 hours before paclitaxel, diphenhydramine (or equivalent) 50 mg IV 30 to 60 minutes before paclitaxel, and an IV H2-blocker 30 to 60 minutes before paclitaxel. After completion of 6 cycles of chemotherapy, administer bevacizumab 15 mg/kg IV every 3 weeks as monotherapy until disease progression up to a maximum of 22 cycles. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. Treatment with bevacizumab plus carboplatin and paclitaxel followed by bevacizumab monotherapy significantly improved median progression-free survival (PFS) compared with carboplatin/paclitaxel alone (18.2 months vs. 12 months) in patients with stage III or IV epithelial ovarian, fallopian tube or primary peritoneal cancer following initial surgical resection in a randomized, double-blind clinical trial; overall survival was not significantly different (43.8 months vs. 40.6 months). Without bevacizumab maintenance therapy, PFS after treatment with bevacizumab/carboplatin/paclitaxel was not significantly different from carboplatin/paclitaxel without bevacizumab (12.8 months vs. 12 months).

    For use as a single-agent in the treatment of recurrent or relapsed ovarian cancer†.
    Intravenous dosage
    Adults

    15 mg/kg IV over 90 minutes every 21 days until unacceptable toxicity or disease progression.  If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. In 2 clinical trials, the overall response rates (ORR) were 15.9% (7/44) and 21% (13/62), and the 6-month progression-free survival (PFS) rates were 27.8% and 40.3%. Due to an unexpectedly high incidence of gastrointestinal perforations (5/44 patients, 1 death), one of these trials was halted prematurely. All patients who developed a perforation in this trial had received at least 3 prior chemotherapy regimens. A small retrospective study that limited the use of bevacizumab (either as a single-agent or in combination with other chemotherapies) to recurrent ovarian cancer patients without clinical symptoms of bowel obstruction, evidence of rectosigmoid involvement on pelvic exam, or bowel involvement on CT scan reported no gastrointestinal perforations in 25 heavily pre-treated patients.

    For the treatment of recurrent, platinum-sensitive, epithelial ovarian, fallopian tube, or primary peritoneal cancer in combination with gemcitabine and carboplatin.
    Intravenous dosage
    Adults

    15 mg/kg IV over 90 minutes on day 1, in combination with carboplatin (AUC 4 IV on day 1) and gemcitabine (1,000 mg/m2 IV on days 1 and 8), every 21 days for 6 to 10 cycles, followed by bevacizumab 15 mg/kg IV every 3 weeks as monotherapy until disease progression or unacceptable toxicity. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. Progression-free survival (12.4 months vs. 8.4 months) and overall response rate (78% vs. 57%) were significantly improved with the addition of bevacizumab to carboplatin and gemcitabine (followed by bevacizumab maintenance) compared with carboplatin/gemcitabine alone in patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who had not received prior chemotherapy in the recurrent setting (or prior bevacizumab therapy) in a randomized, double-blind clinical trial (OCEANS); overall survival was not significantly different between treatment arms.[61552] [60402]

    For the treatment of recurrent, platinum-resistant, epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who have received no more than 2 prior chemotherapy regimens, in combination with paclitaxel.
    Intravenous dosage
    Adults

    10 mg/kg IV over 90 minutes every 2 weeks, in combination with paclitaxel (80 mg/m2 IV over 1 hour on days 1, 8, 15, and 22, every 4 weeks), until disease progression or unacceptable toxicity. To prevent hypersensitivity reactions, all patients should be premedicated with dexamethasone 20 mg PO approximately 12 and 6 hours before paclitaxel, diphenhydramine (or equivalent) 50 mg IV 30 to 60 minutes before paclitaxel, and an IV H2-blocker 30 to 60 minutes before paclitaxel. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. Bevacizumab plus chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan) significantly improved progression-free survival (PFS) compared with chemotherapy alone (6.8 months vs. 3.4 months) in patients with recurrent, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within 6 months from the most recent platinum-based therapy in a randomized, open-label study. Overall survival (OS) was not significantly improved (16.6 months vs. 13.3 months); however, 40% of patients in the chemotherapy alone arm received bevacizumab monotherapy upon progression. The overall response rate was 28% versus 13%, respectively, for a median duration of 9.4 months in the bevacizumab arm compared with 5.4 months for patients receiving chemotherapy alone. In a subgroup analysis, the median PFS was 9.6 months for patients treated with bevacizumab/paclitaxel compared with 3.9 months for those receiving paclitaxel alone; the median OS was 22.4 months versus 13.2 months, respectively.[60402] [58451]

    For the treatment of recurrent, platinum-sensitive, epithelial ovarian, fallopian tube, or primary peritoneal cancer, in combination with carboplatin and paclitaxel.
    Intravenous dosage
    Adults

    15 mg/kg IV over 90 minutes, in combination with paclitaxel (175 mg/m2 IV over 3 hours) and carboplatin (AUC 5 IV), all given on day 1 and repeated every 3 weeks for 6 to 8 cycles, followed by bevacizumab 15 mg/kg IV every 3 weeks as monotherapy until disease progression or unacceptable toxicity. To prevent hypersensitivity reactions, all patients should be premedicated with dexamethasone 20 mg PO approximately 12 and 6 hours before paclitaxel, diphenhydramine (or equivalent) 50 mg IV 30 to 60 minutes before paclitaxel, and an IV H2-blocker 30 to 60 minutes before paclitaxel. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. Treatment with bevacizumab plus paclitaxel and carboplatin followed by bevacizumab maintenance significantly improved progression-free survival compared with carboplatin/paclitaxel alone (13.8 months vs. 10.4 months) in patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who had not received more than 1 previous chemotherapy regimen in a randomized, open-label trial (GOG-0213); the overall response rate was 78% versus 56%, respectively. The primary outcome of overall survival was of borderline clinical significance dependent on the method of stratification, at a median of 42.6 months in the bevacizumab arm compared with 37.3 months in the chemotherapy arm.

    For the treatment of recurrent, platinum-resistant, epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who have received no more than 2 prior chemotherapy regimens, in combination with pegylated liposomal doxorubicin.
    Intravenous dosage
    Adults

    10 mg/kg IV over 90 minutes every 2 weeks in combination with pegylated liposomal doxorubicin (PLD, 40 mg/m2 IV at a rate of 1 mg/minute on day 1, every 4 weeks), until disease progression or unacceptable toxicity. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. Bevacizumab plus chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan) significantly improved progression-free survival (PFS) compared with chemotherapy alone (6.8 months vs. 3.4 months) in patients with recurrent, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within 6 months from the most recent platinum-based therapy in a randomized, open-label study. Overall survival (OS) was not significantly improved (16.6 months vs. 13.3 months); however, 40% of patients in the chemotherapy alone arm received bevacizumab monotherapy upon progression. The overall response rate was 28% versus 13%, respectively, for a median duration of 9.4 months in the bevacizumab arm compared with 5.4 months for patients receiving chemotherapy alone. In a subgroup analysis, the median PFS was 5.1 months for patients treated with bevacizumab/PLD compared with 3.5 months for those receiving PLD alone; the median OS was 13.7 months versus 14.1 months, respectively.[60402] [58451]

    For the treatment of recurrent, platinum-resistant, epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who have received no more than 2 prior chemotherapy regimens, in combination with topotecan.
    Intravenous dosage (WEEKLY TOPOTECAN)
    Adults

    10 mg/kg IV over 90 minutes every 2 weeks in combination with topotecan (4 mg/m2 IV over 30 minutes on days 1, 8, and 15 every 4 weeks), until disease progression or unacceptable toxicity. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. Bevacizumab plus chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan) significantly improved progression-free survival (PFS) compared with chemotherapy alone (6.8 months vs. 3.4 months) in patients with recurrent, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within 6 months from the most recent platinum-based therapy in a randomized, open-label study. Overall survival (OS) was not significantly improved (16.6 months vs. 13.3 months); however, 40% of patients in the chemotherapy alone arm received bevacizumab monotherapy upon progression. The overall response rate was 28% versus 13%, respectively, for a median duration of 9.4 months in the bevacizumab arm compared with 5.4 months for patients receiving chemotherapy alone. In a subgroup analysis, the median PFS was 6.2 months for patients treated with bevacizumab/topotecan compared with 2.1 months for those receiving topotecan alone; the median OS was 13.8 months versus 13.3 months, respectively.[60402] [58451]

    Intravenous dosage (EVERY-3-WEEK TOPOTECAN)
    Adults

    15 mg/kg IV over 90 minutes on day 1 in combination with topotecan (1.25 mg/m2 IV over 30 minutes on days 1 to 5), every 3 weeks until disease progression or unacceptable toxicity. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. Bevacizumab plus chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan) significantly improved progression-free survival (PFS) compared with chemotherapy alone (6.8 months vs. 3.4 months) in patients with recurrent, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within 6 months from the most recent platinum-based therapy in a randomized, open-label study. Overall survival (OS) was not significantly improved (16.6 months vs. 13.3 months); however, 40% of patients in the chemotherapy alone arm received bevacizumab monotherapy upon progression. The overall response rate was 28% versus 13%, respectively, for a median duration of 9.4 months in the bevacizumab arm compared with 5.4 months for patients receiving chemotherapy alone. In a subgroup analysis, the median PFS was 6.2 months for patients treated with bevacizumab/topotecan compared with 2.1 months for those receiving topotecan alone; the median OS was 13.8 months versus 13.3 months, respectively.

    For the first-line maintenance treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in a complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either a deleterious or suspected deleterious BRCA mutation and/or genomic instability, in combination with olaparib†.
    NOTE: Olaparib is FDA-approved in combination with bevacizumab for this indication.
    Intravenous dosage
    Adults

    15 mg/kg IV every 3 weeks for 15 months total, including the period given with chemotherapy and given with maintenance, in combination with olaparib (300 mg PO twice daily until disease progression, unacceptable toxicity, or completion of 2 years of treatment. Patients with a complete response (no radiological evidence of disease) at 2 years should stop treatment with olaparib. Patients with evidence of disease at 2 years can continue treatment with olaparib if the treating healthcare provider feels the patient can derive further benefit. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Maintenance therapy with olaparib plus bevacizumab significantly improved the median progression-free survival compared with patients receiving bevacizumab plus placebo in HRD-positive patients with advanced high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer following first-line platinum-based chemotherapy and bevacizumab in a multicenter, randomized, double-blind clinical trial (PAOLA-1) (37.2 months vs. 17.7 months).

    For the treatment of cervical cancer.
    For the treatment of persistent, recurrent, or metastatic cervical cancer, in combination with paclitaxel and cisplatin.
    Intravenous dosage
    Adults

    15 mg/kg IV over 90 minutes in combination with paclitaxel (175 mg/m2 IV over 3 hours) and cisplatin (50 mg/m2 IV), all on day 1, repeated every 3 weeks until disease progression or unacceptable toxicity. To prevent hypersensitivity reactions, all patients should be premedicated with dexamethasone 20 mg PO approximately 12 and 6 hours before paclitaxel, diphenhydramine 50 mg IV (or equivalent) 30 to 60 minutes before paclitaxel, and an IV H2-blocker 30 to 60 minutes before paclitaxel. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. Alternatively, paclitaxel (either 135 mg/m2 IV over 24 hours OR 175 mg/m2 IV over 3 hours) may be administered on day 1, followed by cisplatin (50 mg/m2 IV) and bevacizumab (15 mg/kg IV) on day 2, repeated every 3 weeks until disease progression or unacceptable toxicity. Treatment with bevacizumab plus chemotherapy (paclitaxel/cisplatin or paclitaxel/topotecan) significantly improved overall survival (16.8 months vs. 12.9 months) compared with chemotherapy alone in patients with persistent, recurrent, or metastatic cervical cancer in a randomized clinical trial; the addition of bevacizumab to chemotherapy trended towards benefit but was not statistically significant when separated into individual subgroups (cisplatin/paclitaxel or cisplatin/topotecan). The objective response rate was 45% in patients treated with bevacizumab plus chemotherapy compared with 34% receiving chemotherapy alone.  

    For the treatment of persistent, recurrent, or metastatic cervical cancer, in combination with paclitaxel and topotecan.
    Intravenous dosage
    Adults

    15 mg/kg IV over 90 minutes IV on day 1, in combination with paclitaxel (175 mg/m2 IV over 3 hours on day 1) and topotecan (0.75 mg/m2 per day IV over 30 minutes on days 1, 2, and 3), repeated every 3 weeks until disease progression or unacceptable toxicity. To prevent hypersensitivity reactions, all patients should be premedicated with dexamethasone 20 mg PO approximately 12 and 6 hours before paclitaxel, diphenhydramine 50 mg IV (or equivalent) 30 to 60 minutes before paclitaxel, and an IV H2-blocker 30 to 60 minutes before paclitaxel. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. Treatment with bevacizumab plus chemotherapy (paclitaxel/cisplatin or paclitaxel/topotecan) significantly improved overall survival (16.8 months vs. 12.9 months) compared with chemotherapy alone in patients with persistent, recurrent, or metastatic cervical cancer in a randomized clinical trial; the addition of bevacizumab to chemotherapy trended towards benefit but was not statistically significant when separated into individual subgroups (cisplatin/paclitaxel or cisplatin/topotecan). The objective response rate was 45% in patients treated with bevacizumab plus chemotherapy compared with 34% receiving chemotherapy alone.  

    For the treatment of hepatocellular cancer.
    For the treatment of unresectable or metastatic hepatocellular cancer (HCC) in patients who have not received prior systemic therapy, in combination with atezolizumab.
    NOTE: Bevacizumab in combination with atezolizumab is designated by the FDA as an orphan drug for this indication.
    Intravenous dosage
    Adults

    15 mg/kg IV over 90 minutes on day 1 following administration of atezolizumab (1,200 mg IV over 60 minutes), every 3 weeks until disease progression or unacceptable toxicity. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes, and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. If the first atezolizumab infusion is tolerated, subsequent doses may be given over 30 minutes. If bevacizumab is discontinued for toxicity, atezolizumab may be continued as monotherapy at 840 mg IV every 2 weeks; 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks. In a multicenter, randomized, open-label clinical trial (IMbrave150), treatment with atezolizumab followed by bevacizumab significantly improved overall survival (not estimable vs. 13.2 months) and progression-free survival (6.8 months vs. 4.3 months) compared with sorafenib in patients with unresectable or metastatic HCC who have not received prior systemic therapy. The overall response rate was also significantly improved for patients treated with bevacizumab/atezolizumab by both RECIST1.1 criteria (28% vs. 12%; complete response [CR], 7% vs. 0%) and mRECIST criteria (33% vs. 13%; CR, 11% vs. 1.8%); the median duration of response was not estimable versus 6.3 months, respectively.

    For the treatment of metastatic breast cancer†.
    For patients who have not previously received chemotherapy for metastatic HER2-negative breast cancer, in combination with paclitaxel†.
    NOTE: In February 2008, the FDA granted accelerated approval to bevacizumab for the treatment of previously untreated metastatic HER2-negative breast cancer in combination with paclitaxel. In December 2010, the FDA's Center for Drug Evaluation and Research (CDER), the agency which granted the accelerated approval, recommended removal of the breast cancer indication for bevacizumab. This recommendation came after reviewing the results of 4 clinical studies of bevacizumab in combination with various chemotherapy agents (e.g., an anthracycline, docetaxel, capecitabine, or paclitaxel) in women with breast cancer and determining that the data indicate that bevacizumab does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression to outweigh the significant risk to patients. Genentech, the manufacturer of Avastin (bevacizumab), disagreed with this assessment and was granted a public hearing on CDER's withdrawal proposal, which took place in June 2011. A final decision to remove the breast cancer indication from the bevacizumab label was rendered by the FDA Commissioner in November 2011.
    Intravenous dosage
    Adults

    10 mg/kg IV over 90 minutes on days 1 and 15 in combination with paclitaxel (90 mg/m2 IV on days 1, 8, and 15) every 28 days until disease progression or unacceptable toxicity. Bevacizumab monotherapy could be continued at the discretion of the clinician if unacceptable toxicity to paclitaxel developed while on combination treatment. To prevent hypersensitivity reactions, all patients should be premedicated with dexamethasone 20 mg PO approximately 12 and 6 hours before paclitaxel, diphenhydramine 50 mg IV (or equivalent) 30 to 60 minutes before paclitaxel, and an IV H2-blocker 30 to 60 minutes before paclitaxel.[29200] If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes, and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes.[60402] [62350] [64400] Treatment with paclitaxel plus bevacizumab significantly improved progression-free survival (11.8 months vs. 5.9 months) and objective response rate (36.9% vs. 21.2%) compared with paclitaxel alone in patients with previously untreated metastatic breast cancer in a phase 3 clinical trial; overall survival was not significantly different between treatment arms (26.7 months vs. 25.2 months).[33131]

    For patients who have not previously received chemotherapy for metastatic or locally recurrent HER2-negative breast cancer, in combination with docetaxel†.
    Intravenous dosage
    Adults

    15 mg/kg IV over 90 minutes on day 1 in combination with docetaxel (100 mg/m2 IV), repeated every 3 weeks. Combination treatment has been administered up to a maximum of 9 cycles, at which point bevacizumab monotherapy was continued until disease progression or unacceptable toxicity.[40633] Premedicate with dexamethasone 8 mg by mouth twice daily for 3 days, beginning 1 day prior to docetaxel administration, to reduce the incidence and severity of fluid retention and hypersensitivity reactions.[60484] If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes.[60402] [62350] [64400] In a clinical trial of patients with metastatic or inoperable locally recurrent breast cancer (n = 736), docetaxel was compared with docetaxel plus bevacizumab 7.5 mg/kg IV or 15 mg/kg IV. After a median follow-up of 25 months, the primary endpoint of progression-free survival (PFS) was significantly increased in the bevacizumab 15 mg/kg arm compared to docetaxel monotherapy (10 months vs. 8.1 months). The overall response rate (ORR) was also significantly improved (64.1% vs. 46.4%). Grade 3 or 4 neutropenia (19.8% vs. 17.3%), febrile neutropenia (16.2% vs. 11.3%), and hypertension (4.5% vs. 1.3%) occurred more frequently in the bevacizumab 15 mg/kg arm. The bevacizumab 7.5 mg/kg arm did not significantly improve PFS or ORR compared to placebo. Overall survival was not significantly different between any of the treatment arms.[40633]

    For relapsed/refractory metastatic breast cancer in combination with capecitabine†.
    Intravenous dosage
    Adults

    15 mg/kg IV over 90 minutes on day 1 with capecitabine 1,250 mg/m2 PO twice daily on days 1 to 14, repeated every 3 weeks. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. In a clinical trial with a primary endpoint of progression-free survival, 462 patients with previously-treated metastatic breast cancer were randomized to receive capecitabine alone or in combination with bevacizumab. The objective response rate showed significant improvement with the addition of bevacizumab therapy, as determined by the independent review facility (IRF) (19.8% vs. 9.1%). However, combination therapy did not increase progression-free survival as compared to capecitabine alone (HR 0.98). The median duration of response and the proportion of patients achieving a response duration of 4 months was similar in both groups.

    For the first-line treatment of HER2-positive locally recurrent or metastatic breast cancer in combination with trastuzumab and docetaxel†.
    Intravenous dosage
    Adults

    15 mg/kg IV over 90 minutes on day 1 in combination with trastuzumab (8 mg/kg IV day 1, then 6 mg/kg IV every 3 weeks) and docetaxel (100 mg/m2 IV day 1), repeated every 3 weeks has been evaluated in a clinical trial. Premedicate with dexamethasone 8 mg by mouth twice daily for 3 days, beginning 1 day prior to docetaxel administration, to reduce the incidence and severity of fluid retention and hypersensitivity reactions. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes, and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. Progression-free survival (PFS) was not extended with the original analysis of the study, but it was significantly improved when an independent review committee assessed PFS.[48880]

    For the treatment of neovascular (wet) age-related macular degeneration† (AMD).
    Intravitreous injection dosage†
    Adults and Geriatrics

    1.25 mg (0.05 mL) once a month by intravitreal injection into affected eye. Prior to intravitreal injection, prepare the eye with a local anesthetic and povidone iodine and/or a broad spectrum antibiotic. Following the injection, monitor patient for elevation in intraocular pressure (IOP) and endophthalmitis. Treatment continues on a monthly basis until macular edema, subretinal fluid, and/or pigment epithelial detachment is resolved. In clinical evaluation, improved visual acuity and central retinal thickness measurements were evident by week 1 of bevacizumab therapy. Improvements continued through the third month of therapy at which time the mean visual acuity improved from 20/160 to 20/125 (p < 0.001) and the mean central retinal thickness decreased by 99.6 micrometers (p < 0.001). A maximum of 4 doses was clinically evaluated.

    For the treatment of diabetic macular edema†.
    Intravitreous injection dosage†
    Adults

    The American Diabetes Association (ADA) recommends intravitreous anti-vascular endothelial growth factor (anti-VEGF) agents, such as bevacizumab, as first-line therapies for the management of eyes with central-involved diabetic macular edema (CIDME). Most patients require near-monthly intravitreous injections during the first 12 months, with fewer injections needed in subsequent years. Data from limited studies suggest a single 1.25 mg (0.05 mL) intravitreal injection into the affected eye as an effective dose. Prior to intravitreal injection, prepare the eye with a local anesthetic and povidone iodine or a broad spectrum antibiotic. Following the injection, monitor patient for elevation in intraocular pressure (IOP) and endophthalmitis. In one clinical trial, 103 eyes of 97 patients were randomized to intravitreal bevacizumab (IVB), IVB plus 2 mg intravitreal triamcinolone (IVB/IVT), or focal or modified grid laser (MPC). At 6 weeks, visual acuity (VA) and central macular thickness (CMT) significantly improved from baseline in both the IVB and IVB/IVT groups (VA: -0.21 +/- 0.19 logMAR and -0.21 +/- 0.22 logMAR, respectively [p < 0.0001 vs. baseline for both groups]; CMT: -62 +/- 102 microns and -90 +/- 133 microns, respectively [p < 0.001 for vs. baseline for both groups]). At week 12, VA was significantly improved compared to baseline in only the IVB group (-0.22 +/- 0.23 logMAR [p < 0.0001]), and CMT was not improved in either group. In the MPC group, VA significantly decreased at weeks 6 and 12; however, beneficial effects of MPC may not be seen before at least 12 weeks. In another study, 14 patients with bilateral disease received an intravitreal injection of 4 mg triamcinolone in one eye and an intravitreal injection of 1.25 mg bevacizumab in the other. VA was significantly improved in both eyes at 4 weeks, but was only significantly improved over baseline in the triamcinolone-treated eye at 12 weeks (48.4%, p = 0.001); VA continued to be improved in only the triamcinolone-eye at week 24 (26.6%, p = 0.03). Additionally, improvement in foveal thickness was significantly better in the triamcinolone treated eye at weeks 4, 12, and 24. There was, however, a significantly higher increase in intraocular pressure in the triamcinolone-treated eyes vs. the bevacizumab-treated eyes at week 24 (p = 0.046).

    For the treatment of proliferative diabetic retinopathy†.
    Intravitreous injection dosage†
    Adults

    According to the American Diabetes Association (ADA), intravitreous anti-vascular endothelial growth factor (anti-VEGF) agents, such as bevacizumab, may be considered for management of proliferative diabetic retinopathy (PDR), especially if high-risk characteristics are present. Limited data suggest 1.25 mg by intravitreous injection alone or as adjunctive treatment to panretinal photocoagulation may be effective in slowing progression. Forty (80 eyes) type-2 diabetic patients with high-risk bilateral PDR and no previous panretinal photocoagulation (PRP) or traction retinal detachment (TRD) were randomized to scatter laser treatment + a single injection of intravitreal bevacizumab (IVB) 1.25 mg in one eye and scatter laser + sham injection in the other eye. Complete regression of neovascularization (NV) was seen in 87.5% (n = 35) of IVB-treated eyes compared to 25% (n = 10) of sham-treated eyes at week 6 (p < 0.005). However, this difference was no longer apparent by week 16. In another study, IVB was shown to be an effective adjunctive treatment to PRP in patients with high-risk PDP, especially in the absence of clinically significant macular edema (CSME). Forty-one eyes were randomized to PRP alone or PRP plus IVB 1.25 mg. CSME was present in 22 eyes at time of randomization. After 3 months, best-corrected visual acuity (BCVA) was significantly worse in the PRP only group compared to baseline (0.23 +/- 0.18 logMAR to 0.29 +/- 0.21 logMAR; p = 0.041); there was no statistically significant change in the PRP/IVB group. Central macular thickness (CMT) was significantly decreased from baseline (294.09 +/- 135.14 microns) in the PRP/IVB group at months 1 (239.09 +/- 71.19 microns; p = 0.012) and 3 (236.81 +/- 61.05 microns; p = 0.008); there was no statistically significant change in the PRP group. There was no significant change in BCVA in the patients with CSME in either treatment group; however, there was a significant improvement from baseline in CMT in the PRP/IVB group at months 1 and 3 (359.43 +/- 127.11 microns to 267.71 +/- 65.28 microns; p = 0.003 and 252.14 +/-48.92 microns; p = 0.001, respectively). In eyes without CSME there was no statistically significant change from baseline in BCVA or CMT in the PRP/IVB group; whereas, in the PRP only group, BCVA was significantly worse at 1 and 3 months (0.18 +/- 0.17 logMAR to 0.26 +/- 0.19 logMAR; p = 0.047 and 0.30 +/- 0.21 logMAR; p = 0.011, respectively) and CMT increased (203.14 +/- 32.92 microns to 242.29 +/- 76.79 microns; p = 0.004 and 248.36 +/- 87.16 microns; p = 0.016, respectively). In eyes without CSME, there was a statistically significant greater proportion of eyes with visual loss >= 0.1 logMAR in the PRP only group than in the PRP/IVB group (p = 0.020); there was no statistically significant difference in both groups in eyes with CSME. Additionally, statistically significant fewer eyes developed vitreous hemorrhage in the PRP/IVB group than in the PRP only group (p = 0.023). In another clinical trial, 38 patients (38 eyes) with active PDR defined as actively vascularized fibrovascular tissue (FVT) refractory to previous PRP or severe fresh VH precluding completion of PRP were given 1 to 3 injections of IVB 1.25 mg. Initial injections were administered at least 3 months after the last session of PRP or at least 1 month after occurrence of VH. Additional IVB was administered at intervals of 6 or 12 weeks if there was incomplete resolution of VH and/or inadequate regression of the active vascular component of FVT to decrease the risk of VH. Statistically significant resolution of VH compared to baseline was demonstrated at 1 (p = 0.014), 12 (p = 0.0001), and 20 (p = 0.002) weeks after the first injection with younger patients showing a greater degree of resolution. Additionally, there was significant improvement in mean BCVA at weeks 1, 6, 12, and 20 compared to baseline (0.86 +/-0.59 logMAR, p = 0.033; 0.78+/-0.65 logMAR, p = 0.035; 0.73+/-0.58 logMAR, p < 0.001; 0.53+/-0.35 logMAR, p = 0.002, respectively vs. 1.13+/-0.84 logMAR). Although the vascular component of FVT appeared to regress, there was no statistically significant change in the extent of FVT compared to baseline. TRD developed in 2 eyes with moderate FVT 1.5 to 2 months after a second IVB injection.

    For the treatment of previously untreated, advanced, unresectable malignant pleural mesothelioma†, in combination with cisplatin and pemetrexed†.
    Intravenous dosage
    Adults

    15 mg/kg IV over 90 minutes on day 1, plus pemetrexed (500 mg/m2 IV over 10 minutes), followed 30 minutes later by cisplatin (75 mg/m2 IV over 2 hours), every 21 days for 6 cycles. After completion of the last cycle, begin maintenance bevacizumab 15 mg/kg IV every 21 days until disease progression or unacceptable toxicity. Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration. Premedicate pemetrexed with dexamethasone 4 mg by mouth twice daily for 3 days, beginning the day before pemetrexed administration to reduce cutaneous reactions. Additionally, supplement with folic acid (400 to 1,000 mcg by mouth daily) and vitamin B12 (1 mg IM every 3 months) beginning 7 days prior to the first dose of pemetrexed and continuing for 21 days after the last dose to reduce the severity and frequency of hematologic and GI toxicities; after the first dose, vitamin B12 may be given on the same day as pemetrexed. Do not substitute oral for IM vitamin B12. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Oncology: 15 mg/kg IV every 3 weeks or 10 mg/kg IV every 2 weeks.
    Ocular: The maximum tolerated intraocular dose has not been determined; in clinical trials, the highest dose was 2.5 mg/0.1 mL monocular.

    Geriatric

    Oncology: 15 mg/kg IV every 3 weeks or 10 mg/kg IV every 2 weeks.
    Ocular: The maximum tolerated intraocular dose has not been determined; in clinical trials, the highest dose was 2.5 mg/0.1 mL monocular.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustment in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustment in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Do NOT administer bevacizumab as an IV push or bolus.
    Administer the first infusion of bevacizumab intravenously (IV) over 90 minutes.
    If the first infusion is tolerated, the second dose may be given IV over 60 minutes.
    All subsequent infusions may be administered IV over 30 minutes if the 60-minute infusion is tolerated.[60402] [62350] [64400]
    Rapid infusion rate†: Bevacizumab has been administered IV at a standard infusion rate of 0.5 mg/kg/minute for all doses incuding the initial infusion (i.e. 5 mg/kg IV over 10 minutes; 10 mg/kg IV over 20 minutes; 15 mg/kg IV over 30 minutes) in one trial (n = 370; 2,311 doses).[41625] In other data, both bevacizumab 5 mg/kg and 7.5 mg/kg have been administered over 10 minutes.[64516] [64518] [64519]
     
    Infusion preparation:
    Withdraw the appropriate amount of bevacizumab and dilute in a total volume of 100 mL of 0.9% Sodium Chloride Injection.
    Do not administer or mix with Dextrose Injection.
    Discard any unused portion left in the preservative-free vial.
    Store diluted bevacizumab under refrigeration at 2 to 8 degrees C (36 to 46 degrees F) for up to 8 hours.[60402] [62350] [64400]

    Other Administration Route(s)

    Intravitreous administration
    NOTE: Bevacizumab is not approved by the FDA for intravitreous administration
    Bevacizumab has been given off-label by intravitreal administration. Only for use by ophthalmologists trained in these specialized administration techniques.
    Adequate anesthesia (e.g., 2% lidocaine subconjunctival or 2 to 4% lidocaine topically) plus povidone-iodine and/or a broad-spectrum microbicide should be given prior to intravitreal injection.
    Use controlled aseptic conditions, which include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent).
    Inspect product visually for particulate matter and discoloration prior to administration.
    Using aseptic technique, withdraw approximately 0.12 mL of bevacizumab from the vial contents into a 1 ml polypropylene tuberculin syringe. Avoid using a filter needle to withdraw the drug, doing so may cause the large proteins to adhere to the filter.
    Before injection in a single eye, a sterile standard 30-gauge needle (5/8 inch) should be placed on the syringe, and the plunger advanced to 0.05 mL so that all the dead space is removed. If the contralateral eye requires treatment, the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before administration to the other eye.
    Following the injection, monitor patient for elevation in intraocular pressure (IOP) and for endophthalmitis.

    STORAGE

    Avastin:
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store between 36 to 46 degrees F
    MVASI:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Infusion-related reactions

    Infusion-related reactions have been reported with bevacizumab therapy. Decrease the rate of infusion in patients who develop mild reactions; hold the infusion in patients who develop clinically significant reactions and consider resuming at a slower rate following symptom resolution. Discontinue bevacizumab therapy in patients who develop a severe infusion reaction and administer medical therapy (e.g., epinephrine, corticosteroids, IV antihistamines, bronchodilators, or oxygen) as appropriate.

    Impaired wound healing, surgery

    Impaired wound healing has occurred in patients treated with bevacizumab; some cases have been fatal. Discontinue bevacizumab at least 28 days prior to elective surgery; do not administer bevacizumab for at least 28 days following major surgery and until adequate wound healing. The safety of resuming bevacizumab after resolution of wound healing complications has not been established. Necrotizing fasciitis, including fatal cases, has occurred in patients treated with bevacizumab following wound healing complications, GI perforation, or fistula formation; discontinue bevacizumab in patients who develop necrotizing fasciitis.

    Fistula, GI obstruction, GI perforation, ovarian cancer, radiation therapy

    Avoid bevacizumab therapy 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/GI obstruction.[60402] Serious fistulae have occurred with bevacizumab therapy, with the highest incidence in patients with cervical cancer. Serious and sometimes fatal GI perforation has also been reported with bevacizumab therapy; the incidence is highest in patients with a history of pelvic radiation therapy. Perforation can be complicated by an intra-abdominal abscess, fistula formation, and the need for diverting ostomies. Patients who develop a GI-vaginal fistula may experience a bowel obstruction and require surgical intervention and/or a diverting ostomy. Discontinue bevacizumab in patients who develop a GI perforation, tracheoesophageal fistula, any grade 4 fistula, or a fistula involving any internal organ.[60402] [62350] [64400]

    Bleeding, GI bleeding, intracranial bleeding, vaginal bleeding

    Serious bleeding events (e.g., CNS hemorrhage/intracranial bleeding, epistaxis, hematemesis, hemoptysis, GI bleeding, and vaginal bleeding) have been reported with bevacizumab therapy; some cases were fatal. Discontinue bevacizumab in patients who develop grade 3 or 4 bleeding; do not administer bevacizumab in patients who have a history of hemoptysis with 1/2 teaspoon or more of red blood.

    Hypertension, hypertensive crisis

    Severe hypertension has been reported with bevacizumab therapy. Monitor blood pressure every 2 to 3 weeks during treatment with bevacizumab and at regular intervals following therapy in patients who develop bevacizumab -induced or -exacerbated hypertension. Administer antihypertensive therapy as appropriate. Hold bevacizumab therapy in patients with severe hypertension that is not controlled with antihypertensive therapy; resume therapy when hypertension is controlled with medical management. Discontinue bevacizumab in patients who develop hypertensive crisis or hypertensive encephalopathy.[60402] [62350] [64400]

    Angina, diabetes mellitus, geriatric, myocardial infarction, stroke, thromboembolic disease

    Arterial (e.g., cerebral infarction/stroke, transient ischemic attack, myocardial infarction, and angina) and venous (e.g., pulmonary embolism (PE)) thromboembolic disease has been reported with bevacizumab therapy; some arterial thromboembolic events (ATE) were fatal. Discontinue bevacizumab therapy in patients who develop a severe ATE or a grade 4 venous thromboembolism including a PE. The safety of restarting bevacizumab after an ATE is resolved is not known. Patients with a history of arterial thromboembolism or diabetes mellitus and geriatric patients aged greater than 65 years may have an increased risk of developing ATE.[60402] [62350] [64400]

    Heart failure

    Use bevacizumab with caution in patients who have a history of heart failure; discontinue bevacizumab in patients who develop congestive heart failure (CHF). Left ventricular dysfunction and CHF have been reported with bevacizumab therapy; the risk is increased in patients who have received prior anthracycline therapy. Bevacizumab is not indicated for use with anthracycline-based chemotherapy.

    Proteinuria, renal impairment

    Severe proteinuria including nephrotic syndrome has been reported with bevacizumab therapy; renal impairment has also occurred. Regularly for proteinuria via serial dipstick urine analyses during bevacizumab therapy and monitor renal function (e.g., serum creatinine/BUN levels); perform a 24-hour urine collection in patients who have a 2+ or greater urine dipstick reading. Data from a postmarketing safety study showed poor correlation between Urine Protein/Creatinine Ratio (UPCR) and 24-hour urine protein. Hold bevacizumab for urine protein levels of 2 grams or more per 24 hours; resume therapy when urine protein levels are less than 2 grams per 24 hours. Discontinue bevacizumab in patients who develop nephrotic syndrome.

    Encephalopathy

    Posterior Reversible Encephalopathy Syndrome (PRES) has been reported with bevacizumab use. Symptoms of PRES include seizures, headache, lethargy, confusion, blindness, and other visual and neurologic disturbances; mild to severe hypertension may be present. Discontinue bevacizumab therapy if PRES is suspected or diagnosed; this syndrome may be confirmed on magnetic resonance imaging. The safety of reinitiating bevacizumab therapy in patients who developed PRES is not known.

    Esophageal varices

    Use bevacizumab with caution in patients with a history of esophageal varices; evaluate patients with hepatocellular cancer (HCC) for the presence of varices within 6 months of initiation of treatment with bevacizumab. The safety of bevacizumab in patients with variceal bleeding within 6 months prior to treatment, untreated or incompletely treated varices with bleeding, or high risk of bleeding varices has not been established as these patients were excluded from clinical trials of bevacizumab in HCC.

    Children, infants, neonates

    The safety and effectiveness of bevacizumab in neonates, infants, children, and adolescents have not been established; bevacizumab is not approved for use in patients under the age of 18 years. Cases of nonmandibular osteonecrosis have been reported in pediatric patients who received bevacizumab. There was no antitumor activity observed in 8 pediatric patients with relapsed glioblastoma following treatment with bevacizumab plus irinotecan. Also, the addition of bevacizumab to standard of care did not improve event-free survival in pediatric patients enrolled in 2 randomized clinical trials, one in high grade glioma (n = 121) and one in metastatic rhabdomyosarcoma or non-rhabdomyosarcoma soft tissue sarcoma (n = 154).[60402] [62350] [64400] Vascular endothelial growth factor (VEGF) is required for normal vascular development in neonates during the first weeks postnatally; inactivation of VEGF at this time may result in regression of the vasculature, renal failure, and death.[28178]

    Pregnancy

    Bevacizumab may cause fetal harm if given during pregnancy based on animal studies and its mechanism of action.[60402] [62350] [64400] Angiogenesis is critical to fetal development, and the inhibition of angiogenesis following administration of bevacizumab is likely to have adverse effects on the pregnancy. Vascular endothelial growth factor (VEGF) is required for angiogenesis during the development of the corpus luteum.[28178] Females of reproductive potential should avoid pregnancy during bevacizumab therapy; these women should be advised of the potential risk to a fetus if pregnancy occurs. Fetal malformations have been reported in postmarketing surveillance of bevacizumab; however, these reports are insufficient to determine drug-associated risks. In animal studies, bevacizumab doses of approximately 1 to 10 times the clinical dose administered during organogenesis in rabbits resulted in fetal resorptions, decreased maternal and fetal weight gain, and multiple congenital malformations including corneal opacities and abnormal ossification of the skull and skeleton including limb and phalangeal defects. Skeletal deformities were observed at all dose levels, with meningocele observed only at 10-times the clinical dose; the number of litters with malformed fetuses increased with increasing dose.[60402] [62350] [64400]

    Contraception requirements, infertility, ovarian failure, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during bevacizumab treatment. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 6 months after treatment with bevacizumab. Women who become pregnant while receiving bevacizumab should be apprised of the potential hazard to the fetus. Ovarian failure has occurred with bevacizumab therapy; therefore, female infertility may occur. Long-term effects on fertility are unknown. Inform females of reproductive potential of the risk of ovarian failure before bevacizumab initiation.

    Breast-feeding

    It is not known if bevacizumab is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Although human IgG is present in human milk, published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in significant amounts. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during bevacizumab therapy and for 6 months after the last dose. One infant was breast-fed, apparently without harm, after maternal intravitreal bevacizumab injections in low doses. The mother was treated with 14 intravitreal bevacizumab injections over a 20-month period and 5 of the injections were given while she was breast-feeding (age of infant not stated). No mention was made of adverse effects in this infant, but she became pregnant again, received 3 additional injections, and delivered an infant who developed normally at 12 months of age.

    ADVERSE REACTIONS

    Severe

    leukopenia / Delayed / 0-53.0
    thrombocytopenia / Delayed / 0-40.0
    neutropenia / Delayed / 0-27.0
    exfoliative dermatitis / Delayed / 0-23.0
    fatigue / Early / 1.5-19.0
    hypertension / Early / 5.0-18.0
    diarrhea / Early / 0-18.0
    abdominal pain / Early / 0-12.0
    thromboembolism / Delayed / 0-11.0
    proteinuria / Delayed / 0.7-10.0
    thrombosis / Delayed / 0-10.0
    asthenia / Delayed / 0-10.0
    hyperkalemia / Delayed / 0-9.0
    infection / Delayed / 0-8.0
    bleeding / Early / 0.4-7.0
    hypokalemia / Delayed / 0-7.0
    back pain / Delayed / 0-6.0
    pelvic pain / Delayed / 0-6.0
    lymphopenia / Delayed / 0-6.0
    epistaxis / Delayed / 0-5.0
    pneumonitis / Delayed / 0-5.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 0-4.5
    ileus / Delayed / 0-4.0
    dyspnea / Early / 0-4.0
    hyponatremia / Delayed / 0-4.0
    headache / Early / 0-4.0
    hematoma / Early / 0-3.0
    bladder fistula / Delayed / 0-1.8
    vaginal fistula / Delayed / 0-1.8
    bronchopleural fistula / Delayed / 0-1.8
    gastrointestinal fistula / Delayed / 0-1.8
    biliary fistula / Delayed / 0-1.8
    tracheoesophageal fistula / Delayed / 0-1.8
    pulmonary embolism / Delayed / 0-1.5
    hearing loss / Delayed / 0-1.5
    nephrotic syndrome / Delayed / 0-1.0
    thrombotic microangiopathy / Delayed / 0-1.0
    infusion-related reactions / Rapid / 0.4-0.4
    anemia / Delayed / 0.4-0.4
    hypertensive crisis / Early / Incidence not known
    GI bleeding / Delayed / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    hemoptysis / Delayed / Incidence not known
    hematemesis / Delayed / Incidence not known
    stroke / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    angina / Early / Incidence not known
    necrotizing fasciitis / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    nasal septum perforation / Delayed / Incidence not known
    osteonecrosis / Delayed / Incidence not known
    pulmonary hypertension / Delayed / Incidence not known
    peptic ulcer / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    aortic dissection / Delayed / Incidence not known

    Moderate

    stomatitis / Delayed / 15.0-33.0
    hypomagnesemia / Delayed / 0-27.0
    hypoalbuminemia / Delayed / 0-16.0
    peripheral edema / Delayed / 0-15.0
    elevated hepatic enzymes / Delayed / 0-15.0
    dysarthria / Delayed / 0-14.0
    dysphonia / Delayed / 0-13.0
    hypocalcemia / Delayed / 0-12.0
    dehydration / Delayed / 0-10.0
    hemorrhoids / Delayed / 0-8.0
    chest pain (unspecified) / Early / 0-8.0
    blurred vision / Early / 0-2.4
    oral ulceration / Delayed / 0-1.8
    gastritis / Delayed / 0-1.5
    antibody formation / Delayed / 0-0.6
    encephalopathy / Delayed / 0-0.5
    peripheral neuropathy / Delayed / Incidence not known
    vaginal bleeding / Delayed / Incidence not known
    confusion / Early / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    wheezing / Rapid / Incidence not known
    hyperglycemia / Delayed / Incidence not known

    Mild

    arthralgia / Delayed / 28.0-45.0
    anorexia / Delayed / 0-36.0
    amenorrhea / Delayed / 0-34.0
    cough / Delayed / 0-30.0
    myalgia / Early / 19.0-29.0
    dizziness / Early / 0-23.0
    weight loss / Delayed / 0-21.0
    insomnia / Early / 0-21.0
    fever / Early / 0-18.0
    anxiety / Delayed / 0-17.0
    weakness / Early / 13.0-15.0
    sinusitis / Delayed / 0-15.0
    rhinorrhea / Early / 0-10.0
    xerosis / Delayed / 0-7.0
    syncope / Early / 0-3.0
    gastroesophageal reflux / Delayed / 0-2.4
    gingivitis / Delayed / 0-2.4
    tinnitus / Delayed / 0-2.1
    acne vulgaris / Delayed / 0-1.5
    vomiting / Early / 0.7-0.7
    nausea / Early / 21.3-0.7
    metallic taste / Early / 10.0
    rhinitis / Early / 10.0
    lacrimation / Early / 10.0
    lethargy / Early / Incidence not known
    diaphoresis / Early / Incidence not known
    chills / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Panitumumab: (Major) Do not use panitumumab with bevacizumab in combination with chemotherapy as increased mortality and toxicity may occur. In an interim analysis of an open-label, multicenter, randomized clinical trial of patient with previously untreated metastatic colorectal cancer, the combination of panitumumab, bevacizumab, and chemotherapy resulted in decreased overall survival and an increased incidence of grade 3 to 5 adverse reactions compared with bevacizumab plus chemotherapy without panitumumab, including fatalities. Patients randomized to the panitumumab arm also received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, and 5-fluorouracil) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Solriamfetol: (Moderate) Monitor blood pressure and heart rate during coadministration of solriamfetol, a norepinephrine and dopamine reuptake inhibitor, and bevacizumab. Concurrent use of solriamfetol and other medications that increase blood pressure and/or heart rate may increase the risk of such effects. Coadministration of solriamfetol with other drugs that increase blood pressure or heart rate has not been evaluated.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

    PREGNANCY AND LACTATION

    Pregnancy

    Bevacizumab may cause fetal harm if given during pregnancy based on animal studies and its mechanism of action.[60402] [62350] [64400] Angiogenesis is critical to fetal development, and the inhibition of angiogenesis following administration of bevacizumab is likely to have adverse effects on the pregnancy. Vascular endothelial growth factor (VEGF) is required for angiogenesis during the development of the corpus luteum.[28178] Females of reproductive potential should avoid pregnancy during bevacizumab therapy; these women should be advised of the potential risk to a fetus if pregnancy occurs. Fetal malformations have been reported in postmarketing surveillance of bevacizumab; however, these reports are insufficient to determine drug-associated risks. In animal studies, bevacizumab doses of approximately 1 to 10 times the clinical dose administered during organogenesis in rabbits resulted in fetal resorptions, decreased maternal and fetal weight gain, and multiple congenital malformations including corneal opacities and abnormal ossification of the skull and skeleton including limb and phalangeal defects. Skeletal deformities were observed at all dose levels, with meningocele observed only at 10-times the clinical dose; the number of litters with malformed fetuses increased with increasing dose.[60402] [62350] [64400]

    It is not known if bevacizumab is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Although human IgG is present in human milk, published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in significant amounts. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during bevacizumab therapy and for 6 months after the last dose. One infant was breast-fed, apparently without harm, after maternal intravitreal bevacizumab injections in low doses. The mother was treated with 14 intravitreal bevacizumab injections over a 20-month period and 5 of the injections were given while she was breast-feeding (age of infant not stated). No mention was made of adverse effects in this infant, but she became pregnant again, received 3 additional injections, and delivered an infant who developed normally at 12 months of age.

    MECHANISM OF ACTION

    Bevacizumab binds to vascular endothelial growth factor (VEGF) and prevents the binding of VEGF with its receptors, VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1/KDR), found on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Administration of bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused a reduction of microvascular growth and inhibition of metastatic disease progression.[60402] [62350] [64400]
     
    In the body, VEGF functions in angiogenesis by regulating both vascular proliferation and permeability. VEGF is unique due to its specificity and potency for vascular endothelium. Also, VEGF has anti-apoptotic effects on cells in newly formed vessels by inducing bcl-2 and A1, anti-apoptotic proteins. Other members of the VEGF gene family have been identified; however, their function has not been fully characterized. VEGF is expressed in tumor cells, macrophages, T-cells, smooth muscle cells, kidney cells, mesangial cells, keratinocytes, astrocytes, and osteoblasts. Expression of VEGF is regulated by differentiation, transformation, cytokines, hormones, and growth factors (e.g., epidermal growth factor, transforming growth factor-beta, keratinocyte growth factor, interleukin-1 beta, prostaglandin E2, and insulin-like growth factor-1), and oxygen deprivation. Under hypoxic conditions, hypoxia-inducible factor-I activates transcription of the VEGF-A gene.[28178] VEGF-A promotes the proliferation of endothelial cells and chemotaxis of endothelial cells and monocytes. Also, VEGF-A can cause differentiation of monocytes into endothelial-like cells and inhibit the maturation of dendritic cells. These effects can deplete host immune cells and could lead to immunosuppression.[28178] VEGF-A also increases vascular permeability leading to a leakage of plasma proteins that results in the formation of an extravascular fibrin gel. The increased vascular permeability results in increased intratumoral interstitial fluid pressure, which reduces the delivery of antineoplastic therapies.[28178] During fetal development and the early post-natal period, VEGF-A is critical for normal maturation; however, its function evolves with age. In mice, at about 4 weeks, vascularization becomes VEGF-independent. In adult animals, VEGF-A inactivation has little effect on the vasculature; although, it is required during the development of the corpus luteum and for wound healing. Reduced levels of VEGF may cause neurodegeneration by impairing neural tissue perfusion.[28179]

    PHARMACOKINETICS

    Bevacizumab is administered as an intravenous infusion. The estimated half-life was 20 days (range, 11 to 50 days), the mean central volume of distribution was 2.9 L (coefficient of variance (CV), 22%), and the mean clearance was 0.23 L/day (CV, 33%) in patients who received 1 to 20 mg/kg of bevacizumab weekly, every 2 weeks, or every 3 weeks in a population pharmacokinetic (PK) analysis (n = 491). Bevacizumab exhibits linear pharmacokinetics (PK), with the predicted time to reach greater than 90% of steady state concentration is 84 days.[60402] [62350] [64400]
     
    Affected cytochrome P450 isoenzymes and drug transporters: None.[60402] [62350] [64400]

    Intravenous Route

    In PK simulations, the median trough level (Cmin) was 80.3 mcg/mL on day 84 following a bevacizumab dose of 5 mg/kg IV given once every 2 weeks. The accumulation ratio was 2.8 following a bevacizumab dose of 10 mg/kg IV given once every 2 weeks.