Avastin

Drug overview for AVASTIN (bevacizumab):

Generic name: BEVACIZUMAB
Drug class: Ophthalmic - Macular Degeneration Agents
Therapeutic class: Ophthalmic Agents

Bevacizumab, bevacizumab-adcd, bevacizumab-awwb, bevacizumab-bvzr, and bevacizumab-maly, recombinant humanized monoclonal antibodies, are antineoplastic agents. Bevacizumab-adcd (Vegzelma(R)), bevacizumab-awwb (Mvasi(R)), bevacizumab-bvzr (Zirabev(R)), and bevacizumab-maly (Alymsys(R)) are biosimilar to bevacizumab (Avastin(R)). FDA defines a biosimilar as a biological product that is highly similar to an FDA-licensed reference biological with the exception of minor differences in clinically inactive components and for which there are no clinically meaningful differences in safety, purity, or potency.

The claim of biosimilarity is based on a totality-of-evidence approach, which includes consideration of data from analytical, animal, and clinical studies (e.g., human pharmacokinetic and pharmacodynamic studies, clinical immunogenicity assessment, additional comparative clinical studies). Therefore, biosimilarity may be established even when there are formulation or minor structural differences as long as these differences are not clinically meaningful. Biosimilars are approved through an abbreviated licensure pathway that establishes biosimilarity between the proposed biological and the reference biological but does not independently establish safety and effectiveness of the proposed biological.

In order to be considered an interchangeable biosimilar, a biological product must meet additional requirements beyond demonstrating biosimilarity to its reference product; these requirements include demonstrating that the biological product can be expected to produce the same clinical results as the reference product in any given patient and, for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is no greater than the risk of using the reference product without such alteration or switch. Biosimilar products that are interchangeable can be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product. None of the currently available bevacizumab biosimilars have interchangeable data at this time. In this monograph, unless otherwise stated, the term ''bevacizumab products'' refers to bevacizumab (the reference drug) and its biosimilars (bevacizumab-adcd, bevacizumab-awwb, bevacizumab-bvzr, and bevacizumab-maly).

Several bevacizumab biosimilars are available. Biosimilarity of these products has been demonstrated for the indications described in Table 1. Biosimilarity to originator bevacizumab is additionally supported by comparative clinical studies in patients with non-small cell lung cancer.

Table 1. Bevacizumab Biosimilar Products and FDA-licensed Indications. FDA Metastat NSCLC GBM Metastat Cervical Ovarian HCC labeled ic CRC ic RCC cancer cancer indicati on Bevacizu X X X X X X mab-adcd (Vegzelm a(R)) Bevacizu X X X X X X mab-awwb (Mvasi(R )) Bevacizu X X X X X X mab-bvzr (Zirabev (R)) Bevacizu X X X X X X mab-maly (Alymsys (R)) Bevacizumab-maly (Alymsys(R)) is only labeled for use in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for the treatment of platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who have received no more than 2 prior chemotherapy regimens.

Other biosimilars have additional ovarian cancer indications (same ovarian cancer indications as originator bevacizumab). CRC, colorectal cancer; GBM, glioblastoma; HCC, hepatocellular carcinoma; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma.

DRUG IMAGES

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The following indications for AVASTIN (bevacizumab) have been approved by the FDA:

Indications:
None.

Professional Synonyms:
None.

The following dosing information is available for AVASTIN (bevacizumab):

Dosing
Administration
Dosing Information
Generic

Bevacizumab product dosage reductions are not recommended in any patient; instead, the drug generally should either be temporarily suspended or permanently discontinued, according to causality (see Table 2).

Table 2. Recommended Dosage Modification for Bevacizumab Product Adverse Reactions.

Adverse Reaction Dosage Modification based on Severity Arterial thromboembolism Discontinue bevacizumab product if severe Congestive heart failure Discontinue bevacizumab product Fistula Grade 4 or involving any internal organ: discontinue bevacizumab product GI perforation Any grade: discontinue bevacizumab product Hemorrhage Grade 3 or 4 hemorrhage: discontinue bevacizumab product Recent history of hemoptysis of 0.5 teaspoon or more: withhold bevacizumab product Hypertension Severe hypertension: withhold bevacizumab product if not controlled with medical management; resume bevacizumab product once controlled Hypertensive crisis or hypertensive encephalopathy: discontinue bevacizumab product Infusion-related reactions Mild, clinically insignificant: decrease infusion rate Clinically significant: interrupt infusion; resume at a decreased rate of infusion after symptoms resolve Severe: discontinue bevacizumab product Necrotizing fasciitis Discontinue bevacizumab product Posterior reversible encephalopathy Discontinue bevacizumab product syndrome (PRES) Renal injury and proteinuria Proteinuria >=2 g per 24 hours in the absence of nephrotic syndrome: withhold bevacizumab product until proteinuria decreases to <2 g per 24 hours Nephrotic syndrome: discontinue bevacizumab product Tracheoesophageal fistula Any grade: discontinue bevacizumab product Venous thromboembolism Grade 4: discontinue bevacizumab product Wound healing complications Withhold bevacizumab product until adequate wound healing has occurred; the safety of resuming bevacizumab products after resolution of wound healing complications has not been established

Bevacizumab products are administered by IV infusion. Bevacizumab products are commercially available in single-dose vials at a concentration of 25 mg/mL. For IV infusion, the appropriate dose of the bevacizumab product should be withdrawn into a syringe and diluted in a total volume of 100 mL of 0.9%

sodium chloride using aseptic technique. Bevacizumab product infusions should not be administered or mixed with dextrose solutions. Any unused portion left in the vial should be discarded since the injection contains no preservative.

The initial dose of bevacizumab products should be infused over 90 minutes; if the first infusion is tolerated, the second dose may be infused over 60 minutes. If this second infusion also is tolerated, all subsequent doses may be infused over 30 minutes. One institution has reported use of shorter infusion times for bevacizumab at an infusion rate of 0.5

mg/kg per minute. The manufacturers state that no incompatibilities have been observed between originator bevacizumab, bevacizumab-awwb (Mvasi(R)), bevacizumab-bvzr (Zirabev(R)), or bevacizumab-maly (Alymsys(R)) and polyvinylchloride or polyolefin bags. No incompatibilities have been observed between bevacizumab-adcd (Vegzelma(R)) and polyolefin (polypropylene and polyethylene) bags.

Bevacizumab product vials should be protected from light and stored in the original carton at 2-8degreesC until use; freezing should be avoided. The injection should not be shaken prior to use. Once diluted, originator bevacizumab and bevacizumab-awwb (Mvasi(R)) may be stored at 2-8degreesC for up to 8 hours, bevacizumab-maly (Alymsys(R)) may be stored at 2-8degreesC for up to 12 hours, and bevacizumab-bvzr (Zirabev(R)) may be stored at 2-8degreesC for up to 16 days. Diluted bevacizumab-adcd (Vegzelma(R)) may be stored at 2-8degreesC for up to 24 hours or at room temperature (up to 30degreesC) for up to 4 hours.

No dosing information available.

No generic dosing information available.

The following precautions are available for AVASTIN (bevacizumab):

Pediatric
Pregnant
Lactation
Geriatric

Safety and efficacy of bevacizumab have not been established in pediatric patients younger than 18 years of age. Addition of bevacizumab to standard of care did not improve event-free survival in pediatric patients with high-grade glioma, metastatic rhabdomyosarcoma, or non-rhabdomyosarcoma soft tissue sarcoma in 2 clinical studies. Antitumor activity was also not observed in 8 pediatric patients who received bevacizumab plus irinotecan for relapsed glioblastoma.

Non-mandibular osteonecrosis has been reported in pediatric patients younger than 18 years of age who have received bevacizumab. Based on a population pharmacokinetic analysis of data from 152 pediatric and young adult patients with cancer (age range: 7 months to 21 years of age), the clearance of bevacizumab normalized by body weight in the pediatric patients was comparable to that in adults.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Based on its mechanism of action and findings from animal studies, bevacizumab may cause fetal harm when administered to pregnant women. Limited postmarketing reports describe cases of fetal malformations with use of bevacizumab in pregnancy; however, these reports are insufficient to determine drug-associated risks. When bevacizumab was administered IV to pregnant rabbits every 3 days during the period of organogenesis at dosages approximately 1-10 times the clinical dosage of 10 mg/kg, 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), were observed.

Animal models also link angiogenesis, VEGF, and VEGFR2 to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus.

It is not known whether bevacizumab is distributed into milk. Human immunoglobulin G1 (IgG1) is distributed into milk; however, published data suggest that antibodies in breast milk do not enter the neonatal and infant circulation in substantial amounts. The effects of bevacizumab on the breast-fed infant and on milk production also are unknown. Because of the potential for serious adverse reactions in nursing infants, advise women not to breast-feed during treatment with bevacizumab and for 6 months after the last dose.

Analysis of pooled data from 5 randomized controlled trials involving 1745 patients (35% were 65 years of age or older) showed that arterial thromboembolic events occurred more frequently in all patients receiving bevacizumab with chemotherapy compared with those receiving chemotherapy alone, regardless of age. However, the increase in the incidence of arterial thromboembolic events associated with concomitant bevacizumab therapy was greater in patients 65 years of age or older (8 versus 3%) compared with those younger than 65 years of age (2 versus 1%).