Bevacizumab is available as a 25-mg/mL injection solution in 4- and 16-mL single-dose (preservative-free) vials.1370 Each mL also contains a,a-trehalose dihydrate 60 mg, sodium phosphate monobasic monohydrate 5.8 mg, sodium phosphate dibasic anhydrous 1.2 mg, and polysorbate 20 0.4 mg in water for injection.1370
Bevacizumab injection solution should be visually inspected for particulate matter and discoloration prior to administration; if the solution is discolored or cloudy or if particulate matter is present, the vial should be discarded.1370 The appropriate volume of the drug should be withdrawn from the vial and diluted in 100 mL of sodium chloride 0.9%.1370
pH
Bevacizumab injection has a pH of 6.2.1370
Trade Name(s)
Avastin
Bevacizumab is administered by intravenous infusion following dilution of the appropriate dose in 100 mL of sodium chloride 0.9%.1370 The manufacturer recommends that the first infusion be administered over 90 minutes.1370 Administration time of the second infusion may be reduced to 60 minutes if the 90-minute infusion was tolerated; administration time of subsequent infusions may be further reduced to 30 minutes if the 60-minute infusion was tolerated.1370
Bevacizumab must not be diluted in or administered with dextrose-containing solutions.1370
Bevacizumab also has been administered by intravitreal injection;1372; 1797; 2117; 2167; 2237; 2456; 2457 this method of administration is not included in the manufacturer's prescribing information.1370
Bevacizumab injection is a clear to slightly opalescent, colorless to pale brown solution.1370 Intact vials should be stored at 2 to 8°C in the original carton until time of use to protect from light.1370 Vials or cartons of the drug should not be frozen or shaken.1370 The manufacturer states that any unused portions should be discarded.1370
The diluted solution in sodium chloride 0.9% may be stored for up to 8 hours at 2 to 8°C.1370 Bevacizumab must not be diluted in or administered with dextrose-containing solutions.1370
When bevacizumab has been administered by intravitreal injection, only small amounts of the injection have been withdrawn from a vial; stability and sterility of the remaining drug has been assessed.1372; 1797; 2117
Bevacizumab (Genentech) injection solution remaining in previously punctured vials was stored at 4°C for up to 6 months.1372 An immunoassay was used to determine the drug’s ability to bind vascular endothelial growth factor (VEGF)-165, and the concentration of bevacizumab was calculated by correlating the amount of bound bevacizumab to a standard curve.1372 In 3 months, 9.6% degradation occurred; maximum degradation of 12.7% occurred in 6 months.1372
Bevacizumab injection solution remaining in vials that were previously punctured for clinical use (i.e., punctured 4 to 5 times during the first month) was stored at 4°C and sampled thereafter at 1, 3, and 6 months.1797 Stability of bevacizumab was assessed by matrix-assisted laser desorption ionization/time-of-flight (MALDI-TOF) mass spectrometry (MS), and the authors concluded from these results that most of the molecular structure of bevacizumab did not degrade within 6 months.1797 Activity of bevacizumab was assessed by the amount of residual active VEGF measured in the in vitro mixture of bevacizumab and VEGF-165 and was expressed as the percentage of VEGF-165 consumed; activity of bevacizumab was noted to be 94.5, 94, and 91.6% at 1, 3, and 6 months, respectively, relative to that of bevacizumab at 0 months.1797 No bacterial or fungal growth was detected in any sample at any time throughout the study.1797
Bevacizumab (Hoffmann-La Roche) injection solution remaining in vials following the withdrawal of multiple 1.25-mg doses for multiple patients (average of 11 punctures for a single vial on a single day within 4 hours’ time) was stored at 4°C for up to 6 months.2117 Based on the results of reverse-phase high-performance liquid chromatography (RP-HPLC), the authors suggested that bevacizumab did not undergo degradation over the 6-month study period.2117 Similarly, the authors suggested that bevacizumab is stable in structure and conformation over the 6-month period based on the results of circular dichroism spectroscopy and fluorescence measurements.2117 While all samples tested negative for bacterial and fungal growth at 7 days, sterility was not evaluated over the entire 6-month period.2117
Freezing Solutions
The manufacturer states that bevacizumab injection solution should not be frozen.1370
Bevacizumab (Genentech) injection solution was packaged in 1-mL tuberculin syringes (Becton Dickinson) capped with a 30-gauge needle (Becton Dickinson) and stored at -10°C for 6 months.1372 An immunoassay was used to determine the drug’s ability to bind VEGF-165, and the concentration of bevacizumab was calculated by correlating the amount of bound bevacizumab to a standard curve.1372 In 6 months, 12% degradation occurred.1372
Packaging of bevacizumab into syringes causes increases in particle concentrations, mostly due to the presence of silicone oil microdroplets.2167 Freezing of bevacizumab injection solution and placebo (a solution closely resembling the vehicle of bevacizumab injection)1370 in syringes at -20°C caused immediate increases in particle concentrations to greater than 1.2 million particles per mL; by comparison, the mean particle concentration in bevacizumab withdrawn directly from the original glass vials was about 64,000 particles per mL.2167 While particle concentrations in bevacizumab syringes incubated at -20°C subsequently remained constant, particle concentrations in placebo syringes increased up to 6 million particles per mL over the 12-week study period.2167 Repeated freeze-thaw cycles (e.g., 5 or 10 cycles) caused increased particle concentrations and greater than 10% bevacizumab monomer loss.2167 Bevacizumab packaged as 0.05 mL in 1-mL tuberculin syringes (Becton Dickinson) and stored at -20°C demonstrated substantially lower particle counts (particularly for particles in the larger size range of 2 to 10 µm) than bevacizumab packaged as 0.05 mL in 0.3-mL plastic insulin syringes (Becton Dickinson).2167
Syringes
Bevacizumab (Genentech) injection solution was packaged in 1-mL tuberculin syringes (Becton Dickinson) capped with a 30-gauge needle (Becton Dickinson) and stored at 4°C for up to 6 months.1372 An immunoassay was used to determine the drug’s ability to bind VEGF-165, and the concentration of bevacizumab was calculated by correlating the amount of bound bevacizumab to a standard curve.1372 In 3 months, 8.8% degradation occurred; maximum degradation of 15.9% occurred in 6 months.1372
Packaging of bevacizumab into syringes causes increases in particle concentrations, mostly due to the presence of silicone oil microdroplets.2167 Bevacizumab injection solution was packaged as 0.05 mL in 0.3-mL plastic insulin syringes (Becton Dickinson) and stored at room temperature with or without exposure to fluorescent light and at 4°C.2167 Mean baseline particle concentration in bevacizumab syringes was 283,675 particles per mL compared with a mean particle concentration in the range of 20,000 to 60,000 particles per mL in bevacizumab withdrawn directly from the original glass vial.2167 Particle concentrations and particle size distribution remained relatively unchanged during 12 weeks of storage at 4°C.2167 During the 12-week period, particle concentrations generally were slightly greater in syringes stored at room temperature than those stored at 4°C.2167 Within 1 week, syringes stored at room temperature with light exposure developed clogged needles.2167 Particle concentrations generally increased more in syringes stored at room temperature with light exposure compared with those stored at room temperature without light exposure over the 12-week period.2167
Bevacizumab (Roche) 25-mg/mL injection solution was packaged as 0.15 mL in 1-mL polypropylene tuberculin syringes (Becton Dickinson) with a 22-gauge capped needle attached and stored at 4°C for 3 months.2237 A variety of techniques were used to assess the primary, secondary, and tertiary structure of bevacizumab, including cation exchange chromatography, size-exclusion chromatography, peptide mapping, second derivative ultraviolet (UV) and infrared (IR) spectroscopy, turbidimetry, diffraction laser spectroscopy, thermal denaturation curves, and microscopic examination and subsequent image analysis.2237 The authors concluded that bevacizumab could be repackaged into polypropylene syringes and stored for up to 3 months at 4°C without changes to the primary, secondary, or tertiary structure of the drug.2237 Silicone oil microdroplets were noted immediately upon repackaging of the drug into syringes and remained relatively constant in both number and size throughout the storage period.2237
Bevacizumab (Roche) 25-mg/mL injection solution was packaged as 1 mL in 1-mL tuberculin syringes (Henke-Sass Wolf) with syringe caps (Braun) and stored at 4°C for up to 54 days.2456 Bevacizumab concentration (measured using only an HPLC method) and pH remained stable over 32 days.2456 Another HPLC method used to screen for the presence of leachables did not show any additional peaks as compared with baseline.2456 The number of particles increased during storage and exceeded USP limits by 7 days.2456 The authors suggested that the particles could be silicone oil microdroplets from the syringes or bevacizumab protein aggregates.2456 While the presence of subvisible particles in intravitreal injections is not tolerated by USP standards, the clinical relevance of such particles in intravitreal injections has not been extensively studied and remains unknown.2456 Based on the results of the particle analysis, the authors concluded that storage of bevacizumab in such syringes should not exceed 3 days.2456
Bevacizumab (Genentech) 25-mg/mL injection solution was packaged as 0.13 mL in 1-mL polycarbonate (Braun) and polypropylene (Becton Dickinson) syringes and stored at 2 to 8°C.2457 Physical stability of bevacizumab was assessed using a variety of techniques, including gel electrophoresis, size-exclusion chromatography, dynamic light scattering, and surface plasmon resonance.2457 The authors concluded that no discernible changes in the physical stability of bevacizumab or its ability to bind VEGF were noted for up to 6 months as compared with bevacizumab injection solution from a freshly opened vial.2457
Sorption
Incompatibilities between bevacizumab injection solution and polyvinyl chloride (PVC) or polyolefin bags have not been observed.1370
Additional Compatibility Information
Infusion Solutions
Bevacizumab must not be administered with any dextrose-containing solutions.1370
For a list of references cited in the text of this monograph, search the monograph titled References.