Beovu Drug Information
Generic name: BROLUCIZUMAB
Uses of Beovu
Neovascular (Wet) Age-related Macular Degeneration (AMD)
Diabetic Macular Edema (DME)
Dosage & Administration of Beovu
Injection Procedure Ensure that the injection is given immediately after preparation of the dose. The intravitreal injection procedure must be carried out under aseptic conditions, which includes the use of surgical hand disinfection, sterile gloves, a sterile drape and a sterile eyelid speculum (or equivalent), and the availability of sterile paracentesis equipment (if required). Adequate anesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid, and ocular surface should be administered prior to the injection.
Inject slowly until the rubber stopper reaches the end of the syringe to deliver the volume of 0.05 mL. Confirm delivery of the full dose by checking that the rubber stopper has reached the end of the syringe barrel. Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure (IOP).
Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, a sterile paracentesis needle should be available. Following intravitreal injection, patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without delay.
Each vial or pre-filled syringe should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new vial or pre-filled syringe should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before BEOVU is administered to the other eye. Any unused medicinal product or waste material should be disposed of in accordance with local regulations.
| Store BEOVU in the refrigerator between 2°C to 8°C (36°F to 46°F); do not freeze. Keep BEOVU in the outer carton to protect from light. | |
| Prior to use, the unopened glass vial or sealed blister pack of BEOVU may be kept at room temperature, 20°C to 25°C (68°F to 77°F) for up to 24 hours. After opening, proceed under aseptic conditions. | |
| BEOVU is a clear to slightly opalescent and colorless to slightly brownish-yellow solution. | |
| BEOVU should be inspected visually upon removal from the refrigerator and prior to administration. If particulates, cloudiness, or discoloration are visible, the BEOVU must not be used. |
| STEP 1: PREPARE Peel the lid off the blister package and, using aseptic technique, remove the sterile syringe. | |
| STEP 2: SNAP OFF SYRINGE CAP Snap off the syringe cap and dispose of it (see Figure 1). Do not turn or twist the syringe cap. | Figure 1: |
| STEP 3: ATTACH INJECTION NEEDLE Aseptically and firmly assemble a 30-gauge x ½ inch sterile injection needle (not included) onto the Luer lock syringe. | |
| STEP 4: DISLODGE AIR BUBBLES To check for air bubbles, hold the syringe with the needle pointing up. If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top (see Figure 2). Carefully remove the needle cap by pulling it straight off. | Figure 2: |
| STEP 5: EXPEL AIR AND SET THE DOSE Hold the syringe at eye level and carefully push the plunger until the edge below the dome of the rubber stopper is aligned with the 0.05 mL dose mark (see Figure 3). This will expel the air and the excess liquid and set the dose to the 0.05 mL dose mark. The syringe is ready for the injection. | Figure 3: |
| STEP 1: Gather the supplies needed. One BEOVU vial (included) One sterile 5-micron blunt filter needle (18-gauge x 1½ inch, 1.2 mm x 40 mm) (included) One sterile 30-gauge x ½ inch injection needle (not included) One sterile 1 mL syringe with a 0.05 mL dose mark (not included) Alcohol swab (not included) | |
| STEP 2: Inspect the solution. If particulates, cloudiness, or discoloration are visible, discard the vial and obtain a new vial. | |
| STEP 3: Remove the vial cap and clean the vial septum (e.g., with alcohol swab) (see Figure 4). | Figure 4: |
| STEP 4: Assemble the 5-micron filter needle (18-gauge x 1½ inch) onto a 1-mL syringe using aseptic technique. | |
| STEP 5: Push the filter needle into the center of the vial septum until the needle touches the bottom of the vial. | |
| STEP 6: To withdraw the liquid, hold the vial slightly inclined and slowly withdraw all the liquid from the vial and filter needle (see Figure 5). Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle. | Figure 5: |
| STEP 7: Disconnect the filter needle from the syringe in an aseptic manner and dispose of it. The filter needle is not to be used for the intravitreal injection. | |
| STEP 8: Aseptically and firmly assemble a 30-gauge x ½ inch injection needle onto the syringe. | |
| STEP 9: Check for air bubbles by holding the syringe with the needle pointing up. If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top (see Figure 6). | Figure 6: |
| STEP 10: Carefully expel the air from the syringe and adjust the dose to the 0.05 mL mark (see Figure 7). The syringe is ready for the injection. | Figure 7: |
Side Effects of Beovu
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of a drug cannot be directly compared with rates in the clinical trials of the same or another drug and may not reflect the rates observed in practice. A total of 1,646 patients treated with brolucizumab constituted the safety population in four Phase 3 studies. Among these, 1,098 patients were treated with the recommended dose of 6 mg.
A total of 1,088 patients treated with brolucizumab, constituted the safety population in the two controlled neovascular AMD Phase 3 studies (HAWK and HARRIER) with a cumulative 96-week exposure to BEOVU, and 730 patients treated with the recommended dose of 6 mg. Table 1: Common Adverse Reactions ≥ In clinical trials, scleritis and episcleritis were reported (incidence < 1%). In a clinical study (MERLIN), patients with nAMD who received BEOVU every 4-week maintenance dosing experienced a higher incidence of intraocular inflammation (including retinal vasculitis) and retinal vascular occlusion than patients who received BEOVU every 8 or 12-week maintenance dosing in the clinical studies (HAWK and HARRIER).
The interval between two BEOVU doses during maintenance treatment should not be less than 8 weeks.
Immunogenicity As with all therapeutic proteins, there is a potential for an immune response in patients treated with BEOVU. The immunogenicity of BEOVU was evaluated in serum samples. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to BEOVU in immunoassays.
The detection of an immune response is highly dependent on the sensitivity and specificity of the assays used, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to BEOVU with the incidence of antibodies to other products may be misleading. Anti-brolucizumab antibodies were detected in the pre-treatment sample of 36% to 64% of treated naive patients.
After initiation of dosing, anti-brolucizumab antibodies were detected in at least one serum sample in 53% to 76% of patients treated with BEOVU. Intraocular inflammation was observed in 6% of patients with anti-brolucizumab antibodies detected during dosing with BEOVU in clinical trials. Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, are immune-mediated adverse events related to exposure to BEOVU.
This treatment-emergent antibody response may develop following the first intravitreal injection. Anti-brolucizumab antibodies were not associated with an impact on clinical efficacy.
| a Including vision blurred, visual acuity reduced, visual acuity reduced transiently, and visual impairment. b Including anterior chamber cell, anterior chamber flare, anterior chamber inflammation, chorioretinitis, eye inflammation, iridocyclitis, iritis, retinal vasculitis, retinal vascular occlusion, uveitis, vitreous haze, vitritis. c Including urticaria, rash, pruritus, erythema. d Including blindness, blindness transient, amaurosis, and amaurosis fugax. | ||||
| BEOVU | Active Control (aflibercept) | |||
| Adverse Drug Reactions | AMD (N = 730) | DME (N = 368) | AMD (N = 729) | DME (N = 368) |
| Vision blurred a | 10% | 2% | 11% | 4% |
| Cataract | 7% | 4% | 11% | 5% |
| Conjunctival hemorrhage | 6% | 6% | 7% | 7% |
| Vitreous floaters | 5% | 3% | 3% | 2% |
| Eye pain | 5% | 3% | 6% | 2% |
| Intraocular inflammation b | 4% | 3% | 1% | 1% |
| Intraocular pressure increased | 4% | 2% | 5% | 1% |
| Retinal hemorrhage | 4% | 3% | 1% | |
| Vitreous detachment | 4% | 2% | 3% | 1% |
| Conjunctivitis | 3% | 2% | 2% | < 1% |
| Retinal pigment epithelial tear | 3% | 1% | ||
| Corneal abrasion | 2% | 1% | 2% | 2% |
| Hypersensitivity c | 2% | 1% | 1% | 1% |
| Punctate keratitis | 1% | 1% | 2% | |
| Retinal tear | 1% | < 1% | 1% | < 1% |
| Endophthalmitis | 1% | < 1% | < 1% | 1% |
| Blindness d | 1% | < 1% | < 1% | |
| Retinal artery occlusion | 1% | 1% | < 1% | < 1% |
| Retinal detachment | 1% | < 1% | 1% | |
| Conjunctival hyperemia | 1% | < 1% | 1% | 1% |
| Lacrimation increased | 1% | < 1% | 1% | < 1% |
| Abnormal sensation in eye | 1% | < 1% | 2% | 1% |
| Detachment of retinal pigment epithelium | 1% | < 1% | ||
| Vitreous hemorrhage | < 1% | 1% | < 1% | 1% |
Warnings & Cautions for Beovu
Endophthalmitis and Retinal Detachment
Intravitreal injections, including those with BEOVU, have been associated with endophthalmitis and retinal detachment. Proper aseptic injection techniques must always be used when administering BEOVU. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately.
Retinal
Vasculitis and/or Retinal Vascular Occlusion Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported with the use of BEOVU. These immune-mediated adverse events may occur following the first intravitreal injection. Discontinue treatment with BEOVU in patients who develop these events.
Patients treated with BEOVU who experience intraocular inflammation may be at risk of developing retinal vasculitis and/or retinal vascular occlusion and should be closely monitored. Patients should be instructed to report any change in vision without delay.
Increase in Intraocular Pressure
Acute increases in intraocular pressure (IOP) have been seen within 30 minutes of intravitreal injection, including with BEOVU. Sustained IOP increases have also been reported. Both IOP and perfusion of the optic nerve head must be monitored and managed appropriately.
Thromboembolic Events
Although there was a low rate of arterial thromboembolic events (ATEs) observed in the BEOVU clinical trials, there is a potential risk of ATEs following intravitreal use of VEGF inhibitors. Arterial thromboembolic events are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause).
Pregnancy Safety for Beovu
Pregnancy Risk Summary There are no adequate and well-controlled studies of BEOVU administration in pregnant women. In an animal reproduction study, intravitreal administration of brolucizumab to pregnant monkeys once every 4 weeks in one eye from organogenesis to birth did not indicate any harmful effects with respect to pre- or postnatal development at 10-fold the maximum recommended human dose (MRHD) on a mg/kg basis ( see Data ). Based on the anti-VEGF mechanism of action for brolucizumab, treatment with BEOVU may pose a risk to human embryo-fetal development.
BEOVU should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. All pregnancies have a background risk of birth defect, loss, and other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Data Animal Data In an enhanced pre- and postnatal development (ePPND) study in pregnant cynomolgus monkeys, brolucizumab was administered to all animals by intravitreal (IVT) injection to one eye at doses of 3 or 6 mg once every 4 weeks until delivery. There was no impact of IVT administration of brolucizumab on embryo-fetal development, pregnancy or parturition; or on the survival, growth, or postnatal development of offspring at 6 mg/eye (10-fold the MRHD on a mg/kg basis). VEGF inhibition has been shown to cause malformations, embryo-fetal resorption, and decreased fetal weight.
VEGF also has been shown to affect follicular development, corpus luteum function, and fertility.
Pediatric Use of Beovu
Pediatric Use The safety and efficacy of BEOVU in pediatric patients has not been established.
Contraindications for Beovu
Ocular or Periocular Infections BEOVU is contraindicated in patients with ocular or periocular infections.
Active Intraocular Inflammation BEOVU is contraindicated in patients with active intraocular inflammation.
Hypersensitivity BEOVU is contraindicated in patients with known hypersensitivity to brolucizumab or any of the excipients in BEOVU. Hypersensitivity reactions may manifest as rash, pruritus, urticaria, erythema, or severe intraocular inflammation.
Clinical Studies of Beovu
Neovascular (Wet) Age-Related Macular Degeneration (AMD)
The safety and efficacy of BEOVU were assessed in two randomized, multi-center, double-masked, active-controlled studies (HAWK - NCT02307682 and HARRIER - NCT02434328) in patients with neovascular AMD. A total of 1,817 patients were treated in these studies for two years (1,088 on brolucizumab and 729 on control). Patient ages ranged from 50 to 97 years with a mean of 76 years.
In both studies, after three initial monthly doses (Week 0, 4, and 8), treating physicians decided whether to treat each individual patient on an every 8-week or 12-week dosing interval guided by visual and anatomical measures of disease activity, although the utility of these measures has not been established. Patients on 12-week dosing intervals could be changed based on the same measures to an 8-week schedule after subsequent treatment visits. Any patient placed on an 8-week schedule, remained on the 8-week dosing interval until the end of the study.
Baseline anatomical measures may have contributed to the regimen selection because the majority of patients on the 12-week dosing schedule at the end of the trial had less baseline macular edema and/or smaller baseline lesions. Both studies demonstrated efficacy in the primary endpoint defined as the change from baseline in Best Corrected Visual Acuity (BCVA) at Week 48, measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score. In both studies, BEOVU treated patients had a similar mean change from baseline in BCVA as the patients treated with aflibercept 2 mg (fixed every 8 weeks).
Detailed results of both studies are shown in Table 2 and Figures 8 and 9 below. The proportion of patients who were maintained on every 12-week dosing through Week 96 was 45% and 39% in HAWK and HARRIER, respectively. Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline visual acuity) in each study were generally consistent with the results in the overall populations.
Figure 8: Mean Change in Visual Acuity From Baseline to Week 96 in HAWK Figure 9: Mean Change in Visual Acuity From Baseline to Week 96 in HARRIER
Diabetic Macular Edema (DME)
The safety and efficacy of BEOVU were assessed in two randomized, multi-center, double-masked, active controlled studies (KESTREL – NCT03481634 and KITE - NCT03481660) in patients with DME. Patient ages ranged from 23 to 87 years with a mean of 63 years. In both studies, after the first five doses Weeks brolucizumab patients were treated every 12 weeks, with the option of adjusting to an every 8-week dosing interval based on disease activity.
Disease activity was assessed by changes in visual acuity and/or anatomical parameters, including CST and/or presence of IRF/SRF although the utility of the specific action parameters used has not been established. Disease activity was assessed by a physician during the first 12-week interval (at Weeks 32 and 36) and at each subsequent scheduled 12-week treatment visit. Patients who showed disease activity at any of these visits were adjusted to an every 8 week treatment interval.
The comparator aflibercept was administered every 8 weeks after the first 5 monthly doses. The primary efficacy endpoint for both studies was the change from baseline to Week 52 in Best Corrected Visual Acuity (BCVA) as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score with the primary objective being to demonstrate non-inferiority of BEOVU vs. aflibercept 2 mg. At Week 52, the median number of injections given over 12 months was 7 in patients treated with BEOVU.
Results of both studies are shown in Table 3 and Figures 10 and 11 below. Table 3: Efficacy Outcomes at Week 52 in Phase 3 - Figure 10: Mean Change in Visual Acuity From Baseline to Week 52 in KESTREL Figure 11: Mean Change in Visual Acuity From Baseline to Week 52 in KITE Treatment effects in evaluable subgroups (i.e., age, gender, baseline HbA1c, baseline visual acuity, baseline central subfield thickness, DME lesion type, duration of DME since diagnosis, retinal fluid status) in each study were generally consistent with the results in the overall population. In both studies, BEOVU demonstrated a significant reduction from baseline in CST starting at Week 4 and continuing up to Week 52.
| Abbreviations: BCVA, Best Corrected Visual Acuity; missing data are imputed using last observation carried forward (LOCF) method; ETDRS, Early Treatment Diabetic Retinopathy Study; SE, standard error. | |||||||
| HAWK | HARRIER | ||||||
| Efficacy outcome | At week | BEOVU (n = 360) | Aflibercept 2 mg (n = 360) | Difference (95% CI) brolucizumab – aflibercept | BEOVU (n = 370) | Aflibercept 2 mg (n = 369) | Difference (95% CI) brolucizumab – aflibercept |
| Mean (SD) BCVA at baseline | 60.8 (13.7) | 60.0 (13.9) | 61.5 (12.6) | 60.8 (12.9) | |||
| Mean (SE) change from baseline in BCVA (measured by ETDRS letters score) | 48 96 | 6.6 (0.71) 5.9 (0.78) | 6.8 (0.71) 5.3 (0.78) | -0.2 (-2.1, 1.8) +0.5 (-1.6, 2.7) | 6.9 (0.61) 6.1 (0.73) | 7.6 (0.61) 6.6 (0.73) | -0.7 (-2.4, 1.0) -0.4 (-2.5, 1.6) |
| Proportion of patients who gained visual acuity (%) (≥ 15 letters of BCVA) | 48 96 | 33.6 34.2 | 25.4 27 | 8.2 (2.2, 15.0) 7.2 (1.4, 13.8) | 29.3 29.1 | 29.9 31.5 | -0.6 (-7.1, 5.8) -2.4 (-8.8, 4.1) |
| Proportion of patients who lost visual acuity (%) (≥ 15 letters of BCVA) | 48 96 | 6.4 8.1 | 5.5 7.4 | 0.9 (-2.7, 4.3) 0.7 (-3.6, 4.6) | 3.8 7.1 | 4.8 7.5 | -1.0 (-3.9, 2.2) -0.4 (-3.8, 3.3) |
| BCVA: Best Corrected Visual Acuity; BCVA assessments after start of alternative DME treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment. | |||||||
| KESTREL | KITE | ||||||
| Efficacy outcome | At Week | BEOVU (n = 189) | aflibercept 2 mg (n = 187) | Difference (95% CI) BEOVU – aflibercept | BEOVU (n = 179) | aflibercept 2 mg (n = 181) | Difference (95% CI) BEOVU – aflibercept |
| Change from baseline in BCVA (measured by ETDRS letters score) – LS mean (SE) | 52 40-52 | 9.2 (0.57) 9.0 (0.53) | 10.5 (0.57) 10.5 (0.53) | -1.3 (-2.9, 0.3) -1.5 (-3.0, 0.0) | 10.6 (0.66) 10.3 (0.62) | 9.4 (0.66) 9.4 (0.62) | 1.2 (-0.6, 3.1) 0.9 (-0.9, 2.6) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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