Beovu Drug Information
Generic name: BROLUCIZUMAB
Dosage & Administration of Beovu
| 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. | ||
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 . A total of 558 patients treated with brolucizumab constituted the safety population in the two controlled DME Phase 3 studies (KESTREL and KITE) from baseline to week 52, including 368 patients treated with the recommended dose of 6 mg . Table 1: Common Adverse Reactions (≥ 1%) in the AMD and DME Clinical Trials 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% 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.
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). The ATE rate in the two controlled 96-week neovascular AMD studies (HAWK and HARRIER) during the first 96 weeks was 4.5% (33 of 730) in the pooled brolucizumab arms compared with 4.7% (34 of 729) in the pooled aflibercept arms .
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. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.
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 HAWK, patients were randomized in a 1:1:1 ratio to the following dosing regimens: 1) brolucizumab 3 mg administered every 8 or 12 weeks after the first 3 monthly doses, 2) brolucizumab 6 mg administered every 8 or 12 weeks after the first 3 monthly doses, 3) aflibercept 2 mg administered every 8 weeks after the first 3 monthly doses. In HARRIER, patients were randomized in a 1:1 ratio to the following dosing regimens: 1) brolucizumab 6 mg administered every 8 or 12 weeks after the first 3 monthly doses, 2) aflibercept 2 mg administered every 8 weeks after the first 3 monthly doses.
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.
Protocol-specified visits in the initial three months occurred every 28 ± 3 days followed by every 28 ± 7 days for the remainder of the studies. 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. Table 2: Efficacy Outcomes at Week 48 and 96 in Phase 3 HAWK and HARRIER Studies 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 60.0 61.5
Mean (SE) change from baseline in
BCVA (measured by ETDRS letters score) 48 96 6.6 5.9 6.8 5.3 -0.2 (-2.1, 1.8) +0.5 (-1.6, 2.7) 6.9 6.1 7.6 6.6 -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 7.2 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) 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 Through Week 48, 56% (HAWK) and 51% (HARRIER) of patients remained on BEOVU every 12 weeks. The proportion of patients who were maintained on every 12-week dosing through Week 96 was 45% and 39% in HAWK and HARRIER, respectively. The probability of remaining on every 12-week dosing from Week 20 to Week 48 was 85% and 82%, and from Week 48 to Week 96 was 82% and 75% 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. A total of 926 patients were treated in these studies for 1 year (558 on brolucizumab and 368 on aflibercept 2 mg). Patient ages ranged from 23 to 87 years with a mean of 63 years. In KESTREL, patients were randomized in a 1:1:1 ratio to the following dosing regimens: 1) brolucizumab 6 mg administered once every 6 weeks for first 5 doses, followed by brolucizumab 6 mg every 8 or 12 weeks. 2) brolucizumab 3 mg administered once every 6 weeks for first 5 doses, followed by brolucizumab 3 mg every 8 or 12 weeks. 3) aflibercept 2 mg administered once every 4 weeks for first 5 doses, followed by aflibercept 2 mg every 8 weeks. In KITE, patients were randomized in a 1:1 ratio to the following dosing regimens: 1) brolucizumab 6 mg administered once every 6 weeks for first 5 doses, followed by brolucizumab 6 mg every 8 or 12 weeks. 2) aflibercept 2 mg administered once every 4 weeks for first 5 doses, followed by aflibercept 2 mg every 8 weeks.
In both studies, after the first five doses (Weeks 0, 6, 12, 18, and 24), 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.
In both studies, BEOVU was non-inferior to aflibercept 2 mg for the change in BCVA from baseline to Week 52 and the change from baseline over the period Week 40 through Week 52. After 5 initial q6w loading doses, the patients in the BEOVU arm could have received between the minimum of 2 and maximum of 3 additional injections through Week 52. At Week 52, the median number of injections given over 12 months was 7 in patients treated with BEOVU. Through Week 52, 55% (KESTREL) and 50% (KITE) of patients remained on BEOVU every 12 weeks. The probability of remaining on every 12-week dosing from Week 36 to Week 52 was 88% and 95% in KESTREL and KITE, respectively. 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 - KESTREL and KITE Studies 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 9.0 10.5 10.5 -1.3 (-2.9, 0.3) -1.5 (-3.0, 0.0) 10.6 10.3 9.4 9.4 1.2 (-0.6, 3.1) 0.9 (-0.9, 2.6) 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. 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
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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