Label: BEOVU- brolucizumab injection, solution
- NDC Code(s): 0078-0827-61, 0078-0827-99
- Packager: Novartis Pharmaceuticals Corporation
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: None
- Marketing Status: Biologic Licensing Application
Updated February 25, 2021
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use BEOVU safely and effectively. See full prescribing information for BEOVU.
BEOVU® (brolucizumab-dbll) injection, for intravitreal use
Initial U.S. Approval: 2019
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
BEOVU is a human vascular endothelial growth factor (VEGF) inhibitor indicated for the treatment of Neovascular (Wet) Age-Related Macular Degeneration (AMD) (1).
DOSAGE AND ADMINISTRATION
BEOVU is administered by intravitreal injection. The recommended dose for BEOVU is 6 mg (0.05 mL of 120 mg/mL solution) monthly (approximately every 25-31 days) for the first three doses, followed by one dose of 6 mg (0.05 mL) every 8-12 weeks (2.2).
DOSAGE FORMS AND STRENGTHS
Intravitreal injection: 6 mg/0.05 mL solution in a single-dose vial (3).
WARNINGS AND PRECAUTIONS
- Endophthalmitis and retinal detachment may occur following intravitreal injections. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay (5.1).
- Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported following BEOVU injections. Patients should be instructed to report any change in vision without delay (5.2).
- Increases in intraocular pressure (IOP) have been seen within 30 minutes of an intravitreal injection (5.3).
- There is a potential risk of arterial thromboembolic events (ATE) following intravitreal use of VEGF inhibitors (5.4).
The most common adverse reactions (≥ 5%) reported in patients receiving BEOVU are vision blurred (10%), cataract (7%), conjunctival hemorrhage (6%), eye pain (5%), and vitreous floaters (5%) (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
Table of Contents
FULL PRESCRIBING INFORMATION: CONTENTS*
- Sections or subsections omitted from the full prescribing information are not listed.
- 1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
For ophthalmic intravitreal injection. BEOVU must be administered by a qualified physician.
2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
The recommended dose for BEOVU is 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection monthly (approximately every 25-31 days) for the first three doses, followed by 6 mg (0.05 mL) by intravitreal injection once every 8-12 weeks.
2.3 Preparation for Administration
Store BEOVU in the refrigerator between 2°C to 8°C (36°F to 46°F); do not freeze. Keep the vial in the outer carton to protect from light. Prior to use, the unopened glass vial 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 the glass vial, 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 glass vial must not be used.
The BEOVU kit includes the sterile glass vial and filter needle which are for single use only. Do not use if the packaging, vial and/or filter needle are damaged or expired [see How Supplied/Storage and Handling (16)].
Use aseptic technique for preparation of the intravitreal injection.
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)
Allow vial to come to room temperature and inspect the solution. If particulates, cloudiness, or discoloration are visible, discard the vial and obtain a new vial.
Remove the vial cap and clean the vial septum (e.g., with alcohol swab) (see Figure 1).
Assemble the 5-micron filter needle (18-gauge x 1½ inch) onto a 1-mL syringe using aseptic technique.
Push the filter needle into the center of the vial septum until the needle touches the bottom of the vial.
To withdraw the liquid, hold the vial slightly inclined and slowly withdraw all the liquid from the vial and filter needle (see Figure 2).
Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle.
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.
Aseptically and firmly assemble a 30-gauge x ½ inch injection needle onto the syringe.
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 3).
Carefully expel the air from the syringe and adjust the dose to the 0.05 mL mark (see Figure 4).
The syringe is ready for the injection.
2.4 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 [see Patient Counseling Information (17)].
Each vial should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new vial 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.
- 3 DOSAGE FORMS AND STRENGTHS
4.1 Ocular or Periocular Infections
BEOVU is contraindicated in patients with ocular or periocular infections.
4.2 Active Intraocular Inflammation
BEOVU is contraindicated in patients with active intraocular inflammation.
5 WARNINGS AND PRECAUTIONS
5.3 Increase in Intraocular Pressure
Acute increases in intraocular pressure (IOP) have been seen within 30 minutes of intravitreal injection, including with BEOVU [see Adverse Reactions (6.1)]. Sustained IOP increases have also been reported. Both IOP and perfusion of the optic nerve head must be monitored and managed appropriately [see Dosage and Administration (2.4)].
5.4 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 [see Clinical Studies (14.1)].
6 ADVERSE REACTIONS
The following potentially serious adverse reactions are described elsewhere in the labeling:
- Hypersensitivity [see Contraindications (4.3)]
- Endophthalmitis and Retinal Detachment [see Warnings and Precautions (5.1)]
- Retinal Vasculitis and/or Retinal Vascular Occlusion [see Warnings and Precautions (5.2)]
- Increase in Intraocular Pressure [see Warnings and Precautions (5.3)]
- Thromboembolic Events [see Warnings and Precautions (5.4)]
6.1 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 1088 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 [see Clinical Studies (14.1)].
Adverse reactions reported to occur in ≥ 1% of patients who received treatment with BEOVU pooled across HAWK and HARRIER, are listed below in Table 1.
Table 1: Common Adverse Reactions (≥ 1%) in the HAWK and HARRIER wet AMD Clinical Trials aIncluding vision blurred, visual acuity reduced, visual acuity reduced transiently, and visual impairment.
bIncluding anterior chamber cell, anterior chamber flare, anterior chamber inflammation, chorioretinitis, eye inflammation, iridocyclitis, iritis, retinal vasculitis, retinal vascular occlusion, uveitis, vitreous haze, vitritis.
cIncluding urticaria, rash, pruritus, erythema.
dIncluding blindness, blindness transient, amaurosis, and amaurosis fugax.
Adverse Drug Reactions BEOVU
(N = 730)
Active Control (aflibercept)
(N = 729)
Vision blurreda 10% 11% Cataract 7% 11% Conjunctival hemorrhage 6% 7% Vitreous floaters 5% 3% Eye pain 5% 6% Intraocular inflammationb 4% 1% Intraocular pressure increased 4% 5% Retinal hemorrhage 4% 3% Vitreous detachment 4% 3% Conjunctivitis 3% 2% Retinal pigment epithelial tear 3% 1% Corneal abrasion 2% 2% Hypersensitivityc 2% 1% Punctate keratitis 1% 2% Retinal tear 1% 1% Endophthalmitis 1% < 1% Blindnessd 1% < 1% Retinal artery occlusion 1% < 1% Retinal detachment 1% < 1% Conjunctival hyperemia 1% 1% Lacrimation increased 1% 1% Abnormal sensation in eye 1% 2% Detachment of retinal pigment epithelium 1% < 1%
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 52% of treatment naive patients. After initiation of dosing, anti-brolucizumab antibodies were detected in at least one serum sample in 53% to 67% of patients treated with BEOVU. Intraocular inflammation was observed in 6% of patients with anti-brolucizumab antibodies detected during dosing with BEOVU.
The significance of anti-brolucizumab antibodies on the clinical effectiveness and safety of BEOVU is not known.
8 USE IN SPECIFIC POPULATIONS
There are no adequate and well-controlled studies of BEOVU administration in pregnant women.
Based on the anti-VEGF mechanism of action for brolucizumab [see Clinical Pharmacology (12.1)], 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%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.
VEGF inhibition has been shown to cause malformations, embryo-fetal resorption, and decreased fetal weight. VEGF inhibition has also been shown to affect follicular development, corpus luteum function, and fertility.
There is no information regarding the presence of brolucizumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production/excretion. Because many drugs are transferred in human milk and because of the potential for absorption and adverse reactions in the breastfed child, breastfeeding is not recommended during treatment and for at least one month after the last dose when stopping treatment with BEOVU.
8.3 Females and Males of Reproductive Potential
Females of reproductive potential should use highly effective contraception (methods that result in less than 1% pregnancy rates) during treatment with BEOVU and for at least one month after the last dose when stopping treatment with BEOVU.
No studies on the effects of brolucizumab on fertility have been conducted and it is not known whether brolucizumab can affect reproductive capacity. Based on its anti-VEGF mechanism of action, treatment with BEOVU may pose a risk to reproductive capacity.
8.5 Geriatric Use
In the two Phase 3 clinical studies, approximately 90% (978/1089) of patients randomized to treatment with BEOVU were ≥ 65 years of age and approximately 60% (648/1089) were ≥ 75 years of age. No significant differences in efficacy or safety were seen with increasing age in these studies. No dosage regimen adjustment is required in patients 65 years and above.
Brolucizumab-dbll is a recombinant human vascular endothelial growth factor inhibitor. Brolucizumab-dbll is a humanized monoclonal single-chain Fv (scFv) antibody fragment. Brolucizumab-dbll has a molecular weight of ~26 kilodaltons and is produced in Escherichia coli cells by recombinant DNA technology.
BEOVU (brolucizumab-dbll) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly brownish-yellow solution in a single-dose vial for intravitreal administration. Each vial is designed to deliver 0.05 mL of solution containing 6 mg brolucizumab-dbll, polysorbate 80 (0.02%), sodium citrate (10 mM), sucrose (5.8%), and Water for Injection, USP and with a pH of approximately 7.2.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Brolucizumab is a human VEGF inhibitor. Brolucizumab binds to the three major isoforms of VEGF-A (e.g., VEGF110, VEGF121, and VEGF165), thereby preventing interaction with receptors VEGFR-1 and VEGFR-2. By inhibiting VEGF-A, brolucizumab suppresses endothelial cell proliferation, neovascularization, and vascular permeability.
Leakage of blood and fluid from choroidal neovascularization (CNV) may cause retinal thickening or edema. Reductions in central retinal subfield thickness (CST) were observed across all treatment arms.
Following a single intravitreal dose of 6 mg BEOVU to 25 AMD patients, the mean (range) serum Cmax of free brolucizumab (unbound to VEGF-A) was 49 ng/mL (9 to 548 ng/mL) and was attained at 24 hours post-dose. Brolucizumab concentrations were near or less than 0.5 ng/mL (lower limit of assay quantitation) at approximately 4 weeks after repeat dose administration and no accumulation in serum was observed in most patients.
The estimated mean (± standard deviation) systemic half-life of brolucizumab is 4.4 days (± 2.0 days) after a single intravitreal dose.
Metabolism of brolucizumab has not been fully characterized. However, free brolucizumab is expected to undergo metabolism via proteolysis.
The excretion of brolucizumab has not been fully characterized. However, free brolucizumab is expected to undergo target-mediated disposition and/or passive renal excretion.
Following repeat intravitreal dose administration of 6 mg BEOVU, no differences in the systemic pharmacokinetics of brolucizumab were observed based on age (50 years and above), sex, or mild to moderate renal impairment (glomerular filtration rate (GFR) = 30 to 70 mL/min, estimated using the Modification of Diet in Renal Disease (MDRD) equation). The effect of severe renal impairment or any degree of hepatic impairment on the pharmacokinetics of BEOVU is unknown. As significant increases in serum brolucizumab exposures are not expected with intravitreal route of administration, no dosage adjustment is needed based on renal or hepatic impairment status.
Drug Interaction Studies
No studies evaluating the drug interaction potential of BEOVU have been conducted.
- 13 NONCLINICAL TOXICOLOGY
14 CLINICAL STUDIES
14.1 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 1817 patients were treated in these studies for two years (1088 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 5 and 6 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)
(n = 360)
brolucizumab – aflibercept
(n = 370)
(n = 369)
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
Proportion of patients who gained visual acuity (%) (≥ 15 letters of BCVA) 48
Proportion of patients who lost visual acuity (%) (≥ 15 letters of BCVA) 48
Figure 5: Mean Change in Visual Acuity From Baseline to Week 96 in HAWK
Figure 6: 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.
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
BEOVU (brolucizumab-dbll) injection is supplied as a clear to slightly opalescent and colorless to slightly brownish-yellow solution in a single-dose vial. Each BEOVU carton (NDC 0078-0827-61) contains one BEOVU vial and one sterile 5 µm blunt filter needle (18-gauge x 1½ inch, 1.2 mm x 40 mm).
17 PATIENT COUNSELING INFORMATION
Advise patients that in the days following BEOVU administration, patients are at risk of developing endophthalmitis, retinal detachment, retinal vasculitis and/or retinal vascular occlusion. If the eye becomes red, sensitive to light, painful, or if a patient develops any change in vision, instruct the patient to seek immediate care from an ophthalmologist [see Warnings and Precautions (5.1, 5.2)].
Patients may experience temporary visual disturbances after an intravitreal injection with BEOVU and the associated eye examination [see Adverse Reactions (6.1)]. Advise patients not to drive or use machinery until visual function has recovered sufficiently.
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
U.S. License Number: 1244
- PRINCIPAL DISPLAY PANEL
INGREDIENTS AND APPEARANCE
brolucizumab injection, solution
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0078-0827 Route of Administration INTRAVITREAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BROLUCIZUMAB (UNII: XSZ53G39H5) (BROLUCIZUMAB - UNII:XSZ53G39H5) BROLUCIZUMAB 6 mg in 0.05 mL Inactive Ingredients Ingredient Name Strength SUCROSE (UNII: C151H8M554) 13.3 mg in 0.05 mL SODIUM CITRATE, UNSPECIFIED FORM (UNII: 1Q73Q2JULR) 0.59 mg in 0.05 mL POLYSORBATE 80 (UNII: 6OZP39ZG8H) 0.05 mg in 0.05 mL SODIUM HYDROXIDE (UNII: 55X04QC32I) NITROGEN (UNII: N762921K75) WATER (UNII: 059QF0KO0R) Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0078-0827-61 1 in 1 CARTON 10/07/2019 1 0.05 mL in 1 VIAL, SINGLE-DOSE; Type 1: Convenience Kit of Co-Package 2 NDC:0078-0827-99 1 in 1 CARTON 10/07/2019 2 0.05 mL in 1 VIAL, SINGLE-DOSE; Type 1: Convenience Kit of Co-Package Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA761125 10/07/2019 Labeler - Novartis Pharmaceuticals Corporation (002147023)