Brolucizumab is a human vascular endothelial growth factor (VEGF) inhibitor approved for the treatment of neovascular (wet) age-related macular degeneration (AMD) and diabetic macular edema (DME). The drug is administered via intravitreal injection and must be given under aseptic conditions by a qualified physician. The initial dosing interval varies by indication. For AMD, the first 3 doses are administered once monthly (approximately every 25 to 31 days); for DME, the first 5 doses are administered once every 6 weeks (approximately every 39 to 45 days). After the initial 3 or 5 doses, the dosing interval is extended to every 8 to 12 weeks for both indications. Brolucizumab is contraindicated for use in patients with ocular or periocular infections and patients with active intraocular inflammation. Instruct patients to immediately report if ocular pain, redness of the eye, photophobia, or blurred vision occurs as these may be signs of a detached retina or of an eye infection.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Must be administered by a qualified physician.
-Adequate anesthesia and broad-spectrum topical microbicides to disinfect the periocular skin, eyelid, and ocular surface should be administered prior to the intravitreal injection.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration. The solution is clear to slightly opalescent and colorless to slightly brownish-yellow. Do not administer solution if particulates, cloudiness, or discoloration are visible. Do not use if the packaging, pre-filled syringe, vial, or filter needle are opened, damaged, or expired.
Other Injectable Administration
Product Preparation
-The product is available as a pre-filled syringe and a vial kit (i.e., single-use glass vial and filter needle).
-Before use, allow the unopened glass vial or sealed blister pack to come to room temperature. The unopened product may be kept at room temperature, between 20 and 25 degrees C (68 to 77 degrees F), for up to 24 hours.
-After opening, the dose must be prepared under aseptic conditions.
-Preparation of the pre-filled syringe:
--Peel the lid off the blister package and, using aseptic technique, remove the sterile syringe.
-Snap off the syringe cap and dispose of it. DO NOT turn or twist the syringe cap.
-Aseptically and firmly assemble a 30-gauge x 0.5 inch sterile injection needle (not included) onto the Luer lock syringe.
-Hold the syringe with the needle pointing up to check for air bubbles. If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top.
-Carefully remove the needle cap by pulling it straight off.
-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. This will expel the air and excess liquid.
-Preparation of the vial kit:
--Gather the needle supplies: one brolucizumab vial (included), one sterile 5-micron blunt filter needle (included), one sterile 30-gauge x 0.5 inch injection needle (not included), one sterile 1 mL syringe with a 0.05 mL dose mark (not included), alcohol swab (not included).
-Remove the vial cap and clean the vial septum with an alcohol swab.
-Attach the 5-micron filter needle (18-gauge by 1.5 inches) 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. 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 and dispose of it. The filter needle MUST NOT be used for the intravitreal injection.
-Aseptically and firmly attach a 30-gauge by 0.5 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.
-Carefully expel the air from the syringe and adjust the dose to the 0.05 mL mark.
Intravitreal Administration
-Ensure the injection is administered immediately after preparation of the dose.
-The intravitreal injection procedure must be carried out under aseptic conditions, which includes use of surgical hand disinfection, sterile gloves, a sterile drape, and sterile eyelid speculum (or equivalent). Also, ensure 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.
-Slowly inject the dose until the rubber stopper reaches the end of the syringe to deliver the 0.05 mL volume. 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, monitor for elevation of intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry.
-Instruct patients to urgently report any symptoms suggestive of endophthalmitis or retinal detachment (e.g., ocular pain, redness of the eye, photophobia, blurred vision).
-Each vial or pre-filled syringe should only be used for 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, gloves, drapes, eyelid speculum, syringe, and filter and injection needles should be changed.
Intravitreal use of vascular endothelial growth factor (VEGF) inhibitors, such as brolucizumab, may be associated with an increased risk for arterial thromboembolic events (ATEs), such as thromboembolism, nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). In 2 controlled 96-week studies, 4.5% (n = 33 of 730) of brolucizumab recipients experienced an ATE compared to 4.7% (n = 34 of 729) in the patients who received aflibercept.
In clinical trials comparing brolucizumab (n = 1,098) to aflibercept (n = 1,097) for neovascular, age-related macular degeneration (AMD) or diabetic macular edema (DME), ocular adverse events included visual impairment (i.e., decrease visual acuity and blurred vision; 2% to 10% brolucizumab group vs. 4% to 11% aflibercept group), cataracts (4% to 7% vs. 5% to 11%), conjunctival or ocular hemorrhage (6% vs. 7%), retinal hemorrhage (4% vs. 1% to 3%), vitreous floaters (3% to 5% vs. 2% to 3%), ocular pain (3% to 5% vs. 2% to 6%), vitreous detachment (2% to 4% vs. 1% to 3%), conjunctivitis (2% to 3% vs. up to 2%), retinal pigment epithelium tear (3% vs. 1%), retinal tear (up to 1% vs. up to 1%), corneal erosion or abrasion (1% to 2% vs. 2%), punctate keratitis (1% vs. 2%), blindness or amaurosis (up to 1% vs. less than 1%), retinal artery occlusion (1% vs. less than 1%), conjunctival hyperemia (up to 1% vs. 1%), lacrimation increased (up to 1% vs. up to 1%), and foreign body sensation (up to 1% vs. 1% to 2%). Instruct patients to immediately report if ocular pain, redness of the eye, photophobia, or blurred vision occurs as these may be signs of a detached retina or of an eye infection.
Intravitreal injections of brolucizumab have been associated with endophthalmitis, retinal detachment, and detached retinal pigment epithelium in up to 1% of patients. Proper aseptic injection technique should always be used to help minimize the likelihood of an ocular infection. Instruct patients to seek immediate care if symptoms of endophthalmitis or retinal detachment develop (e.g., ocular pain, redness of the eye, photophobia, or blurred vision).
Increased intraocular pressure (ocular hypertension) was reported in 2% to 4% of brolucizumab treated patients during clinical trials. Acute increases in intraocular pressure have been noted within 30 minutes of intravitreal brolucizumab injection. Sustained increases in intraocular pressure have also been reported. After the injection, monitor the intraocular pressure and optic nerve head perfusion; medical management of any abnormality may be needed. Monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, a sterile paracentesis needle should be available.
During clinical trials, ocular inflammation was observed in 3% to 4% of patients receiving brolucizumab compared to 1% of patients treated with aflibercept. Ocular inflammation was defined as anterior chamber flare or inflammation, chorioretinitis, iridocyclitis, iritis, retinal vasculitis, retinal vascular occlusion, uveitis, vitreous haze, and vitritis. A higher incidence of ocular inflammation (including retinal vasculitis and retinal vascular occlusion) was observed in patients who received every 4-week maintenance dosing as compared to those who received brolucizumab maintenance doses every 8 or 12 weeks. Ensure the recommended maintenance dosing interval of no less than every 8 weeks is followed.
During clinical trials, hypersensitivity reactions were reported by 1% to 2% of patients receiving brolucizumab compared to 1% of patients treated with aflibercept. Hypersensitivity reactions were defined as erythema, pruritus, rash, and urticaria.
As with all therapeutic proteins, antibody formation to brolucizumab may occur. In clinical trials, anti-brolucizumab antibodies were detected in pre-treatment (baseline) sample of 36% to 64% of treatment-naive patients. After initiation of therapy, anti-brolucizumab antibodies were detected in 53% to 76% of drug recipients. In addition, intraocular inflammation was observed in 6% of patients with detectable anti-brolucizumab antibodies during therapy. Retinal vasculitis and retinal vascular occlusion are immune mediated adverse events related to brolucizumab exposure that typically occur in the presence of intraocular inflammation. These events may develop following the first intravitreal injection. Anti-brolucizumab antibodies have not been associated with an impact on clinical efficacy.
As with other intravitreal injections, brolucizumab is contraindicated for use in patients with ocular infection, periocular infection, or ocular inflammation. Intravitreal injections, including those with brolucizumab, have been associated with endophthalmitis and retinal detachment, which may lead to blindness. A broad-spectrum ocular microbicide should be given prior to the injection to disinfect the periocular skin, eyelid, and ocular surface. Use controlled aseptic conditions during the procedure, which includes the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Treatment with brolucizumab has also been associated with the development of retinal vasculitis and retinal vascular occlusion. These immune-mediated adverse events typically occur when the drug is administered in the presence of intraocular inflammation, and may develop following the first intravitreal injection. Discontinue treatment in patients who develop these events. Instruct patients to report any symptoms suggestive of endophthalmitis or retinal detachment, vasculitis, or occlusion (e.g., ocular pain, redness of the eye, photophobia, changes in vision or blurred vision) without delay.
Acute increased intraocular pressure (IOP) may develop within 30 minutes of intravitreal injections, including brolucizumab. Sustained increases in IOP have also been reported. Patients with uncontrolled glaucoma, defined as intraocular pressure greater than 25 mmHg while on medication, were excluded from brolucizumab clinical trials. May be prudent to use caution in patients with a history of glaucoma. Monitor for increased IOP and perfusion of the optic nerve head. Ensure a sterile paracentesis needle is available if needed.
Caution is advised when administering brolucizumab to patients with a history of thromboembolic disease. Arterial thromboembolic events (defined as nonfatal stroke, nonfatal myocardial infarction, and vascular deaths) were observed during clinical trials in patients receiving intravitreal brolucizumab injections. Patients with history of stroke or myocardial infarction within the 90-day (HAWK trial) or 6-month (HARRIER trial) period prior to baseline were excluded from clinical trials.
Patients may experience temporary visual disturbances after brolucizumab administration. Advise drug recipients to avoid driving or operating machinery until visual function has recovered.
Safety and efficacy of brolucizumab have not been established in pediatric patients (i.e., neonates, infants, children, or adolescents).
There are no adequate and well-controlled studies regarding the use of brolucizumab during human pregnancy. 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. Brolucizumab is a vascular endothelial growth factor (VEGF) inhibitor. In animal studies, VEGF inhibition has been shown to cause malformations, embryo-fetal resorption, and decreased fetal weight. Based on the anti-VEGF mechanism of action, treatment with brolucizumab may pose a risk to human embryo-fetal development. The drug should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.
Counsel patients about brolucizumab associated reproductive risk and contraception requirements. Females of reproductive age are advised to use highly effective contraception (methods that result in less than 1% pregnancy rates) during treatment and for at least 1 month after the last dose. In addition, based on the anti-vascular endothelial growth factor (VEGF) mechanism of action, the potential exists for brolucizumab to pose a risk to human reproductive capacity; however, no studies have been conducted to associate use of the drug with human infertility.
The manufacturer recommends against breast-feeding during brolucizumab treatment and for at least 1 month after the last dose. It is unknown whether brolucizumab is excreted in human milk, affects milk production, or has an adverse effect on the breastfed infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For the treatment of neovascular (wet) age-related macular degeneration (AMD):
Intravitreal dosage:
Adults: 6 mg (0.05 mL) via intravitreal injection into the affected eye(s) once monthly (approximately every 25 to 31 days) for the first 3 doses. Then give 6 mg (0.05 mL) intravitreally every 8 to 12 weeks.
For the treatment of diabetic macular edema (DME):
Intravitreal dosage:
Adults: 6 mg by intravitreal injection in the affected eye(s) every 6 weeks for the first 5 doses, followed by 6 mg by intravitreal injection in the affected eye(s) every 8 to 12 weeks. Guidelines recommend intravitreous anti-vascular endothelial growth factor agents, such as brolucizumab, as first-line therapies for the management of central-involved diabetic macular edema.
Maximum Dosage Limits:
-Adults
6 mg per eye intravitreally.
-Geriatric
6 mg per eye intravitreally.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Brolucizumab products.
Brolucizumab is a recombinant humanized monoclonal single-chain Fv (scFv) antibody fragment. The drug binds to and blocks the 3 major isoforms of vascular endothelial growth factor-A (e.g., VEGF110, VEGF121, and VEGF165). VEGF-A is a member of the VEGF family of angiogenic factors that act as mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF-A interacts with 2 receptors, VEGFR-1 and VEGFR-2, on the surface of endothelial cells. Activation of VEGFR-1 and VEGFR-2 can result in neovascularization and vascular permeability. By blocking VEGF-A, brolucizumab suppresses endothelial cell proliferation, neovascularization, and vascular permeability.
Brolucizumab is administered via intravitreal injection.
The pharmacokinetics of brolucizumab have not been fully characterized; however, systemically circulating drug is expected to undergo metabolism via proteolysis. Excretion is thought to occur by target-mediated disposition and passive renal excretion. The estimated mean systemic half-life of a single intravitreal dose is 4.4 days (+/- 2 days).
Affected cytochrome P450 isoenzymes and transporters: none
-Route-Specific Pharmacokinetics
Other Route(s)
Intravitreal Route
Administration of a single 6 mg intravitreal dose to 25 patients resulted in a mean maximum plasma concentration (Cmax) of free brolucizumab that was 49 ng/mL (range: 9 to 548 ng/mL); the time to reach peak concentration (i.e., Tmax) was 24 hours post-dose. Brolucizumab systemic concentrations were near or less than 0.5 ng/mL (lower limit of assay quantitation) at approximately 4 weeks after repeated dose administration. Drug accumulation was not observed in most patients.
-Special Populations
Hepatic Impairment
The effect of any degree of hepatic impairment on the pharmacokinetics of brolucizumab is unknown. No dosage adjustments are needed based on hepatic impairment.
Renal Impairment
No difference in the systemic pharmacokinetics of brolucizumab were observed based on mild to moderate renal impairment (GFR 30 to 70 mL/min). The effect of severe renal impairment on the pharmacokinetics of brolucizumab is unknown. No dosage adjustments are needed based on renal impairment.
Geriatric
No difference in the systemic pharmacokinetics of brolucizumab were observed based on age (i.e., 50 years and older).
Gender Differences
No difference in the systemic pharmacokinetics of brolucizumab were observed based on gender.