BROLUCIZUMAB: 682 Adverse Event Reports & Safety Profile

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, clear to slightly opalescent, colorless to slightly brownish-yellow solution in a single-dose pre-filled syringe or a single-dose vial for intravitreal administration. Each single-dose pre-filled syringe and 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. This product does not contain an antimicrobial preservative.

AND USAGE BEOVU ® is indicated for the treatment of: BEOVU is a human vascular endothelial growth factor (VEGF) inhibitor indicated for the treatment of: Neovascular (Wet) Age-Related Macular Degeneration (AMD) ( 1.1 )

Diabetic Macular

Edema (DME) ( 1.2 )

1.1 Neovascular (Wet) Age-related Macular Degeneration (AMD)

1.2 Diabetic Macular Edema (DME)

AND ADMINISTRATION Neovascular (Wet) Age-Related Macular Degeneration (AMD) 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 ).

Diabetic Macular

Edema (DME) The recommended dose for BEOVU is 6 mg (0.05 mL of 120 mg/mL solution) every six weeks (approximately every 39-45 days) for the first five doses, followed by one dose of 6 mg (0.05 mL of 120 mg/mL solution) every 8-12 weeks ( 2.3 ).

2.1 General Dosing Information For ophthalmic intravitreal injection. BEOVU must be administered by a qualified physician. BEOVU is available packaged as follows <span class="opacity-50 text-xs">[see How Supplied/Storage and Handling (16)]</span> : Pre-filled Syringe Vial kit with injection components (vial, filter needle)

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 to 31 days) for the first three doses, followed by 6 mg (0.05 mL) by intravitreal injection once every 8 to 12 weeks.

2.3 Diabetic Macular Edema (DME) The recommended dose for BEOVU is 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every six weeks (approximately every 39-45 days) for the first five doses, followed by 6 mg (0.05 mL) by intravitreal injection once every 8-12 weeks.

2.4 Preparation for Administration – Pre-filled Syringe and Vial 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. Use aseptic technique for preparation of the intravitreal injection. Pre-filled Syringe The BEOVU pre-filled glass syringe is sterile and for the treatment of a single eye. It should be inspected visually prior to administration. Do not use if the packaging, or pre-filled syringe are opened, damaged, or expired <span class="opacity-50 text-xs">[see How Supplied/Storage and Handling (16)]</span> . 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: Vial The BEOVU vial kit includes the sterile glass vial and filter needle which are sterile and for the treatment of a single eye. It should be inspected visually prior to administration. Do not use if the packaging, vial, and/or filter needle are damaged or expired [see How Supplied/Storage and Handling (16)] . 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: Preparation for Administration - Store BEOVU in the refrigerator between 2 to 8°C (36 to 46°F); do not freeze. Keep the vial in the outer carton to protect from light. Preparation for Administration - Prior to use, the unopened glass vial of BEOVU may be kept at room temperature, 20 to 25°C (68 to 77°F) for up to 24 hours. After opening the glass vial, proceed under aseptic conditions. Preparation for Administration - 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)]. Vial-Figure 4: Vial-Figure 5: Vial-Figure 6: Vial-Figure 7: Pre-filled Syringe Pre-filled Syringe-Figure 1: Pre-filled Syringe-Figure 2: Pre-filled Syringe-Figure 3:

2.5 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 <span class="opacity-50 text-xs">[see Patient Counseling Information (17)]</span> . 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.

Ocular or Periocular Infections ( 4.1 )

Active Intraocular

Inflammation ( 4.2 ) Hypersensitivity ( 4.3 )

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.

4.3 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.

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)] The most common adverse reactions reported in patients receiving BEOVU are vision blurred, cataract, conjunctival hemorrhage, eye pain, and vitreous floaters ( 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 .

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 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 <span class="opacity-50 text-xs">[see Clinical Studies (14.1)]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Studies (14.2)]</span> .

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.

6.2 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.

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 ).

5.1 Endophthalmitis and Retinal Detachment Intravitreal injections, including those with BEOVU, have been associated with endophthalmitis and retinal detachment <span class="opacity-50 text-xs">[see Contraindications (4.1) and Adverse Reactions (6.1)]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) and Patient Counseling Information (17)]</span> .

5.2 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 <span class="opacity-50 text-xs">[see Contraindications (4.2) and Adverse Reactions (6.1, 6.2)]</span> . Patients should be instructed to report any change in vision without delay.

5.3 Increase in Intraocular Pressure Acute increases in intraocular pressure (IOP) have been seen within 30 minutes of intravitreal injection, including with BEOVU <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . Sustained IOP increases have also been reported. Both IOP and perfusion of the optic nerve head must be monitored and managed appropriately <span class="opacity-50 text-xs">[see Dosage and Administration (2.4)]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Studies (14.1)]</span> .