0.05 ML ranibizumab 10 MG/ML Injection

INDICATIONS AND USAGE SUSVIMO (ranibizumab injection) is a vascular endothelial growth factor (VEGF) inhibitor indicated for the treatment of patients with: Neovascular (wet) Age-related Macular Degeneration (AMD) who have previously responded to at least two intravitreal injections of a VEGF inhibitor ( 1.1 ). Diabetic Macular Edema (DME) who have previously responded to at least two intravitreal injections of a VEGF inhibitor ( 1.2 ). Diabetic Retinopathy (DR) who have previously responded to at least two intravitreal injections of a VEGF inhibitor ( 1.3 ). 1.1 Neovascular (wet) Age-related Macular Degeneration (AMD) SUSVIMO (ranibizumab injection) is indicated for the treatment of patients with Neovascular (wet) Age-related Macular Degeneration (AMD) who have previously responded to at least two intravitreal injections of a Vascular Endothelial Growth Factor (VEGF) inhibitor medication. 1.2 Diabetic Macular Edema (DME) SUSVIMO (ranibizumab injection) is indicated for the treatment of patients with Diabetic Macular Edema (DME) who have previously responded to at least two intravitreal injections of a Vascular Endothelial Growth Factor (VEGF) inhibitor medication. 1.3 Diabetic Retinopathy (DR) SUSVIMO (ranibizumab injection) is indicated for the treatment of patients with Diabetic Retinopathy (DR) who have previously responded to at least two intravitreal injections of a Vascular Endothelial Growth Factor (VEGF) inhibitor medication.

DOSAGE AND ADMINISTRATION For intravitreal use via SUSVIMO ocular implant. ( 2.1 ) Neovascular (wet) Age-related Macular Degeneration (AMD) and Diabetic Macular Edema (DME) The recommended dose of SUSVIMO (ranibizumab injection) is 2 mg (0.02 mL of 100 mg/mL solution) continuously delivered via the SUSVIMO implant with refills every 24 weeks (approximately 6 months). ( 2.2 ) Diabetic Retinopathy (DR) The recommended dose of SUSVIMO (ranibizumab injection) is 2 mg (0.02 mL of 100 mg/mL solution) continuously delivered via the SUSVIMO implant with refills every 36 weeks (approximately 9 months). ( 2.3 ) Supplemental treatment with 0.5 mg intravitreal ranibizumab injection may be administered in the affected eye if clinically necessary. ( 2.4 ) Perform the initial implantation, refill-exchange, and implant removal (if necessary) procedures under strict aseptic conditions. ( 2.5 , 2.6 , 2.7 , 2.8 ) 2.1 General Information For Intravitreal Use via SUSVIMO ocular implant. The SUSVIMO initial fill and ocular implant insertion and implant removal procedures must be performed under aseptic conditions by a physician experienced in vitreoretinal surgery. The SUSVIMO ocular implant must be surgically implanted in the eye or removed from the eye (if medically necessary) in an operating room using aseptic technique. See SUSVIMO Instructions for Use and the standardized steps to optimize surgical outcomes. SUSVIMO refill-exchange procedures must be performed under aseptic conditions by a physician experienced in ophthalmic surgery [see Dosage and Administration (2.7) ] . Do not administer SUSVIMO (ranibizumab injection) as a bolus intravitreal injection. Do not substitute SUSVIMO (ranibizumab injection) with other ranibizumab products. Initial Fill : One SUSVIMO initial fill needle (34-gauge, with integrated 5 μm filter and blue cap) is included. A 5-micron sterile filter needle (19-gauge × 1½ inch), and a 1 mL Luer lock syringe are needed but not included . Refill-Exchange : One SUSVIMO refill needle (34-gauge with integrated 5 μm filter and clear cap) is included. A 5-micron sterile filter needle (19-gauge × 1½ inch), and a 1 mL Luer lock syringe are needed but not included . 2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD) and Diabetic Macular Edema (DME) The recommended dose of SUSVIMO (ranibizumab injection) is 2 mg (0.02 mL of 100 mg/mL solution) continuously delivered via the SUSVIMO ocular implant with refills administered every 24 weeks (approximately 6 months). 2.3 Diabetic Retinopathy (DR) The recommended dose of SUSVIMO (ranibizumab injection) is 2 mg (0.02 mL of 100 mg/mL solution) continuously delivered via the SUSVIMO ocular implant with refills administered every 36 weeks (approximately 9 months). 2.4 Supplemental Treatment with Intravitreal Ranibizumab Injection Supplemental treatment with 0.5 mg (0.05 mL of 10 mg/mL) intravitreal ranibizumab injection may be administered in the affected eye while the SUSVIMO implant is in place and if clinically necessary [see Clinical Studies (14) ] . 2.5 Ocular Implant Initial Fill The implant initial fill procedure must be performed by a physician experienced in vitreoretinal surgery [ see Dosage and Administration (2.1) ]. The implant will be filled using aseptic technique with 0.02 mL of SUSVIMO (ranibizumab injection) prior to insertion of the implant into the patient's eye [see Dosage and Administration (2.6) ]. Refer to the complete SUSVIMO Instructions for Use for the initial fill and implant procedure included in the insertion tool assembly carton for further details. Use aseptic technique to carry out the following preparation steps prior to insertion of the ocular implant into the patient's eye: Step 1: Gather the supplies needed. One SUSVIMO ocular implant with insertion tool assembly (included) One SUSVIMO initial fill needle (34-gauge with integrated 5 μm filter) with blue cap (included) One SUSVIMO (ranibizumab injection) 100 mg/mL vial (included) One sterile 5-micron filter needle (19-gauge × 1½ inch) (not included) One sterile 1 mL Luer Lock syringe (not included) Step 2: Transfer Dose from Vial to Syringe Note: Use the filter needle (not included) to withdraw SUSVIMO (ranibizumab injection) from the vial. Figure 1 Do not use the SUSVIMO initial fill needle for this step. Prepare SUSVIMO (ranibizumab injection) vial by removing the flip-off cap and disinfecting the rubber vial septum with alcohol. Attach a filter needle to the syringe by screwing it tightly onto the Luer lock (see Figure 1 ). Carefully remove the needle cap by pulling it straight off. Using aseptic technique, withdraw all of the contents of the SUSVIMO (ranibizumab injection) vial through the filter needle into the syringe. Step 3: Remove Air from Syringe With the filter needle attached, 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 (Figure 2). Slowly push the plunger rod just until all air is expelled from the syringe and needle. – It is important to preserve as much drug as possible in order to completely fill the implant. Remove and properly dispose of the filter needle after air is removed from syringe. Figure2 Step 4: Attach SUSVIMO Initial Fill Needle Do not use the filter needle to fill the implant. Attach the SUSVIMO initial fill needle (included) firmly onto the syringe by screwing it tightly onto the Luer lock (see Figure 3 ). Ensure that the initial fill needle is attached to the syringe. Carefully remove the needle cap by pulling straight off. Do not wipe the needle at any time. Figure 3 Step 5: Remove Any Remaining Air from Syringe With the initial fill needle attached, 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 4 ). Slowly push the plunger rod just until all air is expelled from the syringe and needle, and a drop of drug solution is seen at the needle tip (see Figure 5 ). Figure 4 Figure 5 Note: It is important to preserve as much drug as possible in order to completely fill the implant. Step 6: Inspect the Syringe for Air Bubbles Inspect the syringe and the needle hub to ensure that no air bubbles are present (see Figure 6 ). If air bubbles are present, continue to remove air from the syringe and reinspect. Figure 6 Note: Use the syringe within 15 minutes of removing all air to avoid ranibizumab drying in the needle and impeding fluid flow. Do not use the initial fill needle if the needle is clogged. Step 7: Load Syringe into the Carrier Do not hold or push on the plunger rod of the syringe while inserting the needle into the implant septum. Retrieve insertion tool carrier with pre-positioned implant from the inner tray. Align the syringe Luer lock above the Luer lock slot in the carrier to protect the needle from being damaged. Lower the syringe into the carrier (see Figure 7 ). Push the syringe forward until it stops, taking care to avoid touching the plunger rod (see Figure 8 ) With the syringe loaded, (see Figure 9 ) the initial fill needle should now be penetrating the implant septum. Figure 7: Align and lower the syringe into the carrier Figure 8: Push the syringe into the carrier Figure 9: Syringe with initial fill needle inserted through the implant septum Step 8: Fill Ocular Implant with SUSVIMO (ranibizumab injection) Under Microscope Under the microscope, slowly administer SUSVIMO (ranibizumab injection) into the ocular implant by slightly tilting the carrier upwards (see Figure 10 ). The ocular implant should be filled over approximately 5 to 10 seconds , to help avoid air entrapment in the implant reservoir. Figure 10: Administer ranibizumab into the implant Figure 11: Dome of drug solution forms at tip of implant as viewed under magnification Note: When filling the ocular implant, drug solution should only exit the ocular implant from the release control element. If dr

WARNINGS AND PRECAUTIONS The SUSVIMO implant and/or implant-related procedures have been associated with endophthalmitis, rhegmatogenous retinal detachment, implant dislocation, septum dislodgement, vitreous hemorrhage, conjunctival erosion, conjunctival retraction, and conjunctival blebs. Patients should be instructed to report any signs or symptoms that could be associated with these events without delay. In some cases, these events can present asymptomatically. The implant and the tissue overlying the implant flange should be monitored routinely following the implant insertion, and refill-exchange procedures to permit early medical or surgical intervention as necessary. Special precautions need to be taken when handling SUSVIMO components [see How Supplied/Storage and Handling (16.3) ]. The SUSVIMO implant and/or implant-related procedures have been associated with endophthalmitis, rhegmatogenous retinal detachment, implant dislocation, septum dislodgement, vitreous hemorrhage, conjunctival retraction, conjunctival erosion, and conjunctival bleb. Patients should be instructed to report signs or symptoms that could be associated with these events without delay. Additional surgical and/or medical management may be required. ( 5.1 , 5.2 , 5.3 , 5.4 , 5.5 , 5.6 , 5.7 ) Vitreous Hemorrhage : Temporarily discontinue antithrombotic medication prior to the implant insertion procedure to reduce the risk of vitreous hemorrhage. Vitrectomy may be needed. ( 5.5 ) Postoperative Decrease in Visual Acuity : A decrease in visual acuity usually occurs over the first two postoperative months. ( 5.8 ) 5.1 Endophthalmitis In the active comparator period of controlled clinical trials in AMD, the ranibizumab implant has been associated with a 3-fold higher rate of endophthalmitis than monthly intravitreal injections of ranibizumab (1.7% in the SUSVIMO arm vs 0.5% in the intravitreal arm). When including extension phases of clinical trials, 2% (11/555) of patients receiving the ranibizumab implant experienced an episode of endophthalmitis. Reports occurred between days 5 and 853, with a median of 173 days. Many, but not all, of the cases of endophthalmitis reported a preceding or concurrent conjunctival retraction or erosion event. In the active comparator period of the controlled clinical trial in DME, 0% of patients in the SUSVIMO arm compared to 0.3% in the intravitreal arm experienced an episode of endophthalmitis. When including the extension phase of the clinical trial, 0.7% (4/556) of patients receiving the ranibizumab implant experienced an episode of endophthalmitis. Reports occurred between days 625 and 1016, with a median of 824 days. In the period with an observational comparator arm of the clinical trial in DR, there were no patients (0/105) in the SUSVIMO arm who experienced an episode of endophthalmitis [see Clinical Studies (14.3) ] . When including the extension phase of the clinical trial 0.8% (1/128) patients receiving the ranibizumab implant experienced an episode of endophthalmitis, with the event reported on day 695. Endophthalmitis should be treated promptly in an effort to reduce the risk of vision loss and maximize recovery. The SUSVIMO (ranibizumab injection) dose (refill-exchange) should be delayed until resolution of endophthalmitis [see Dosage and Administration (2.10) and Adverse Reactions (6.1) ] . Patients should not have an active or suspected ocular or periocular infection or severe systemic infection at the time of any SUSVIMO implant or refill procedure. Appropriate intraoperative handling followed by secure closure of the conjunctiva and Tenon's capsule, and early detection and surgical repair of conjunctival erosions or retractions and strict/controlled aseptic technique conditions throughout refill-exchange procedures may reduce the risk of endophthalmitis [see Dosage and Administration (2.1) and Warnings and Precautions (5.5) ] . 5.2 Rhegmatogenous Retinal Detachment Rhegmatogenous retinal detachments have occurred in clinical trials of SUSVIMO and may result in vision loss. Rhegmatogenous retinal detachments should be promptly treated with an intervention (e.g., pneumatic retinopexy, vitrectomy, or laser photocoagulation). SUSVIMO (ranibizumab injection) dose (refill-exchange) should be delayed in the presence of a retinal detachment or retinal break [see Dosage and Administration (2.10) ] . Careful evaluation of the retinal periphery is recommended to be performed, and any suspected areas of abnormal vitreo-retinal adhesion or retinal breaks should be treated before inserting the implant in the eye. 5.3 Implant Dislocation In clinical trials, the device has dislocated/subluxated into the vitreous cavity or has extended outside the vitreous cavity into or beyond the subconjunctival space. Device dislocation requires urgent surgical intervention. Strict adherence to the scleral incision length and appropriate targeting of the pars plana during laser ablation may reduce the risk of implant dislocation. 5.4 Septum Dislodgement In clinical trials, a type of implant damage where the septum has dislodged into the implant body has been reported. Perform a dilated slit lamp exam and/or dilated indirect ophthalmoscopy to inspect the implant in the vitreous cavity through the pupil prior to and after the refill-exchange procedure to identify if septum dislodgement has occurred. Discontinue treatment with SUSVIMO (ranibizumab injection) following septum dislodgement and consider implant removal should the benefit of the removal procedure outweigh the risk [ see Dosage and Administration (2.9) ]. The benefits and risks of retaining, removing, or removing and replacing an implant with a dislodged septum are not well characterized. Appropriate handling and insertion of the refill needle into the septum (avoid twisting and/or rotation) is required to minimize the risk of septum dislodgement [ see Dosage and Administration (2.8) ]. 5.5 Vitreous Hemorrhage Vitreous hemorrhages may result in temporary vision loss. Vitrectomy may be needed in the case of a non-clearing vitreous hemorrhage [see Dosage and Administration (2.10) ] . In clinical trials of SUSVIMO including the extension phases in patients with AMD, vitreous hemorrhages were reported in 5.2% (23/443) of patients receiving SUSVIMO. In the clinical trial of SUSVIMO including the extension phases in patients with DME, vitreous hemorrhages were reported in 10.1% (56/556) of patients receiving SUSVIMO. In the clinical trial of SUSVIMO including the extension phase in patients with DR, vitreous hemorrhages were reported in 9.4% (12/128) of patients receiving SUSVIMO. The majority of these hemorrhages occurred within the first post-operative month following surgical implantation and the majority of vitreous hemorrhages resolved spontaneously. Patients on antithrombotic medication (e.g., oral anticoagulants, aspirin, nonsteroidal anti-inflammatory drugs) may be at increased risk of vitreous hemorrhage. Antithrombotic medications are recommended to be temporarily interrupted prior to the implant insertion procedure. The SUSVIMO (ranibizumab injection) dose (refill-exchange) should be delayed in the event of sight-threatening vitreous hemorrhage. The use of pars plana laser ablation and scleral cauterization should be performed to reduce the risk of vitreous hemorrhage. 5.6 Conjunctival Erosion or Retraction A conjunctival erosion is a full thickness degradation or breakdown of the conjunctiva in the area of the implant flange. A conjunctival retraction is a recession or opening of the limbal and/or radial peritomy. Conjunctival erosions or retractions have been associated with an increased risk of endophthalmitis, especially if the implant becomes exposed. Surgical intervention (e.g., conjunctival/Tenon's capsule repair) is recommended to be performed in case of conjunctival erosion or retraction with or without exposure of the implant flange. In clinical trials of SUSVIMO including the extens

CONTRAINDICATIONS Ocular or periocular infections ( 4.1 ) Active intraocular inflammation ( 4.2 ) Hypersensitivity ( 4.3 ) 4.1 Ocular or Periocular Infections SUSVIMO (ranibizumab injection) is contraindicated in patients with ocular or periocular infections. 4.2 Active Intraocular Inflammation SUSVIMO (ranibizumab injection) is contraindicated in patients with active intraocular inflammation. 4.3 Hypersensitivity SUSVIMO (ranibizumab injection) is contraindicated in patients with known hypersensitivity to ranibizumab products or any of the excipients in SUSVIMO (ranibizumab injection).

Mechanism of Action Ranibizumab products bind to the receptor binding site of active forms of VEGF-A, including the biologically active, cleaved form of this molecule, VEGF 110 . VEGF-A has been shown to cause neovascularization and leakage in models of ocular angiogenesis and vascular occlusion and is thought to contribute to pathophysiology of neovascular AMD, mCNV, DR, DME and macular edema following RVO. The binding of ranibizumab products to VEGF-A prevents the interaction of VEGF-A with its receptors (VEGFR1 and VEGFR2) on the surface of endothelial cells, reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation.