Susvimo

1 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.

2 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…

5 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 hav…

4 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).

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of SUSVIMO (ranibizumab injection) administration in pregnant women. Administration of ranibizumab to pregnant monkeys throughout the period of organogenesis resulted in a low incidence of skeletal abnormalities at intravitreal doses up to 41 times the human exposure (based on serum levels following the recommended clinical dose). No skeletal abnormalities were observed at serum trough levels similar to the human exposure after a single eye treatment at the recommended clinical dose ( see Data ) . Animal reproduction studies are not always predictive of human response, and it is not known whether ranibizumab can cause fetal harm when administered to a pregnant woman. Based on the anti-VEGF mechanism of action for ranibizumab [see Clinical Pharmacology (12.1) ] , treatment with SUSVIMO (ranibizumab injection) may pose a risk to human embryofetal development. All pregnancies have a background risk of birth defects, 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. Data Animal Data An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received intravitreal injections of ranibizumab every 14 days starting on Day 20 of gestation, until Day 62 at doses of 0, 0.125, and 1 mg/eye. Skeletal abnormalities including incomplete and/or irregular ossification of bones in the skull, vertebral column, and hindlimbs and shortened supernumerary ribs were seen at a low incidence in fetuses from animals treated with 1 mg/eye of ranibizumab. The 1 mg/eye dose resulted in trough serum ranibizumab levels up to 41 times higher than observed human C max levels of SUSVIMO (ranibizumab injection) after treatment of a single eye. No skeletal abnormalities were seen at the lower dose of 0.125 mg/eye, a dose which resulted in trough exposures similar to single eye treatment with SUSVIMO (ranibizumab injection) in humans. No effect on the weight or structure of the placenta, maternal toxicity, or embryotoxicity was observed.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Endophthalmitis [see Warnings and Precautions (5.1) ] Rhegmatogenous Retinal Detachment [see Warnings and Precautions (5.2) ] Implant Dislocation [see Warnings and Precautions (5.3) ] Septum Dislodgement [see Warnings and Precautions (5.4) ] Vitreous Hemorrhage [see Warnings and Precautions (5.5) ] Conjunctival Erosion or Retraction [see Warnings and Precautions (5.6) ] Conjunctival Bleb [see Warnings and Precautions (5.7) ] Postoperative Decrease in Visual Acuity [see Warnings and Precautions (5.8) ] The most common adverse reactions (≥ 10%) were conjunctival hemorrhage, conjunctival hyperemia, iritis, eye pain, conjunctival disorder, cataract and vitreous hemorrhage. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 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. The data below ( Table 2 ) reflect exposure of 248 patients with AMD in the Archway study through Week 40, 320 patients with DME in the Pagoda study up to Week 64, and 105 patients with DR in the Pavillion study through Week 52 following the SUSVIMO initial fill and implant insertion, refill, and implant removal (if necessary) procedures. In clinical trials of SUSVIMO in AMD patients, the most common (≥ 10%) adverse reactions up to Week 40 were conjunctival hemorrhage (72%), conjunctival hyperemia (26%), iritis (23%), and eye pain (10%). Septum dislodgement was reported in 0.4% of the AMD patient population. In clinical trials of SUSVIMO in DME patients, patient population the most common (≥ 10%) adverse reactions up to Week 64 were conjunctival hemorrhage (62%), conjunctival hyperemia (15%), iritis (14%), eye pain (13%), cataract (11%), conjunctival disorder (10%) and vitreous hemorrhage (10%). In clinical trials of SUSVIMO in DR patients, the most common (≥ 10%) adverse reactions up to Week 52 were conjunctival hemorrhage (73%), conjunctival disorder (14%), iritis (12%) and conjunctival hyperemia (11%). Table 2 Adverse Reactions occurring in ≥ 4% of patients in the SUSVIMO arm Adverse Reactions AMD Week 40 DME Week 64 DR Week 52 SUSVIMO n = 248 Intravitreal ranibizumab n = 167 SUSVIMO n = 320 Intravitreal ranibizumab 0.5 mg n = 314 SUSVIMO n = 105 Conjunctival hemorrhage 72% 6% 62% 18% 73% Conjunctival hyperemia 26% 2% 15% 0 11% Iritis Iritis includes: iritis, anterior chamber flare, anterior chamber inflammation, and anterior chamber cell. 23% 0.6% 14% 2% 12% Eye pain 10% 5% 13% 6% 9% Conjunctival disorder Conjunctival disorder includes: conjunctival adhesion, conjunctival disorder, conjunctival edema, conjunctival erosion, conjunctival retraction, and subconjunctival fibrosis. 9% 0 10% 0.3% 14% Vitreous floaters 9% 2% 4% 5% 2% Conjunctival bleb/ filtering bleb leak Conjunctival bleb/filtering bleb leak includes: conjunctival bleb, conjunctival filtering bleb leak, conjunctival cyst, subconjunctival cyst, and implant site cyst. 8% 0 8% 0 2% Foreign body sensation in eyes 7% 1% 3% 2% 9% Headache Headache includes: headache and procedural headache. 6% 2% 6% 4% 9% Hypotony of eye 6% 0 3% 0 0 Vitreous detachment 6% 5% 8% 5% 9% Vitreous hemorrhage 5% 2% 10% 2% 6% Cataract Cataract includes: cataract, cortical cataract, nuclear cataract, and subcapsular cataract. 4% 4% 11% 7% 7% Corneal disorder 4% 0 1% 0 1% Corneal abrasion Corneal abrasion includes: corneal abrasion and vital dye staining cornea present. 4% 0.6% 4% 1% 4% Corneal edema 4% 0 4% 0.3% 4% In clinical trials of SUSVIMO, hyphema was reported in 0.4% of AMD patients, 1.9% of DME patients, and 1.9% of DR patients.