SUSVIMO- ranibizumab_injection, solution

Ranibizumab binds to the receptor binding site of multiple biologically active forms of VEGF-A, including VEGF 110 The SUSVIMO implant provides a continuous release of ranibizumab where the release of ranibizumab into the vitreous decreases over time as the concentration in the implant decreases. The ranibizumab serum and aqueous humor concentrations with a SUSVIMO 24-week and 36-week treatment interval are maintained below the maximum and above the minimum concentrations experienced with monthly 0. 5 mg intravitreal ranibizumab. Distribution Ranibizumab did not accumulate in serum when administered with refills every 24 weeks or every 36 weeks. Following implant insertion of SUSVIMO in patients with AMD, the mean (+/-SD) maximum ranibizumab serum concentration (C max max Elimination Metabolism The metabolism of SUSVIMO (ranibizumab injection) has not been studied. SUSVIMO (ranibizumab injection) is a monoclonal antibody fragment and antibodies are cleared principally by catabolism. Excretion The full excretion profile for ranibizumab following administration of SUSVIMO is unknown. Specific Populations Patients with renal impairment were included in the population pharmacokinetic analysis of SUSVIMO (ranibizumab injection). Across all indications, systemic clearance of ranibizumab was slightly lower in renally impaired patients but was not clinically significant. No clinically significant differences in the pharmacokinetics of ranibizumab were observed based on age in the patient population. As with all therapeutic proteins, there is potential for immune response in patients treated with ranibizumab including SUSVIMO. The detection of an immune response is highly dependent on the sensitivity, specificity, and drug tolerance level of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the study described below with the incidence of antibodies in other studies or to other products may be misleading. Prior to treatment with SUSVIMO, 2. 6% of patients with AMD, DME, or DR tested positive for anti-ranibizumab antibodies. In patients with AMD, after the SUSVIMO implant insertion and treatment, 12% (29 of 247) patients tested positive for anti-ranibizumab antibodies. In patients with DME, after 4 doses of intravitreal ranibizumab, and SUSVIMO implant insertion and treatment, 13% (41 of 320) patients tested positive for anti-ranibizumab antibodies. In patients with DR, after 2 doses of intravitreal ranibizumab, and SUSVIMO implant insertion and treatment, 17% (17 of 99) patients tested positive for anti-ranibizumab antibodies. No clinically meaningful differences in the pharmacokinetics, efficacy, or safety in patients testing positive for anti-ranibizumab antibodies were observed.

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 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. 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. 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.

For intravitreal use via SUSVIMO ocular implant. 1 Neovascular (wet) Age-related Macular Degeneration (AMD) and Diabetic Macular Edema (DME) 2. 2 Diabetic Retinopathy (DR) 2. 3 Supplemental treatment with 0. 5 mg intravitreal ranibizumab injection may be administered in the affected eye if clinically necessary. 4 Perform the initial implantation, refill-exchange, and implant removal (if necessary) procedures under strict aseptic conditions. 8 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 not included Refill-Exchange not included 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). 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). Supplemental treatment with 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) The implant initial fill procedure must be performed by a physician experienced in vitreoretinal surgery [ Dosage and Administration (2. 1) [see Dosage and Administration (2. 6) Refer to the complete SUSVIMO Instructions for Use 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 mum 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 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. en dash Remove and properly dispose of the filter needle after air is removed from syringe. Figure2 Step 4: Attach SUSVIMO Initial Fill Needle Do not Attach the SUSVIMO initial fill needle (included) firmly onto the syringe by screwing it tightly onto the Luer lock (see Figure 3 Carefully remove the needle cap by pulling straight off. Do not Figure 3 Step 5: Remove Any Remaining Air from Syringe With the initial fill needle attached, hold the syringe with the needle pointing up. 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 Do not Step 7: Load Syringe into the Carrier Do not 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 Figure 7: Figure 8: Figure 9: Step 8: Fill Ocular Implant with SUSVIMO (ranibizumab injection) Under Microscope Under the microscope, slowly Figure 10 The ocular implant should be filled over approximately 5 to 10 seconds Figure 10: Figure 11: Note: When filling the ocular implant, drug solution should only exit the ocular implant from the release control element. If drug solution is leaking from the implant at a different location, such as the side of the implant, do not Continue filling the ocular implant until the implant is completely full of drug solution and all air has been expelled as evidenced by a dome of drug solution formed at the tip of the implant on the release control element (see Figure 11 Step 9: Inspect the Filled Ocular Implant Under the Microscope Inspect the ocular implant under the microscope to ensure that the ocular implant is completely full of drug solution (see Figure 12 Figure 12: Note: Minimize air bubbles within the implant reservoir as they may cause slower drug release. If an air bubble is present, it must be no larger than 1/3 of the widest diameter of the implant. If excess air is observed, do not Note: No more than 30 minutes Step 10: Remove the Syringe and Guide Sleeve from the Carrier Remove the syringe and guide sleeve from the carrier by pulling back on the syringe (see Figure 13 Properly dispose of the used syringe together with the needle and guide sleeve in a sharps disposal container or in accordance with local requirements. Figure 13: Step 11: Slide the Insertion Tool Handle into the Carrier Slide the insertion tool handle into the guide channel of the carrier, ensuring that both components are facing upwards (see Figure 14 Push the handle forward as far as it will go into the gripper tips (see Figure 15 Figure 14: Figure 15: Note: Do not Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 SUSVIMO ocular implant insertion is a surgical procedure that is performed in an operating room. The procedure must be performed under aseptic conditions by a physician experienced in vitreoretinal surgery [see Dosage and Administration (2. 1) The ocular implant is filled with SUSVIMO (ranibizumab injection) immediately prior to insertion. No more than 30 minutes should pass between the initial fill of the ocular implant and the insertion into the patient's eye. After placing an infusion line in the eye, create at least a 6×6 mm peritomy of the conjunctiva and Tenon's capsule centered around the selected SUSVIMO implant location in the supero-temporal quadrant. Perform careful conjunctival incision, hemostasis of the underlying sclera, and generous undermining of Tenon's capsule. Using aseptic technique, fill the ocular implant [see Dosage and Administration (2. 5) Instructions for Use Removal of the SUSVIMO ocular implant is a surgical procedure that is performed in an operating room. 1) After placing an infusion line in the eye, create at least a 6×6 mm peritomy of the conjunctiva and Tenon's capsule around the SUSVIMO ocular implant flange. Remove any fibrous capsule or scar tissue that may have formed over the implant flange and septum using scalpel and forceps. With the explant tool oriented perpendicular to the globe, align the contoured tips with the long axis of the implant flange and grasp underneath the implant flange. Once the implant is secured in the explant tool, pull the implant from the eye in a perpendicular motion. Clear any vitreous prolapse present within or around the scleral wound using a vitrector. Completely close the scleral incision with multiple non-absorbable sutures. Close the Tenon's capsule and conjunctiva to completely cover the scleral incision. Refer to the complete Instructions for Use The SUSVIMO ocular implant refill-exchange procedure must be performed under strict aseptic conditions by a physician experienced in ophthalmic surgery [see Dosage and Administration (2. 1) Prior to and after the refill-exchange procedure, perform a dilated slit lamp exam and/or dilated indirect ophthalmoscopy to inspect the implant in the vitreous cavity through the pupil to identify if dislodgement of the implant septum has occurred [ see Figure 31 Warnings and Precautions (5. 4) Step 1: Gather the supplies needed. One SUSVIMO Refill Needle (34-gauge with a 5 µm integrated filter) with clear cap (included) One SUSVIMO (ranibizumab injection) 100 mg/mL vial (included) One sterile 1 mL Luer Lock syringe (not included) One sterile 5-micron filter needle (19-gauge × 1½ inch) (not included) Anesthetic ophthalmic solutions Ophthalmic broad-spectrum microbicide solution Cotton tips and gauze Sterile powder free gloves Face masks Lid speculum Magnification such as visor or loupes Task lighting Indirect ophthalmoscope and lens Sterile drape (optional for refill-exchange procedure) Step 2: Inspect Packaging and Components Prior to use in the clinic, inspect the packaging of the components for damage. Do not Check the expiration date printed on the label. Remove the vial from the carton. Note Use aseptic technique sterile refill needle Inspect components and place onto sterile field (see Figure 16 Figure 16 Step 3: Inspect SUSVIMO (ranibizumab injection) Visually inspect the contents of the SUSVIMO (ranibizumab injection) vial for particulate matter and discoloration. SUSVIMO should be colorless to pale brown Do not Step 4: Patient Preparation Dilate the pupil of the eye. Perform slit lamp examination and/or indirect ophthalmoscopy to inspect the implant and its components in the vitreous cavity through the dilated pupil. Position the patient on exam chair in the supine position at approximately 20° to 30° angle for optimal visualization of the implant. Apply a broad-spectrum microbicide to the periocular skin, eyelid, and ocular surface prior to the refill-exchange procedure. The use of a sterile drape is up to the physician's discretion. Perform the procedure under topical anesthesia. If needed, subconjunctival anesthesia may be administered in the nasal quadrant, away from the implant. Step 5: Transfer Dose from Vial to Syringe Figure 17 Note: Use the filter needle to withdraw SUSVIMO (ranibizumab injection) from the vial. Do not Prepare ranibizumab 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 17 Carefully remove the needle cap by pulling it straight off. Step 6: 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 18). Slowly push the plunger rod just until the air is expelled from the syringe and needle. en dash Remove and properly dispose of the filter needle after air is removed from the syringe. Figure 18 Step 7: Attach SUSVIMO Refill Needle Do not Attach the SUSVIMO refill needle firmly onto the syringe by screwing it tightly onto the Luer lock (see Figure 19 Carefully remove the needle cap, pulling straight off to avoid damage to the needle cannula. Do not Figure 19 Step 8: Remove Any Remaining Air from Syringe and Adjust Drug Dose With the refill 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 20 Slowly push the plunger rod until all air is expelled from the syringe and needle and the uppermost edge of the black plunger tip is aligned with the 0. 1 mL Figure 21 Figure 20 Figure 21 Step 9: Inspect the Syringe for Air Bubbles Figure 22 Note: Ensure no air bubbles are present in the syringe and needle hub. Air injected into the implant could result in slower drug release. Inspect the syringe and the needle hub using magnification to ensure that no air bubbles are present (see Figure 22 Note: Use the syringe within 15 minutes Do not Step 10: Stabilize the globe and orient the refill needle Figure 23 Figure 24 Note: Perform the refill-exchange procedure using magnification (e. , loupes, reading glasses, magnifiers) for visual assistance. After placing the lid speculum in the eye, stabilize the globe with a cotton-tipped applicator to minimize eye movement (see Figure 23 en dash Orient the refill needle perpendicular to the globe (see Figure 24 Step 11: Insert the Refill Needle Figure 25 Figure 26 Note: Insert needle at the very center of the implant septum and perpendicular to the implant to ensure the needle inserts fully. Do not Do not Targeting the center of the implant septum, insert the refill needle perpendicularly through the conjunctiva and into the implant septum (see Figure 25 en dash en dash Do not Continue inserting the needle until the soft stop of the refill needle makes physical contact with the conjunctiva (see Figure 26 Step 12: Refill the SUSVIMO Implant Refill the implant slowly 5 to 10 seconds As ranibizumab is administered into the implant, existing solution from the implant should immediately begin to fill the refill needle fluid collection chamber (see Figure 27 If fluid is not observed collecting in the refill needle fluid collection reservoir, stop injecting and ensure the refill needle is inserted into the center of the implant septum at a perpendicular angle and the soft stop is in contact with the conjunctiva. Administer all of the syringe contents in order to achieve the target replacement ranibizumab concentration in the implant reservoir. Figure 27 Step 13: Withdraw the Syringe Withdraw the syringe perpendicular to the globe to avoid damaging the septum (see Figure 28 A cotton-tipped applicator may be used to provide counter traction to the conjunctiva during needle withdrawal. Figure 28 Step 14: Dispose of the Used Components Do not Step 15: Perform Indirect Ophthalmoscopy Perform dilated indirect ophthalmoscopy (and slit lamp exam as needed) to ensure continued proper position of the implant and its components (e. , septum) in the vitreous cavity and to examine for complications. Figure 16 Figure 17 Figure 18 Figure 19 Figure 20 Figure 21 Figure 22 Figure 23 Figure 24 Figure 25 Figure 26 Figure 27 Figure 28 For patients with AMD or DME, if a planned dose (refill-exchange) of SUSVIMO (ranibizumab injection) is missed, it should be administered as soon as possible and the subsequent refill-exchange procedures should be performed 24 weeks (approximately 6 months) thereafter. For patients with DR, if a planned dose (refill-exchange) of SUSVIMO (ranibizumab injection) is missed, it should be administered as soon as possible and the subsequent refill-exchange procedures should be performed 36 weeks (approximately 9 months) thereafter. Table 1 [see Warnings and Precautions (5) Table 1: Dosage (Refill-Exchange) Modifications for Adverse Reactions Adverse Reactions Dosage Modification Intraocular inflammation >= 1 + cells or flare Withhold dose (refill-exchange) Sight threatening events (e. , rhegmatogenous retinal detachment, vitreous hemorrhage, unexplained vision loss, etc. ) Withhold dose (refill-exchange) Local infections of either eye Withhold dose (refill-exchange) Infectious endophthalmitis Withhold dose (refill-exchange) Severe systemic infection Withhold dose (refill-exchange) Observed damage to the implant Withhold dose (refill-exchange) and consider SUSVIMO implant removal [see Dosage and Administration (2.

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. 1 To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 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, 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%), vitreous hemorrhage (10%) and cataract (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 DME DR SUSVIMO Intravitreal ranibizumab SUSVIMO Intravitreal ranibizumab SUSVIMO 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. 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. 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. 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.

Ocular or periocular infections ( 4. 1 Active intraocular inflammation ( 4. 2 Hypersensitivity ( 4. 3 SUSVIMO (ranibizumab injection) is contraindicated in patients with ocular or periocular infections. SUSVIMO (ranibizumab injection) is contraindicated in patients with active intraocular inflammation. SUSVIMO (ranibizumab injection) is contraindicated in patients with known hypersensitivity to ranibizumab products or any of the excipients in SUSVIMO (ranibizumab injection).

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) 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. general population, the estimated background risk of major birth defects is 2% en dash 4% and of miscarriage is 15% en dash 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 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. Risk Summary There are no data available on the presence of ranibizumab in human milk, the effects of ranibizumab on the breastfed infant or the effects of ranibizumab on milk production/excretion. Because many drugs are excreted in human milk, and because the potential for absorption and harm to infant growth and development exists, caution should be exercised when SUSVIMO is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SUSVIMO (ranibizumab injection) and any potential adverse effects on the breastfed child from ranibizumab. Contraception Females of reproductive potential should use effective contraception during treatment with SUSVIMO (ranibizumab injection) and for at least 12 months after the last dose of SUSVIMO (ranibizumab injection). Infertility No studies on the effects of ranibizumab on fertility have been conducted and it is not known whether ranibizumab can affect reproduction capacity. Based on the anti-VEGF mechanism of action for ranibizumab, treatment with SUSVIMO (ranibizumab injection) may pose a risk to reproductive capacity. The safety and efficacy of SUSVIMO (ranibizumab injection) in pediatric patients have not been established. In the Archway study, 90% (222 of 248) of the patients randomized to treatment with SUSVIMO were >= 65 years old and approximately 57% (141 of 248) were >= 75 years old. No notable difference in treatment effect or safety was seen with increasing age.

NONCLINICAL TOXICOLOGY
No studies have been conducted to determine the carcinogenic or mutagenic potential of SUSVIMO (ranibizumab injection). Based on the anti-VEGF mechanism of action for ranibizumab, treatment with SUSVIMO (ranibizumab injection) may pose a risk to reproductive capacity [see Females and Males of Reproductive Potential (8.3)
CLINICAL STUDIES
The clinical efficacy and safety of SUSVIMO (ranibizumab injection) was assessed in a randomized, visual assessor-masked, active treatment-controlled study (Archway-NCT03677934) in patients with AMD. A total of 415 patients (248 in the SUSVIMO arm and 167 in the intravitreal ranibizumab arm) were enrolled and treated in this study. Patients were diagnosed with AMD within the 9 months prior to screening and received >= 3 doses of anti-VEGF intravitreal agents in the study eye within the last 6 months prior to screening. Each patient was required to have demonstrated a response to an anti-VEGF intravitreal agent prior to randomization. Patients were randomized in a 3:2 ratio to receive continuous delivery of SUSVIMO (ranibizumab injection) via the SUSVIMO implant every 24 weeks or 0. 5 mg intravitreal ranibizumab injections every 4 weeks. For patients randomized to the SUSVIMO arm, supplemental treatment with 0. 5 mg intravitreal ranibizumab injections was available at Weeks 16, 20, 40, 44, 64, 68, 88, and 92, if needed. In the first 24 weeks, 1. 6% of patients assessed for supplemental treatment received 1 or more supplemental treatment(s) and in the following 24 weeks, 5. 4% of patients assessed for supplemental treatment received 1 or more supplemental treatment(s). The primary efficacy endpoint of change from baseline in distance Best Corrected Visual Acuity (BCVA) score averaged over Week 36 and Week 40 demonstrated that SUSVIMO was equivalent to intravitreal ranibizumab injections administered every 4 weeks. Detailed efficacy results are shown in Table 3 Figure 29 Table 3 Visual Acuity outcomes at Week 40 in Archway (GR40548) Study Outcome Measure BCVA measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart at a starting distance of 4 meters. SUSVIMO (100 mg/mL) Intravitreal ranibizumab 0. 5 mg (10 mg/mL) Difference All estimates are adjusted estimates based on a mixed-effect model with repeated measures. SUSVIMO arm - intravitreal ranibizumab arm. 95% is a rounding of 95. 03% CI; The type 1 error was adjusted for interim safety monitoring. BCVA = Best corrected visual acuity Adjusted Mean change from baseline in BCVA score averaged over Weeks 36 and 40 0. 3 Equivalence margins were +/-4. Q24W = every 24 weeks; Q4W = every 4 weeks Figure 29 Adjusted Mean change from Baseline in Best Corrected Visual Acuity in study eye through Week 48 in the Archway (GR40548) study Prior to study treatment, a median of 4 doses of anti-VEGF intravitreal agents were administered in the study eye of patients in the SUSVIMO and intravitreal ranibizumab arms. Decrease in BCVA at Week 4 during post-operative recovery period. Consistent results were observed across patient subgroup analyses for mean change from baseline in BCVA score (age, gender, number of prior anti-VEGF intravitreal injections, and baseline BCVA score). Figure 29 The clinical efficacy and safety of SUSVIMO were assessed in a randomized, visual assessor-masked, active treatment-controlled study [Pagoda (GR40550) NCT04108156] in patients with DME. A total of 634 patients (381 in the SUSVIMO arm and 253 in the intravitreal ranibizumab 0. 5 mg arm) were enrolled and treated in this study. Patients were randomized in a 3:2 ratio to receive continuous delivery of SUSVIMO via the implant every 24 weeks or 0. Prior to study treatment, a median of 4 doses of intravitreal ranibizumab 0. 5 mg were administered in the study eye of patients in the SUSVIMO and intravitreal ranibizumab arms. Patient ages ranged from 29 to 89 years with a mean of 60. A total of 21% of patients were previously treated for DME. At baseline, the overall mean visual acuity was 65. 3 letters (range: 25 to 89 letters). The primary efficacy endpoint of change from baseline in distance Best Corrected Visual Acuity (BCVA) score averaged over Week 60 and Week 64 demonstrated that SUSVIMO was non-inferior to intravitreal ranibizumab injections administered every 4 weeks. Detailed efficacy results are shown in Table 4 Figure 30 Table 4 Key efficacy outcomes at Week 60 and Week 64 in the Pagoda (GR40550) Study Outcome Measure SUSVIMO 100 mg/mL Intravitreal ranibizumab 0. 5 mg Difference All estimates are adjusted estimates based on a mixed-effect model with repeated measures. 05% CI; The type 1 error was adjusted for interim safety monitoring. BCVA = Best corrected visual acuity Change in BCVA BCVA measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart at a starting distance of 4 meters. 6) Figure 30 Adjusted Mean change from Baseline in Best Corrected Visual Acuity in study eye through Week 64 in the Pagoda (GR40550) study Consistent results were observed across patient subgroup analyses for mean change from baseline in BCVA score (age, ethnicity, gender, baseline HbA1c score, focal/macular laser history, baseline BCVA score, prior intravitreal anti-VEGF treatment and DR severity). Figure 30 The clinical efficacy and safety of SUSVIMO were assessed in a randomized, visual assessor and reading center-masked study [Pavilion (GR 41675)- NCT04503551] in patients with moderately-severe to severe non-proliferative diabetic retinopathy (NPDR) [Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (ETDRS-DRSS) of 47 or 53], without center-involved DME (CI-DME), and who had not received prior treatment in the study eye for DR. A total of 174 patients (106 in the SUSVIMO arm and 68 in the observational comparator arm) were enrolled in this study. Patients who had not received prior treatment in the study eye for DR were randomized in a 5:3 ratio to continuous delivery of SUSVIMO via the implant every 36 weeks or to clinical observation. Prior to the implant procedure, two loading doses of intravitreal ranibizumab 0. 5 mg were administered in the study eye. The observational comparator arm did not receive loading doses of intravitreal ranibizumab. For patients who developed CI-DME or proliferative diabetic retinopathy/anterior segment neovascularization in either arm, supplemental treatment with intravitreal injections of 0. 5 mg ranibizumab was available per investigator''s clinical judgment at any non-refill-exchange study visit. Patient ages ranged from 24 to 83 years with a mean of 53. At baseline, the overall mean visual acuity was 82. 4 letters (range: 69 to 97 letters). The primary efficacy endpoint was the proportion of patients with a >= 2-step improvement on the ETDRS-DRSS from baseline at Week 52 versus clinical observation. SUSVIMO with two loading doses of intravitreal ranibizumab was superior to clinical observation at Week 52. Detailed results are shown in Table 5 Figure 31 Table 5 Efficacy Outcomes through Week 52 in the Pavilion (GR41675) Study Outcome Measure SUSVIMO Clinical Observation Difference All estimates are adjusted estimates based on the CMH method. 04% CI; the type 1 error was adjusted for interim safety monitoring. 01 compared with clinical observation. ETDRS-DRSS = Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scores Adjusted proportion of patients with >= 2-step improvement from baseline on the ETDRS-DRSS at Week 52 80% 9% 71% (61%, 81%) Figure 31 Adjusted Proportion of Patients with a >= 2-Step Improvement from Baseline on ETDRS-DRSS in Study Eye over Time through Week 52 in the Pavilion (GR41675) Study In the SUSVIMO arm, none of the patients assessed for supplemental treatment received any supplemental injections of intravitreal ranibizumab and 40% of patients in the observational comparator arm received 1 or more supplemental treatments through Week 52. Consistent results were observed across patient subgroup analyses for ETDRS-DRSS score including age, race, ethnicity, baseline hemoglobin (HbA1c) and baseline ETDRS-DRSS score.

Genentech, Inc.

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