DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For intravitreal use via SUSVIMO ocular implant. (2.1) The recommended dose of SUSVIMO (ranibizumab injection) is mg (0.02 mL of 100 mg/mL solution) continuously delivered via the SUSVIMO implant with refills every 24 weeks (approximately months). (2.2) Supplemental treatment with 0.5 mg intravitreal ranibizumab injection may be administered in the affected eye if clinically necessary. (2.3) Perform the initial implantation, refill-exchange, and implant removal (if necessary) procedures under strict aseptic conditions. (2.4, 2.5, 2.6, 2.7). For intravitreal use via SUSVIMO ocular implant. (2.1). The recommended dose of SUSVIMO (ranibizumab injection) is mg (0.02 mL of 100 mg/mL solution) continuously delivered via the SUSVIMO implant with refills every 24 weeks (approximately months). (2.2). Supplemental treatment with 0.5 mg intravitreal ranibizumab injection may be administered in the affected eye if clinically necessary. (2.3). Perform the initial implantation, refill-exchange, and implant removal (if necessary) procedures under strict aseptic conditions. (2.4, 2.5, 2.6, 2.7). 2.1General 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 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 physician experienced in ophthalmic surgery [see Dosage and Administration (2.7)].Do not administer SUSVIMO (ranibizumab injection) as bolus intravitreal injection. Do not substitute SUSVIMO (ranibizumab injection) with other ranibizumab products.. Initial Fill: One SUSVIMO initial fill needle (34-gauge, with integrated um filter and blue cap) is included. 5-micron sterile filter needle (19-gauge 1 1/2 inch), and 1 mL Luer lock syringe are needed but not included.. Refill-Exchange: One SUSVIMO refill needle (34-gauge with integrated um filter and clear cap) is included. 5-micron sterile filter needle (19-gauge 1 1/2 inch), and 1 mL Luer lock syringe are needed but not included.. 2.2Neovascular (Wet) Age-Related Macular Degeneration (AMD). The recommended dose of SUSVIMO (ranibizumab injection) is mg (0.02 mL of 100 mg/mL solution) continuously delivered via the SUSVIMO ocular implant with refills administered every 24 weeks (approximately months).. 2.3Supplemental 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)].. 2.4Ocular Implant Initial Fill The implant initial fill procedure must be performed by 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 patients eye [see Dosage and Administration (2.5)]. 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 patients 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 um filter) with blue cap (included)One SUSVIMO (ranibizumab injection) 100 mg/mL vial (included)One sterile 5-micron filter needle (19-gauge 1 1/2 inch) (not included) One sterile mL Luer Lock syringe (not included) Step 2: Transfer Dose from Vial to SyringeNote: Use the filter needle (not included) to withdraw SUSVIMO (ranibizumab injection) from the vial. Figure 1Do 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 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.Remove and properly dispose of the filter needle after withdrawal of the vial contents. Step 3: Attach SUSVIMO Initial Fill NeedleDo 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 2). 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 2Step 4: Remove Air from SyringeHold 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 3).Slowly push the plunger rod just until all air is expelled from the syringe and needle, and drop of drug solution is seen at the needle tip (see Figure 4).Figure 3Figure 4Note: It is important to preserve as much drug as possible in order to completely fill the implant. Step 5: Inspect the Syringe for Air Bubbles Inspect the syringe and the needle hub to ensure that no air bubbles are present (see Figure 5).If air bubbles are present, continue to remove air from the syringe and reinspect.Figure 5Note: 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 6: Load Syringe into the CarrierDo 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 6).Push the syringe forward until it stops, taking care to avoid touching the plunger rod (see Figure 7)With the syringe loaded, (see Figure 8) the initial fill needle should now be penetrating the implant septum.Figure 6: Align and lower the syringe into the carrierFigure 7: Push the syringe into the carrierFigure 8: Syringe with initial fill needle inserted through the implant septumStep 7: Fill Ocular Implant with SUSVIMO (ranibizumab injection) Under MicroscopeUnder the microscope, slowly administer SUSVIMO (ranibizumab injection) into the ocular implant by slightly tilting the carrier upwards (see Figure 9).The ocular implant should be filled over approximately to 10 seconds, to help avoid air entrapment in the implant reservoir.Figure 9: Administer ranibizumab into the implantFigure 10: Dome of drug solution forms at tip of implant as viewed under magnificationNote: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 different location, such as the side of the implant, do not use the ocular implant.If fluid is leaking from the septum at the needle insertion site, the needle may not be fully penetrating the implant septum. Fully push the syringe forward before continuing to fill the ocular implant. Continue filling the ocular implant until the implant is completely full of drug solution and all air has been expelled as evidenced by dome of drug solution formed at the tip of the implant on the release control element (see Figure 10).Step 8: Inspect the Filled Ocular Implant Under the MicroscopeInspect the ocular implant under the microscope to ensure that the ocular implant is completely full of drug solution (see Figure 11).Figure 11: Proper appearance of implant after initial filling with ranibizumabNote: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 use the ocular implant.Note:No more than 30 minutes should pass between the initial fill of the implant and the insertion into the patients eye to ensure that the release control element remains saturated with SUSVIMO (ranibizumab injection). If SUSVIMO (ranibizumab injection) dries in the release control element, the implant may not release the drug properly into the vitreous after insertion.Step 9: Remove the Syringe and Guide Sleeve from the CarrierRemove the syringe and guide sleeve from the carrier by pulling back on the syringe (see Figure 12). The syringe will be locked into the guide sleeve.Properly dispose of the used syringe together with the needle and guide sleeve in sharps disposal container or in accordance with local requirements.Figure 12: Remove the syringe and guide sleeve from the insertion tool carrierStep 10: Slide the Insertion Tool Handle into the CarrierSlide the insertion tool handle into the guide channel of the carrier, ensuring that both components are facing upwards (see Figure 13).Push the handle forward as far as it will go into the gripper tips (see Figure 14).Figure 13: Insert the handle into the insertion tool carrierFigure 14: Fully inserted handleNote:Do not withdraw the handle and implant until the eye is ready for insertion. Contact between the implant and any surface or object even within the sterile field may result in the introduction of foreign body into the vitreous.. One SUSVIMO ocular implant with insertion tool assembly (included). One SUSVIMO initial fill needle (34-gauge with integrated um filter) with blue cap (included). One SUSVIMO (ranibizumab injection) 100 mg/mL vial (included). One sterile 5-micron filter needle (19-gauge 1 1/2 inch) (not included) One sterile mL Luer Lock syringe (not included) Prepare SUSVIMO (ranibizumab injection) vial by removing the flip-off cap and disinfecting the rubber vial septum with alcohol.. Attach 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.. Remove and properly dispose of the filter needle after withdrawal of the vial contents.. Attach the SUSVIMO initial fill needle (included) firmly onto the syringe by screwing it tightly onto the Luer lock (see Figure 2). 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.. 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 3).. Slowly push the plunger rod just until all air is expelled from the syringe and needle, and drop of drug solution is seen at the needle tip (see Figure 4).. Inspect the syringe and the needle hub to ensure that no air bubbles are present (see Figure 5).. If air bubbles are present, continue to remove air from the syringe and reinspect.. 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 6).. Push the syringe forward until it stops, taking care to avoid touching the plunger rod (see Figure 7). With the syringe loaded, (see Figure 8) the initial fill needle should now be penetrating the implant septum.. Under the microscope, slowly administer SUSVIMO (ranibizumab injection) into the ocular implant by slightly tilting the carrier upwards (see Figure 9).. The ocular implant should be filled over approximately to 10 seconds, to help avoid air entrapment in the implant reservoir.. Continue filling the ocular implant until the implant is completely full of drug solution and all air has been expelled as evidenced by dome of drug solution formed at the tip of the implant on the release control element (see Figure 10).. Inspect the ocular implant under the microscope to ensure that the ocular implant is completely full of drug solution (see Figure 11).. Remove the syringe and guide sleeve from the carrier by pulling back on the syringe (see Figure 12). The syringe will be locked into the guide sleeve.. Properly dispose of the used syringe together with the needle and guide sleeve in sharps disposal container or in accordance with local requirements.. Slide the insertion tool handle into the guide channel of the carrier, ensuring that both components are facing upwards (see Figure 13).. Push the handle forward as far as it will go into the gripper tips (see Figure 14).. 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. 2.5Ocular Implant Insertion SUSVIMO ocular implant insertion is surgical procedure that is performed in an operating room. The procedure must be performed under aseptic conditions by 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 patients eye. After placing an infusion line in the eye, create at least 6x6 mm peritomy of the conjunctiva and Tenons 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 Tenons capsule. Using aseptic technique, fill the ocular implant [see Dosage and Administration (2.4)]. Using an MVR blade, create full thickness dissection of the sclera mm from the limbus until the pars plana is fully visible, with final target scleral incision length of 3.5 mm. Using 532 nm laser endoprobe, apply contiguous, overlapping laser spots starting at 300 mW 1000 ms along the full length of the exposed pars plana and repeat until complete ablation is achieved. Pass 3.2 mm slit knife perpendicularly through the center of the scleral dissection to open the underlying pars plana. Use the insertion tool to slowly insert the SUSVIMO implant into the sclero-pars plana incision perpendicular to the globe, ensuring that the long axis of the implant flange is properly aligned with the sclero-pars plana incision. Using the closed gripper tips of the insertion tool, seat the implant flush against the sclera. Clean any residual vitreous around the implant flange using vitrector. Suture both Tenons capsule and conjunctiva, using scleral anchoring at the apex of the peritomy, ensuring complete coverage of the implant flange. 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.. 2.6Ocular Implant Removal. Removal of the SUSVIMO ocular implant is surgical procedure that is performed in an operating room. The procedure must be performed under aseptic conditions by physician experienced in vitreoretinal surgery [see Dosage and Administration (2.1)].After placing an infusion line in the eye, create at least 6x6 mm peritomy of the conjunctiva and Tenons 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 perpendicular motion. Clear any vitreous prolapse present within or around the scleral wound using vitrector. Completely close the scleral incision with multiple non-absorbable sutures. Close the Tenons capsule and conjunctiva to completely cover the scleral incision. Refer to the complete Instructions for Use for the implant removal procedure included in the explant tool carton for further details.. 2.7Ocular Implant Refill-Exchange Procedure. The SUSVIMO ocular implant refill-exchange procedure must be performed under strict aseptic conditions by physician experienced in ophthalmic surgery [see Dosage and Administration (2.1)]. This includes the use of surgical mask, sterile gloves, and lid speculum.Step 1: Gather the supplies needed.One SUSVIMO Refill Needle (34-gauge with 5 um integrated filter) with clear cap (included)One SUSVIMO (ranibizumab injection) 100 mg/mL vial (included)One sterile mL Luer Lock syringe (not included) One sterile 5-micron filter needle (19-gauge 1 1/2 inch) (not included) Additional materials required to perform the procedure but are not provided are:Anesthetic ophthalmic solutionsOphthalmic broad-spectrum microbicide solutionCotton tips and gauzeSterile powder free glovesFace masksLid speculumMagnification such as visor or loupesTask lightingIndirect ophthalmoscope and lensSterile drape (optional for refill-exchange procedure) Step 2: Inspect Packaging and ComponentsPrior to use in the clinic, inspect the packaging of the components for damage. Do not use if the sterility has been compromised or the contents have been dropped, damaged, or tampered with.Check the expiration date printed on the label.Remove the vial from the carton. Note: the outside of the vial is not sterile.Use aseptic technique to open packaging and remove the sterile refill needle from the tray.Inspect components and place onto sterile field (see Figure 15).Figure 15Step 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 brownDo not use if particulate, cloudiness, or discoloration are visible.Step 4: Patient PreparationPosition the patient on exam chair in the supine position at approximately 20 to 30 angle for optimal visualization of the implant.Apply broad-spectrum microbicide to the periocular skin, eyelid, and ocular surface prior to the refill-exchange procedure. The use of sterile drape is up to the physicians discretion.Dilate the pupil of the eye.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 SyringeFigure 16Note:Use the filter needle to withdraw SUSVIMO (ranibizumab injection) from the vial.Do not use the SUSVIMO refill needle for this step.Prepare ranibizumab vial by removing the flip-off cap and disinfecting the rubber vial septum with alcohol.Attach filter needle to the syringe by screwing it tightly onto the Luer lock (see Figure 16).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.Remove and properly dispose of the filter needle after withdrawal of the vial contents. Step 6: Attach SUSVIMO Refill NeedleDo not use the filter needle to fill the implant.Attach the SUSVIMO refill needle firmly onto the syringe by screwing it tightly onto the Luer lock (see Figure 17). Ensure that the refill needle is attached to the syringe. Carefully remove the needle cap, pulling straight off to avoid damage to the needle cannula.Do not wipe the needle at any time. Figure 17Step 7: Remove Air from Syringe and Adjust Drug DoseHold 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 18).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 dose mark (see Figure 19).Figure 18Figure 19Step 8: Inspect the Syringe for Air BubblesFigure 20Note: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 20). Note:Use the syringe within 15 minutes of removing all air and adjusting the drug dose to avoid drug solution drying in the needle and impeding fluid flow. Do not use the refill needle or syringe if the needle is clogged.Step 9: Stabilize the globe and orient the refill needleFigure 21Figure 22Note:Perform the refill-exchange procedure using magnification (e.g., loupes, reading glasses, magnifiers) for visual assistance.After placing the lid speculum in the eye, stabilize the globe with cotton-tipped applicator to minimize eye movement (see Figure 21).-Recommend standing on the contralateral side of the implanted eye, with the patient looking down and toward their nose to optimally expose the implant. Orient the refill needle perpendicular to the globe (see Figure 22).Step 10: Insert the Refill NeedleFigure 23Figure 24Note:Insert needle at the very center of the implant septum and perpendicular to the implant to ensure the needle inserts fully. Do not maneuver if there is resistance as it will bend the needle. Do not use bent refill needle; replace if bent or if damage is suspected.Targeting the center of the implant septum, insert the refill needle perpendicularly through the conjunctiva and into the implant septum (see Figure 23).-If excessive resistance, withdraw the refill needle. Orient and insert again.-Once the needle is aligned with the septum, if resistance is encountered slight rotation of the refill needle around its axis may help to facilitate the passage of the needle. Do not twist when encountering conjunctiva and Tenons capsule to gain access to the septum, as damage to the overlying tissue and to the septum of the device may result. Continue inserting the needle until the soft stop of the refill needle makes physical contact with the conjunctiva (see Figure 24) to provide tactile cue that optimal contact has been made.Step 11: Refill the SUSVIMO ImplantRefill the implant slowly, by delivering the entire contents of the syringe into the implant, over approximately to 10 seconds, to avoid pressure build-up in the implant reservoir. The soft stop of the refill needle must remain in contact with the conjunctiva throughout the procedure.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 25).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 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 25Step 12: Withdraw the SyringeWithdraw the syringe perpendicular to the globe to avoid damaging the septum (see Figure 26).A cotton-tipped applicator may be used to provide counter traction to the conjunctiva during needle withdrawal.Figure 26Step 13: Dispose of the Used ComponentsDo not recap the needle or detach it from the syringe. Dispose of the used syringe together with the refill needle in sharps disposal container or in accordance with local requirements.Step 14: Perform Indirect OphthalmoscopyPerform indirect ophthalmoscopy to ensure continued proper position of the implant in the vitreous cavity and to examine for complications.. One SUSVIMO Refill Needle (34-gauge with 5 um integrated filter) with clear cap (included). One SUSVIMO (ranibizumab injection) 100 mg/mL vial (included). One sterile mL Luer Lock syringe (not included) One sterile 5-micron filter needle (19-gauge 1 1/2 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) Prior to use in the clinic, inspect the packaging of the components for damage. Do not use if the sterility has been compromised or the contents have been dropped, damaged, or tampered with.. Check the expiration date printed on the label.. Remove the vial from the carton. Note: the outside of the vial is not sterile.. Use aseptic technique to open packaging and remove the sterile refill needle from the tray.. Inspect components and place onto sterile field (see Figure 15).. Visually inspect the contents of the SUSVIMO (ranibizumab injection) vial for particulate matter and discoloration.. SUSVIMO should be colorless to pale brown. Position the patient on exam chair in the supine position at approximately 20 to 30 angle for optimal visualization of the implant.. Apply broad-spectrum microbicide to the periocular skin, eyelid, and ocular surface prior to the refill-exchange procedure. The use of sterile drape is up to the physicians discretion.. Dilate the pupil of the eye.. Perform the procedure under topical anesthesia.. If needed, subconjunctival anesthesia may be administered in the nasal quadrant, away from the implant.. Prepare ranibizumab vial by removing the flip-off cap and disinfecting the rubber vial septum with alcohol.. Attach filter needle to the syringe by screwing it tightly onto the Luer lock (see Figure 16).. 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.. Remove and properly dispose of the filter needle after withdrawal of the vial contents.. Attach the SUSVIMO refill needle firmly onto the syringe by screwing it tightly onto the Luer lock (see Figure 17). Ensure that the refill needle is attached to the syringe.. Carefully remove the needle cap, pulling straight off to avoid damage to the needle cannula.. Do not wipe the needle at any time.. 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 18).. 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 dose mark (see Figure 19).. Inspect the syringe and the needle hub using magnification to ensure that no air bubbles are present (see Figure 20). After placing the lid speculum in the eye, stabilize the globe with cotton-tipped applicator to minimize eye movement (see Figure 21).-Recommend standing on the contralateral side of the implanted eye, with the patient looking down and toward their nose to optimally expose the implant. -Recommend standing on the contralateral side of the implanted eye, with the patient looking down and toward their nose to optimally expose the implant.. Orient the refill needle perpendicular to the globe (see Figure 22).. Targeting the center of the implant septum, insert the refill needle perpendicularly through the conjunctiva and into the implant septum (see Figure 23).-If excessive resistance, withdraw the refill needle. Orient and insert again.-Once the needle is aligned with the septum, if resistance is encountered slight rotation of the refill needle around its axis may help to facilitate the passage of the needle. Do not twist when encountering conjunctiva and Tenons capsule to gain access to the septum, as damage to the overlying tissue and to the septum of the device may result. -If excessive resistance, withdraw the refill needle. Orient and insert again.. -Once the needle is aligned with the septum, if resistance is encountered slight rotation of the refill needle around its axis may help to facilitate the passage of the needle. Do not twist when encountering conjunctiva and Tenons capsule to gain access to the septum, as damage to the overlying tissue and to the septum of the device may result.. Continue inserting the needle until the soft stop of the refill needle makes physical contact with the conjunctiva (see Figure 24) to provide tactile cue that optimal contact has been made.. Refill the implant slowly, by delivering the entire contents of the syringe into the implant, over approximately to 10 seconds, to avoid pressure build-up in the implant reservoir. The soft stop of the refill needle must remain in contact with the conjunctiva throughout the procedure.. 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 25).. 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 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.. Withdraw the syringe perpendicular to the globe to avoid damaging the septum (see Figure 26).. cotton-tipped applicator may be used to provide counter traction to the conjunctiva during needle withdrawal.. Do not recap the needle or detach it from the syringe. Dispose of the used syringe together with the refill needle in sharps disposal container or in accordance with local requirements.. Perform indirect ophthalmoscopy to ensure continued proper position of the implant in the vitreous cavity and to examine for complications.. Figure 15. Figure 16. Figure 17. Figure 18. Figure 19. Figure 20. Figure 21. Figure 22. Figure 23. Figure 24. Figure 25. Figure 26. 2.8Delayed or Missed Doses. If 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 months) thereafter.. 2.9Dosage (Refill-Exchange) Modifications for Adverse Reactions. Table describes dosage modifications for specific adverse Reactions [see Warnings and Precautions (5)]. No dosage reductions for SUSVIMO are recommended.Table 1:Dosage (Refill-Exchange) Modifications for Adverse ReactionsAdverse ReactionsDosage ModificationIntraocular inflammation >= + cells or flareWithhold dose (refill-exchange)Sight threatening events (e.g., rhegmatogenous retinal detachment, vitreous hemorrhage, unexplained vision loss, etc.)Withhold dose (refill-exchange)Local infections of either eyeWithhold dose (refill-exchange)Infectious endophthalmitisWithhold dose (refill-exchange)Severe systemic infectionWithhold dose (refill-exchange)Observed damage to the implantWithhold dose (refill-exchange) and consider SUSVIMO implant removal [see Dosage and Administration (2.6)].

INSTRUCTIONS FOR USE SECTION.

Susvimo(TM)(ranibizumab injection)For Susvimo ocular implant useInstructions for UseInitial Fill and Implant ProcedureCaution: Federal Law (USA) restricts this device to sale by or on the order of physician.Susvimo procedures should be performed by an ophthalmologist experienced in vitreoretinal surgery.Refer to the Susvimo (ranibizumab injection) 100 mg/mL prescribing information for complete list of indications, contraindications, warnings, precautions, and adverse events.ContentsIntroduction3Device Description4Components8Intended Use/Indications for Use8Contraindications8Warnings9Precautions10How Supplied, Handling, and StorageInstructions for Use11Introduction and Materials13Preparatory Procedures14Infusion Line Placement Procedure15Conjunctival Dissection Procedure17Syringe Preparation and Initial Implant Fill24Implant Insertion34Disposal and Post-insertion Procedures35Explanation of symbols on product or package labeling36Susvimo(TM) Implant CardIntroductionThese instructions include only the procedure for filling and inserting the Susvimo implant. For more information, refer to the Susvimo prescribing information for the refill-exchange procedure and Susvimo Instructions for Use for the implant removal procedure.Device DescriptionSusvimo is an intraocular drug delivery system designed to be used specifically with Susvimo (ranibizumab injection) 100 mg/mL. The system consists of an intraocular implant along with ancillary devices used to fill, insert, and explant (if needed) the implant.The implant is refillable drug reservoir that is inserted into the eye through the pars plana. The implant is secured within the scleral incision, with the extrascleral flange that remains visible through the conjunctiva following insertion. Once filled with ranibizumab, the implant is designed to provide continuous release of ranibizumab. The implant will be refilled with ranibizumab in an office-based setting via an administration through the conjunctiva and implant septum.ComponentsFigure 1Susvimo components for initial fill and implant procedureSusvimo implant (packaged with insertion tool assembly)Susvimo implant (Figure and Figure 3) is refillable reservoir inserted into the eye through the pars plana. The body of the implant, which includes the release control element, extends into the vitreous cavity.Figure 2Susvimo implantFigure 3Susvimo implant detailTable 1Susvimo implant component descriptionImplant componentsDescriptionExtrascleral flangeThe extrascleral flange provides secure anchoring of the implant within the scleral incision and is encased in silicone.SeptumThe septum is self-sealing interface through which ranibizumab is administered into the implant both prior to insertion and during subsequent refills in an office-based setting.BodyThe body of the implant contains hollow drug reservoir, capable of holding 0.02 mL of drug.Release control elementThe titanium release control element controls the rate of ranibizumab diffusion from the drug reservoir into the vitreous.Susvimo insertion tool assemblySusvimo insertion tool assembly is designed to facilitate handling of the implant during the initial fill and implant procedure. The insertion tool assembly is comprised of carrier and handle (Figure and Figure 5), described in more detail below:Figure 4Susvimo insertion tool carrierFigure 5Susvimo insertion tool handleTable 2Susvimo insertion tool assembly component descriptionInsertion tool assembly componentsDescriptionGripper tipsThe implant is provided pre-positioned in the insertion tool assembly gripper tips. After initial fill of the implant with ranibizumab, the implant and gripper tips are transferred from the insertion tool carrier to the insertion tool handle.Luer lock slotThe syringe is loaded into the insertion tool carrier by aligning the syringe Luer lock with the insertion tool carrier Luer lock slot.Guide channelThe guide channel serves to direct the syringe and initial fill needle in the insertion tool carrier during the initial fill of the implant.Release buttonPressing the release button on the insertion tool handle will open the gripper tips and release the implant.Susvimo (ranibizumab injection) 100 mg/mL vialSusvimo (ranibizumab injection) (Figure 6) is used to fill the implant prior to insertion or during subsequent refill-exchange in an office-based setting.Figure 6Susvimo (ranibizumab injection) 100 mg/mL vialSusvimo initial fill needleSusvimo initial fill needle (Figure 7) is designed to fill the implant with ranibizumab prior to implant insertion. The initial fill needle is distinguished by its blue cap.Figure 7Susvimo initial fill needleTable 3Susvimo initial fill needle component descriptionInitial fill needle componentsDescriptionNeedle34 needleIntegrated filterIntegrated um filter within needle hubIntended Use/Indications for UseSusvimo ocular implant is approved for use with Susvimo (ranibizumab injection). Refer to the Susvimo (ranibizumab injection) prescribing information for complete list of indications, contraindications, warnings, precautions, and adverse events.ContraindicationsSusvimo is contraindicated in patients with ocular or periocular infections, with active intraocular inflammation, or with known hypersensitivity to ranibizumab or any of the excipients in Susvimo (ranibizumab injection) 100 mg/mL. Hypersensitivity reactions may manifest as severe intraocular inflammation.WarningsDo not use if the sterility has been compromised or the contents have been dropped, damaged or tampered with.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 after initial fill, do not use the implant.Perpendicular entry of the implant is important to avoid contact between the implant and intraocular structures such as the lens, as contact between the implant and the intraocular structures may cause adverse events such as traumatic cataract.Avoid excessive force on the globe by first ensuring that the tip of the implant has passed through the sclero-pars plana incision before slowly pushing the implant into place.PrecautionsRead and follow all instructions, warnings, and cautions prior to use.Susvimo procedures should be performed by an ophthalmologist experienced in vitreoretinal surgery.Use the Susvimo components and materials as specified in these instructions to perform the implant insertion procedure including initial fill.Avoid contact between sharp surgical instruments and the implant as the material of the septum and silicone encasing are soft and susceptible to damage.The implant is MR Conditional. The Patient Implant card is provided with instructions and must be completed and given to the patient after implant insertion. For further information please refer to the Post-insertion patient instructions section.Use with Standard ProceduresSusvimo implant is compatible for use with the following standard procedures: A-scan ophthalmic ultrasound, slit lamp examination, indirect ophthalmoscopy, tonometry, optical coherence tomography (OCT), visual field (perimetry), standard lasers for ophthalmic treatments, radiography (x-ray), computed tomography (CT) scan, fluorescein/ indocyanine angiography, and fundus autofluorescence.Use caution when performing ophthalmic procedures that may cause deflection of the implant and subsequent injury. For example, B-scan ophthalmic ultrasound, scleral depression, or gonioscopy.Magnetic Resonance Imaging (MRI) Safety InformationMR Conditional.Non-clinical testing has demonstrated that the Susvimo implant is MR Conditional. patient with this device can be safely scanned in an MR system meeting the following conditions:Static magnetic field of 1.5-Tesla (1.5 T) or 3-Tesla (3 T)Maximum spatial field gradient of 3,000 G/cm (30 T/m)Maximum MR system reported, whole body averaged specific absorption rate (SAR) of 4.0 W/kg (First Level Controlled Operating Mode)Under the scan conditions defined above, the Susvimo implant is expected to produce maximum temperature rise of less than 1C after 15 minutes of continuous scanning.In non-clinical testing, the image artifact caused by the device extends approximately mm from the Susvimo implant when imaged with gradient echo pulse sequence in 3 MRI system.How Supplied, Handling, and StorageAll Susvimo components are supplied sterile. Do not reprocess or resterilize.All Susvimo components are for single use only. Do not reuse Susvimo components.Do not open sealed tray until time of use.Do not use if the package is damaged or broken as sterility may be compromised.Do not use past the expiration date printed on the label.Susvimo ocular implant and insertion tool assemblyThe sealed tray has been sterilized with ethylene oxide gas.Store the Susvimo implant and insertion tool assembly at room temperature 15C to 25C (59F to 77F).Susvimo (ranibizumab injection) and initial fill needle kitSusvimo initial fill kit should be stored at 2C to 8C (36F to 46F). Do not freeze. Protect from light. Do not shake. Prior to use, the unopened vial may be kept at 9C to 30C (48F to 86F) for up to 24 hours.Susvimo initial fill needle has been sterilized with electron beam processing.See Susvimo (ranibizumab injection) prescribing information for additional information.Instructions for UseIntroduction and MaterialsImplant insertion is surgical procedure that is performed in an operating room. The implant is filled with Susvimo (ranibizumab injection) immediately prior to insertion.Materials ListThe materials that are required in the operating room on the day of the procedure are listed in Tables and 5.Table 4Susvimo components provided for initial fill and implant procedure Item DescriptionSusvimo ocular implant with insertion tool assemblySusvimo initial fill needle, 34 G, with blue capSusvimo (ranibizumab injection) 100 mg/mLSusvimo explant tool (Refer to Susvimo implant removal Instructions for Use for information on implant removal.)Table 5Additional materials required but not provided for initial fill and implant procedureItem DescriptionOne sterile mL Luer Lock syringe (not included) One sterile 5-micron filter needle (19-gauge 1 1/2 inch) (not included) Surgical microscopeVitrectomy surgical control systemStandard 25 or 27 vitrectomy set up23 or 25 532 nm Endolaser probe and associated sourceStandard vitrectomy tray (including adjustable caliper, 0.12 straight toothed forceps, blunt wescott scissors) Cauterization equipment (including standard fine tip diathermy and eraser tip wet-field cautery) Ophthalmic broad-spectrum microbicide solutionMarking pad3.5 mm and 4.0 mm fixed caliper or equivalent fixed tool 3.5 mm fixed width gauge or equivalent fixed tool 19 or 20 MVR Straight KnifeSlit Knife, 3.2 mm StraightGut or Vicryl sutures for conjunctival tissues (suggested 7-0 to 9-0: monofilament recommended) Indirect ophthalmoscope and lensDrapesPreparatory Procedures1.Inspect packaging and componentsPrior to use in the operating room, inspect the packaging of the components for damage.Check the expiration date printed on the label.Remove the vial from the carton. NOTE: the outside of the vial is not sterile.Open sterile packaging and using aseptic technique, remove the components from their tray.Inspect components and place onto sterile field (Figure 8).WarningDo not use if the sterility has been compromised or the contents have been dropped, damaged, or tampered with.Figure 8Susvimo components on sterile field2.Inspect Susvimo (ranibizumab injection)Visually inspect the contents of the ranibizumab vial for particulate matter and discoloration.The drug solution should be colorless to pale brown.CautionDo not use if particulate, cloudiness or discoloration are visible.3.Patient PreparationDilate the pupil of the eye.Place the patient in supine position on the operating table.Implant insertion is surgical procedure and therefore requires sterile controls (i.e. use of broad-spectrum microbicide solution on eye including lids and lashes and draping) be in place to minimize the risk of ocular infection.Perform the procedure under local anesthesia using either peribulbar, retrobulbar, or sub-Tenons technique.Place lid speculum.Infusion Line Placement Procedure1.Place infusion linePlace an infusion cannula in the inferotemporal quadrant via an angled entry wound.-Alternate placement is acceptable based on patient anatomy per physician discretion (superotemporal placement should be avoided).-Alternatively, the line may be placed after the peritomy but prior to the scleral dissection. Attach the infusion line. Keep the infusion line off (Figure 9).Figure 9Place infusion cannula in inferotemporal quadrantConjunctival Dissection Procedure1.Identify the site of insertionIdentify the site in the superotemporal quadrant mm posterior to the limbus where the implant will be inserted (Figure 10 and Figure 11).Placing traction suture is strongly recommended for better visualization of the superotemporal quadrant throughout the entire implant insertion procedure. Figure 10Superotemporal quadrantFigure 114 mm posterior to the limbus2.Create conjunctival peritomyCautionThe peritomy size should be at least mm by mm centered around the selected implant location to ensure the proper clearance of the conjunctiva and Tenons capsule from the implant flange once the implant is inserted into the eye.Measure with adjustable caliper and create at least 6mm by 6mm peritomy of the conjunctiva and Tenons capsule around the selected implant location, using wet field cautery (eraser tip) to achieve hemostasis of the underlying episcleral tissues (Figure 12).-A peritomy size of at least mm by mm centered around the selected implant location provides proper clearance of the conjunctiva and Tenons capsule for the implant flange (long axis of implant flange 4.6 mm).-A peritomy size of at least mm by mm facilitates implant placement away from radial relaxing incision.-Appropriate peritomy size is vital for ease of subsequent surgery. Figure 12Conjunctival peritomy with blue dot representing selected implant location-Only one radial incision is recommended, to avoid excessive conjunctival suturing and longer healing process.-Careful incision creation is key to maintain integrity of conjunctiva and Tenons capsule. Careful and generous undermining is key to minimize mechanical tension and adequate coverage of the implant while closing the conjunctiva and Tenons capsule.Maintain hemostasis around the scleral incision throughout the surgery to facilitate the identification and management of incisional bleeding, to avoid post-operative vitreous hemorrhage.Syringe Preparation and Initial Implant FillUsing aseptic technique, the implant will be filled with 0.02 mL of ranibizumab prior to insertion of the implant into the patients eye.1.Transfer dose from vial to syringeCautionUse the filter needle to withdraw ranibizumab from the vial.Do not use the initial fill needle for this step.Prepare ranibizumab vial by removing the flip-off cap and disinfecting the rubber vial septum with alcohol.Attach filter needle to the syringe by screwing it tightly onto the Luer lock (Figure 13).Carefully remove the needle cap by pulling it straight off.Using aseptic technique, withdraw all of the contents of the ranibizumab vial through the filter needle into the syringe.Remove and properly dispose of the filter needle after withdrawal of the vial contents.Figure 13Filter needle attached to syringe and cap removal2.Attach initial fill needleAttach the initial fill needle firmly onto the syringe by screwing it tightly onto the Luer lock (Figure 14).Carefully remove the needle cap by pulling straight off.Do not wipe the needle at any time.CautionEnsure that the initial fill needle is attached to the syringe.Do not use the filter needle to fill the implant.Figure 14Initial fill needle attached to syringe and cap removal3.Remove air from syringeHold 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 15).Slowly push the plunger rod just until all air is expelled from the syringe and needle, and drop of drug solution is seen at the needle tip (Figure 16).-It is important to preserve as much drug as possible in order to completely fill the implant. Figure 15Gently tap the syringe to dislodge bubblesFigure 16No air bubbles and drop of drug at the needle tip4.Inspect the syringe for air bubblesInspect the syringe and the needle hub to ensure that no air bubbles are present (Figure 17).If air bubbles are present, continue to remove air from the syringe and reinspect.CautionUse 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.Figure 17No air bubbles in the syringe and needle hub5.Load syringe into the carrierCautionDo 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 (Figure 18).Push the syringe forward until it stops, taking care to avoid touching the plunger rod (Figure 19).With the syringe loaded, (Figure 20) the initial fill needle should now be penetrating the implant septum.Figure 18Align and lower the syringe into the carrierFigure 19Push the syringe into the carrierFigure 20Syringe with initial fill needle inserted through the implant septum6.Fill implant with ranibizumab under microscopeUnder the microscope, slowly administer ranibizumab into the implant by slightly tilting the carrier upwards (Figure 21).The implant should be filled over approximately to 10 seconds, to help avoid air entrapment in the implant reservoir.Continue filling the implant until the implant is completely full of drug solution and all air has been expelled as evidenced by dome of drug solution formed at the tip of the implant on the release control element (Figure 22). CautionWhen filling the implant, fluid should only exit the implant from the release control element. If fluid is leaking from the implant at different location, such as the side of the implant, do not use the implant. If fluid is leaking from the septum at the needle insertion site, the needle may not be fully penetrating the implant septum. Fully push the syringe forward before continuing to fill the implant. Figure 21Administer ranibizumab into the implantFigure 22Dome of drug solution forms at tip of implant as viewed under magnification7.Inspect the filled implant under the microscopeInspect the implant under the microscope to ensure that the implant is completely full of drug solution (Figure 23). Warning 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 use the implant. Caution No more than 30 minutes should pass between the initial fill of the implant and the insertion into the patients eye to ensure that the release control element remains saturated with ranibizumab. If ranibizumab dries in the release control element, the implant may not release the drug properly into the vitreous after insertion.Figure 23Proper appearance of implant after initial filling with ranibizumab8.Remove the syringe and guide sleeve from the carrierRemove the syringe and guide sleeve from the carrier by pulling back on the syringe (Figure 24). The syringe will be locked into the guide sleeve.Properly dispose of the used syringe together with the needle and guide sleeve in sharps disposal container or in accordance with local requirements.Figure 24Remove the syringe and guide sleeve from the insertion tool carrier9.Slide the insertion tool handle into the carrierSlide the insertion tool handle into the guide channel of the carrier, ensuring that both components are facing upwards (Figure 25).Push the handle forward as far as it will go into the gripper tips (Figure 26).CautionDo not withdraw the handle and implant until the eye is ready for insertion. Contact between the implant and any surface or object even within the sterile field may result in the introduction of foreign body into the vitreous.Figure 25Insert the handle into the insertion tool carrierFigure 26Fully inserted handleImplant Insertion1.Verify hemostasis of the scleral surfaceClear any excess blood from the scleral surface.Perform careful scleral wet field cauterization as needed, particularly in the area of the sclero-pars plana incision.2.Mark incision siteKeep sclera dry and create discrete ink marks using light touch.Mark location mm from the limbus using an inked fixed width caliper (or equivalent) at the selected implant location (Figure 27).Mark 3.5 mm length for scleral dissection parallel to and mm posterior to the limbus using an inked fixed width caliper (or equivalent) (Figure 28).Figure 274 mm posterior to the limbusFigure 28Fixed width caliper measurement3.Perform scleral incisionUsing an MVR blade, create full thickness dissection of the sclera until the pars plana is fully visible (Figure 29).-Ensure scleral dissection location is away from the radial conjunctival incision. CautionThe final target length for the scleral incision is 3.5 mm. Keep in mind that laser may further result in enlargement of incision and limit the secureness of the fit of the implant. Confirm the length of the incision by using the largest width of the 3.5 mm incision gauge (Figure 30).If the incision is over 3.5 mm, as indicated by loose fit/side to side motion of 3.5 mm gauge, place suture through the wound opposite the relaxing incision to reduce the incision down to 3.5 mm, and bury the knot. After suturing, confirm the incision length is 3.5 mm (Figure 30).If there are any areas of visible bleeding from the wound, carefully perform diathermy. Figure 29Stabilize the globe and perform full thickness scleral incisionFigure 30Confirm correct length of scleral incision4.Perform laser treatment of the pars planaCautionLaser treatment may result in enlargement of the incision. Laser treatment should not be used to intentionally enlarge the length of scleral incision.CautionCarefully apply the laser only to the choroidal tissue in the exposed pars plana. Minimize any laser application to the surrounding scleral tissue to avoid damaging tissue integrity. Confirm pars plana is dry before laser treatment and keep dry throughout the procedure (with surgical sponge).-Consider placing surgical sponge as wick at one end of the incision. Figure 31Laser treatment of the pars planaUsing 532 nm laser endoprobe, apply contiguous, overlapping laser spots starting at 300 mW 1000 ms along the full length of the exposed pars plana (Figure 31). Repeat until complete ablation is achieved.-Maintain focus of laser on exposed pars plana.-Keep foot pedal depressed to achieve full 1000 ms spots (expect smoke).-Ensure the pars plana at the corners of scleral incision is adequately treated.-Do not use painting strokes with the laser.-Do not contact the pars plana directly with laser probe. Repeat application of laser along the full length of the pars plana until full or partial split of the pars plana, or other visual endpoints are achieved, as indicated by:-Gray color change.-Uniform perforated appearance.-Domes of vitreous fluid percolating through pars plana. If visual endpoint is not achieved after several passes with the laser, increase laser power in 100 mW increments.Once laser ablation of pars plana is completed, remeasure the entire length (including corners) of the scleral incision with 3.5 mm gauge to confirm the final post-laser incision is 3.5 mm. If final incision is greater than 3.5 mm, as indicated by loose fit/side to side motion of 3.5 mm gauge, place suture through the wound opposite the relaxing incision to reduce incision down to 3.5 mm.CautionA final post-laser incision length of 3.5 mm provides secure fit for the implant.Do not enlarge the scleral dissection beyond 3.5 mm as final incision length greater than 3.5 mm may result in an improperly seated implant and will require additional suturing.5.Perform pars plana incisionPass 3.2 mm slit knife perpendicularly through the center of the scleral incision to open the underlying pars plana (Figure 32 and Figure 33).Ensure widest part of the blade passes through the incision.Ensure adequate hemostasis.Carefully check for any active bleeding from the pars plana incision; if active bleeding is present, address it with fine tip diathermy within the incision before proceeding.CautionDo not enlarge the pars plana incision with lateral movements. The incision width of 3.2 mm ensures that the pars plana incision is within the laser-treated area of the pars plana and reduces the risk of vitreous hemorrhage.Aim to the center of the globe.Insert blade straight in and straight out.Avoid sideways motion.Avoid enlargement of the incision.Avoid the edges of the wound.Figure 32Pars plana incisionFigure 33Perpendicular entry of slit knife6.Withdraw the insertion tool handle with filled implantWithdraw the insertion tool handle, which is now attached to the gripper tips and implant, by slowly pulling the carrier and handle apart (Figure 34).Take care not to touch implant to any surface other than incision.CautionWhen holding the insertion tool handle, take care not to touch the implant to any surface other than the sclero-pars plana incision during the insertion procedure. Do not use the implant if it is inadvertently released or is contaminated through contact with any surface other than the exposed sclera, including objects within the surgical field.Figure 34Withdraw the insertion tool handle with filled implant7.Stabilize the globePrior to inserting the implant, stabilize the globe with forceps to prevent unwanted eye movement (Figure 35).The forceps should remain in place until the insertion procedure is complete.Figure 35Stabilize the globe with forceps8.Orient the implantOrient the long axis of the implant flange with the length of the sclero-pars plana incision (Figure 36).Aligning the implant in this direction enables the intended seating of the implant within the sclero-pars plana incision.Figure 36The long axis of the implant aligned with the length of the sclero-pars plana incision9.Insert the implantWarningPerpendicular entry of the implant is important to avoid contact between the implant and intraocular structures such as the lens, as contact between the implant and the intraocular structures may cause adverse events such as traumatic cataract.WarningAvoid excessive force on the globe by first ensuring that the tip of the implant has passed through the sclero-pars plana incision before slowly pushing the implant into place.Slowly insert the implant through the sclero-pars plana incision perpendicular to the globe (Figure 37 and Figure 38).A slight initial twisting motion may be helpful to ease the implant through the sclero-pars plana incision (Figure 39).Continue pressing the implant slowly through the incision until the insertion tool handle gripper tips abut the sclera.Per the surgeons discretion, the infusion line may be turned on while inserting the implant.If excess vitreous prolapses from the incision, use the vitrector to remove it and then place the implant.If small amount of vitreous prolapse is present, place the implant first and then use the vitrector to remove the excess. Only use the vitrector to remove vitreous prolapse (do not use surgical sponge and/or scissors).Figure 37Perpendicular entry of the implantFigure 38Implant insertionFigure 39Implant insertion with slight initial twisting motion10.Release the implantEnsure that the long axis of the implant is properly aligned with the sclero-pars plana incision before releasing the implant from the insertion tool.The forceps that are stabilizing the globe should remain in place.Release the implant by depressing the release button completely (Figure 40 and Figure 41).CautionIf the implant flange is not parallel to the limbus after releasing, it needs to be repositioned solely using the gripper tips of the insertion tool handle. Reposition gently to avoid damage to the implant and to avoid contact between the implant and intraocular structures such as the lens. Avoid excessive manipulation of the implant flange.Do not use any other rigid instruments to reposition.Figure 40Release implant with the release buttonFigure 41Implant release11.Seat the implantCautionUse the insertion tool gripper tips to seat the implant.Do not use any other rigid instruments as they may damage the implant. Caution Ensure that the long axis of the implant is aligned with the length of the sclero-pars plana incision and that the implant is seated flush against the sclera.Remove finger from the release button to close the insertion tool gripper tips.Gently press the closed gripper tips against the center of the implant to seat the implant flush against the sclera (Figure 42).Clean any residual vitreous around the implant flange using vitrector.Figure 42Seat the implant12.Suture Tenons capsule and conjunctivaClose both Tenons capsule and conjunctiva, with Vicryl or gut sutures, ensuring complete coverage of the implant flange.Use scleral anchoring at the apex of the peritomy.Ensure suture placement away from the implant (Figure 43).CautionDo not place suture directly over the implant, otherwise adverse events including incomplete healing, infection, and discomfort can occur. Caution Complete closure of both Tenons capsule and conjunctiva across the surgical site is critical to minimize potential complications such as conjunctival retraction over the implant.Figure 43Suture conjunctiva13.Remove infusion cannulaIf the infusion was previously turned on, then set the infusion pressure to 20 mmHg before removing the infusion cannula.Check for persistent leaks at the infusion cannula site and suture if necessary.14.Check Intraocular Pressure (IOP)Using digital palpation, check the IOP. If necessary, inject additional fluid to restore IOP.15.Check implant placementPerform indirect ophthalmoscopy to confirm implant position and to examine for the presence of any complications.Disposal and Post-insertion Procedures 1.Dispose of used Susvimo components and toolsDo not recap the needle or detach it from the syringe. Dispose of the used Susvimo components and tools in sharps disposal container or in accordance with local requirements.2.Perform post-insertion proceduresPost-insertion procedures are consistent with standard post-surgical procedures.3.Post-insertion patient instructionsProvide the patient with the following post-operative instructions:Positioning:-Keep head above shoulder level for the rest of the day.-Sleep with head elevated on or more pillows if lying down during the day and night after implant insertion. Information on caring for the eye after the procedure, including but not limited to the following:-Do not remove the eye shield until they are instructed to do so by their physician. At bedtime, continue to wear the eye shield for at least nights following implant insertion.-Administer all post-operative eye medications, as directed by their physician.-Do not push on the eye, rub the eye, or touch the region of the eye where the implant is located (underneath the eyelid in the upper and outer part of the eye) for 30 days following implant insertion. Avoid rubbing the eye or touching the area where the implant is located as much as possible at all other times but if necessary to do so, make sure hands are cleaned prior to touching the eye.-Do not participate in strenuous activities until month after implant insertion or after discussion with their physician. Monitor for symptoms that may require immediate medical attention while the implant is in place.MR Conditional information:-The surgeon should inform the patient that the implant is MR Conditional (as noted on their Susvimo implant card) and if patient needs to undergo an MRI, they should let their doctor know they have Susvimo implanted in their eye.-After implant insertion, the surgeon should give the patient the implant card (enclosed in this IFU on the last page) with the appropriate information filled in, and should advise the patient to keep the card in safe place, e.g. his or her wallet, for future reference. The surgeon should advise the patient that this implant card contains important information related to the Susvimo implant and that the card should be shown to their current and future health care providers. Explanation of symbols on product or package labelingTable Symbols on blister tray and cartonSymbolTitleManufacturerPrescription onlyDo not re-useDo not use if package is damagedConsult Instructions for UseSterilized by irradiationSterilized using ethylene oxideTemperature limitExpiration date/Use by dateLot/Batch numberMR ConditionalNote The Implant LOT number can be found on the carton and blister tray of the Susvimo(TM) Insertion Tool AssemblyManufactured by:Genentech, Inc.A Member of the Roche Group1 DNA WaySouth San Francisco, CA 94080-4990U.S. License No.: 1048SUSVIMO is trademark of Genentech, Inc. (C)2021 Genentech, Inc. All rights reserved.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Approved: 10/2021. Do not use if the sterility has been compromised or the contents have been dropped, damaged or tampered with.. 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 after initial fill, do not use the implant.. Perpendicular entry of the implant is important to avoid contact between the implant and intraocular structures such as the lens, as contact between the implant and the intraocular structures may cause adverse events such as traumatic cataract.. Avoid excessive force on the globe by first ensuring that the tip of the implant has passed through the sclero-pars plana incision before slowly pushing the implant into place.. Read and follow all instructions, warnings, and cautions prior to use.. Susvimo procedures should be performed by an ophthalmologist experienced in vitreoretinal surgery.. Use the Susvimo components and materials as specified in these instructions to perform the implant insertion procedure including initial fill.. Avoid contact between sharp surgical instruments and the implant as the material of the septum and silicone encasing are soft and susceptible to damage.. The implant is MR Conditional. The Patient Implant card is provided with instructions and must be completed and given to the patient after implant insertion. For further information please refer to the Post-insertion patient instructions section.. Static magnetic field of 1.5-Tesla (1.5 T) or 3-Tesla (3 T). Maximum spatial field gradient of 3,000 G/cm (30 T/m). Maximum MR system reported, whole body averaged specific absorption rate (SAR) of 4.0 W/kg (First Level Controlled Operating Mode). All Susvimo components are supplied sterile. Do not reprocess or resterilize.. All Susvimo components are for single use only. Do not reuse Susvimo components.. Do not open sealed tray until time of use.. Do not use if the package is damaged or broken as sterility may be compromised.. Do not use past the expiration date printed on the label.. The sealed tray has been sterilized with ethylene oxide gas.. Store the Susvimo implant and insertion tool assembly at room temperature 15C to 25C (59F to 77F).. Susvimo initial fill kit should be stored at 2C to 8C (36F to 46F). Do not freeze. Protect from light. Do not shake. Prior to use, the unopened vial may be kept at 9C to 30C (48F to 86F) for up to 24 hours.. Susvimo initial fill needle has been sterilized with electron beam processing.. Prior to use in the operating room, inspect the packaging of the components for damage.. Check the expiration date printed on the label.. Remove the vial from the carton. NOTE: the outside of the vial is not sterile.. Open sterile packaging and using aseptic technique, remove the components from their tray.. Inspect components and place onto sterile field (Figure 8).. Visually inspect the contents of the ranibizumab vial for particulate matter and discoloration.. The drug solution should be colorless to pale brown.. Dilate the pupil of the eye.. Place the patient in supine position on the operating table.. Implant insertion is surgical procedure and therefore requires sterile controls (i.e. use of broad-spectrum microbicide solution on eye including lids and lashes and draping) be in place to minimize the risk of ocular infection.. Perform the procedure under local anesthesia using either peribulbar, retrobulbar, or sub-Tenons technique.. Place lid speculum.. Place an infusion cannula in the inferotemporal quadrant via an angled entry wound.-Alternate placement is acceptable based on patient anatomy per physician discretion (superotemporal placement should be avoided).-Alternatively, the line may be placed after the peritomy but prior to the scleral dissection. -Alternate placement is acceptable based on patient anatomy per physician discretion (superotemporal placement should be avoided).. -Alternatively, the line may be placed after the peritomy but prior to the scleral dissection.. Attach the infusion line. Keep the infusion line off (Figure 9).. Identify the site in the superotemporal quadrant mm posterior to the limbus where the implant will be inserted (Figure 10 and Figure 11).. Placing traction suture is strongly recommended for better visualization of the superotemporal quadrant throughout the entire implant insertion procedure. Measure with adjustable caliper and create at least 6mm by 6mm peritomy of the conjunctiva and Tenons capsule around the selected implant location, using wet field cautery (eraser tip) to achieve hemostasis of the underlying episcleral tissues (Figure 12).-A peritomy size of at least mm by mm centered around the selected implant location provides proper clearance of the conjunctiva and Tenons capsule for the implant flange (long axis of implant flange 4.6 mm).-A peritomy size of at least mm by mm facilitates implant placement away from radial relaxing incision.-Appropriate peritomy size is vital for ease of subsequent surgery. -A peritomy size of at least mm by mm centered around the selected implant location provides proper clearance of the conjunctiva and Tenons capsule for the implant flange (long axis of implant flange 4.6 mm).. -A peritomy size of at least mm by mm facilitates implant placement away from radial relaxing incision.. -Appropriate peritomy size is vital for ease of subsequent surgery.. -Only one radial incision is recommended, to avoid excessive conjunctival suturing and longer healing process.. -Careful incision creation is key to maintain integrity of conjunctiva and Tenons capsule. Careful and generous undermining is key to minimize mechanical tension and adequate coverage of the implant while closing the conjunctiva and Tenons capsule.. Maintain hemostasis around the scleral incision throughout the surgery to facilitate the identification and management of incisional bleeding, to avoid post-operative vitreous hemorrhage.. Prepare ranibizumab vial by removing the flip-off cap and disinfecting the rubber vial septum with alcohol.. Attach filter needle to the syringe by screwing it tightly onto the Luer lock (Figure 13).. Carefully remove the needle cap by pulling it straight off.. Using aseptic technique, withdraw all of the contents of the ranibizumab vial through the filter needle into the syringe.. Remove and properly dispose of the filter needle after withdrawal of the vial contents.. Attach the initial fill needle firmly onto the syringe by screwing it tightly onto the Luer lock (Figure 14).. Carefully remove the needle cap by pulling straight off.. Do not wipe the needle at any time.. 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 15).. Slowly push the plunger rod just until all air is expelled from the syringe and needle, and drop of drug solution is seen at the needle tip (Figure 16).-It is important to preserve as much drug as possible in order to completely fill the implant. -It is important to preserve as much drug as possible in order to completely fill the implant.. Inspect the syringe and the needle hub to ensure that no air bubbles are present (Figure 17).. If air bubbles are present, continue to remove air from the syringe and reinspect.. 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 (Figure 18).. Push the syringe forward until it stops, taking care to avoid touching the plunger rod (Figure 19).. With the syringe loaded, (Figure 20) the initial fill needle should now be penetrating the implant septum.. Under the microscope, slowly administer ranibizumab into the implant by slightly tilting the carrier upwards (Figure 21).. The implant should be filled over approximately to 10 seconds, to help avoid air entrapment in the implant reservoir.. Continue filling the implant until the implant is completely full of drug solution and all air has been expelled as evidenced by dome of drug solution formed at the tip of the implant on the release control element (Figure 22). CautionWhen filling the implant, fluid should only exit the implant from the release control element. If fluid is leaking from the implant at different location, such as the side of the implant, do not use the implant. If fluid is leaking from the septum at the needle insertion site, the needle may not be fully penetrating the implant septum. Fully push the syringe forward before continuing to fill the implant. Inspect the implant under the microscope to ensure that the implant is completely full of drug solution (Figure 23). Warning 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 use the implant. Caution No more than 30 minutes should pass between the initial fill of the implant and the insertion into the patients eye to ensure that the release control element remains saturated with ranibizumab. If ranibizumab dries in the release control element, the implant may not release the drug properly into the vitreous after insertion.. Remove the syringe and guide sleeve from the carrier by pulling back on the syringe (Figure 24). The syringe will be locked into the guide sleeve.. Properly dispose of the used syringe together with the needle and guide sleeve in sharps disposal container or in accordance with local requirements.. Slide the insertion tool handle into the guide channel of the carrier, ensuring that both components are facing upwards (Figure 25).. Push the handle forward as far as it will go into the gripper tips (Figure 26).. Clear any excess blood from the scleral surface.. Perform careful scleral wet field cauterization as needed, particularly in the area of the sclero-pars plana incision.. Keep sclera dry and create discrete ink marks using light touch.. Mark location mm from the limbus using an inked fixed width caliper (or equivalent) at the selected implant location (Figure 27).. Mark 3.5 mm length for scleral dissection parallel to and mm posterior to the limbus using an inked fixed width caliper (or equivalent) (Figure 28).. Using an MVR blade, create full thickness dissection of the sclera until the pars plana is fully visible (Figure 29).-Ensure scleral dissection location is away from the radial conjunctival incision. CautionThe final target length for the scleral incision is 3.5 mm. Keep in mind that laser may further result in enlargement of incision and limit the secureness of the fit of the implant. Confirm the length of the incision by using the largest width of the 3.5 mm incision gauge (Figure 30).If the incision is over 3.5 mm, as indicated by loose fit/side to side motion of 3.5 mm gauge, place suture through the wound opposite the relaxing incision to reduce the incision down to 3.5 mm, and bury the knot. After suturing, confirm the incision length is 3.5 mm (Figure 30).If there are any areas of visible bleeding from the wound, carefully perform diathermy. -Ensure scleral dissection location is away from the radial conjunctival incision.. Confirm the length of the incision by using the largest width of the 3.5 mm incision gauge (Figure 30).. If the incision is over 3.5 mm, as indicated by loose fit/side to side motion of 3.5 mm gauge, place suture through the wound opposite the relaxing incision to reduce the incision down to 3.5 mm, and bury the knot. After suturing, confirm the incision length is 3.5 mm (Figure 30).. If there are any areas of visible bleeding from the wound, carefully perform diathermy.. Confirm pars plana is dry before laser treatment and keep dry throughout the procedure (with surgical sponge).-Consider placing surgical sponge as wick at one end of the incision. -Consider placing surgical sponge as wick at one end of the incision.. Using 532 nm laser endoprobe, apply contiguous, overlapping laser spots starting at 300 mW 1000 ms along the full length of the exposed pars plana (Figure 31). Repeat until complete ablation is achieved.-Maintain focus of laser on exposed pars plana.-Keep foot pedal depressed to achieve full 1000 ms spots (expect smoke).-Ensure the pars plana at the corners of scleral incision is adequately treated.-Do not use painting strokes with the laser.-Do not contact the pars plana directly with laser probe. -Maintain focus of laser on exposed pars plana.. -Keep foot pedal depressed to achieve full 1000 ms spots (expect smoke).. -Ensure the pars plana at the corners of scleral incision is adequately treated.. -Do not use painting strokes with the laser.. -Do not contact the pars plana directly with laser probe.. Repeat application of laser along the full length of the pars plana until full or partial split of the pars plana, or other visual endpoints are achieved, as indicated by:-Gray color change.-Uniform perforated appearance.-Domes of vitreous fluid percolating through pars plana. -Gray color change.. -Uniform perforated appearance.. -Domes of vitreous fluid percolating through pars plana.. If visual endpoint is not achieved after several passes with the laser, increase laser power in 100 mW increments.. Once laser ablation of pars plana is completed, remeasure the entire length (including corners) of the scleral incision with 3.5 mm gauge to confirm the final post-laser incision is 3.5 mm. If final incision is greater than 3.5 mm, as indicated by loose fit/side to side motion of 3.5 mm gauge, place suture through the wound opposite the relaxing incision to reduce incision down to 3.5 mm.. Pass 3.2 mm slit knife perpendicularly through the center of the scleral incision to open the underlying pars plana (Figure 32 and Figure 33).. Ensure widest part of the blade passes through the incision.. Ensure adequate hemostasis.. Carefully check for any active bleeding from the pars plana incision; if active bleeding is present, address it with fine tip diathermy within the incision before proceeding.. Aim to the center of the globe.. Insert blade straight in and straight out.. Avoid sideways motion.. Avoid enlargement of the incision.. Avoid the edges of the wound.. Withdraw the insertion tool handle, which is now attached to the gripper tips and implant, by slowly pulling the carrier and handle apart (Figure 34).. Take care not to touch implant to any surface other than incision.. Prior to inserting the implant, stabilize the globe with forceps to prevent unwanted eye movement (Figure 35).. The forceps should remain in place until the insertion procedure is complete.. Orient the long axis of the implant flange with the length of the sclero-pars plana incision (Figure 36).. Aligning the implant in this direction enables the intended seating of the implant within the sclero-pars plana incision.. Slowly insert the implant through the sclero-pars plana incision perpendicular to the globe (Figure 37 and Figure 38).. slight initial twisting motion may be helpful to ease the implant through the sclero-pars plana incision (Figure 39).. Continue pressing the implant slowly through the incision until the insertion tool handle gripper tips abut the sclera.. Per the surgeons discretion, the infusion line may be turned on while inserting the implant.. If excess vitreous prolapses from the incision, use the vitrector to remove it and then place the implant.. If small amount of vitreous prolapse is present, place the implant first and then use the vitrector to remove the excess. Only use the vitrector to remove vitreous prolapse (do not use surgical sponge and/or scissors).. Ensure that the long axis of the implant is properly aligned with the sclero-pars plana incision before releasing the implant from the insertion tool.. The forceps that are stabilizing the globe should remain in place.. Release the implant by depressing the release button completely (Figure 40 and Figure 41).. Remove finger from the release button to close the insertion tool gripper tips.. Gently press the closed gripper tips against the center of the implant to seat the implant flush against the sclera (Figure 42).. Clean any residual vitreous around the implant flange using vitrector.. Close both Tenons capsule and conjunctiva, with Vicryl or gut sutures, ensuring complete coverage of the implant flange.. Use scleral anchoring at the apex of the peritomy.. Ensure suture placement away from the implant (Figure 43).. If the infusion was previously turned on, then set the infusion pressure to 20 mmHg before removing the infusion cannula.. Check for persistent leaks at the infusion cannula site and suture if necessary.. Using digital palpation, check the IOP. If necessary, inject additional fluid to restore IOP.. Perform indirect ophthalmoscopy to confirm implant position and to examine for the presence of any complications.. Do not recap the needle or detach it from the syringe. Dispose of the used Susvimo components and tools in sharps disposal container or in accordance with local requirements.. Post-insertion procedures are consistent with standard post-surgical procedures.. Positioning:-Keep head above shoulder level for the rest of the day.-Sleep with head elevated on or more pillows if lying down during the day and night after implant insertion. -Keep head above shoulder level for the rest of the day.. -Sleep with head elevated on or more pillows if lying down during the day and night after implant insertion.. Information on caring for the eye after the procedure, including but not limited to the following:-Do not remove the eye shield until they are instructed to do so by their physician. At bedtime, continue to wear the eye shield for at least nights following implant insertion.-Administer all post-operative eye medications, as directed by their physician.-Do not push on the eye, rub the eye, or touch the region of the eye where the implant is located (underneath the eyelid in the upper and outer part of the eye) for 30 days following implant insertion. Avoid rubbing the eye or touching the area where the implant is located as much as possible at all other times but if necessary to do so, make sure hands are cleaned prior to touching the eye.-Do not participate in strenuous activities until month after implant insertion or after discussion with their physician. -Do not remove the eye shield until they are instructed to do so by their physician. At bedtime, continue to wear the eye shield for at least nights following implant insertion.. -Administer all post-operative eye medications, as directed by their physician.. -Do not push on the eye, rub the eye, or touch the region of the eye where the implant is located (underneath the eyelid in the upper and outer part of the eye) for 30 days following implant insertion. Avoid rubbing the eye or touching the area where the implant is located as much as possible at all other times but if necessary to do so, make sure hands are cleaned prior to touching the eye.. -Do not participate in strenuous activities until month after implant insertion or after discussion with their physician.. Monitor for symptoms that may require immediate medical attention while the implant is in place.. MR Conditional information:-The surgeon should inform the patient that the implant is MR Conditional (as noted on their Susvimo implant card) and if patient needs to undergo an MRI, they should let their doctor know they have Susvimo implanted in their eye.-After implant insertion, the surgeon should give the patient the implant card (enclosed in this IFU on the last page) with the appropriate information filled in, and should advise the patient to keep the card in safe place, e.g. his or her wallet, for future reference. The surgeon should advise the patient that this implant card contains important information related to the Susvimo implant and that the card should be shown to their current and future health care providers. -The surgeon should inform the patient that the implant is MR Conditional (as noted on their Susvimo implant card) and if patient needs to undergo an MRI, they should let their doctor know they have Susvimo implanted in their eye.. -After implant insertion, the surgeon should give the patient the implant card (enclosed in this IFU on the last page) with the appropriate information filled in, and should advise the patient to keep the card in safe place, e.g. his or her wallet, for future reference. The surgeon should advise the patient that this implant card contains important information related to the Susvimo implant and that the card should be shown to their current and future health care providers.. Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. Image. Image. Figure 8. Image. Figure 9. Figure 10. Figure 11. Image. Figure 12. Image. Figure 13. Image. Figure 14. Figure 15. Figure 16. Image. Figure 17. Image. Figure 18. Figure 19. Figure 20. Image. Figure 21. Figure 22. Image. Image. Figure 23. Figure 24. Image. Figure 25. Figure 26. Figure 27. Figure 28. Image. Figure 29. Figure 30. Image. Image. Figure 31. Image. Image. Figure 32. Figure 33. Image. Figure 34. Figure 35. Figure 36. Image. Image. Figure 37. Figure 38. Figure 39. Image. Figure 40. Figure 41. Image. Image. Figure 42. Image. Image. Figure 43. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image.

BOXED WARNING SECTION.

WARNING: ENDOPHTHALMITIS. The SUSVIMO implant has been associated with 3-fold higher rate of endophthalmitis than monthly intravitreal injections of ranibizumab. Many of these events were associated with conjunctival retractions or erosions. Appropriate conjunctiva management and early detection with surgical repair of conjunctival retractions or erosions may reduce the risk of endophthalmitis. In clinical trials, 2.0% of patients receiving ranibizumab implant experienced at least one episode of endophthalmitis [see Contraindications (4.1), Warnings and Precautions (5.1)]. WARNING: ENDOPHTHALMITISSee full prescribing information for complete boxed warning.The SUSVIMO implant has been associated with 3-fold higher rate of endophthalmitis than monthly intravitreal injections of ranibizumab. In clinical trials, 2.0% of patients receiving an implant experienced an episode of endophthalmitis.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 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 risk to reproductive capacity [see Females and Males of Reproductive Potential (8.3)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1How Supplied. Each SUSVIMO initial fill needle kit (NDC 50242-078-55) contains:One SUSVIMO 100 mg/mL single-dose glass vialOne SUSVIMO initial fill needle (34-gauge needle with 5 um integrated filter) with blue capEach SUSVIMO (ranibizumab injection) carton (NDC 50242-078-12) contains one SUSVIMO (ranibizumab injection) 100 mg/mL that is clear to slightly opalescent, colorless to pale brown solution in single-dose glass vial.Each SUSVIMO refill needle carton contains SUSVIMO refill needle (34-gauge vented needle with 5 um integrated filter) with clear cap.Device and Materials DescriptionComponentsFigure 28SUSVIMO implantSUSVIMO implant (Figure 29) is capable of holding 0.02 mL of drug, and is secured within the sclera, by the extrascleral flange that remains visible through the conjunctiva following insertion.The septum is self-sealing interface through which ranibizumab is administered to fill the implant.Figure 29SUSVIMO (ranibizumab injection) 100 mg/mL vialSUSVIMO (ranibizumab injection) (Figure 30) is used to fill the implant with ranibizumab prior to insertion or during subsequent refill-exchange in an office-based setting.Figure 30SUSVIMO refill needleSUSVIMO refill needle (Figure 31) consists of 34 vented needle assembly, silicone soft stop, and 5 um integrated filter within the needle hub. It is designed to simultaneously exchange the contents of the implant reservoir with replacement ranibizumab in an office-based setting. As replacement ranibizumab is administered into the implant through the stainless-steel cannula, fluid remaining in the implant flows through openings in the vented needle and is collected in the fluid collection reservoir.SUSVIMO refill needle is distinguished by its clear cap.Figure 31Materials ListMaterials that are required and supplied to perform the procedure are:SUSVIMO refill needle, 34 G, with clear capSUSVIMO (ranibizumab injection) 100 mg/mLAdditional materials required to perform the procedure but are not provided are:One sterile mL Luer Lock syringe (not included) One sterile 5-micron filter needle (19-gauge 1 1/2 inch) (not included)Anesthetic ophthalmic solutionsOphthalmic broad-spectrum microbicide solutionCotton tips and gauzeSterile powder free glovesFace masksLid speculumMagnification such as visor or loupesTask lightingIndirect ophthalmoscope and lensSterile drape (optional for refill-exchange procedure) One SUSVIMO 100 mg/mL single-dose glass vial. One SUSVIMO initial fill needle (34-gauge needle with 5 um integrated filter) with blue cap. SUSVIMO implant (Figure 29) is capable of holding 0.02 mL of drug, and is secured within the sclera, by the extrascleral flange that remains visible through the conjunctiva following insertion.. The septum is self-sealing interface through which ranibizumab is administered to fill the implant.. SUSVIMO (ranibizumab injection) (Figure 30) is used to fill the implant with ranibizumab prior to insertion or during subsequent refill-exchange in an office-based setting.. SUSVIMO refill needle (Figure 31) consists of 34 vented needle assembly, silicone soft stop, and 5 um integrated filter within the needle hub. It is designed to simultaneously exchange the contents of the implant reservoir with replacement ranibizumab in an office-based setting. As replacement ranibizumab is administered into the implant through the stainless-steel cannula, fluid remaining in the implant flows through openings in the vented needle and is collected in the fluid collection reservoir.. SUSVIMO refill needle is distinguished by its clear cap.. SUSVIMO refill needle, 34 G, with clear cap. SUSVIMO (ranibizumab injection) 100 mg/mL. One sterile mL Luer Lock syringe (not included) One sterile 5-micron filter needle (19-gauge 1 1/2 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) Figure 28. Figure 29. Figure 30. Figure 31. 16.2 Storage. Store SUSVIMO initial fill needle kit at 2C to 8C (36F to 46F). Do not freeze. Protect from light. Do not shake. The SUSVIMO initial fill needle has been sterilized with electron beam processing.Store SUSVIMO (ranibizumab injection) 100 mg/ mL vial at 2C to 8C (36F to 46F). Do not freeze. Protect from light. Do not shake. Prior to use, the unopened vial may be kept at 9C to 30C (48F to 86F) for up to 24 hours provided it is protected from light.Store the SUSVIMO implant and insertion tool assembly, refill needle and explant tool at room temperature 15C to 25C (59F to 77F). The SUSVIMO implant and insertion tool assembly has been sterilized with ethylene oxide gas. The SUSVIMO refill needle and explant tool have been sterilized with electron beam processing.. 16.3Handling. SUSVIMO components are supplied sterile and are for single-use only. Do not reprocess, re-sterilize, or reuse SUSVIMO components. Do not use if the sterility has been compromised or the contents have been dropped, damaged or tampered with. Do not use past the expiration date printed on the label. Do not open sealed tray until time of use. Avoid contact between sharp surgical instruments and the SUSVIMO implant as the material of the septum and silicone encasing is soft and susceptible to damage.. Important Device Handling InformationUse caution when performing ophthalmic procedures that may cause deflection of the implant and subsequent injury. For example, B-scan ophthalmic ultrasound, scleral depression, or gonioscopy.. Use caution when performing ophthalmic procedures that may cause deflection of the implant and subsequent injury. For example, B-scan ophthalmic ultrasound, scleral depression, or gonioscopy.. Ocular Implant Initial Fill ProcedureMinimize 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 after initial fill, do not use the implant.. 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 after initial fill, do not use the implant.. Ocular Implant Insertion ProcedurePerpendicular entry of the implant is important to avoid contact between the implant and intraocular structures such as the lens, as contact between the implant and the intraocular structures may cause adverse reactions such as traumatic cataract.Avoid excessive force on the globe by first ensuring that the tip of the implant has passed through the sclero-pars plana incision before slowly pushing the implant into place.. Perpendicular entry of the implant is important to avoid contact between the implant and intraocular structures such as the lens, as contact between the implant and the intraocular structures may cause adverse reactions such as traumatic cataract.. Avoid excessive force on the globe by first ensuring that the tip of the implant has passed through the sclero-pars plana incision before slowly pushing the implant into place.. Ocular Implant Removal ProcedureDo not grasp the implant by the short axis of the implant flange. Remove the implant in gentle manner. Perpendicular exit of the implant is important to avoid contact between the implant and intraocular structures such as the lens.. Do not grasp the implant by the short axis of the implant flange. Remove the implant in gentle manner. Perpendicular exit of the implant is important to avoid contact between the implant and intraocular structures such as the lens.

ADVERSE REACTIONS SECTION.

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)] Vitreous Hemorrhage [see Warnings and Precautions (5.4)] Conjunctival Erosion or Retraction [see Warnings and Precautions (5.5)] Conjunctival Bleb [see Warnings and Precautions (5.6)] Postoperative Decrease in Visual Acuity [see Warnings and Precautions (5.7)] Endophthalmitis [see Warnings and Precautions (5.1)] Rhegmatogenous Retinal Detachment [see Warnings and Precautions (5.2)] Implant Dislocation [see Warnings and Precautions (5.3)] Vitreous Hemorrhage [see Warnings and Precautions (5.4)] Conjunctival Erosion or Retraction [see Warnings and Precautions (5.5)] Conjunctival Bleb [see Warnings and Precautions (5.6)] Postoperative Decrease in Visual Acuity [see Warnings and Precautions (5.7)] The most common adverse reactions were conjunctival hemorrhage (72%), conjunctival hyperemia (26%), iritis (23%) and eye pain (10%) (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 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 nAMD in the Archway study following the SUSVIMO initial fill and implant insertion, refill, and implant removal (if necessary) procedures up to Week 40. In this patient population the most common (>= 10%) adverse reactions up to Week 40 were conjunctival hemorrhage (72%), conjunctival hyperemia (26%), iritis (23%), and eye pain (10%).Table 2Adverse Reactions in nAMD patients occurring in >= 4% of patients in the SUSVIMO arm Adverse ReactionsWeek 40SUSVIMOn 248Intravitreal ranibizumabn 167Conjunctival hemorrhage72%6%Conjunctival hyperemia26%2%IritisIritis includes: iritis, anterior chamber flare, and anterior chamber cell 23%0.6%Eye pain10%5%Vitreous floaters9%2%Conjunctival bleb/ filtering bleb leakConjunctival bleb/filtering bleb leak includes: conjunctival bleb, conjunctival filtering bleb leak, conjunctival cyst, subconjunctival cyst, and implant site cyst 9%0Foreign body sensation in eyes7%1%HeadacheHeadache includes: headache and procedural headache 7%2%Hypotony of eye6%0Vitreous detachment6%5%Vitreous hemorrhage5%2%Conjunctival edema5%0Corneal disorder4%0Corneal abrasionCorneal abrasion includes: corneal abrasion and vital dye staining cornea present. 4%0.6%Corneal edema4%0. 6.2 Immunogenicity. 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.In previously treated nAMD patients, anti-ranibizumab antibodies were detected in 2.1% (5 of 243) of patients prior to insertion of the SUSVIMO implant. After the SUSVIMO implant insertion and treatment, anti-ranibizumab antibodies developed in 12% (29 of 247) patients. No clinically meaningful differences in the pharmacokinetics, efficacy, or safety in patients with treatment-emergent anti-ranibizumab antibodies were observed.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Ranibizumab binds to the receptor binding site of multiple biologically active forms of VEGF-A, including VEGF110. 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. The binding of ranibizumab 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.. 12.3 Pharmacokinetics. The SUSVIMO implant provides continuous release of ranibizumab where the release of ranibizumab into the vitreous decreases over time as the concentration in the implant decreases with half-life of approximately 25 weeks. The ranibizumab serum concentrations with SUSVIMO 24-week treatment interval are maintained below the maximum and above the minimum concentrations experienced with monthly 0.5 mg intravitreal ranibizumab.. DistributionFollowing implant insertion of SUSVIMO, the mean (+-SD) maximum ranibizumab serum concentration (Cmax) was 0.48 (+-0.17) ng/mL and median (range) time to maximum serum concentration (Tmax) was 26 (1 89) days. Following the initial fill and refill of SUSVIMO in patients with AMD, maximum serum concentrations of ranibizumab were below the ranibizumab concentration necessary to inhibit the biological activity of VEGF by 50%. Ranibizumab did not accumulate in serum when administered with refills every 24 weeks.. Elimination. MetabolismThe metabolism of SUSVIMO (ranibizumab injection) has not been studied. SUSVIMO (ranibizumab injection) is monoclonal antibody fragment and antibodies are cleared principally by catabolism.. ExcretionThe full excretion profile for ranibizumab following administration of SUSVIMO is unknown. Specific PopulationsIn population pharmacokinetic analysis of AMD patients with SUSVIMO, 75% (220 of 295) had renal impairment (42% mild [CrCL 60 to 89 mL/min], 30% moderate [CrCL 30 to 59 mL/min] and 2% severe [CrCL 30mL/min]). 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The clinical efficacy and safety of SUSVIMO (ranibizumab injection) was assessed in randomized, visual assessor-masked, active treatment-controlled study (Archway-NCT03677934) in patients with AMD. 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 nAMD within the months prior to screening and received >= doses of anti-VEGF intravitreal agents in the study eye within the last months prior to screening. Each patient was required to have demonstrated response to an anti-VEGF intravitreal agent prior to randomization. Patients were randomized in 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 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 or more supplemental treatment(s) and in the following 24 weeks, 5.4% of patients assessed for supplemental treatment received 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 weeks. Detailed efficacy results are shown in Table and Figure 27 below.Table 3Visual acuity outcomes at Week 40 in Archway (GR40548) StudyOutcome MeasureBCVA measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart at starting distance of meters SUSVIMO (100 mg/mL)n=248Intravitreal ranibizumab 0.5 mg (10 mg/mL)n=167Difference(95% CI)All estimates are adjusted estimates based on mixed-effect model with repeated measures. SUSVIMO arm intravitreal ranibizumab arm. 95% is rounding of 95.03% CI; The type error was adjusted for interim sensitivity monitoring. BCVA Best corrected visual acuityAdjusted Mean change from baseline in BCVA score averaged over Weeks 36 and 400.20.5-0.3(-1.7, 1.1)Equivalence margins were +-4.5 letters. Q24W every 24 weeks; Q4W every weeksFigure 27 Adjusted Mean change from Baseline in Best Corrected Visual Acuity in study eye through Week 48 in the Archway (GR40548) studyPrior to study treatment, median of 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 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 27.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of 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 nAMD in the Archway study following the SUSVIMO initial fill and implant insertion, refill, and implant removal (if necessary) procedures up to Week 40. In this patient population the most common (>= 10%) adverse reactions up to Week 40 were conjunctival hemorrhage (72%), conjunctival hyperemia (26%), iritis (23%), and eye pain (10%).Table 2Adverse Reactions in nAMD patients occurring in >= 4% of patients in the SUSVIMO arm Adverse ReactionsWeek 40SUSVIMOn 248Intravitreal ranibizumabn 167Conjunctival hemorrhage72%6%Conjunctival hyperemia26%2%IritisIritis includes: iritis, anterior chamber flare, and anterior chamber cell 23%0.6%Eye pain10%5%Vitreous floaters9%2%Conjunctival bleb/ filtering bleb leakConjunctival bleb/filtering bleb leak includes: conjunctival bleb, conjunctival filtering bleb leak, conjunctival cyst, subconjunctival cyst, and implant site cyst 9%0Foreign body sensation in eyes7%1%HeadacheHeadache includes: headache and procedural headache 7%2%Hypotony of eye6%0Vitreous detachment6%5%Vitreous hemorrhage5%2%Conjunctival edema5%0Corneal disorder4%0Corneal abrasionCorneal abrasion includes: corneal abrasion and vital dye staining cornea present. 4%0.6%Corneal edema4%0.

CONTRAINDICATIONS SECTION.

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

DESCRIPTION SECTION.

11 DESCRIPTION. Ranibizumab is recombinant humanized IgG1 kappa isotype monoclonal antibody fragment for intraocular use. Ranibizumab binds to and inhibits the biologic activity of human vascular endothelial growth factor-A (VEGF-A). Ranibizumab, which lacks an Fc region, has molecular weight of approximately 48 kilodaltons and is produced by an E. coli expression system in nutrient medium containing the antibiotic tetracycline. Tetracycline is not detectable in the final product.SUSVIMO (ranibizumab injection) is supplied as sterile, clear to slightly opalescent, colorless to pale brown solution for intravitreal use via the SUSVIMO implant. Each single-dose vial contains 10 mg of ranibizumab, histidine HCl (0.1 mg), polysorbate 20 (0.01 mg), sucrose (8.2 mg), and Water for Injection, in 0.1 mL of solution with pH of 5.5. The SUSVIMO implant is designed to contain approximately 0.02 mL (2 mg) of ranibizumab solution when filled. SUSVIMO does not contain an antimicrobial preservative.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 100 mg/mL, clear to slightly opalescent, colorless to pale brown solution in single-dose vial. Injection: 100 mg/mL solution in single-dose vial (3).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. ContraceptionFemales 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).. InfertilityNo 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 risk to reproductive capacity.

IMMUNOGENICITY.

6.2 Immunogenicity. 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.In previously treated nAMD patients, anti-ranibizumab antibodies were detected in 2.1% (5 of 243) of patients prior to insertion of the SUSVIMO implant. After the SUSVIMO implant insertion and treatment, anti-ranibizumab antibodies developed in 12% (29 of 247) patients. No clinically meaningful differences in the pharmacokinetics, efficacy, or safety in patients with treatment-emergent anti-ranibizumab antibodies were observed.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. 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 Vascular Endothelial Growth Factor (VEGF) inhibitor medication.. SUSVIMO (ranibizumab injection), vascular endothelial growth factor (VEGF) inhibitor, 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 VEGF inhibitor (1.0).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. Advise patients on the following after the implant insertion procedure:. Positioning:Keep head above shoulder level for the rest of the day.Sleep with head on or more pillows during the day and the night after surgery.. Keep head above shoulder level for the rest of the day.. Sleep with head on or more pillows during the day and the night after surgery.. How to care for the treated eye after the procedure:Do not remove the eye shield until they are instructed to do so by their healthcare provider. At bedtime, continue to wear the eye shield for at least nights following the implant surgery.Administer all post-operative eye medications as directed by their healthcare provider.Do not push on the eye, rub the eye, or touch the area of the eye where the implant is located (underneath the eyelid in the upper and outer part of the eye) for 30 days following the implant insertion.Do not participate in strenuous activities until 1-month after the implant insertion or after discussion with their healthcare provider.. Do not remove the eye shield until they are instructed to do so by their healthcare provider. At bedtime, continue to wear the eye shield for at least nights following the implant surgery.. Administer all post-operative eye medications as directed by their healthcare provider.. Do not push on the eye, rub the eye, or touch the area of the eye where the implant is located (underneath the eyelid in the upper and outer part of the eye) for 30 days following the implant insertion.. Do not participate in strenuous activities until 1-month after the implant insertion or after discussion with their healthcare provider.. Magnetic Resonance (MR) Conditional information:The SUSVIMO implant is MR conditional. Inform their healthcare provider that they have SUSVIMO implanted in their eye and show their healthcare provider the SUSVIMO implant card should they require Magnetic resonance imaging (MRI).. The SUSVIMO implant is MR conditional. Inform their healthcare provider that they have SUSVIMO implanted in their eye and show their healthcare provider the SUSVIMO implant card should they require Magnetic resonance imaging (MRI).. Advise patients on the following after the Refill-Exchange procedure:Refrain from pushing on the treated eye, rubbing the eye, or touching the eye in the area of the implant (located underneath the eyelid in the upper and outer part of your eye) for days following the refill-exchange procedure.Administer eye drops as directed by their healthcare provider.. Refrain from pushing on the treated eye, rubbing the eye, or touching the eye in the area of the implant (located underneath the eyelid in the upper and outer part of your eye) for days following the refill-exchange procedure.. Administer eye drops as directed by their healthcare provider.. Advise patients on the following after the implant removal procedure (if it is deemed medically necessary):Keep your head above shoulder level for the rest of the day.Sleep with your head on or more pillows if lying down during the day and night after the implant removal.Wear an eye shield for at least nights following the implant removal.Do not participate in strenuous activities until 14 days following the implant removal.Administer all post-operative anti-inflammatory and antimicrobial drops, as directed by your healthcare provider.. Keep your head above shoulder level for the rest of the day.. Sleep with your head on or more pillows if lying down during the day and night after the implant removal.. Wear an eye shield for at least nights following the implant removal.. Do not participate in strenuous activities until 14 days following the implant removal.. Administer all post-operative anti-inflammatory and antimicrobial drops, as directed by your healthcare provider.. Advise patients on the following throughout SUSVIMO treatment:Do not drive or use machinery until the eye shield can be removed and visual function has recovered sufficiently [see Adverse Reactions (6.1)].The SUSVIMO implant and/or implant related procedures have been associated with conjunctival reactions (bleb, erosion, retraction), vitreous hemorrhage, endophthalmitis, rhegmatogenous retinal detachment, the dislocation of the implant, and temporary decrease in vision.While the implant is in the eye, avoid rubbing the eye or touching the area as much as possible. However, if necessary to do so, make sure hands are cleaned prior to touching the eye.Seek immediate care from an ophthalmologist if there are sudden changes in their vision (an increase in moving spots, the appearance of spider webs, flashing lights, or loss in vision), increasing eye pain, progressive vision loss, sensitivity to light, redness in the white of the eye, sudden sensation that something is in their eye, or eye discharge or watering [see Warnings and Precautions (5)].. Do not drive or use machinery until the eye shield can be removed and visual function has recovered sufficiently [see Adverse Reactions (6.1)].. The SUSVIMO implant and/or implant related procedures have been associated with conjunctival reactions (bleb, erosion, retraction), vitreous hemorrhage, endophthalmitis, rhegmatogenous retinal detachment, the dislocation of the implant, and temporary decrease in vision.. While the implant is in the eye, avoid rubbing the eye or touching the area as much as possible. However, if necessary to do so, make sure hands are cleaned prior to touching the eye.. Seek immediate care from an ophthalmologist if there are sudden changes in their vision (an increase in moving spots, the appearance of spider webs, flashing lights, or loss in vision), increasing eye pain, progressive vision loss, sensitivity to light, redness in the white of the eye, sudden sensation that something is in their eye, or eye discharge or watering [see Warnings and Precautions (5)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 nursing woman.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for SUSVIMO (ranibizumab injection) and any potential adverse effects on the breastfed child from ranibizumab.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Ranibizumab binds to the receptor binding site of multiple biologically active forms of VEGF-A, including VEGF110. 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. The binding of ranibizumab 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 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 risk to reproductive capacity [see Females and Males of Reproductive Potential (8.3)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL Kit Carton. NDC 50242-078-55 Susvimo(TM)(ranibizumab injection)See instructions for useincluded with the Susvimo ocular implantwith insertion tool assembly 100 mg/mLVial contains 10 mg/0.1 mL ranibizumab For use with Susvimo ocular implantDispense the enclosed Medication Guide to each patient.Carton contents:One Susvimo single-dose vialOne Susvimo initial fill needle Rx onlyGenentech10233586. One Susvimo single-dose vial. One Susvimo initial fill needle. PRINCIPAL DISPLAY PANEL Kit Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and efficacy of SUSVIMO (ranibizumab injection) in pediatric patients have not been established.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The SUSVIMO implant provides continuous release of ranibizumab where the release of ranibizumab into the vitreous decreases over time as the concentration in the implant decreases with half-life of approximately 25 weeks. The ranibizumab serum concentrations with SUSVIMO 24-week treatment interval are maintained below the maximum and above the minimum concentrations experienced with monthly 0.5 mg intravitreal ranibizumab.. DistributionFollowing implant insertion of SUSVIMO, the mean (+-SD) maximum ranibizumab serum concentration (Cmax) was 0.48 (+-0.17) ng/mL and median (range) time to maximum serum concentration (Tmax) was 26 (1 89) days. Following the initial fill and refill of SUSVIMO in patients with AMD, maximum serum concentrations of ranibizumab were below the ranibizumab concentration necessary to inhibit the biological activity of VEGF by 50%. Ranibizumab did not accumulate in serum when administered with refills every 24 weeks.. Elimination. MetabolismThe metabolism of SUSVIMO (ranibizumab injection) has not been studied. SUSVIMO (ranibizumab injection) is monoclonal antibody fragment and antibodies are cleared principally by catabolism.. ExcretionThe full excretion profile for ranibizumab following administration of SUSVIMO is unknown. Specific PopulationsIn population pharmacokinetic analysis of AMD patients with SUSVIMO, 75% (220 of 295) had renal impairment (42% mild [CrCL 60 to 89 mL/min], 30% moderate [CrCL 30 to 59 mL/min] and 2% severe [CrCL 30mL/min]). 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere 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 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 single eye treatment at the recommended clinical dose [see Animal 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 pregnant woman. Based on the anti-VEGF mechanism of action for ranibizumab [see Clinical Pharmacology (12.1)], treatment with SUSVIMO (ranibizumab injection) may pose risk to human embryofetal development.All pregnancies have 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 DataAn 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 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 low incidence in fetuses from animals treated with mg/eye of ranibizumab. The mg/eye dose resulted in trough serum ranibizumab levels up to 41 times higher than observed human Cmax levels of SUSVIMO (ranibizumab injection) after treatment of single eye.No skeletal abnormalities were seen at the lower dose of 0.125 mg/eye, 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.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug AdministrationApproved: 10/2021MEDICATION GUIDESUSVIMO(TM) (suss-VIH-moh)(ranibizumab injection)for intravitreal use via SUSVIMO ocular implantWhat is the most important information should know about SUSVIMOSUSVIMO (ranibizumab injection) is delivered into the eye using the SUSVIMO implant. The SUSVIMO implant and the procedures to insert, fill, refill and remove the eye (ocular) implant can cause serious side effects including:an eye infection (endophthalmitis). Endophthalmitis is an infection of the eyeball that can cause permanent damage to your eye including blindness. Call your healthcare provider right away if you have increasing eye pain, vision loss, sensitivity to light, or redness in the white of the eye. Endophthalmitis requires urgent (same day) medical or surgical treatment.a missing layer on top of the white part of the eye (conjunctival erosion). Conjunctival erosion is an area that becomes missing (defect) in the layer (conjunctiva) that covers the white part of the eye which may result in exposure of the implant. Call your healthcare provider right away if you have sudden feeling that something is in your eye, if you have eye discharge, or watering of the eye. Conjunctival erosion may require surgical treatment.an opening of the layer that covers the white part of the eye (conjunctival retraction). Conjunctival retraction is an opening or gaping in the layer (conjunctiva) that covers the white part of the eye which may cause the implant to be exposed. Call your healthcare provider right away if you have sudden feeling that something is in your eye, if you have eye discharge, or watering of the eye. Conjunctival retraction may require surgical treatment.See What are the possible side effects of SUSVIMO for other serious side effects that may happen while in treatment with SUSVIMO. To help prevent or keep these side effects from becoming more serious follow all post-procedure instructions your healthcare provider gives you. See How will receive SUSVIMO. What is SUSVIMOSUSVIMO (ranibizumab injection) is prescription medicine used to treat adults with Neovascular (wet) Age-related Macular Degeneration (AMD) who have responded to at least two injections of Vascular Endothelial Growth Factor (VEGF) inhibitor in the gel-like part of the eye (intravitreal).It is not known if SUSVIMO is safe and effective in children. Do not receive SUSVIMO if you:have an infection in or around your eye.have active swelling around your eye that may include pain and redness.are allergic to ranibizumab or any of the ingredients in SUSVIMO. See the end of this Medication Guide for complete list of ingredients in SUSVIMO.Talk to your healthcare provider before receiving this SUSVIMO if you have any of these conditions.Before receiving SUSVIMO, tell your healthcare provider about all of your medical conditions, including if you:are currently taking or have recently taken medicines that lower the chance of blood clots forming in the body such as warfarin, low or regular doses of aspirin, or nonsteroidal anti-inflammatory drugs (NSAID).are pregnant or plan to become pregnant. It is not known if SUSVIMO will harm your unborn baby. You should use birth control during your treatment with SUSVIMO and for 12 months after your last dose of SUSVIMO. are breastfeeding or plan to breastfeed. It is not known if SUSVIMO passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive SUSVIMO.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive SUSVIMOSUSVIMO is implanted through the white part of the eye (sclera) by your healthcare provider. Your healthcare provider will refill your implant device every months (about every 24 weeks).If you miss scheduled refill, call your healthcare provider as soon as possible to reschedule your refill. Your next refill should be given months after your last refill. Your healthcare provider will give you instructions to follow after the implant insertion, the refill procedure, and the implant removal. The instructions may include:After the Implant Insertion:Positioning of your headKeep your head above shoulder level for the rest of the day.Sleep with your head on or more pillows during the day and night after your implant insertion.How to care for your eyeDo not remove the eye shield from your eye until you are told to by your healthcare provider. At bedtime, continue to wear an eye shield for at least nights following the implant insertion.Take all post-operative eye medicines as your healthcare provider tells you to.Do not push on the eye, rub the eye, or touch the area of the eye where the implant is located (underneath the eyelid in the upper and outer part of your eye) for 30 days following the implant insertion.Do not participate in strenuous activities until month after the implant insertion or after talking to your healthcare provider.Magnetic Resonance Imaging (MRI) Implant CardGet your implant card from your healthcare provider after receiving the implant and keep the card in safe place for future reference. The implant card contains important information about your SUSVIMO implant.Show your current and future healthcare providers your implant card. This is important if you need to have an MRI. You may only receive an MRI under very specific conditions if you have the SUSVIMO implant. Your healthcare provider will review the information on the implant card and will let you know if you should receive an MRI. After the Refill Procedure:Do not push on the eye, rub the eye, or touch the area of the eye where the implant is located (underneath the eyelid in the upper and outer part of your eye) for days following the refill procedure.Take eye drops exactly as your healthcare provider tells you to take them.After the Implant Removal: Keep your head above shoulder level for the rest of the day.Sleep with your head on or more pillows if lying down during the day and night after implant removal.Wear an eye shield for at least nights following the implant removal.Do not participate in strenuous activities until 14 days following the implant removal.Give all post-operative drops, as told by your healthcare provider.These are not all the instructions you may receive from your healthcare provider. Following all post-procedure instructions may help prevent serious side effects or keep side effects from becoming more serious. See What is the most important information should know about SUSVIMO.What should avoid while receiving SUSVIMODo not drive or use machinery until the eye shield can be removed and you can see.Avoid rubbing your eye or touching the area of your eye where the implant is located as much as possible while the implant is in place. If you have to rub or touch your eye, wash your hands first.What are the possible side effects of SUSVIMOSee What is the most important information should know about SUSVIMO on the first page. In addition to those side effects listed on page one, the SUSVIMO implant and the procedures to insert, fill, refill and remove the eye (ocular) implant can cause other serious side effects including: Tear and separation of layers of the retina (Rhegmatogenous retinal detachment). Rhegmatogenous retinal detachment is tear and separation of one of the layers of the retina in the back of the eye that senses light. Call your healthcare provider or go to the emergency room right away if you see flashing lights, see curtain or veil covering part of your vision, have change in your vision, or loss of vision. Rhegmatogenous retinal detachment requires surgical treatment.Implant movement (Implant dislocation): Tell your healthcare provider right away if you notice that the implant has moved out of place. This movement may require surgical treatment to correct.Bleeding (Vitreous hemorrhage): Vitreous hemorrhage is bleeding within the gel-like substance (vitreous) inside of your eye. Call your healthcare provider right away if you have an increase in moving spots or what looks like spider webs in your vision as you may need an additional eye surgery.Bump on top of the white layer of the eye (Conjunctival bleb): Conjunctival bleb is small bulge in the layer (conjunctiva) that covers the white part of the eye where the implant is inserted. This may be due to leakage of fluid from the inside of the eye. Call your healthcare provider right away if you have sudden feeling that something is in your eye (foreign body sensation), see bulge over the white part of your eye, if you have eye discharge, or watering in the eye. You may need medical or surgical treatment.Temporary decrease in vision after the SUSVIMO procedure.The most common side effects of SUSVIMO include:blood on the white of the eyeeye painredness in the white of the eyesensitivity to lightThese are not all the possible side effects of SUSVIMO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Genentech at 1-888-835-2555.General information about the safe and effective use of SUSVIMO.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your pharmacist or healthcare provider for information about SUSVIMO that is written for health professionals.What are the ingredients in SUSVIMO (ranibizumab injection)Active ingredient: ranibizumab Inactive ingredients: histidine HCl, polysorbate 20, sucrose.Manufactured by: Genentech, Inc., Member of the Roche Group, DNA Way, South San Francisco, CA 94080-4990U.S. License No.: 1048 an eye infection (endophthalmitis). Endophthalmitis is an infection of the eyeball that can cause permanent damage to your eye including blindness. Call your healthcare provider right away if you have increasing eye pain, vision loss, sensitivity to light, or redness in the white of the eye. Endophthalmitis requires urgent (same day) medical or surgical treatment.. missing layer on top of the white part of the eye (conjunctival erosion). Conjunctival erosion is an area that becomes missing (defect) in the layer (conjunctiva) that covers the white part of the eye which may result in exposure of the implant. Call your healthcare provider right away if you have sudden feeling that something is in your eye, if you have eye discharge, or watering of the eye. Conjunctival erosion may require surgical treatment.. an opening of the layer that covers the white part of the eye (conjunctival retraction). Conjunctival retraction is an opening or gaping in the layer (conjunctiva) that covers the white part of the eye which may cause the implant to be exposed. Call your healthcare provider right away if you have sudden feeling that something is in your eye, if you have eye discharge, or watering of the eye. Conjunctival retraction may require surgical treatment.. have an infection in or around your eye.. have active swelling around your eye that may include pain and redness.. are allergic to ranibizumab or any of the ingredients in SUSVIMO. See the end of this Medication Guide for complete list of ingredients in SUSVIMO.. are currently taking or have recently taken medicines that lower the chance of blood clots forming in the body such as warfarin, low or regular doses of aspirin, or nonsteroidal anti-inflammatory drugs (NSAID).. are pregnant or plan to become pregnant. It is not known if SUSVIMO will harm your unborn baby. You should use birth control during your treatment with SUSVIMO and for 12 months after your last dose of SUSVIMO. are breastfeeding or plan to breastfeed. It is not known if SUSVIMO passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive SUSVIMO.. SUSVIMO is implanted through the white part of the eye (sclera) by your healthcare provider. Your healthcare provider will refill your implant device every months (about every 24 weeks).. If you miss scheduled refill, call your healthcare provider as soon as possible to reschedule your refill. Your next refill should be given months after your last refill. Positioning of your headKeep your head above shoulder level for the rest of the day.Sleep with your head on or more pillows during the day and night after your implant insertion.. Keep your head above shoulder level for the rest of the day.. Sleep with your head on or more pillows during the day and night after your implant insertion.. How to care for your eyeDo not remove the eye shield from your eye until you are told to by your healthcare provider. At bedtime, continue to wear an eye shield for at least nights following the implant insertion.Take all post-operative eye medicines as your healthcare provider tells you to.Do not push on the eye, rub the eye, or touch the area of the eye where the implant is located (underneath the eyelid in the upper and outer part of your eye) for 30 days following the implant insertion.Do not participate in strenuous activities until month after the implant insertion or after talking to your healthcare provider.. Do not remove the eye shield from your eye until you are told to by your healthcare provider. At bedtime, continue to wear an eye shield for at least nights following the implant insertion.. Take all post-operative eye medicines as your healthcare provider tells you to.. Do not push on the eye, rub the eye, or touch the area of the eye where the implant is located (underneath the eyelid in the upper and outer part of your eye) for 30 days following the implant insertion.. Do not participate in strenuous activities until month after the implant insertion or after talking to your healthcare provider.. Magnetic Resonance Imaging (MRI) Implant CardGet your implant card from your healthcare provider after receiving the implant and keep the card in safe place for future reference. The implant card contains important information about your SUSVIMO implant.Show your current and future healthcare providers your implant card. This is important if you need to have an MRI. You may only receive an MRI under very specific conditions if you have the SUSVIMO implant. Your healthcare provider will review the information on the implant card and will let you know if you should receive an MRI. Get your implant card from your healthcare provider after receiving the implant and keep the card in safe place for future reference. The implant card contains important information about your SUSVIMO implant.. Show your current and future healthcare providers your implant card. This is important if you need to have an MRI. You may only receive an MRI under very specific conditions if you have the SUSVIMO implant. Your healthcare provider will review the information on the implant card and will let you know if you should receive an MRI. Do not push on the eye, rub the eye, or touch the area of the eye where the implant is located (underneath the eyelid in the upper and outer part of your eye) for days following the refill procedure.. Take eye drops exactly as your healthcare provider tells you to take them.. Keep your head above shoulder level for the rest of the day.. Sleep with your head on or more pillows if lying down during the day and night after implant removal.. Wear an eye shield for at least nights following the implant removal.. Do not participate in strenuous activities until 14 days following the implant removal.. Give all post-operative drops, as told by your healthcare provider.. Do not drive or use machinery until the eye shield can be removed and you can see.. Avoid rubbing your eye or touching the area of your eye where the implant is located as much as possible while the implant is in place. If you have to rub or touch your eye, wash your hands first.. Tear and separation of layers of the retina (Rhegmatogenous retinal detachment). Rhegmatogenous retinal detachment is tear and separation of one of the layers of the retina in the back of the eye that senses light. Call your healthcare provider or go to the emergency room right away if you see flashing lights, see curtain or veil covering part of your vision, have change in your vision, or loss of vision. Rhegmatogenous retinal detachment requires surgical treatment.. Implant movement (Implant dislocation): Tell your healthcare provider right away if you notice that the implant has moved out of place. This movement may require surgical treatment to correct.. Bleeding (Vitreous hemorrhage): Vitreous hemorrhage is bleeding within the gel-like substance (vitreous) inside of your eye. Call your healthcare provider right away if you have an increase in moving spots or what looks like spider webs in your vision as you may need an additional eye surgery.. Bump on top of the white layer of the eye (Conjunctival bleb): Conjunctival bleb is small bulge in the layer (conjunctiva) that covers the white part of the eye where the implant is inserted. This may be due to leakage of fluid from the inside of the eye. Call your healthcare provider right away if you have sudden feeling that something is in your eye (foreign body sensation), see bulge over the white part of your eye, if you have eye discharge, or watering in the eye. You may need medical or surgical treatment.. Temporary decrease in vision after the SUSVIMO procedure.. blood on the white of the eye. eye pain. redness in the white of the eye. sensitivity to light.

SPL UNCLASSIFIED SECTION.

2.1General 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 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 physician experienced in ophthalmic surgery [see Dosage and Administration (2.7)].Do not administer SUSVIMO (ranibizumab injection) as bolus intravitreal injection. Do not substitute SUSVIMO (ranibizumab injection) with other ranibizumab products.. Initial Fill: One SUSVIMO initial fill needle (34-gauge, with integrated um filter and blue cap) is included. 5-micron sterile filter needle (19-gauge 1 1/2 inch), and 1 mL Luer lock syringe are needed but not included.. Refill-Exchange: One SUSVIMO refill needle (34-gauge with integrated um filter and clear cap) is included. 5-micron sterile filter needle (19-gauge 1 1/2 inch), and 1 mL Luer lock syringe are needed but not included.

STORAGE AND HANDLING SECTION.

16.2 Storage. Store SUSVIMO initial fill needle kit at 2C to 8C (36F to 46F). Do not freeze. Protect from light. Do not shake. The SUSVIMO initial fill needle has been sterilized with electron beam processing.Store SUSVIMO (ranibizumab injection) 100 mg/ mL vial at 2C to 8C (36F to 46F). Do not freeze. Protect from light. Do not shake. Prior to use, the unopened vial may be kept at 9C to 30C (48F to 86F) for up to 24 hours provided it is protected from light.Store the SUSVIMO implant and insertion tool assembly, refill needle and explant tool at room temperature 15C to 25C (59F to 77F). The SUSVIMO implant and insertion tool assembly has been sterilized with ethylene oxide gas. The SUSVIMO refill needle and explant tool have been sterilized with electron beam processing.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere 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 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 single eye treatment at the recommended clinical dose [see Animal 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 pregnant woman. Based on the anti-VEGF mechanism of action for ranibizumab [see Clinical Pharmacology (12.1)], treatment with SUSVIMO (ranibizumab injection) may pose risk to human embryofetal development.All pregnancies have 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 DataAn 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 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 low incidence in fetuses from animals treated with mg/eye of ranibizumab. The mg/eye dose resulted in trough serum ranibizumab levels up to 41 times higher than observed human Cmax levels of SUSVIMO (ranibizumab injection) after treatment of single eye.No skeletal abnormalities were seen at the lower dose of 0.125 mg/eye, 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.. 8.2 Lactation. Risk SummaryThere 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 nursing woman.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for SUSVIMO (ranibizumab injection) and any potential adverse effects on the breastfed child from ranibizumab.. 8.3 Females and Males of Reproductive Potential. ContraceptionFemales 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).. InfertilityNo 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 risk to reproductive capacity.. 8.4 Pediatric Use. The safety and efficacy of SUSVIMO (ranibizumab injection) in pediatric patients have not been established.. 8.5 Geriatric Use. 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. The SUSVIMO implant and/or implant-related procedures have been associated with endophthalmitis, rhegmatogenous retinal detachment, implant dislocation, 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, 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)Vitreous Hemorrhage: Temporarily discontinue antithrombotic medication prior to the implant insertion procedure to reduce the risk of vitreous hemorrhage. Vitrectomy may be needed. (5.4)Postoperative Decrease in Visual Acuity: decrease in visual acuity usually occurs over the first two postoperative months. (5.7). The SUSVIMO implant and/or implant-related procedures have been associated with endophthalmitis, rhegmatogenous retinal detachment, implant dislocation, 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). Vitreous Hemorrhage: Temporarily discontinue antithrombotic medication prior to the implant insertion procedure to reduce the risk of vitreous hemorrhage. Vitrectomy may be needed. (5.4). Postoperative Decrease in Visual Acuity: decrease in visual acuity usually occurs over the first two postoperative months. (5.7). 5.1Endophthalmitis. In the active comparator period of controlled clinical trials, the ranibizumab implant has been associated with 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, 2.0% (11/555) of patients receiving the ranibizumab implant experienced an episode of endophthalmitis. Reports occurred between days and 853, with median of 173 days. Many, but not all, of the cases of endophthalmitis reported preceding or concurrent conjunctival retraction or erosion event.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 (2.9) 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 Tenons capsule, and early detection and surgical repair of conjunctival erosions or retractions may reduce the risk of endophthalmitis [see Warnings and Precautions (5.5)].. 5.2Rhegmatogenous 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 retinal detachment or retinal break [see Dosage and Administration (2.9].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.. 5.3Implant 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.. 5.4Vitreous Hemorrhage. Vitreous hemorrhages may result in temporary vision loss. Vitrectomy may be needed in the case of non-clearing vitreous hemorrhage [see Dosage and Administration (2.9].In clinical trials of SUSVIMO including extension phases, vitreous hemorrhages were reported in 5.2% (23/443) 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.. 5.5Conjunctival Erosion or Retraction. conjunctival erosion is full thickness degradation or breakdown of the conjunctiva in the area of the implant flange. conjunctival retraction is 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/Tenons 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 extension phases, 3.6% (16/443) of patients receiving SUSVIMO reported conjunctival erosion and 1.6% (7/443) of patients receiving SUSVIMO reported conjunctival retraction in the study eye.Appropriate intraoperative handling of conjunctiva and Tenons capsule to preserve tissue integrity and secure closure of peritomy while ensuring placement of sutures away from implant edge may reduce the risk of conjunctival erosion or retraction. The implant and the tissue overlying the implant flange should be monitored routinely following the implant insertion.. 5.6Conjunctival Bleb. conjunctival bleb is an encapsulated elevation of the conjunctiva above the implant flange, which may be secondary to subconjunctival thickening or fluid. Conjunctival blebs may require surgical management to avoid further complications, especially if the implant septum is no longer identifiable due to the conjunctival bleb.In clinical trials of SUSVIMO including extension phases, 5.9% (26/443) of patients receiving SUSVIMO reported conjunctival bleb/conjunctival filtering bleb leak in the study eye. Strict adherence to the scleral incision length, appropriate intraoperative handling of conjunctiva and Tenons capsule to preserve tissue integrity and secure closure of peritomy, and proper seating of the refill needle during refill-exchange procedures may reduce the risk of conjunctival bleb.. 5.7Postoperative Decrease in Visual Acuity. Visual acuity was decreased by letters on average in the first postoperative month and letters on average in the second postoperative month following initial implantation of SUSVIMO [see Clinical studies (14)].. 5.8Air Bubbles Causing Improper Filling of the Implant Minimize air bubbles within the implant reservoir as they may cause slower drug release. During the initial fill procedure, 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 after initial fill, do not use the implant. During the refill-exchange procedure, if excess air is present in the syringe and needle do not use the syringe and needle. If excess air bubbles are observed after the refill-exchange procedure, consider repeating the refill-exchange procedure.. 5.9Deflection of the Implant. Use caution when performing ophthalmic procedures that may cause deflection of the implant and subsequent injury. For example, B-scan ophthalmic ultrasound, scleral depression, or gonioscopy.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.4, 2.7)4/2022Warnings and Precautions (5.4)4/2022.