RANIBIZUMAB: 15,284 Adverse Event Reports & Safety Profile

Ranibizumab is a 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 a molecular weight of approximately 48 kilodaltons and is produced by an E. coli expression system in a nutrient medium containing the antibiotic tetracycline. Tetracycline is not detectable in the final product. SUSVIMO (ranibizumab injection) is supplied as a sterile, clear to slightly opalescent, colorless to slightly brownish 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 a 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.

AND USAGE SUSVIMO (ranibizumab injection) is a vascular endothelial growth factor (VEGF) inhibitor indicated for the treatment of patients with: Neovascular (wet) Age-related Macular Degeneration (AMD) who have previously responded to at least two intravitreal injections of a VEGF inhibitor ( 1.1 ).

Diabetic Macular

Edema (DME) who have previously responded to at least two intravitreal injections of a VEGF inhibitor ( 1.2 ).

Diabetic

Retinopathy (DR) who have previously responded to at least two intravitreal injections of a VEGF inhibitor ( 1.3 ).

1.1 Neovascular (wet) Age-related Macular Degeneration (AMD) SUSVIMO (ranibizumab injection) is indicated for the treatment of patients with Neovascular (wet) Age-related Macular Degeneration (AMD) who have previously responded to at least two intravitreal injections of a Vascular Endothelial Growth Factor (VEGF) inhibitor medication.

1.2 Diabetic Macular Edema (DME) SUSVIMO (ranibizumab injection) is indicated for the treatment of patients with Diabetic Macular Edema (DME) who have previously responded to at least two intravitreal injections of a Vascular Endothelial Growth Factor (VEGF) inhibitor medication.

1.3 Diabetic Retinopathy (DR) SUSVIMO (ranibizumab injection) is indicated for the treatment of patients with Diabetic Retinopathy (DR) who have previously responded to at least two intravitreal injections of a Vascular Endothelial Growth Factor (VEGF) inhibitor medication.

AND ADMINISTRATION For intravitreal use via SUSVIMO ocular implant. ( 2.1 ) Neovascular (wet) Age-related Macular Degeneration (AMD) and Diabetic Macular Edema (DME) The recommended dose of SUSVIMO (ranibizumab injection) is 2 mg (0.02 mL of 100 mg/mL solution) continuously delivered via the SUSVIMO implant with refills every 24 weeks (approximately 6 months). ( 2.2 )

Diabetic

Retinopathy (DR) The recommended dose of SUSVIMO (ranibizumab injection) is 2 mg (0.02 mL of 100 mg/mL solution) continuously delivered via the SUSVIMO implant with refills every 36 weeks (approximately 9 months). ( 2.3 ) Supplemental treatment with 0.5 mg intravitreal ranibizumab injection may be administered in the affected eye if clinically necessary. ( 2.4 ) Perform the initial implantation, refill-exchange, and implant removal (if necessary) procedures under strict aseptic conditions. ( 2.5 , 2.6 , 2.7 , 2.8 )

2.1 General Information For Intravitreal Use via SUSVIMO ocular implant. The SUSVIMO initial fill and ocular implant insertion and implant removal procedures must be performed under aseptic conditions by a physician experienced in vitreoretinal surgery. The SUSVIMO ocular implant must be surgically implanted in the eye or removed from the eye (if medically necessary) in an operating room using aseptic technique. See SUSVIMO Instructions for Use and the standardized steps to optimize surgical outcomes. SUSVIMO refill-exchange procedures must be performed under aseptic conditions by a physician experienced in ophthalmic surgery <span class="opacity-50 text-xs">[see Dosage and Administration (2.7) ]</span> . Do not administer SUSVIMO (ranibizumab injection) as a bolus intravitreal injection. Do not substitute SUSVIMO (ranibizumab injection) with other ranibizumab products.

Initial

Fill : One SUSVIMO initial fill needle (34-gauge, with integrated 5 μm filter and blue cap) is included. A 5-micron sterile filter needle (19-gauge × 1½ inch), and a 1 mL Luer lock syringe are needed but not included . Refill-Exchange : One SUSVIMO refill needle (34-gauge with integrated 5 μm filter and clear cap) is included. A 5-micron sterile filter needle (19-gauge × 1½ inch), and a 1 mL Luer lock syringe are needed but not included .

2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD) and Diabetic Macular Edema (DME) The recommended dose of SUSVIMO (ranibizumab injection) is 2 mg (0.02 mL of 100 mg/mL solution) continuously delivered via the SUSVIMO ocular implant with refills administered every 24 weeks (approximately 6 months).

2.3 Diabetic Retinopathy (DR) The recommended dose of SUSVIMO (ranibizumab injection) is 2 mg (0.02 mL of 100 mg/mL solution) continuously delivered via the SUSVIMO ocular implant with refills administered every 36 weeks (approximately 9 months).

2.4 Supplemental Treatment with Intravitreal Ranibizumab Injection Supplemental treatment with 0.5 mg (0.05 mL of 10 mg/mL) intravitreal ranibizumab injection may be administered in the affected eye while the SUSVIMO implant is in place and if clinically necessary <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> .

2.5 Ocular Implant Initial Fill The implant initial fill procedure must be performed by a physician experienced in vitreoretinal surgery [ see Dosage and Administration (2.1) ]. The implant will be filled using aseptic technique with 0.02 mL of SUSVIMO (ranibizumab injection) prior to insertion of the implant into the patient&apos;s eye <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) ]</span>. Refer to the complete SUSVIMO Instructions for Use for the initial fill and implant procedure included in the insertion tool assembly carton for further details. Use aseptic technique to carry out the following preparation steps prior to insertion of the ocular implant into the patient&apos;s eye: Step 1: Gather the supplies needed. One SUSVIMO ocular implant with insertion tool assembly (included) One SUSVIMO initial fill needle (34-gauge with integrated 5 μm filter) with blue cap (included) One SUSVIMO (ranibizumab injection) 100 mg/mL vial (included) One sterile 5-micron filter needle (19-gauge × 1½ inch) (not included) One sterile 1 mL Luer Lock syringe (not included)

Step

2: Transfer Dose from Vial to Syringe Note: Use the filter needle (not included) to withdraw SUSVIMO (ranibizumab injection) from the vial.

Figure

1 Do not use the SUSVIMO initial fill needle for this step. Prepare SUSVIMO (ranibizumab injection) vial by removing the flip-off cap and disinfecting the rubber vial septum with alcohol. Attach a filter needle to the syringe by screwing it tightly onto the Luer lock (see Figure 1 ). Carefully remove the needle cap by pulling it straight off. Using aseptic technique, withdraw all of the contents of the SUSVIMO (ranibizumab injection) vial through the filter needle into the syringe.

Step

3: Remove Air from Syringe With the filter needle attached, hold the syringe with the needle pointing up. If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top (Figure 2). Slowly push the plunger rod just until all air is expelled from the syringe and needle. – It is important to preserve as much drug as possible in order to completely fill the implant. Remove and properly dispose of the filter needle after air is removed from syringe. Figure2 Step 4: Attach SUSVIMO Initial Fill Needle Do not use the filter needle to fill the implant. Attach the SUSVIMO initial fill needle (included) firmly onto the syringe by screwing it tightly onto the Luer lock (see Figure 3 ). Ensure that the initial fill needle is attached to the syringe. Carefully remove the needle cap by pulling straight off. Do not wipe the needle at any time.

Figure

3 Step 5: Remove Any Remaining Air from Syringe With the initial fill needle attached, hold the syringe with the needle pointing up. If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top (see Figure 4 ). Slowly push the plunger rod just until all air is expelled from the syringe and needle, and a drop of drug solution is seen at the needle tip (see Figure 5 ).

Figure

4 Figure 5 Note: It is important to preserve as much drug as possible in order to completely fill the implant.

Step

6: Inspect the Syringe for Air Bubbles Inspect the syringe and the needle hub to ensure that no air bubbles are present (see Figure 6 ). If air bubbles are present, continue to remove air from the syringe and reinspect.

Figure

6 Note: Use the syringe within 15 minutes of removing all air to avoid ranibizumab drying in the needle and impeding fluid flow. Do not use the initial fill needle if the needle is clogged.

Step

7: Load Syringe into the Carrier Do not hold or push on the plunger rod of the syringe while inserting the needle into the implant septum. Retrieve insertion tool carrier with pre-positioned implant from the inner tray. Align the syringe Luer lock above the Luer lock slot in the carrier to protect the needle from being damaged. Lower the syringe into the carrier (see Figure 7 ). Push the syringe forward until it stops, taking care to avoid touching the plunger rod (see Figure 8 ) With the syringe loaded, (see Figure 9 ) the initial fill needle should now be penetrating the implant septum.

Figure

7: Align and lower the syringe into the carrier Figure 8: Push the syringe into the carrier Figure 9: Syringe with initial fill needle inserted through the implant septum Step 8: Fill Ocular Implant with SUSVIMO (ranibizumab injection)

Under Microscope

Under the microscope, slowly administer SUSVIMO (ranibizumab injection) into the ocular implant by slightly tilting the carrier upwards (see Figure 10 ). The ocular implant should be filled over approximately 5 to 10 seconds , to help avoid air entrapment in the implant reservoir.

Figure

10: Administer ranibizumab into the implant Figure 11: Dome of drug solution forms at tip of implant as viewed under magnification Note: When filling the ocular implant, drug solution should only exit the ocular implant from the release control element. If drug solution is leaking from the implant at a 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 a dome of drug solution formed at the tip of the implant on the release control element (see Figure 11 ).

Step

9: Inspect the Filled Ocular Implant Under the Microscope Inspect the ocular implant under the microscope to ensure that the ocular implant is completely full of drug solution (see Figure 12 ).

Figure

12: Proper appearance of implant after initial filling with ranibizumab Note: Minimize air bubbles within the implant reservoir as they may cause slower drug release. If an air bubble is present, it must be no larger than 1/3 of the widest diameter of the implant. If excess air is observed, do not use the ocular implant. Note: No more than 30 minutes should pass between the initial fill of the implant and the insertion into the patient's 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

10: Remove the Syringe and Guide Sleeve from the Carrier Remove the syringe and guide sleeve from the carrier by pulling back on the syringe (see Figure 13 ). The syringe will be locked into the guide sleeve. Properly dispose of the used syringe together with the needle and guide sleeve in a sharps disposal container or in accordance with local requirements.

Figure

13: Remove the syringe and guide sleeve from the insertion tool carrier Step 11: Slide the Insertion Tool Handle into the Carrier Slide the insertion tool handle into the guide channel of the carrier, ensuring that both components are facing upwards (see Figure 14 ). Push the handle forward as far as it will go into the gripper tips (see Figure 15 ).

Figure

14: Insert the handle into the insertion tool carrier Figure 15: Fully inserted handle Note: 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 a foreign body into the vitreous.

Figure

1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15

2.6 Ocular Implant Insertion SUSVIMO ocular implant insertion is a surgical procedure that is performed in an operating room. The procedure must be performed under aseptic conditions by a physician experienced in vitreoretinal surgery <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> . The ocular implant is filled with SUSVIMO (ranibizumab injection) immediately prior to insertion. No more than 30 minutes should pass between the initial fill of the ocular implant and the insertion into the patient&apos;s eye. After placing an infusion line in the eye, create at least a 6×6 mm peritomy of the conjunctiva and Tenon&apos;s capsule centered around the selected SUSVIMO implant location in the supero-temporal quadrant. Perform careful conjunctival incision, hemostasis of the underlying sclera, and generous undermining of Tenon&apos;s capsule. Using aseptic technique, fill the ocular implant <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span> . Using an MVR blade, create a full thickness dissection of the sclera 4 mm from the limbus until the pars plana is fully visible, with final target scleral incision length of 3.5 mm. Using a 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 a 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 a vitrector. Suture both Tenon&apos;s 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.

2.7 Ocular Implant Removal Removal of the SUSVIMO ocular implant is a surgical procedure that is performed in an operating room. The procedure must be performed under aseptic conditions by a physician experienced in vitreoretinal surgery <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> . After placing an infusion line in the eye, create at least a 6×6 mm peritomy of the conjunctiva and Tenon&apos;s capsule around the SUSVIMO ocular implant flange. Remove any fibrous capsule or scar tissue that may have formed over the implant flange and septum using scalpel and forceps. With the explant tool oriented perpendicular to the globe, align the contoured tips with the long axis of the implant flange and grasp underneath the implant flange. Once the implant is secured in the explant tool, pull the implant from the eye in a perpendicular motion. Clear any vitreous prolapse present within or around the scleral wound using a vitrector. Completely close the scleral incision with multiple non-absorbable sutures. Close the Tenon&apos;s 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.

2.8 Ocular Implant Refill-Exchange Procedure The SUSVIMO ocular implant refill-exchange procedure must be performed under strict aseptic conditions by a physician experienced in ophthalmic surgery <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> . This includes the use of a surgical mask, sterile gloves, and a lid speculum. Prior to and after the refill-exchange procedure, perform a dilated slit lamp exam and/or dilated indirect ophthalmoscopy to inspect the implant in the vitreous cavity through the pupil to identify if dislodgement of the implant septum has occurred [ see Figure 33 and Warnings and Precautions (5.4) ]. If the septum has dislodged, any further refill-exchange procedures should not be performed because normal device functioning cannot be assured. Discontinue treatment with SUSVIMO (ranibizumab injection) following septum dislodgement and consider implant removal should the benefit of the removal procedure outweigh the risk.

Step

1: Gather the supplies needed. One SUSVIMO Refill Needle (34-gauge with a 5 µm integrated filter) with clear cap (included) One SUSVIMO (ranibizumab injection) 100 mg/mL vial (included) One sterile 1 mL Luer Lock syringe (not included) One sterile 5-micron filter needle (19-gauge × 1½ inch) (not included) Additional materials required to perform the procedure but are not provided are: Anesthetic ophthalmic solutions Ophthalmic broad-spectrum microbicide solution Cotton tips and gauze Sterile powder free gloves Face masks Lid speculum Magnification such as visor or loupes Task lighting Indirect ophthalmoscope and lens Sterile drape (optional for refill-exchange procedure)

Step

2: Inspect Packaging and Components Prior to use in the clinic, inspect the packaging of the components for damage. Do not 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 16 ).

Figure

16 Step 3: Inspect SUSVIMO (ranibizumab injection) Visually inspect the contents of the SUSVIMO (ranibizumab injection) vial for particulate matter and discoloration. SUSVIMO should be colorless to slightly brownish Do not use if particulate, cloudiness, or discoloration are visible.

Step

4: Patient Preparation Dilate the pupil of the eye. Perform slit lamp examination and/or indirect ophthalmoscopy to inspect the implant and its components in the vitreous cavity through the dilated pupil. Position the patient on exam chair in the supine position at approximately 20° to 30° angle for optimal visualization of the implant. Apply a broad-spectrum microbicide to the periocular skin, eyelid, and ocular surface prior to the refill-exchange procedure. The use of a sterile drape is up to the physician's discretion. Perform the procedure under topical anesthesia. If needed, subconjunctival anesthesia may be administered in the nasal quadrant, away from the implant.

Step

5: Transfer Dose from Vial to Syringe Figure 17 Note: Use the filter needle to withdraw SUSVIMO (ranibizumab injection) from the vial. Do not 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 a filter needle to the syringe by screwing it tightly onto the Luer lock (see Figure 17 ). Carefully remove the needle cap by pulling it straight off. Using aseptic technique, withdraw all of the contents of the SUSVIMO (ranibizumab injection) vial through the filter needle into the syringe.

Step

6: Remove Air from Syringe With the filter needle attached, hold the syringe with the needle pointing up. If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top (Figure 18). Slowly push the plunger rod just until the air is expelled from the syringe and needle. – It is important to preserve as much drug as possible in order to completely refill the implant Remove and properly dispose of the filter needle after air is removed from the syringe.

Figure

18 Step 7: Attach SUSVIMO Refill Needle Do not 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 19 ). 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

19 Step 8: Remove Any Remaining Air from Syringe and Adjust Drug Dose With the refill needle attached, hold the syringe with the needle pointing up. If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top (see Figure 20 ). Slowly push the plunger rod until all air is expelled from the syringe and needle and the uppermost edge of the black plunger tip is aligned with the 0.1 mL dose mark (see Figure 21 ).

Figure

20 Figure 21 Step 9: Inspect the Syringe for Air Bubbles Figure 22 Note: Ensure no air bubbles are present in the syringe and needle hub. Air injected into the implant could result in slower drug release. Inspect the syringe and the needle hub using magnification to ensure that no air bubbles are present (see Figure 22 ). Note: Use the syringe within 15 minutes 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

10: Stabilize the globe and orient the refill needle Figure 23 Figure 24 Note: 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 a cotton-tipped applicator to minimize eye movement (see Figure 23 ). – 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 24 ).

Step

11: Insert the Refill Needle Figure 25 Figure 26 Note: Insert needle at the very center of the implant septum and perpendicular to the implant to ensure the needle inserts fully. Do not maneuver if there is resistance as it will bend the needle. Do not use a 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 25 ). – If excessive resistance, withdraw the refill needle. Orient and insert again. – Do not twist when encountering conjunctiva and Tenon's 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 26 ) to provide a tactile cue that optimal contact has been made.

Step

12: Refill the SUSVIMO Implant Refill the implant slowly , by delivering the entire contents of the syringe into the implant, over approximately 5 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 27 ). If fluid is not observed collecting in the refill needle fluid collection reservoir, stop injecting and ensure the refill needle is inserted into the center of the implant septum at a perpendicular angle and the soft stop is in contact with the conjunctiva. Administer all of the syringe contents in order to achieve the target replacement ranibizumab concentration in the implant reservoir.

Figure

27 Step 13: Withdraw the Syringe Withdraw the syringe perpendicular to the globe to avoid damaging the septum (see Figure 28 ). A cotton-tipped applicator may be used to provide counter traction to the conjunctiva during needle withdrawal.

Figure

28 Step 14: Dispose of the Used Components Do not recap the needle or detach it from the syringe. Dispose of the used syringe together with the refill needle in a sharps disposal container or in accordance with local requirements.

Step

15: Perform Indirect Ophthalmoscopy Perform dilated indirect ophthalmoscopy (and slit lamp exam as needed) to ensure continued proper position of the implant and its components (e.g., septum) in the vitreous cavity and to examine for complications.

Figure

16 Figure 17 Figure 18 Figure 19 Figure 20 Figure 21 Figure 22 Figure 23 Figure 24 Figure 25 Figure 26 Figure 27 Figure 28

2.9 Delayed or Missed Doses For patients with AMD or DME, if a planned dose (refill-exchange) of SUSVIMO (ranibizumab injection) is missed, it should be administered as soon as possible and the subsequent refill-exchange procedures should be performed 24 weeks (approximately 6 months) thereafter. For patients with DR, if a planned dose (refill-exchange) of SUSVIMO (ranibizumab injection) is missed, it should be administered as soon as possible and the subsequent refill-exchange procedures should be performed 36 weeks (approximately 9 months) thereafter.

2.10 Dosage (Refill-Exchange) Modifications for Adverse Reactions Table 1 describes dosage modifications for specific adverse Reactions <span class="opacity-50 text-xs">[see Warnings and Precautions (5) ]</span> . No dosage reductions for SUSVIMO are recommended.

Table

1: Dosage (Refill-Exchange) Modifications for Adverse Reactions Adverse Reactions Dosage Modification Intraocular inflammation ≥ 1 + cells or flare Withhold dose (refill-exchange) Sight threatening events (e.g., rhegmatogenous retinal detachment, vitreous hemorrhage, unexplained vision loss, etc.) Withhold dose (refill-exchange) Local infections of either eye Withhold dose (refill-exchange) Infectious endophthalmitis Withhold dose (refill-exchange) Severe systemic infection Withhold dose (refill-exchange) Observed damage to the implant Withhold dose (refill-exchange) and consider SUSVIMO implant removal [see Dosage and Administration (2.8 , 2.9) ] .

Ocular or periocular infections ( 4.1 ) Active intraocular inflammation ( 4.2 ) Hypersensitivity ( 4.3 )

4.1 Ocular or Periocular Infections SUSVIMO (ranibizumab injection) is contraindicated in patients with ocular or periocular infections.

4.2 Active Intraocular Inflammation SUSVIMO (ranibizumab injection) is contraindicated in patients with active intraocular inflammation.

4.3 Hypersensitivity SUSVIMO (ranibizumab injection) is contraindicated in patients with known hypersensitivity to ranibizumab products or any of the excipients in SUSVIMO (ranibizumab injection).

REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label:

• Endophthalmitis and Retinal Detachments [see Warnings and Precautions ( 5.1 )]
• Increases in Intraocular Pressure [see Warnings and Precautions ( 5.2 )]
• Thromboembolic Events [see Warnings and Precautions ( 5.3 )]
• Fatal Events in patients with DME and DR at baseline [see Warnings and Precautions ( 5.4 )] The most common adverse reactions (reported more frequently in ranibizumab-treated subjects than control subjects) are conjunctival hemorrhage, eye pain, vitreous floaters, and increased IOP ( 6.2 ). To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Injection Procedure Serious adverse reactions related to the injection procedure have occurred in &lt; 0.1% of intravitreal injections, including endophthalmitis <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> , rhegmatogenous retinal detachment, and iatrogenic traumatic cataract.

6.2 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to 0.5 mg ranibizumab in 440 patients with neovascular AMD in Studies AMD-1, AMD-2, and AMD-3; in 259 patients with macular edema following RVO. The data also reflect exposure to 0.3 mg ranibizumab in 250 patients with DME and DR at baseline <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . Safety data observed in 224 patients with mCNV, as well as Studies AMD-4 and D-3, were consistent with these results. On average, the rates and types of adverse reactions in patients were not significantly affected by dosing regimen.

Ocular Reactions Table

1 shows frequently reported ocular adverse reactions in ranibizumab-treated patients compared with the control group.

Table

1 Ocular Reactions in the DME and DR, AMD, and RVO Studies Adverse Reaction DME and DR 2-year AMD 2-year AMD 1-year RVO 6-month Ranibizumab 0.3 mg Control Ranibizumab 0.5 mg Control Ranibizumab 0.5 mg Control Ranibizumab 0.5 mg Control n=250 n=250 n=379 n=379 n=440 n=441 n=259 n=260 Conjunctival hemorrhage 47% 32% 74% 60% 64% 50% 48% 37% Eye pain 17% 13% 35% 30% 26% 20% 17% 12% Vitreous floaters 10% 4% 27% 8% 19% 5% 7% 2% Intraocular pressure increased 18% 7% 24% 7% 17% 5% 7% 2% Vitreous detachment 11% 15% 21% 19% 15% 15% 4% 2% Intraocular inflammation 4% 3% 18% 8% 13% 7% 1% 3% Cataract 28% 32% 17% 14% 11% 9% 2% 2% Foreign body sensation in eyes 10% 5% 16% 14% 13% 10% 7% 5% Eye irritation 8% 5% 15% 15% 13% 12% 7% 6% Lacrimation increased 5% 4% 14% 12% 8% 8% 2% 3% Blepharitis 3% 2% 12% 8% 8% 5% 0% 1% Dry eye 5% 3% 12% 7% 7% 7% 3% 3% Visual disturbance or vision blurred 8% 4% 18% 15% 13% 10% 5% 3% Eye pruritis 4% 4% 12% 11% 9% 7% 1% 2% Ocular hyperemia 9% 9% 11% 8% 7% 4% 5% 3% Retinal disorder 2% 2% 10% 7% 8% 4% 2% 1% Maculopathy 5% 7% 9% 9% 6% 6% 11% 7% Retinal degeneration 1% 0% 8% 6% 5% 3% 1% 0% Ocular discomfort 2% 1% 7% 4% 5% 2% 2% 2% Conjunctival hyperemia 1% 2% 7% 6% 5% 4% 0% 0% Posterior capsule opacification 4% 3% 7% 4% 2% 2% 0% 1% Injection site hemorrhage 1% 0% 5% 2% 3% 1% 0% 0% Non-Ocular Reactions Non-ocular adverse reactions with an incidence of ≥ 5% in patients receiving ranibizumab for DR, DME, AMD, and/or RVO and which occurred at a ≥ 1% higher frequency in patients treated with ranibizumab compared to control are shown in Table 2. Though less common, wound healing complications were also observed in some studies.

Table

2 Non-Ocular Reactions in the DME and DR, AMD, and RVO Studies Adverse Reaction DME and DR 2-year AMD 2-year AMD 1-year RVO 6-month Ranibizumab 0.3 mg Control Ranibizumab 0.5 mg Control Ranibizumab 0.5 mg Control Ranibizumab 0.5 mg Control n=250 n=250 n=379 n=379 n=440 n=441 n=259 n=260 Nasopharyngitis 12% 6% 16% 13% 8% 9% 5% 4% Anemia 11% 10% 8% 7% 4% 3% 1% 1% Nausea 10% 9% 9% 6% 5% 5% 1% 2% Cough 9% 4% 9% 8% 5% 4% 1% 2% Constipation 8% 4% 5% 7% 3% 4% 0% 1% Seasonal allergy 8% 4% 4% 4% 2% 2% 0% 2% Hypercholesterolemia 7% 5% 5% 5% 3% 2% 1% 1% Influenza 7% 3% 7% 5% 3% 2% 3% 2% Renal failure 7% 6% 1% 1% 0% 0% 0% 0% Upper respiratory tract infection 7% 7% 9% 8% 5% 5% 2% 2% Gastroesophageal reflux disease 6% 4% 4% 6% 3% 4% 1% 0% Headache 6% 8% 12% 9% 6% 5% 3% 3% Edema peripheral 6% 4% 3% 5% 2% 3% 0% 1% Renal failure chronic 6% 2% 0% 1% 0% 0% 0% 0% Neuropathy peripheral 5% 3% 1% 1% 1% 0% 0% 0% Sinusitis 5% 8% 8% 7% 5% 5% 3% 2% Bronchitis 4% 4% 11% 9% 6% 5% 0% 2% Atrial fibrillation 3% 3% 5% 4% 2% 2% 1% 0% Arthralgia 3% 3% 11% 9% 5% 5% 2% 1% Chronic obstructive pulmonary disease 1% 1% 6% 3% 3% 1% 0% 0% Wound healing complications 1% 0% 1% 1% 1% 0% 0% 0%

6.3 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ranibizumab or of other ranibizumab products. The pre-treatment incidence of immunoreactivity to ranibizumab was 0%-5% across treatment groups. After monthly dosing with ranibizumab for 6 to 24 months, antibodies to ranibizumab were detected in approximately 1%-9% of patients. The clinical significance of immunoreactivity to ranibizumab products is unclear at this time. Among neovascular AMD patients with the highest levels of immunoreactivity, some were noted to have iritis or vitritis. Intraocular inflammation was not observed in patients with DME and DR at baseline, or RVO patients with the highest levels of immunoreactivity.

6.4 Postmarketing Experience The following adverse reaction has been identified during post-approval use of ranibizumab products. Because this reaction was reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

• Ocular: Tear of retinal pigment epithelium among patients with neovascular AMD

AND PRECAUTIONS The SUSVIMO implant and/or implant-related procedures have been associated with endophthalmitis, rhegmatogenous retinal detachment, implant dislocation, septum dislodgement, vitreous hemorrhage, conjunctival erosion, conjunctival retraction, and conjunctival blebs. Patients should be instructed to report any signs or symptoms that could be associated with these events without delay. In some cases, these events can present asymptomatically. The implant and the tissue overlying the implant flange should be monitored routinely following the implant insertion, and refill-exchange procedures to permit early medical or surgical intervention as necessary. Special precautions need to be taken when handling SUSVIMO components [see How Supplied/Storage and Handling (16.3) ]. The SUSVIMO implant and/or implant-related procedures have been associated with endophthalmitis, rhegmatogenous retinal detachment, implant dislocation, septum dislodgement, vitreous hemorrhage, conjunctival retraction, conjunctival erosion, and conjunctival bleb. Patients should be instructed to report signs or symptoms that could be associated with these events without delay. Additional surgical and/or medical management may be required. ( 5.1 , 5.2 , 5.3 , 5.4 , 5.5 , 5.6 , 5.7 )

Vitreous

Hemorrhage : Temporarily discontinue antithrombotic medication prior to the implant insertion procedure to reduce the risk of vitreous hemorrhage. Vitrectomy may be needed. ( 5.5 )

Postoperative

Decrease in Visual Acuity : A decrease in visual acuity usually occurs over the first two postoperative months. ( 5.8 )

5.1 Endophthalmitis In the active comparator period of controlled clinical trials in AMD, the ranibizumab implant has been associated with a 3-fold higher rate of endophthalmitis than monthly intravitreal injections of ranibizumab (1.7% in the SUSVIMO arm vs 0.5% in the intravitreal arm). When including extension phases of clinical trials, 2% (11/555) of patients receiving the ranibizumab implant experienced an episode of endophthalmitis. Reports occurred between days 5 and 853, with a median of 173 days. Many, but not all, of the cases of endophthalmitis reported a preceding or concurrent conjunctival retraction or erosion event. In the active comparator period of the controlled clinical trial in DME, 0% of patients in the SUSVIMO arm compared to 0.3% in the intravitreal arm experienced an episode of endophthalmitis. When including the extension phase of the clinical trial, 0.7% (4/556) of patients receiving the ranibizumab implant experienced an episode of endophthalmitis. Reports occurred between days 625 and 1016, with a median of 824 days. In the period with an observational comparator arm of the clinical trial in DR, there were no patients (0/105) in the SUSVIMO arm who experienced an episode of endophthalmitis <span class="opacity-50 text-xs">[see Clinical Studies (14.3) ]</span> . When including the extension phase of the clinical trial 0.8% (1/128) patients receiving the ranibizumab implant experienced an episode of endophthalmitis, with the event reported on day 695. Endophthalmitis should be treated promptly in an effort to reduce the risk of vision loss and maximize recovery. The SUSVIMO (ranibizumab injection) dose (refill-exchange) should be delayed until resolution of endophthalmitis <span class="opacity-50 text-xs">[see Dosage and Administration (2.10) and Adverse Reactions (6.1) ]</span> . Patients should not have an active or suspected ocular or periocular infection or severe systemic infection at the time of any SUSVIMO implant or refill procedure. Appropriate intraoperative handling followed by secure closure of the conjunctiva and Tenon&apos;s capsule, and early detection and surgical repair of conjunctival erosions or retractions and strict/controlled aseptic technique conditions throughout refill-exchange procedures may reduce the risk of endophthalmitis <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) and Warnings and Precautions (5.5) ]</span> .

5.2 Rhegmatogenous Retinal Detachment Rhegmatogenous retinal detachments have occurred in clinical trials of SUSVIMO and may result in vision loss. Rhegmatogenous retinal detachments should be promptly treated with an intervention (e.g., pneumatic retinopexy, vitrectomy, or laser photocoagulation). SUSVIMO (ranibizumab injection) dose (refill-exchange) should be delayed in the presence of a retinal detachment or retinal break <span class="opacity-50 text-xs">[see Dosage and Administration (2.10) ]</span> . Careful evaluation of the retinal periphery is recommended to be performed, and any suspected areas of abnormal vitreo-retinal adhesion or retinal breaks should be treated before inserting the implant in the eye.

5.3 Implant Dislocation In clinical trials, the device has dislocated/subluxated into the vitreous cavity or has extended outside the vitreous cavity into or beyond the subconjunctival space. Device dislocation requires urgent surgical intervention. Strict adherence to the scleral incision length and appropriate targeting of the pars plana during laser ablation may reduce the risk of implant dislocation.

5.4 Septum Dislodgement In clinical trials, a type of implant damage where the septum has dislodged into the implant body has been reported. Perform a dilated slit lamp exam and/or dilated indirect ophthalmoscopy to inspect the implant in the vitreous cavity through the pupil prior to and after the refill-exchange procedure to identify if septum dislodgement has occurred. Discontinue treatment with SUSVIMO (ranibizumab injection) following septum dislodgement and consider implant removal should the benefit of the removal procedure outweigh the risk [ see Dosage and Administration (2.9) ]. The benefits and risks of retaining, removing, or removing and replacing an implant with a dislodged septum are not well characterized. Appropriate handling and insertion of the refill needle into the septum (avoid twisting and/or rotation) is required to minimize the risk of septum dislodgement [ see Dosage and Administration (2.8) ].

5.5 Vitreous Hemorrhage Vitreous hemorrhages may result in temporary vision loss. Vitrectomy may be needed in the case of a non-clearing vitreous hemorrhage <span class="opacity-50 text-xs">[see Dosage and Administration (2.10) ]</span> . In clinical trials of SUSVIMO including the extension phases in patients with AMD, vitreous hemorrhages were reported in 5.2% (23/443) of patients receiving SUSVIMO. In the clinical trial of SUSVIMO including the extension phases in patients with DME, vitreous hemorrhages were reported in 10.1% (56/556) of patients receiving SUSVIMO. In the clinical trial of SUSVIMO including the extension phase in patients with DR, vitreous hemorrhages were reported in 9.4% (12/128) of patients receiving SUSVIMO. The majority of these hemorrhages occurred within the first post-operative month following surgical implantation and the majority of vitreous hemorrhages resolved spontaneously. Patients on antithrombotic medication (e.g., oral anticoagulants, aspirin, nonsteroidal anti-inflammatory drugs) may be at increased risk of vitreous hemorrhage. Antithrombotic medications are recommended to be temporarily interrupted prior to the implant insertion procedure. The SUSVIMO (ranibizumab injection) dose (refill-exchange) should be delayed in the event of sight-threatening vitreous hemorrhage. The use of pars plana laser ablation and scleral cauterization should be performed to reduce the risk of vitreous hemorrhage.

5.6 Conjunctival Erosion or Retraction A conjunctival erosion is a full thickness degradation or breakdown of the conjunctiva in the area of the implant flange. A conjunctival retraction is a recession or opening of the limbal and/or radial peritomy. Conjunctival erosions or retractions have been associated with an increased risk of endophthalmitis, especially if the implant becomes exposed. Surgical intervention (e.g., conjunctival/Tenon&apos;s capsule repair) is recommended to be performed in case of conjunctival erosion or retraction with or without exposure of the implant flange. In clinical trials of SUSVIMO including the extension phases in patients with AMD, 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. In the clinical trial of SUSVIMO including the extension phases of patients with DME, 2.2% (12/556) of patients receiving SUSVIMO reported conjunctival erosion and 1.3% (7/556) of patients receiving SUSVIMO reported conjunctival retraction in the study eye. In the clinical trial of SUSVIMO including the extension phase in patients with DR, 2.3% (3/128) of patients receiving SUSVIMO reported conjunctival erosion and 1.6% (2/128) of patients receiving SUSVIMO reported conjunctival retraction in the study eye. Appropriate intraoperative handling of conjunctiva and Tenon&apos;s 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.

5.7 Conjunctival Bleb A 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 the extension phases in patients with AMD, 5.9% (26/443) of patients receiving SUSVIMO reported conjunctival bleb/conjunctival filtering bleb leak in the study eye. In the clinical trial of SUSVIMO including the extension phases in patients with DME, 9% (50/556) of patients receiving SUSVIMO reported conjunctival bleb/conjunctival filtering bleb leak in the study eye. In the clinical trial of SUSVIMO including the extension phase in patients with DR, 3.9% (5/128) 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 Tenon&apos;s 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.

5.8 Postoperative Decrease in Visual Acuity Visual acuity was decreased by 4 letters on average in the first postoperative month and 2 letters on average in the second postoperative month following initial implantation of SUSVIMO in patients with AMD <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span> . Visual acuity was decreased by 7 letters on average in the first postoperative month and 3 to 4 letters on average in the second postoperative month following initial implantation of SUSVIMO in patients with DME and DR <span class="opacity-50 text-xs">[see Clinical Studies (14.2 and 14.3) ]</span> .

5.9 Postoperative Intraocular Inflammation Postoperative intraocular inflammation has occurred following SUSVIMO implantation. The majority of cases occurred during the first week following implantation and resolved within the first month.

5.10 Air 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.

5.11 Deflection or Movement of the Implant Use caution when performing ophthalmic procedures (e.g., B-scan ophthalmic ultrasound, scleral depression, or gonioscopy) that may cause deflection or movement of the implant and subsequent injury.

INTERACTIONS Drug interaction studies have not been conducted with ranibizumab products. Ranibizumab intravitreal injection has been used adjunctively with Photodynamic Therapy (PDT). Twelve of 105 (11%) patients with neovascular AMD developed serious intraocular inflammation; in 10 of the 12 patients, this occurred when ranibizumab was administered 7 days (± 2 days) after PDT.