SYFOVRE

General Dosing Information

SYFOVRE must be administered by a qualified physician.

Recommended Dosage

The recommended dose for SYFOVRE is 15 mg (0.1 mL of 150 mg/mL solution) administered by intravitreal injection to each affected eye once every 25 to 60 days.

Preparation for Administration

	Store SYFOVRE in the refrigerator between 2°C to 8°C (36°F to 46°F); Keep the vial in the original carton to protect from light.
	Remove the carton from the refrigerator. Keep the vial in the original carton at room temperature 20°C to 25°C (68°F to 77°F), for at least 15 minutes prior to injection, but no longer than 8 hours. Fill the syringe immediately prior to the injection.
	Do not shake the vial. The vial is for use in a single eye.
	Inspect the solution. It is a clear, colorless to light yellow aqueous solution. Do not use if: particulates, cloudiness, or discoloration are visible, the vial shows signs of damage or tampering, or if the expiration date has passed

STEP 1 Gather the supplies needed:
One SYFOVRE vial (included) One sterile 5-micron filter needle (not included) One sterile 1-mL Luer-lock syringe with a 0.1 mL dose mark (not included) One sterile ½ inch: 29-gauge thin-wall injection needle with Luer-lock hub or a 27-gauge needle with Luer-lock hub (not included) Note: Increased injection forces and/or increased injection time could be experienced if a smaller diameter injection needle is used (e.g., 30-gauge) Alcohol swab (not included)
Use aseptic technique to carry out the following preparation steps:
STEP 2 Remove the flip-off cap from the vial (see FIGURE 1A) and clean the vial septum with an alcohol swab and wait for the alcohol to dry out (see FIGURE 1B).
Figure 1a:		Figure 1b:
STEP 3 Attach the 5-micron filter needle onto a 1-mL Luer-lock syringe (see FIGURE 2) by twisting it onto the Luer-lock syringe tip.
Figure 2:
STEP 4 Push the filter needle into the center of the vial septum until the needle is submerged in the drug product to prevent withdrawal of air (see FIGURE 3A). To withdraw the entire contents of the vial into the syringe, hold the vial at a slightly inclined position. Withdraw the drug product slowly to prevent air bubbles. Continue to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the liquid until all of the fluid is withdrawn from the vial (see FIGURE 3B). *Do not tap the syringe to remove air bubbles. While maintaining the filter needle within the vial, invert the syringe and move the plunger down and up until bubbles move to the top (see FIGURE 3C).
Figure 3a:		Figure 3b:
Figure 3c:
STEP 5 Using aseptic technique, disconnect the filter needle from the syringe and dispose of it. Do not use the filter needle for injection.
STEP 6 Aseptically and firmly attach the injection needle onto the 1-mL Luer-lock syringe (see FIGURE 4).
Figure 4:
STEP 7 Check for air bubbles by holding the syringe with the needle pointing up. *Do not tap the syringe to remove air bubbles. If there are any air bubbles, remove the needle cap and with the needle end facing up gently advance the plunger to the 0.1 mL dose mark (see FIGURE 5). Only 0.1 mL (15 mg of SYFOVRE) should be administered to deliver a single dose. Any excess volume should be disposed. The syringe is ready for injection.
Figure 5:

 Injection Procedure

Only 0.1 mL (15 mg of SYFOVRE) should be administered to deliver a single dose. Any excess volume should be disposed. Ensure that the injection is given immediately after the preparation of the dose.

Prior to the intravitreal injection, patients should be monitored for elevated intraocular pressure (IOP) using tonometry [see WARNINGS AND PRECAUTIONS (5.4)]. If necessary, ocular hypotensive medication can be given to lower the IOP. The intravitreal injection procedure should be carried out under aseptic conditions, which includes the use of surgical hand disinfection, sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid, and ocular surface should be administered prior to the injection.

Inject slowly until the rubber stopper reaches the end of the syringe to deliver the volume of 0.1 mL. Confirm delivery of the full dose by checking that the rubber stopper has reached the end of the syringe barrel.

Immediately following the intravitreal injection, patients should be monitored for elevations in IOP. Additional evaluation may include checking for perfusion of the optic nerve head and tonometry.

Following intravitreal injection patients should be instructed to report any symptoms suggestive of endophthalmitis (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without delay [see PATIENT COUNSELING INFORMATION (17)].

Each vial should only be used for the treatment of a single eye. If the fellow eye requires treatment, a new sterile, vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before SYFOVRE administration. Repeat same procedure steps as above.

Any unused medicinal product or waste material should be disposed of in accordance with local regulations.

SYFOVRE is contraindicated in patients with ocular or periocular infections [see WARNINGS AND PRECAUTIONS (5.1)].

Active Intraocular Inflammation

SYFOVRE is contraindicated in patients with active intraocular inflammation.

 Endophthalmitis and Retinal Detachments

Intravitreal injections, including those with SYFOVRE, may be associated with endophthalmitis and retinal detachments [see ADVERSE REACTIONS (6.1)]. Proper aseptic injection technique must always be used when administering SYFOVRE in order to minimize the risk of endophthalmitis [see DOSAGE AND ADMINISTRATION (2.4)]. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately.

Neovascular AMD

In clinical trials, use of SYFOVRE was associated with increased rates of neovascular (wet) AMD or choroidal neovascularization (12% when administered monthly, 7% when administered every other month and 3% in the control group ) by Month 24. Patients receiving SYFOVRE should be monitored for signs of neovascular AMD. In case anti-Vascular Endothelial Growth Factor (anti-VEGF) is required, it should be given separately from SYFOVRE administration.

Intraocular Inflammation

In clinical trials, use of SYFOVRE was associated with episodes of intraocular inflammation including: vitritis, vitreal cells, iridocyclitis, uveitis, anterior chamber cells, iritis, and anterior chamber flare. After inflammation resolves patients may resume treatment with SYFOVRE.

 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.

A total of 839 patients with GA in two Phase 3 studies (OAKS and DERBY) were treated with intravitreal SYFOVRE, 15 mg (0.1 mL of 150 mg/mL solution). Four hundred nineteen (419) of these patients were treated in the affected eye monthly and 420 were treated in the affected eye every other month. Four hundred seventeen (417) patients were assigned to sham.

The most common adverse reactions (≥5%) reported in patients receiving SYFOVRE were ocular discomfort, neovascular age-related macular degeneration, vitreous floaters, and conjunctival hemorrhage.

Endophthalmitis, retinal detachment, hyphema and retinal tears were reported in less than 1% of patients.

Optic ischemic neuropathy was reported in 1.7% of patients treated monthly, 0.2% of patients treated every other month and 0.0% of patients assigned to sham. Deaths were reported in 6.7% of patients treated monthly, 3.6% of patients treated every other month and 3.8% of patients assigned to sham. The rates and causes of death were consistent with the elderly study population.

Lactation

Females and Males of Reproductive Potential

Pediatric Use

The safety and effectiveness of SYFOVRE in pediatric patients have not been established.

Geriatric Use

In clinical studies, approximately 97% (813/839) of patients randomized to treatment with SYFOVRE were ≥ 65 years of age and approximately 72% (607/839) were ≥ 75 years of age. No significant differences in efficacy or safety were seen with increasing age in these studies. No dosage regimen adjustment is recommended based on age.

Pegcetacoplan binds to complement protein C3 and its activation fragment C3b with high affinity thereby regulating the cleavage of C3 and the generation of downstream effectors of complement activation

Pharmacodynamics

Pharmacokinetics

SYFOVRE is administered directly into the vitreous to exert local effects in the eye.

Following repeat intravitreal administration of pegcetacoplan at a dose of 15 mg, geometric mean (%CV) serum Cmax value at steady state was 2.2 μg/mL (28.7%) and 1.5 μg/mL (58.1%) for GA patients dosed monthly and every other month, respectively. The steady state geometric mean (%CV) serum trough concentrations were 1.0 μg/mL (52.3%) and 0.2 μg/mL (89.6%) for patients treated monthly and every other month, respectively.

Immunogenicity

The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Difference in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies.

In the 24-month period in studies OAKS and DERBY, the incidence of anti-pegcetacoplan peptide antibodies in patients treated with pegcetacoplan was 4% (18/415 evaluable patients) and 2.5% (10/404 evaluable patients), respectively. Because of the low incidence of anti-pegcetacoplan peptide antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of pegcetacoplan is unknown.

Carcinogenesis, Mutagenesis, Impairment of Fertility

How Supplied

SYFOVRE (pegcetacoplan injection) is supplied as a clear, colorless to light yellow aqueous solution. Each SYFOVRE carton (NDC 73606-020-01) contains one single-dose glass vial. Each glass vial contains an overfill amount to allow for administration of a single 0.1 mL dose of solution containing 15 mg of SYFOVRE.

 Storage and Handling

Refrigerate SYFOVRE between 2°C to 8°C (36°F to 46°F). Store the vial in the original carton to protect from light.

Do not use beyond the expiration date on the carton.

Do not shake.