IZERVAY (avacincaptad pegol) injection

IZERVAY must be administered by a qualified physician.

The recommended dosage for IZERVAY is 2 mg (0.1 mL of 20 mg/mL solution) administered by intravitreal injection to each affected eye once monthly (approximately every 28 ± 7 days).

Important information you should know before you begin:

• Read all the instructions carefully before using IZERVAY.
• The IZERVAY kit includes a glass vial, filter needle, and an empty syringe. The glass vial, filter needle, and empty syringe are for single use only.
• Store IZERVAY in the refrigerator at temperatures between 2ºC to 8ºC (36ºF to 46ºF). Do not freeze. Do not shake.
• Prior to use, allow IZERVAY to reach room temperature, 20⁰C to 25⁰C (68⁰F to 77⁰F). The IZERVAY vial may be kept at room temperature for up to 24 hours. Keep the vial in the original carton to protect from light.
• Use aseptic technique to carry out the preparation of the intravitreal injection.
• Each vial should only be used for the treatment of a single eye.

Step 1: Gather Supplies   Gather the following supplies (see Figure A ): a.One IZERVAY vial (included) b.One sterile 5-micron filter needle 18-gauge x 1½ inch (included) c.One sterile 1 mL Luer lock syringe with a 0.1 mL dose mark (included) d.One sterile injection needle 30‑gauge x ½ inch (not included)  NOTE: a 30-gauge injection needle is recommended to avoid increased injection forces that could be experienced with smaller diameter needles. e.Alcohol swab (not included)

Figure A Figure A

Step 2: Inspect Vial   Inspect the liquid in the vial. It should be a clear to slightly opalescent, colorless to slightly yellow liquid solution (see Figure B ).   Do not use if particulates, cloudiness, or discoloration are visible.     Do not use if the packaging, vial, filter needle, injection needle, and/or empty syringe are expired, damaged, or have been tampered with.

Figure B Figure B

Step 3: Orient Vial   Place the vial upright on a flat surface for about 1 minute after removal from packaging to make sure all liquid settles at the bottom of the vial (see Figure C).   Gently tap the vial with your finger to remove any liquid that may stick to the top of the vial (see Figure D).

Figure C Figure C ______________________________________                                                                                     Figure D Figure D

Step 4: Clean Vial   Remove the flip-off cap from the vial (see Figure E ).   Gently wipe the vial septum with an alcohol swab (see Figure F ).

Figure E and F Figure E                                                        Figure F

Step 5: Attach Filter Needle   Using aseptic technique, firmly attach the included 18-gauge x 1½ inch filter needle onto the 1 mL Luer lock syringe and twist clockwise to secure (see Figure G).

Figure G Figure G

Step 6: Insert Filter Needle into Vial   Using aseptic technique, push the filter needle all the way into the center of the vial septum (see Figure H).   Tilt the vial slightly so that the needle touches the bottom edge of the vial (see Figure I).   Rotate the filter needle so that the bevel is submerged into the liquid to avoid introduction of air.

Figure H and I Figure H                                                                Figure I

Step 7: Withdraw Liquid   Slowly withdraw all the liquid from the vial (see Figure J ).   Draw the plunger rod back far enough to completely empty the filter needle.

Figure J Figure J

Step 8: Disconnect Filter Needle   Disconnect the filter needle from the syringe and dispose of it in accordance with local regulations (see Figure K ).   Do not use the filter needle for the intravitreal injection.

Figure K Figure K

Step 9: Attach Injection Needle   Using aseptic technique, firmly attach the 30-gauge x ½ inch injection needle onto the Luer lock syringe. (see Figure L ). Carefully remove the plastic needle shield from the needle by pulling it straight off (see Figure M ).

Figure L Figure L ________________________________________                                                 Figure M Figure M

Step 10: Check Syringe   Check for air bubbles by holding 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 N).

Figure N Figure N

Step 11: Prepare Appropriate Dose   Slowly depress the plunger to: Expel the air from the syringe Align the rubber stopper tip to the 0.1 mL dose mark. The syringe is now ready for the injection (see Figure O).   Make sure to give the injection immediately after preparing the dose.

Figure O Figure O

Only 0.1 mL (2 mg) should be administered to deliver a single dose. Any excess volume should be disposed.

Prior to the intravitreal injection, patients should be monitored for elevated intraocular pressure (IOP) using tonometry [see Warnings and Precautions (5.3)]. If necessary, ocular hypotensive medication can be given to lower the IOP.

The intravitreal injection procedure must be carried out under controlled 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 should be given 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 elevation in intraocular pressure (IOP). Appropriate monitoring may consist of a check for perfusion of the optic nerve head or 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 and syringe should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new vial and syringe should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter needle, and injection needle should be changed before IZERVAY is administered to the other eye. Repeat the same procedure steps as above.

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

IZERVAY is contraindicated in patients with ocular or periocular infections.

IZERVAY is contraindicated in patients with active intraocular inflammation.

Intravitreal injections may be associated with endophthalmitis and retinal detachments [see Adverse Reactions (6.1)]. Proper aseptic injection techniques must always be used when administering IZERVAY 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, to permit prompt and appropriate management [see Patient Counseling Information (17)].

In the GATHER1 and GATHER2 clinical trials, use of IZERVAY was associated with increased rates of neovascular (wet) AMD or choroidal neovascularization (7% when administered monthly and 4% in the sham group) by Month 12.

Over 24 months, the rate of neovascular (wet) AMD or choroidal neovascularization in the GATHER2 trial was 12% in the IZERVAY group and 9% in the sham group. Patients receiving IZERVAY should be monitored for signs of neovascular AMD.

Transient increases in intraocular pressure (IOP) have been observed after an intravitreal injection, including with IZERVAY [see Adverse Reactions (6.1)]. Perfusion of the optic nerve head should be monitored following the injection and managed as needed [see Dosage and Administration (2.4)].

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 safety of avacincaptad pegol was evaluated in 733 patients with AMD in two sham-controlled studies (GATHER1 and GATHER2). Of these patients, 292 were treated with intravitreal IZERVAY 2 mg (0.1 mL of 20 mg/mL solution) [see Clinical Studies (14)]. Three hundred thirty-two (332) patients were assigned to sham.

Adverse reactions reported in ≥2% of patients who received treatment with IZERVAY for up to 12 months pooled across the GATHER1 and GATHER2 studies are listed below in Table 1.

Adverse reactions reported in ≥ 2% of patients who received treatment with IZERVAY for up to 24 months in the GATHER2 study are listed below in Table 2.

Photopsia, optic ischemic neuropathy, vitreous hemorrhage, vitreal cells, vitritis, and endophthalmitis were each reported in ≤ 1% of patients treated with IZERVAY for up to 24 months across the GATHER1 and GATHER2 studies.

Risk Summary

There are no adequate and well-controlled studies of IZERVAY administration in pregnant women. The use of IZERVAY may be considered following an assessment of the risks and benefits.

Administration of avacincaptad pegol to pregnant rats and rabbits throughout the period of organogenesis resulted in no evidence of adverse effects to the fetus or pregnant female at intravenous (IV) doses 5.5 times and 3.4 times the human exposure, respectively, based on Area Under the Curve (AUC), following a single 2 mg intravitreal (IVT) dose (see Data).

In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15%-20%, respectively.

Data

Animal Data

An embryo fetal developmental toxicity study was conducted with pregnant rats. Pregnant rats received daily IV injections of avacincaptad pegol from day 6 to day 17 of gestation at 0.1, 0.4, 1.2 mg/kg/day. No maternal or embryofetal adverse effects were observed at any dose evaluated. An increase in the incidence of a non-adverse skeletal variation, described as short thoracolumbar (ossification site without distal cartilage) supernumerary ribs, was observed at all doses evaluated. The clinical relevance of this finding is unknown. Plasma exposures at the high dose were 5.5 times the human AUC of 999 ngday/mL (23976 nghr/mL) following a single 2 mg IVT dose.

An embryo fetal developmental toxicity study was conducted with pregnant rabbits. Pregnant rabbits received daily IV injections of avacincaptad pegol from day 7 to day 19 of gestation at 0.12, 0.4, 1.2 mg/kg/day. No maternal or embryofetal adverse effects were observed at any dose evaluated. Plasma exposure in pregnant rabbits at the highest dose of 1.2 mg/kg/day was 3.4 times the human AUC of 999 ngday/mL (23976 nghr/mL) following a single 2 mg IVT dose.

Risk Summary

There is no information regarding the presence of avacincaptad pegol in human milk, the effects of the drug on the breastfed infant, or the effects of avacincaptad pegol on milk production. Many drugs are transferred in human milk with the potential for absorption and adverse reactions in the breastfed child.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for IZERVAY, and any potential adverse effects on the breastfed infant from IZERVAY.

Safety and effectiveness of IZERVAY in pediatric patients have not been established.

Of the total number of patients who received IZERVAY in the two clinical trials, 90% (263/292) were ≥65 years and 61% (178/292) were ≥75 years of age. No significant differences in efficacy or safety of avacincaptad pegol were seen with increasing age in these studies. No dose adjustment is required in patients 65 years and above.

Avacincaptad pegol is an RNA aptamer, a PEGylated oligonucleotide that binds to and inhibits complement protein C5. By inhibiting C5, avacincaptad pegol may prevent its cleavage to C5a and C5b thus decreasing membrane attack complex (MAC) formation.

Increased GA area growth is reflective of loss of photoreceptors and AMD disease progression. Reductions in the rate of GA growth were observed across avacincaptad pegol treatment groups in studies GATHER1 and GATHER2.

Absorption/Distribution

Following monthly dosing of avacincaptad pegol, at steady‑state maximum avacincaptad pegol plasma concentrations (C_max) are estimated to occur approximately 3 days post-dose and geometric mean (GeoCV%) free avacincaptad pegol plasma C_max is estimated to be 347 ng/mL (59.0%) in GA secondary to AMD patients. The AUC_0-τ days following monthly dosing is 4726 day∙ng/mL, where tau is 28 days.

In humans, avacincaptad pegol plasma concentrations are predicted to be approximately 1,400-fold lower than vitreal concentrations.

Metabolism/Elimination

Metabolism and elimination of avacincaptad pegol has not been fully characterized. Avacincaptad pegol is expected to be catabolized by endonucleases and exonucleases to oligonucleotides of shorter lengths. The estimated apparent systemic half-life of avacincaptad pegol is approximately 8 days.

Specific Populations

Following repeat monthly intravitreal dose administration of 2 mg avacincaptad pegol, no differences in the systemic pharmacokinetics of avacincaptad pegol were observed based on age, gender, and body weight. No special dosage modification is required for any of the populations that have been studied (e.g., age, gender, and body weight). The effect of severe renal impairment or any degree of hepatic impairment on the pharmacokinetics of avacincaptad pegol is unknown. As significant increases in plasma avacincaptad pegol exposures are not expected with intravitreal route of administration, no dosage adjustment is needed based on renal or hepatic impairment status.

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

In the 18‑month treatment period in study ISEE2009, the incidence of anti‑avacincaptad pegol antibody formation was 1.1% (3 of 268 IZERVAY‑treated patients post treatment). Because of the low occurrence of ADA, the effect of these antibodies on the pharmacokinetics and/or safety of IZERVAY is unknown. The effect of anti‑avacincaptad pegol antibody on the pharmacodynamics and/or effectiveness of IZERVAY is also unknown.

Carcinogenesis

No studies have been conducted on the carcinogenic potential of avacincaptad pegol.

Mutagenesis

Avacincaptad pegol was negative in in vitro (bacterial reverse mutation assay, chromosomal aberration in mammalian cells) and in vivo (mouse bone marrow micronucleus) assays.

Impairment of Fertility

Studies to evaluate the effect of avacincaptad pegol on male or female fertility in animals have not been performed.

IZERVAY (avacincaptad pegol intravitreal solution) is supplied as a sterile, clear to slightly opalescent, colorless to slightly yellowish 20 mg/mL solution in a single-dose glass vial. Each glass vial contains an overfill amount to allow administration of a single 0.1 mL dose of solution containing 2 mg of avacincaptad pegol (oligonucleotide basis). Each IZERVAY carton (NDC 82829-002-01) contains one glass vial, one sterile 5-micron transfer filter needle (18-gauge x 1½ inch, 1.2 mm x 40 mm), and one sterile 1 mL Luer lock syringe.

Store IZERVAY in the refrigerator between 2°C to 8°C (36°F to 46°F). Do not freeze. Do not shake. Keep the vial in the original carton to protect from light.

Prior to use, the unopened glass vial of IZERVAY may be kept at room temperature, 20°C to 25°C (68°F to 77°F), for up to 24 hours. Ensure that the injection is given immediately after preparation of the dose.