VABYSMO

Retinal vascular diseases (RVDs) such as diabetic macular edema (DME), age-related macular degeneration (AMD), and retinal vein occlusion (RVO) are typically caused by retinal ischemia and subsequent neovascularization (NV). 1, 2, 3 Vascular endothelial growth factor A (VEGF-A) is a well-known mediator of retinal NV, and many currently approved RVD therapies such as aflibercept and ranibizumab solely target VEGF-A. However, another set of factors, the Tie/Ang axis, comprising the transmembrane Tie-2 receptor and its soluble ligands Ang-1 and Ang-2, has been shown to play critical roles in mediating VEGF-A-induced NV. 1, 2, 3 Faricimab is an IgG 1 -derived bispecific antibody capable of simultaneously binding to and depleting VEGF-A and Ang-2, which has been developed to improve therapeutic efficacy, especially in patients that respond poorly to anti-VEGF-A monotherapy. 1, 2, 3, 4, 5, 6 Faricimab was approved by the FDA on January 28, 2022, and is currently marketed under the trademark VABYSMO by Genentech, Inc.

It received subsequent approval for the same indications in Canada in May 2022.

In July 2022, the EMA's Committee for Medicinal Products for Human Use (CHMP) recommended faricimab be granted marketing authorization for the treatment of neovascular age-related macular degeneration and diabetic macular edema.

Faricimab is indicated for the treatment of neovascular (wet) age-related macular degeneration (nAMD) and diabetic macular edema (DME).

Faricimab is a bispecific antibody (bsAb) based on human IgG 1 comprising two different heavy and two different light chains capable of simultaneously binding to both VEGF-A and Ang-2. 3, 5, 6 Faricimab suppresses endothelial proliferation, neovascularization, and vascular permeability, which are associated with the increased retinal thickness observed in nAMD and DME.

In four phase 3 studies in nAMD and DME, faricimab reduced central subfield thickness through the first year in all treatment arms.

As with other medications administered intravitreally, faricimab carries a risk of transient increases in intraocular pressure, endophthalmitis, and retinal detachment.

Proper injection techniques should always be observed, and patients monitored carefully following injection.

Low risk of arterial thromboembolic events, defined as nonfatal stroke or myocardial infarction and vascular death, has been documented with faricimab.

Vascular endothelial growth factor

A, long form Antagonist Angiopoietin-2 Antagonist.

Faricimab unbound plasma

C max are estimated to be 0.23 ± 0.07 and 0.22 ± 0.07 μg/mL in nAMD and DME patients, respectively; these plasma levels are achieved approximately two days post-dose (T max ).

Following repeated intravitreal administration on a q8w schedule, mean plasma trough free faricimab concentrations are predicted to be 0.002-0.003 μg/mL.

No accumulation is expected in either the vitreal fluid or plasma.

Faricimab metabolism has not been fully characterized; as an antibody, faricimab is expected to be catabolized like endogenous immunoglobulins.

Faricimab elimination has not been fully characterized; faricimab may be excreted renally following its breakdown into smaller peptides and amino acids through cellular catabolism.

Faricimab has an estimated mean apparent systemic half-life of 7.5 days.

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information regarding faricimab is not readily available.

Patients experiencing an overdose are at an increased risk of severe adverse effects such as conjunctival hemorrhage.

Symptomatic and supportive measures are recommended.

Due to its mechanism of action, faricimab may pose a risk to reproductive capacity.

Ocular or periocular infection Active intraocular inflammation Hypersensitivity 4.1 Ocular or Periocular.

Infections VABYSMO is contraindicated in patients with ocular or periocular infections. 4.2 Active Intraocular Inflammation VABYSMO is contraindicated in patients with active intraocular inflammation. 4.3 Hypersensitivity VABYSMO is contraindicated in patients with known hypersensitivity to faricimab or any of the excipients in VABYSMO.

Hypersensitivity reactions may manifest as rash, pruritus, urticaria, erythema, or severe intraocular inflammation.

For intravitreal injection.

Neovascular (Wet) Age-Related Macular Degeneration (nAMD) The recommended dose for VABYSMO is 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 ± 7 days, monthly) for the first 4 doses, followed by optical coherence tomography and visual acuity evaluations and 12 weeks later to inform whether to give a 6 mg dose via intravitreal injection on one of the following three regimens: 1) Weeks and 44; 2) Weeks and 48; or 3) Weeks and 44.

Although additional efficacy was not demonstrated in most patients when VABYSMO was dosed every 4 weeks compared to every 8 weeks, some patients may need every 4 week (monthly) dosing after the first 4 doses.

Patients should be assessed regularly.

Edema (DME) VABYSMO is recommended to be dosed by following one of these two dose regimens: 1) 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days ± 7 days, monthly) for at least 4 doses.

If after at least 4 doses, resolution of edema based on the central subfield thickness (CST) of the macula as measured by optical coherence tomography is achieved, then the interval of dosing may be modified by extensions of up to 4 week interval increments or reductions of up to 8 week interval increments based on CST and visual acuity evaluations; or 2) 6 mg dose of VABYSMO can be administered every 4 weeks for the first 6 doses, followed by 6 mg dose via intravitreal injection at intervals of every 8 weeks (2 months).

Occlusion (RVO) The recommended dose for VABYSMO is 6 mg (0.05 mL of 120 mg/mL) administered by intravitreal injection every 4 weeks (approximately every 28 ± 7 days, monthly). 2.1 General Dosing Information For intravitreal injection.

VABYSMO must be administered by a qualified physician.

VABYSMO is available as

Prefilled syringe: A sterile injection filter needle (30-gauge × ½-inch, Extra Thin Wall) with an integrated filter in the hub is provided.

Each prefilled syringe should only be used for the treatment of a single eye.

A sterile 5-micron, blunt transfer filter needle (18-gauge × 1½-inch) is provided.

Each vial should only be used for the treatment of a single eye. 2.2 Neovascular (wet) Age-Related Macular Degeneration (nAMD) The recommended dose for VABYSMO is 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 ± 7 days, monthly) for the first 4 doses, followed by optical coherence tomography and visual acuity evaluations and 12 weeks later to inform whether to give a 6 mg dose via intravitreal injection on one of the following three regimens: 1) Weeks and 44; 2) Weeks and 48; or 3) Weeks and 44.

Patients should be assessed regularly. 2.3 Diabetic Macular Edema (DME) VABYSMO is recommended to be dosed by following one of these two dose regimens: 1) 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days ± 7 days, monthly) for at least 4 doses.

Patients should be assessed regularly. 2.4 Macular Edema Following Retinal Vein Occlusion (RVO) The recommended dose for VABYSMO is 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 ± 7 days, monthly).

In clinical studies, patients received monthly injections of VABYSMO for 6 months. 2.5 Preparation for Administration.

• Prefilled Syringe Before you start Read all the instructions carefully before using VABYSMO.

The VABYSMO carton includes

A sterile prefilled syringe in a sealed tray.

The prefilled syringe is for treatment of a single eye.

A sterile injection filter needle (30-gauge × ½ inch, Extra Thin Wall) with an integrated filter in the hub.

The injection filter needle is for single use only.

Only use the provided injection filter needle for the administration.

VABYSMO should be refrigerated at temperatures between 2°C to 8°C (36°F to 46°F).

Do not freeze.

VABYSMO to reach room temperature, 20°C to 25°C (68°F to 77°F) before proceeding with the administration.

Prior to use, keep the sealed tray in the original carton to protect the prefilled syringe from light.

The prefilled syringe may be kept at room temperature in the original carton for up to 24 hours.

VABYSMO should be inspected visually prior to administration.

Do not use if the carton seals have been tampered with.

Do not use if the packaging, prefilled syringe, injection filter needle is expired, damaged, or have been tampered with.

Do not use if the injection filter needle is missing.

Do not remove the finger grip from the syringe.

Do not use if the syringe cap is detached from the Luer lock.

Do not use if particulates, cloudiness, or discoloration are visible.

VABYSMO is a clear to opalescent and colorless to brownish-yellow liquid solution.

Note: the dose must be set to the 0.05 mL dose mark.

Use aseptic technique to carry out the following preparation steps: Open Tray and Remove Syringe Cap 1 Peel the lid off the syringe tray and aseptically remove the prefilled syringe.

Hold the syringe by the white collar; snap off the syringe cap.

Do not twist off the cap.

Needle 3 Aseptically remove the provided injection filter needle from its packaging.

Aseptically and firmly attach the injection filter needle onto the syringe Luer lock.

C 5 Carefully remove the needle cap by pulling it straight off.

Bubbles 6 Hold the syringe with the injection filter needle pointing up.

Check the syringe for air bubbles.

If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top.

Figure D Expel Air and Adjust the Dose 8 Hold the syringe at eye level and slowly push the plunger rod until the lower edge of the rubber stopper's dome is aligned with the 0.05 mL dose mark.

This will expel the air and the excess solution and set the dose to 0.05 mL.

Ensure that the injection is given immediately after preparation of the dose.

Figure E Image Image Image Image Image Image Image Figure A Figure B Figure C Figure D Figure E 2.6 Preparation for Administration.

• Vial Before you start Read all the instructions carefully before using VABYSMO.

VABYSMO kit includes a glass vial and transfer filter needle.

The glass vial is for a single dose only.

The filter needle is for treatment of a single eye.

VABYSMO should be stored refrigerated at temperatures between 2°C to 8°C (36°F to 46°F).

Do not shake.

Keep the vial in the original carton to protect from light.

VABYSMO vial may be kept at room temperature for up to 24 hours.

VABYSMO vial should be inspected visually for particulate matter and discoloration prior to administration.

Do not use if the packaging, vial and/or transfer filter needle are expired, damaged, or have been tampered with.

Use aseptic technique to carry out the preparation of the intravitreal injection.

Gather the following supplies

One VABYSMO vial (included) One sterile 5-micron blunt transfer filter needle 18-gauge × 1½ inch (included) One sterile 1 mL Luer lock syringe with a 0.05 mL dose mark ( not included ) Note that a 30-gauge injection needle is recommended to avoid increased injection forces that could be experienced with smaller diameter needles.

One sterile injection needle 30-gauge × ½ inch ( not included ) Alcohol swab ( not included ).

To ensure all liquid settles at the bottom of the vial, place the vial upright on a flat surface (for about 1 minute) after removal from packaging.

Gently tap the vial with your finger, as liquid may stick to the top of the vial.

H 3 Remove the flip-off cap from the vial and wipe the vial septum with an alcohol swab.

J 4 Aseptically and firmly attach the included 18-gauge × 1½ inch transfer filter needle onto a 1 mL Luer lock syringe.

K 5 Using aseptic technique, push the transfer filter needle into the center of the vial septum, push it all the way in, then tilt the vial slightly so that the needle touches the bottom edge of the vial.

M 6 Hold the vial slightly inclined and slowly withdraw all the liquid from the vial.

Keep the bevel of the transfer filter needle submerged in the liquid, to avoid introduction of air.

N 7 Ensure that the plunger rod is drawn sufficiently back when emptying the vial, in order to completely empty the transfer filter needle.

Disconnect the transfer filter needle from the syringe and dispose of it in accordance with local regulations.

Do not use the transfer filter needle for the intravitreal injection.

Aseptically and firmly attach a 30-gauge × ½ inch injection needle onto the Luer lock syringe.

O 10 Carefully remove the plastic needle shield from the needle by pulling it straight off.

To check for air bubbles, hold the syringe with the needle pointing up.

P 12 Carefully expel the air from the syringe and needle, and slowly depress the plunger to align the rubber stopper tip to the 0.05 mL dose mark.

The syringe is ready for the injection.

Figure Q Image Image Image Image Image Figure F Figure G Figure H Figure I Figure J Figure K Figure L Figure M Figure N Figure O Figure P Figure Q 2.7 Injection Procedure The intravitreal injection procedure must 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), and the availability of sterile paracentesis equipment (if required).

Adequate anesthesia and a broad-spectrum microbicide should be administered prior to the injection.

Inject slowly until the rubber stopper reaches the end of the syringe to deliver the volume of 0.05 mL.

Note for the pr.

VABYSMO (faricimab-svoa) injection is supplied as a clear to opalescent, colorless to brownish-yellow solution as 6 mg (0.05 mL of 120 mg/mL solution) in a single-dose prefilled syringe or single-dose vial.

Each prefilled syringe or vial is for treatment of a single eye.

VABYSMO is supplied in the following presentations: NDC NUMBER CARTON TYPE CARTON CONTENTS 50242-096-06 Prefilled Syringe one 6 mg (0.05 mL of 120 mg/mL solution) single-dose prefilled glass syringe, in a sealed tray one sterile injection filter needle (30-gauge × ½ inch, 0.30 mm × 12.7 mm, Extra Thin Wall) one Prescribing Information 50242-096-01 Vial one 6 mg (0.05 mL of 120 mg/mL solution) single-dose glass vial one sterile 5-micron blunt transfer filter needle (18-gauge × 1½ inch, 1.2 mm × 40 mm) one Prescribing Information 16.2 Storage and Handling Store VABYSMO in the refrigerator between 2°C to 8°C (36°F to 46°F).

Do not freeze.

Do not shake.

Keep the sealed tray containing the prefilled syringe or the vial in the original carton to protect from light.

Prior to use, the unopened prefilled syringe or glass vial of VABYSMO 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.

VABYSMO in the refrigerator between 2°C to 8°C (36°F to 46°F).

Do not freeze.

Do not shake.

Keep the sealed tray containing the prefilled syringe or the vial in the original carton to protect from light.

Prior to use, the unopened prefilled syringe or glass vial of VABYSMO 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.

Risk Summary There are no adequate and well-controlled studies of VABYSMO administration in pregnant women.

Administration of

VABYSMO to pregnant monkeys throughout the period of organogenesis resulted in an increased incidence of abortions at intravenous (IV) doses 158 times the human exposure (based on C max ) of the maximum recommended human dose.

Based on the mechanism of action of VEGF and Ang-2 inhibitors, there is a potential risk to female reproductive capacity, and to embryo-fetal development.

VABYSMO should not be used during pregnancy unless the potential benefit to the patient outweighs the potential risk to the fetus.

All pregnancies have a background risk of birth defect, 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.

An embryo fetal developmental toxicity study was performed on pregnant cynomolgus monkeys.

Pregnant animals received 5 weekly IV injections of VABYSMO starting on day of gestation at 1 or 3 mg/kg. A non-dose dependent increase in pregnancy loss (abortions) was observed at both doses evaluated.

Serum exposure (C max ) in pregnant monkeys at the low dose of 1 mg/kg was 158 times the human exposure at the maximum recommended intravitreal dose of 6 mg once every 4 weeks.

A no observed adverse effect level (NOAEL) was not identified in this study.

The safety and efficacy of

VABYSMO in pediatric patients have not been established.

In the six clinical studies, approximately 58% (1,496/2,571) of patients randomized to treatment with VABYSMO were ≥ 65 years of age.

No significant differences in efficacy or safety of faricimab were seen with increasing age in these studies.

No dose adjustment is required in patients 65 years and above.