PAVBLU 40 mg/ml Injectable Solution in Pre-filled Syringe

Introduction

Package Leaflet: Information for the Patient

PAVBLU 40 mg/ml solution for injection in a pre-filled syringe

aflibercept

This medicinal product is subject to additional monitoring, which will allow for quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

Read all of this leaflet carefully before you are given this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor.
• If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

1. What PAVBLU is and what it is used for
2. What you need to know before you are given PAVBLU
3. How PAVBLU will be given to you
4. Possible side effects
5. How to store PAVBLU
6. Contents of the pack and other information

1. What PAVBLU is and what it is used for

PAVBLU is a solution that is injected into the eye to treat certain eye diseases in adult patients, known as:

• neovascular (exudative) age-related macular degeneration, commonly known as wet AMD
• visual impairment due to macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO)
• visual impairment due to diabetic macular edema (DME)
• visual impairment due to myopic choroidal neovascularization (mCNV).

Aflibercept, the active substance in PAVBLU, blocks the activity of a group of factors known as vascular endothelial growth factor A (VEGF-A) and placental growth factor (PlGF).

In patients with wet AMD and mCNV, when these factors are present in excessive amounts, they promote the formation of abnormal new blood vessels in the eye. These new blood vessels can cause leakage of blood components into the eye, resulting in damage to the eye tissues responsible for vision.

In patients with CRVO, there is a blockage of the main vein that carries blood from the retina. As a result, VEGF levels increase, causing fluid leakage in the retina and subsequent swelling of the macula (the part of the retina responsible for fine vision), known as macular edema. When the macula becomes filled with fluid, central vision becomes blurred.

In patients with BRVO, there is a blockage of one or more branches of the main blood vessel that carries blood from the retina. As a result, VEGF levels increase, causing fluid leakage in the retina and subsequent swelling of the macula.

Diabetic macular edema is a swelling of the retina that occurs in patients with diabetes due to fluid leakage from the macula blood vessels. The macula is the part of the retina responsible for fine vision. When the macula becomes swollen with fluid, central vision becomes blurred.

PAVBLU has been shown to stop the growth of abnormal new blood vessels in the eye that often bleed or leak fluid. PAVBLU may help to stabilize and, in many cases, improve vision loss caused by wet AMD, CRVO, BRVO, DME, and mCNV.

2. What you need to know before you are given PAVBLU

You must not be given PAVBLU

• if you are allergic to aflibercept or any of the other ingredients of this medicine (listed in section 6)
• if you have an active infection or suspect that you may have an infection in or around the eye (ocular or periocular infection)
• if you have severe inflammation of the eye (indicated by pain or redness).

Warnings and precautions

Tell your doctor before you are given PAVBLU:

• If you have glaucoma.
• If you have a history of flashes of light or floaters or if you suddenly experience an increase in the size and number of floaters.
• If you have had surgery or are scheduled to have surgery on your eye within the previous or next 4 weeks.
• If you have a severe form of CRVO or BRVO (ischemic CRVO or BRVO), treatment with PAVBLU is not recommended.

In addition, it is important that you know that:

• The safety and efficacy of PAVBLU when administered in both eyes at the same time have not been studied, and if used in this way, it may increase the risk of side effects.
• PAVBLU injections may cause an increase in pressure inside the eye (intraocular pressure) in some patients within 60 minutes after the injection. Your doctor will monitor you after each injection.
• If you develop an infection or inflammation inside the eye (endophthalmitis) or other complications, you may notice pain or increased discomfort in the eye, worsening of redness, blurred or decreased vision, and increased sensitivity to light. It is essential that any symptoms that appear are diagnosed and treated as soon as possible.
• Your doctor will check if you have other risk factors that may increase the likelihood of a tear or detachment of the posterior layers of the eye (retinal tear or detachment, or retinal pigment epithelial tear or detachment), in which case PAVBLU will be administered with caution.
• PAVBLU must not be used during pregnancy, unless the potential benefit outweighs the potential risk to the fetus.
• Women of childbearing age must use effective contraceptive methods during treatment and for at least 3 months after the last injection of PAVBLU.

The systemic use of VEGF inhibitors, substances similar to those contained in PAVBLU, is potentially related to the risk of blockage of blood vessels by blood clots (arterial thromboembolic events) that can lead to a heart attack or stroke. After injection of PAVBLU into the eye, there is a theoretical risk that these events may occur. Data on the safety of treatment of patients with CRVO, BRVO, DME, and mCNV who have suffered a stroke, transient ischemic attack, or myocardial infarction in the last 6 months are limited. If any of these cases apply to you, PAVBLU will be administered with caution.

Experience is limited in the treatment of:

• Patient with DME due to type 1 diabetes.
• Diabetic patients with very high average blood sugar levels (HbA1c above 12%).
• Diabetic patients with a diabetic eye disease known as proliferative diabetic retinopathy.

There is no experience in the treatment of:

• Patient with acute infections.
• Patient with other eye diseases such as retinal detachment or macular hole.
• Diabetic patients with uncontrolled hypertension.
• Non-Asian patients with mCNV.
• Patient who have been previously treated for mCNV.
• Patient with damage outside the central part of the macula (extrafoveal lesions) due to mCNV.

If any of the above applies to you, your doctor will take into account this lack of information when treating you with PAVBLU.

Children and adolescents

PAVBLU has not been studied in children and adolescents under 18 years of age, as wet AMD, CRVO, BRVO, DME, and mCNV mainly occur in adults. Therefore, its use in this age group is not recommended.

Other medicines and PAVBLU

Tell your doctor if you are using, have recently used, or might use any other medicines.

Pregnancy and breastfeeding

• Women of childbearing age must use effective contraceptive methods during treatment and for at least 3 months after the last injection of PAVBLU.
• There is no experience with the use of PAVBLU in pregnant women. PAVBLU must not be used during pregnancy, unless the potential benefit outweighs the potential risk to the fetus. If you are pregnant or plan to become pregnant, tell your doctor before treatment with PAVBLU.
• Small amounts of PAVBLU may pass into breast milk. The effects on newborns/infants are unknown. PAVBLU is not recommended during breastfeeding. If you are breastfeeding, tell your doctor before treatment with PAVBLU.

Driving and using machines

After injection of PAVBLU, you may experience some temporary visual disturbances. Do not drive or use machines while these disturbances last.

PAVBLU contains

This medicine contains less than 1 mmol of sodium (23 mg) per dose unit, which is essentially "sodium-free".

This medicine contains 0.005 mg of polysorbate 80 in each 0.05 ml dose, equivalent to 0.1 mg/ml. Polysorbates may cause allergic reactions. Tell your doctor if you have any known allergies.

3. How PAVBLU will be given to you

PAVBLU will be administered to you by a doctor with experience in administering eye injections, under aseptic conditions (clean and sterile).

The recommended dose is 2 mg of aflibercept (0.05 ml).

PAVBLU is administered as an intravitreal injection into the eye.

Before the injection, your doctor will use an antiseptic eye wash to carefully clean your eye to prevent infection. Your doctor will also administer a local anesthetic to reduce or prevent any pain you may feel with the injection.

Wet AMD

Patient with wet AMD will be treated with one injection per month for the first three doses, followed by another injection after two months.

Your doctor will then decide if the treatment interval between injections can be maintained every two months or gradually extended to intervals of 2 or 4 weeks if your disease has stabilized.

If your disease worsens, the interval between injections may be shortened.

It is not necessary for your doctor to see you between injections, unless your doctor considers it necessary or you experience any problems.

Macular edema secondary to branch or central retinal vein occlusion

Your doctor will determine the most suitable treatment schedule for you. Your treatment will start with a series of PAVBLU injections administered once a month.

The interval between two injections must not be less than one month.

Your doctor may decide to discontinue treatment with PAVBLU if you do not benefit from continued treatment.

Treatment will continue with one injection per month until your disease has stabilized. You may need three or more monthly injections.

Your doctor will monitor your response to treatment and may continue treatment, gradually increasing the interval between injections to stabilize your disease. If your disease worsens with a longer treatment interval, your doctor will reduce the interval between injections.

Based on your response to treatment, your doctor will decide on the follow-up and treatment schedule.

Diabetic macular edema (DME)

Patient with DME will be treated with one injection per month for the first five consecutive doses, and then one injection every two months.

The interval between treatments may be maintained every two months or adjusted according to your disease, based on the examination performed by your doctor. Your doctor will decide on the follow-up visit schedule.

Your doctor may decide to discontinue treatment with PAVBLU if you do not benefit from continued treatment.

Myopic choroidal neovascularization (mCNV)

Patient with mCNV will be treated with a single injection. You will only receive additional injections if your doctor's examinations reveal that your disease has not improved.

The interval between two injections must not be less than one month.

If your disease disappears and then recurs, your doctor may restart treatment.

Your doctor will decide on the follow-up schedule.

Detailed instructions for use are presented at the end of this leaflet in "How to prepare and administer PAVBLU".

If you miss a dose of PAVBLU

Make a new appointment to be examined and to receive the injection.

Discontinuing treatment with PAVBLU

Talk to your doctor before stopping treatment.

If you have any further questions on the use of this medicine, ask your doctor.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

Potentially, allergic reactions(hypersensitivity) may occur. These can be serious and require immediate contact with your doctor.

With the administration of PAVBLU, some adverse effects that affect the eyes may occur due to the injection procedure. Some may be serious, including blindness, a severe infection or inflammation inside the eye(endophthalmitis), detachment, tear, or hemorrhage of the light-sensitive layer at the back of the eye(retinal detachment or tear), clouding of the lens(cataract), bleeding in the eye(vitreous hemorrhage), detachment of the gel-like substance inside the eye from the retina(vitreous detachment), and increased pressure inside the eye(see section 2). These serious eye-related adverse effects occurred in less than 1 in 1,900 injections during clinical trials.

If you notice a sudden decrease in vision or an increase in pain and redness in the eye after injection, consult your doctor immediately.

List of Reported Adverse Effects

The following is a list of adverse effects reported as possibly related to the injection procedure or the medicine. You should not be alarmed, as you may not experience any of them. Always consult your doctor about any suspected adverse effect.

Very Common Adverse Effects(may affect more than 1 in 10 people):

• vision impairment
• bleeding in the back of the eye (retinal hemorrhage)
• blood in the eye due to bleeding from small blood vessels in the outer layers of the eye
• eye pain

Common Adverse Effects(may affect up to 1 in 10 people):

• detachment or tear of one of the layers in the back of the eye that produce flashes of light with floating spots, which may progress to vision loss (retinal pigment epithelial tear/detachment, retinal tear/detachment)
• retinal degeneration (causing vision disturbances)
• bleeding in the eye (vitreous hemorrhage)
• certain forms of clouding of the lens (cataract)
• damage to the outer layer of the eyeball (cornea)
• increased pressure inside the eye
• spots in vision (floaters)
• detachment of the gel-like substance inside the eye from the retina (vitreous detachment, resulting in flashes of light with floating spots)
• sensation of having something in the eye
• increased tear production
• eyelid swelling
• bleeding at the injection site
• eye redness

*Adverse effects known to be associated with exudative age-related macular degeneration; observed only in patients with exudative age-related macular degeneration.

Uncommon Adverse Effects(may affect up to 1 in 100 people):

• allergic reactions (hypersensitivity)**
• inflammation or severe infection inside the eye (endophthalmitis)
• inflammation of the iris or other parts of the eye (iritis, uveitis, iridocyclitis, cells in the anterior chamber)
• abnormal sensation in the eye
• irritation of the eyelid
• swelling of the outer layer of the eyeball (cornea)

**Allergic reactions were reported as rash, itching (pruritus), hives (urticaria), and some cases of severe allergic reactions (anaphylactic/anaphylactoid).

Rare Adverse Effects(may affect up to 1 in 1,000 people):

• blindness
• clouding of the lens due to injury (traumatic cataract)
• inflammation of the gel-like substance inside the eye
• pus in the eye

Frequency Not Known(cannot be estimated from the available data):

• inflammation of the white part of the eye associated with redness and pain (scleritis)

In clinical trials, an increased incidence of bleeding from small blood vessels in the outer layers of the eye (conjunctival hemorrhage) was observed in patients with exudative age-related macular degeneration who were receiving treatment with anticoagulant medications. This increased incidence was comparable in patients treated with ranibizumab and aflibercept.

The use of VEGF inhibitors systemically, substances similar to those contained in PAVBLU, is potentially related to the risk of forming blood clots that block blood vessels (arterial thromboembolic events) that can cause a heart attack or embolism. There is a theoretical risk that this type of event may occur after injection of PAVBLU into the eye.

As with all therapeutic proteins, there is a possibility of an immune reaction (formation of antibodies) with PAVBLU.

Reporting of Adverse Effects

If you experience any type of adverse effect, consult your doctor, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of PAVBLU

• Keep this medicine out of the sight and reach of children.
• Do not use this medicine after the expiration date stated on the carton and label after "EXP". The expiration date is the last day of the month indicated.
• Store in a refrigerator (between 2 °C and 8 °C). Do not freeze.
• The unopened blister pack in the outer packaging can be stored outside the refrigerator for a maximum of 30 °C for a maximum of 3 days.
• Store in the original packaging to protect it from light.
• Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of the packaging and any unused medicine. This will help protect the environment.

6. Package Contents and Additional Information

Composition of PAVBLU

• The active substance is: aflibercept. A pre-filled syringe contains an extractable volume of at least 0.09 ml, equivalent to at least 3.6 mg of aflibercept. A pre-filled syringe provides a dose of 2 mg of aflibercept in 0.05 ml.
• The other ingredients are: polysorbate 80, sucrose, α,α-trehalose dihydrate, water for injections.

See "PAVBLU contains" in section 2 for more information.

Appearance of the Product and Package Contents

PAVBLU is an injectable solution (injectable) in a pre-filled syringe. The solution is clear to opalescent, colorless to slightly yellow.

Package with 1 pre-filled syringe.

Marketing Authorization Holder and Manufacturer

Amgen Technology (Ireland) UC

Pottery Road, Dun Laoghaire

Co. Dublin,

A96 F2A8

Ireland

Marketing Authorization Holder

Amgen Technology (Ireland) UC

Pottery Road, Dun Laoghaire

Co. Dublin,

A96 F2A8

Ireland

Manufacturer

Amgen NV

Telecomlaan 5-7

1831 Diegem

Belgium

You can request more information about this medicine by contacting the local representative of the marketing authorization holder:

Date of Last Revision of this Leaflet:

Other Sources of Information

Detailed information on this medicine is available on the European Medicines Agency website: https://www.ema.europa.eu.

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This information is intended only for healthcare professionals:

How to Prepare and Administer PAVBLU

The pre-filled syringe must be used for the treatment of a single eye.

Do not open the blister pack with the sterile pre-filled syringe outside the clean room.

The pre-filled syringe contains more than the recommended dose of 2 mg of aflibercept (equivalent to 0.05 ml). The excess volume must be eliminated before administration.

Before administration, the solution must be visually inspected for the presence of particles and/or a change in color or any change in physical appearance. If you observe any of these, do not use the medicine. Do not use if the package is open or damaged.

The unopened blister pack in the outer packaging can be stored outside the refrigerator for a maximum of 30 °C for a maximum of 3 days. After opening the blister pack, proceed under aseptic conditions.

For intravitreal injection, a 30 G × ½ inch (1.27 cm) injection needle must be used.

Instructions for Use of the Pre-filled Syringe:

1. When you are ready to administer PAVBLU, open the box and remove the sterilized blister pack. Carefully peel off the blister pack's lamination, ensuring the sterility of its contents. Keep the syringe on the sterile tray until you are ready for assembly.

1. Using an aseptic technique, remove the syringe from the sterilized blister pack.

1. To remove the closure cap from the syringe, hold the syringe with one hand while using the other to grasp the closure cap between your index finger and thumb. Important note: you must twist the closure cap (do not break it).

1. Using an aseptic technique, firmly attach the injection needle to the tip of the syringe with the Luer Lock adapter by making a twisting motion.

Note:When you are ready to administer PAVBLU, remove the plastic needle protection and place it in a sharps container.

1. Hold the syringe with the needle pointing upwards and check that there are no bubbles inside. If there are, gently tap the syringe with your finger until they rise to the top.

1. Eliminate all bubbles and expel excess medication by slowly pressing the plunger until the base of the plunger's dome (not the tip of the dome) is aligned with the dosing line on the syringe(equivalent to 0.05 ml, i.e., 2 mg of aflibercept).

Note:This exact positioning of the plunger is very important, as incorrect positioning of the plunger may result in administering more or less than the recommended dose.

1. Inject while cautiously pressing the plunger with constant pressure. Do not apply additional pressure once the plunger has reached the bottom of the syringe. Do not administer any residual solution observed in the syringe.

1. The pre-filled syringe is for single use. Withdrawing multiple doses from a pre-filled syringe may increase the risk of contamination and subsequent infection.

The disposal of unused medicine and all materials that have come into contact with it will be carried out in accordance with local regulations.