Why is this medication prescribed?

Aflibercept injection is used to treat wet age-related macular degeneration (AMD; an ongoing disease of the eye that causes loss of the ability to see straight ahead and may make it more difficult to read, drive, or perform other daily activities). Aflibercept injection is in a class of medications called vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) antagonists. It works by stopping abnormal blood vessel growth and leakage in the eye(s) that may cause vision loss in people with wet AMD.

How should this medicine be used?

Aflibercept injection comes as a solution (liquid) to be injected into the eye by a doctor. It is usually given in a doctor's office once a month for 3 months and then once every 2 months.

Before you receive an aflibercept injection, your doctor will clean your eye to prevent infection and numb your eye to reduce discomfort during the injection. After your injection, your doctor will need to examine your eyes before you leave the office.

Aflibercept injection controls wet AMD but does not cure it. Your doctor will watch you carefully to see how well aflibercept injection works for you. Talk to your doctor about how long you should continue treatment with aflibercept injection.

Other uses for this medicine

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before receiving aflibercept injection,

• tell your doctor and pharmacist if you are allergic to aflibercept, any other medications, or any of the ingredients in aflibercept injection. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take.
• tell your doctor if you have an infection or swelling in or around the eye. Your doctor will probably tell you that you should not receive aflibercept injection.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while receiving aflibercept injection, call your doctor.
• you should know that aflibercept injection may cause vision problems. Do not drive a car or operate machinery until you know how this medication affects you.

What special dietary instructions should I follow?

Unless your doctor tells you otherwise, continue your normal diet.

What should I do if I forget a dose?

If you miss an appointment to receive aflibercept injection, call your doctor as soon as possible.

What side effects can this medication cause?

Aflibercept injection may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• feeling that something is in your eye
• teary eyes

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately or get emergency medical treatment:

• eye redness or pain
• blurred vision
• eye sensitivity to light
• change in vision
• bleeding in or around the eye
• seeing ''floaters'' or small specks
• seeing flashes of lights
• chest pain
• shortness of breath
• sweating
• slow or difficult speech
• dizziness or faintness
• weakness or numbness of an arm or leg

Aflibercept injection may cause other side effects. Call your doctor if you have any unusual problems while receiving this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online [at http://www.fda.gov/Safety/MedWatch] or by phone [0-000-000-0000].

In case of emergency/overdose

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

What other information should I know?

Keep all appointments with your doctor.
Ask your pharmacist any questions you have about aflibercept injection.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

1 INDICATIONS AND USAGE

Aflibercept is indicated for the treatment of patients with:

1.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)

1.2 Macular Edema Following Central Retinal Vein Occlusion (CRVO)

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY. Aflibercept must only be administered by a qualified physician.

2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD)

The recommended dose for Aflibercept is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection every 4 weeks (monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although Aflibercept may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated when Aflibercept was dosed every 4 weeks compared to every 8 weeks.

2.3 Macular Edema Following Central Retinal Vein Occlusion (CRVO)

The recommended dose for Aflibercept is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection once every 4 weeks (monthly).

2.4 Preparation for Administration

Aflibercept should be inspected visually prior to administration. If particulates, cloudiness, or discoloration are visible, the vial must not be used.

Using aseptic technique, the intravitreal injection should be performed with a 30-gauge × ½-inch injection needle.

Vial

The glass vial is for single use only.

1. Remove the protective plastic cap from the vial.

   

2. Clean the top of the vial with an alcohol wipe.

   

3. Remove the 19-gauge × 1½-inch, 5-micron, filter needle from its pouch and remove the 1-mL syringe supplied in the carton from its pouch. Attach the filter needle to the syringe by twisting it onto the Luer lock syringe tip.

   

4. Push the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or bottom edge of the vial.
5. Using aseptic technique withdraw all of the Aflibercept vial contents into the syringe, keeping the vial in an upright position, slightly inclined to ease complete withdrawal. To deter the introduction of air, ensure the bevel of the filter needle is submerged into the liquid. Continue to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the liquid.

   

6. Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle.
7. Remove the filter needle from the syringe and properly dispose of the filter needle. Note: Filter needle is not to be used for intravitreal injection.
8. Remove the 30-gauge × ½-inch injection needle from the plastic pouch and attach the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip.

   

9. When ready to administer Aflibercept, remove the plastic needle shield from the needle.
10. Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top.

    

11. To eliminate all of the bubbles and to expel excess drug, SLOWLY depress the plunger so that the plunger tip aligns with the line that marks 0.05 mL on the syringe.

2.5 Administration

The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a topical broad–spectrum microbicide should be given prior to the injection.

Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, a sterile paracentesis needle should be available.

Following intravitreal injection, patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without delay.

Each vial should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before Aflibercept is administered to the other eye.

After injection, any unused product must be discarded.

No special dosage modification is required for any of the populations that have been studied (e.g., gender, elderly).

3 DOSAGE FORMS AND STRENGTHS

Single-use, glass vial designed to provide 0.05 mL of 40 mg/mL solution for intravitreal injection.

4 CONTRAINDICATIONS

4.1 Ocular or Periocular Infections

Aflibercept is contraindicated in patients with ocular or periocular infections.

4.2 Active Intraocular Inflammation

Aflibercept is contraindicated in patients with active intraocular inflammation.

4.3 Hypersensitivity

Aflibercept is contraindicated in patients with known hypersensitivity to aflibercept or any of the excipients in Aflibercept. Hypersensitivity reactions may manifest as severe intraocular inflammation.

5 WARNINGS AND PRECAUTIONS

5.1 Endophthalmitis and Retinal Detachments

Intravitreal injections, including those with Aflibercept, have been associated with endophthalmitis and retinal detachments. Proper aseptic injection technique must always be used when administering Aflibercept. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately.

5.2 Increase in Intraocular Pressure

Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including with Aflibercept. Sustained increases in intraocular pressure have also been reported after repeated intravitreal dosing with VEGF inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately.

5.3 Thromboembolic Events

There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors, including Aflibercept. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). The incidence in the VIEW1 and VIEW2 wet AMD studies during the first year was 1.8% (32 out of 1824) in the combined group of patients treated with Aflibercept. The incidence in the COPERNICUS and GALILEO CRVO studies during the first 6 months was 0% (0/218) in patients treated with Aflibercept 2 mg every 4 weeks compared with 1.4% (2/142) in patients receiving sham treatment.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in the section of the labeling:

• Endophthalmitis and retinal detachments
• Increased intraocular pressure
• Thromboembolic events

The most common adverse reactions (≥5%) reported in patients receiving Aflibercept were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and increased intraocular pressure.

6.1 Injection Procedure

Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal injections with Aflibercept including endophthalmitis, traumatic cataract, increased intraocular pressure, and vitreous detachment.

6.2 Clinical Studies 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 other clinical trials of the same or another drug and may not reflect the rates observed in practice.

A total of 2042 patients treated with Aflibercept constituted the safety population in four phase 3 studies. Among those, 1441 patients were treated with the recommended dose of 2 mg.

Neovascular (Wet) Age-Related Macular Degeneration (AMD)

The data described below reflect exposure to Aflibercept in 1824 patients with wet AMD, including 1223 patients treated with the 2-mg dose, in 2 double-masked, active-controlled clinical studies (VIEW1 and VIEW2) for 12 months.

Less common serious adverse reactions reported in <1% of the patients treated with Aflibercept were hypersensitivity, retinal detachment, retinal tear, and endophthalmitis.

Macular Edema Following Central Retinal Vein Occlusion (CRVO)

The data described below reflect exposure to Aflibercept in 218 patients with macular edema following CRVO treated with 2 mg dose in 2 double-masked, controlled clinical studies (COPERNICUS and GALILEO) for 6 months.

Less common adverse reactions reported in <1% of the patients treated with Aflibercept were cataract, eyelid edema, corneal edema, retinal tear, hypersensitivity, and endophthalmitis.

6.3 Immunogenicity

As with all therapeutic proteins, there is a potential for an immune response in patients treated with Aflibercept. The immunogenicity of Aflibercept was evaluated in serum samples. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to Aflibercept in immunoassays. The detection of an immune response is highly dependent on the sensitivity and specificity of the assays used, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Aflibercept with the incidence of antibodies to other products may be misleading.

In the wet AMD and CRVO studies, the pre-treatment incidence of immunoreactivity to Aflibercept was 1% to 3% across treatment groups. After dosing with Aflibercept for 52 weeks (wet AMD), or 24 weeks (CRVO), antibodies to Aflibercept were detected in a similar percentage range of patients. Both in the wet AMD and in the CRVO studies, there were no differences in efficacy or safety between patients with or without immunoreactivity.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C. Aflibercept produced embryo-fetal toxicity when administered every three days during organogenesis to pregnant rabbits at intravenous doses ≥3 mg per kg, or every six days at subcutaneous doses ≥0.1 mg per kg. Adverse embryo-fetal effects included increased incidences of postimplantation loss and fetal malformations, including anasarca, umbilical hernia, diaphragmatic hernia, gastroschisis, cleft palate, ectrodactyly, intestinal atresia, spina bifida, encephalomeningocele, heart and major vessel defects, and skeletal malformations (fused vertebrae, sternebrae, and ribs; supernumerary vertebral arches and ribs; and incomplete ossification). The maternal No Observed Adverse Effect Level (NOAEL) in these studies was 3 mg per kg. Aflibercept produced fetal malformations at all doses assessed in rabbits and the fetal NOAEL was less than 0.1 mg per kg. Administration of the lowest dose assessed in rabbits (0.1 mg per kg) resulted in systemic exposure (AUC) that was approximately 10 times the systemic exposure observed in humans after an intravitreal dose of 2 mg.

There are no adequate and well-controlled studies in pregnant women. Aflibercept should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is unknown whether aflibercept is excreted in human milk. Because many drugs are excreted in human milk, a risk to the breastfed child cannot be excluded. Aflibercept is not recommended during breastfeeding. A decision must be made whether to discontinue nursing or to discontinue treatment with Aflibercept, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

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

8.5 Geriatric Use

In the clinical studies, approximately 85% (1728/2034) of patients randomized to treatment with Aflibercept were ≥65 years of age and approximately 58% (1177/2034) were ≥75 years of age. No significant differences in efficacy or safety were seen with increasing age in these studies.

11 DESCRIPTION

Aflibercept (aflibercept) is a recombinant fusion protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 formulated as an iso-osmotic solution for intravitreal administration. Aflibercept is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa. Aflibercept is produced in recombinant Chinese hamster ovary (CHO) cells.

Aflibercept is a sterile, clear, and colorless to pale yellow solution. Aflibercept is supplied as a preservative-free, sterile, aqueous solution in a single-use, glass vial designed to deliver 0.05 mL (50 microliters) of Aflibercept (40 mg/mL in 10 mM sodium phosphate, 40 mM sodium chloride, 0.03% polysorbate 20, and 5% sucrose, pH 6.2).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases, VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on the surface of leucocytes. Activation of these receptors by VEGF-A can result in neovascularization and vascular permeability.

Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF, and thereby can inhibit the binding and activation of these cognate VEGF receptors.

12.2 Pharmacodynamics

Neovascular (Wet) Age-Related Macular Degeneration (AMD)

In the clinical studies anatomic measures of disease activity improved similarly in all treatment groups from baseline to week 52. Anatomic data were not used to influence treatment decisions.

Macular Edema Following Central Retinal Vein Occlusion (CRVO)

Reductions in mean retinal thickness were observed in COPERNICUS and GALILEO at week 24 compared to baseline. Anatomic data were not used to influence treatment decisions.

12.3 Pharmacokinetics

Aflibercept is administered intravitreally to exert local effects in the eye. In patients with wet AMD or CRVO, following intravitreal administration of Aflibercept, a fraction of the administered dose is expected to bind with endogenous VEGF in the eye to form an inactive aflibercept: VEGF complex. Once absorbed into the systemic circulation, aflibercept presents in the plasma as free aflibercept (unbound to VEGF) and a more predominant stable inactive form with circulating endogenous VEGF (i.e., aflibercept: VEGF complex).

Absorption/Distribution

Following intravitreal administration of 2 mg per eye of Aflibercept to patients with wet AMD and CRVO, the mean Cmax of free aflibercept in the plasma was 0.02 mcg/mL (range: 0 to 0.054 mcg/mL) and 0.05 mcg/mL (range 0 to 0.081 mcg/mL), respectively and was attained in 1 to 3 days. The free aflibercept plasma concentrations were undetectable two weeks post-dosing in all patients. Aflibercept did not accumulate in plasma when administered as repeated doses intravitreally every 4 weeks. It is estimated that after intravitreal administration of 2 mg to patients, the mean maximum plasma concentration of free aflibercept is more than 100 fold lower than the concentration of aflibercept required to half-maximally bind systemic VEGF.

The volume of distribution of free aflibercept following intravenous (I.V.) administration of aflibercept has been determined to be approximately 6L.

Metabolism/Elimination

Aflibercept is a therapeutic protein and no drug metabolism studies have been conducted. Aflibercept is expected to undergo elimination through both target-mediated disposition via binding to free endogenous VEGF and metabolism via proteolysis. The terminal elimination half-life (t1/2) of free aflibercept in plasma was approximately 5 to 6 days after I.V. administration of doses of 2 to 4 mg/kg aflibercept.

Specific Populations

Renal Impairment

Pharmacokinetic analysis of a subgroup of patients (n=492) in one wet AMD study, of which 43% had renal impairment (mild n=120, moderate n=74, and severe n=16), revealed no differences with respect to plasma concentrations of free aflibercept after intravitreal administration every 4 or 8 weeks. Similar results were seen in patients in a CRVO study. No dose adjustment based on renal impairment status is needed for either wet AMD or CRVO patients.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept. Effects on male and female fertility were assessed as part of a 6-month study in monkeys with intravenous administration of aflibercept at weekly doses ranging from 3 to 30 mg per kg. Absent or irregular menses associated with alterations in female reproductive hormone levels and changes in sperm morphology and motility were observed at all dose levels. In addition, females showed decreased ovarian and uterine weight accompanied by compromised luteal development and reduction of maturing follicles. These changes correlated with uterine and vaginal atrophy. A No Observed Adverse Effect Level (NOAEL) was not identified. Intravenous administration of the lowest dose of aflibercept assessed in monkeys (3 mg per kg) resulted in systemic exposure (AUC) that was approximately 1500 times higher than the systemic exposure observed in humans after an intravitreal dose of 2 mg. All changes were reversible within 20 weeks after cessation of treatment.

13.2 Animal Toxicology and/or Pharmacology

Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated with aflibercept intravitreally were observed at intravitreal doses of 2 or 4 mg per eye. At the NOAEL of 0.5 mg per eye in monkeys, the systemic exposure (AUC) was 56 times higher than the exposure observed in humans after an intravitreal dose of 2 mg. Similar effects were not seen in clinical studies.

14 CLINICAL STUDIES

14.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)

The safety and efficacy of Aflibercept were assessed in two randomized, multi-center, double-masked, active-controlled studies in patients with wet AMD. A total of 2412 patients were treated and evaluable for efficacy (1817 with Aflibercept) in the two studies (VIEW1 and VIEW2). In each study, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens: 1) Aflibercept administered 2 mg every 8 weeks following 3 initial monthly doses (Aflibercept 2Q8); 2) Aflibercept administered 2 mg every 4 weeks (Aflibercept 2Q4); 3) Aflibercept 0.5 mg administered every 4 weeks (Aflibercept 0.5Q4); and 4) ranibizumab administered 0.5 mg every 4 weeks (ranibizumab 0.5 mg Q4). Patient ages ranged from 49 to 99 years with a mean of 76 years.

In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at week 52 compared to baseline. Data are available through week 52. Both Aflibercept 2Q8 and Aflibercept 2Q4 groups were shown to have efficacy that was clinically equivalent to the ranibizumab 0.5 mg Q4 group.

Detailed results from the analysis of the VIEW1 and VIEW2 studies are shown in Table 3 and Figure8 below.

Figure 8: Mean Change in Visual Acuity from Baseline to Week 52 in VIEW1 and VIEW2 Studies

14.2 Macular Edema Following Central Retinal Vein Occlusion (CRVO)

The safety and efficacy of Aflibercept were assessed in two randomized, multi-center, double-masked, sham-controlled studies in patients with macular edema following CRVO. A total of 358 patients were treated and evaluable for efficacy (217 with Aflibercept) in the two studies (COPERNICUS and GALILEO). In both studies, patients were randomly assigned in a 3:2 ratio to either 2 mg Aflibercept administered every 4 weeks (2Q4), or sham injections (control group) administered every 4 weeks for a total of 6 injections. Patient ages ranged from 22 to 89 years with a mean of 64 years.

In both studies, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA compared to baseline. At week 24, the Aflibercept 2 mg Q4 group was superior to the control group for the primary endpoint.

Figure 9: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 24 in COPERNICUS and GALILEO Studies

Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline visual acuity, retinal perfusion status, and CRVO duration) in each study and in the combined analysis were in general consistent with the results in the overall populations.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each Vial is for single eye use only. Aflibercept is supplied in the following presentation.

Aflibercept should be refrigerated at 2°C to 8ºC (36°F to 46ºF). Do Not Freeze. Do not use beyond the date stamped on the carton and container label. Protect from light. Store in the original carton until time of use.

17 PATIENT COUNSELING INFORMATION

In the days following Aflibercept administration, patients are at risk of developing endophthalmitis or retinal detachment. If the eye becomes red, sensitive to light, painful, or develops a change in vision, advise patients to seek immediate care from an ophthalmologist.

Patients may experience temporary visual disturbances after an intravitreal injection with Aflibercept and the associated eye examinations. Advise patients not to drive or use machinery until visual function has recovered sufficiently.