Aflibercept

The dosage of Aflibercept varies significantly depending on the condition being treated and the specific product used. Healthcare providers follow strict protocols to ensure safety and efficacy.

For Wet Age-Related Macular Degeneration (nAMD)

• Standard Eylea (2 mg): The typical starting dose is 2 mg administered by intravitreal injection every 4 weeks (monthly) for the first 3 to 12 weeks. Following the loading phase, the frequency may be adjusted to once every 8 weeks (2 months). Some patients may eventually transition to a 'treat-and-extend' regimen where the interval between doses is gradually increased based on visual outcomes.
• Eylea HD (8 mg): The recommended dose is 8 mg every 4 weeks for the first 3 doses, followed by 8 mg every 8 to 16 weeks.

For Diabetic Macular Edema (DME) and Diabetic Retinopathy

• Standard Eylea (2 mg): Initially, 2 mg is injected every 4 weeks for the first 5 injections. After this, the dose is usually maintained at 2 mg every 8 weeks. Your doctor may adjust this based on your response.

For Metastatic Colorectal Cancer (mCRC)

• Zaltrap (4 mg/kg): The recommended dose is 4 mg per kilogram of body weight, administered as an intravenous infusion over 1 hour. This is given every 2 weeks in combination with the FOLFIRI chemotherapy regimen. Treatment continues until the disease progresses or side effects become unacceptable.

Aflibercept is approved for a very specific pediatric condition: Retinopathy of Prematurity (ROP).

• Dosage for ROP: The recommended dose is 0.4 mg (0.01 mL of a 40 mg/mL solution) administered via intravitreal injection. This may be repeated in each eye if necessary. The safety and effectiveness of Aflibercept for other conditions in pediatric patients have not been established. Use in children for cancer or adult-onset retinal diseases is generally not recommended.

Renal Impairment

• Ophthalmic Use: No specific dosage adjustments are required for patients with kidney disease, as systemic absorption is minimal.
• Oncologic Use: Clinical studies of Zaltrap have shown that no dose adjustment is required for patients with mild to moderate renal impairment. Data for patients with severe renal impairment are limited, and these patients should be monitored closely.

Hepatic Impairment

• Ophthalmic Use: No adjustments are necessary.
• Oncologic Use: No formal studies have been conducted in patients with severe hepatic impairment. For mild to moderate impairment, no specific dose adjustment is typically recommended, but liver function tests must be monitored regularly.

Elderly Patients

No specific dose adjustments are required for elderly patients. However, older adults may be at a higher risk for certain systemic side effects, such as hypertension, when receiving the intravenous form.

Aflibercept is never self-administered. It must be given by a qualified healthcare professional in a clinical setting.

• Intravitreal Injection: The eye is numbed with local anesthesia and cleaned with an antiseptic to prevent infection. The doctor then injects the medication into the vitreous (the jelly-like substance inside the eye). You may feel pressure but should not feel sharp pain.
• Intravenous Infusion: Zaltrap is diluted in a 0.9% sodium chloride or 5% dextrose solution. It is administered through an IV line or a central port over exactly 60 minutes. It must not be given as an IV bolus or 'push.'
• Storage: Vials should be stored in a refrigerator (2°C to 8°C or 36°F to 46°F) and protected from light. They should not be frozen or shaken.

If you miss an appointment for an Aflibercept injection or infusion, contact your healthcare provider immediately to reschedule. Maintaining a consistent schedule is vital for preventing vision loss or controlling cancer growth. For the eye injection, missing a dose can lead to a rapid return of fluid and permanent vision damage.

An overdose of Aflibercept in the eye may lead to increased intraocular pressure (pressure inside the eye). Signs include eye pain, redness, and sudden blurring of vision. In the case of an intravenous overdose, side effects like severe high blood pressure may occur. Emergency measures include monitoring intraocular pressure (for Eylea) or blood pressure (for Zaltrap) and providing supportive care. If you suspect an overdose, seek emergency medical attention or contact a poison control center immediately.

> Important: Follow your healthcare provider's dosing instructions precisely. Do not adjust your treatment schedule without professional medical guidance.

Side effects vary greatly depending on whether Aflibercept is injected into the eye or given intravenously.

Ophthalmic (Eylea)

• Conjunctival Hemorrhage: A small, bright red spot on the white of the eye caused by a broken blood vessel. This is usually harmless and resolves on its own.
• Eye Pain: Mild discomfort or a 'gritty' sensation in the eye following the injection.
• Vitreous Floaters: Small specks or clouds moving in your field of vision. These are often caused by the medication itself or air bubbles introduced during the injection.
• Increased Intraocular Pressure: A temporary rise in the pressure inside the eye immediately following the procedure.

Oncologic (Zaltrap)

• Leukopenia and Neutropenia: A decrease in white blood cells, which can increase the risk of infection.
• Diarrhea: Frequent, loose stools that can lead to dehydration.
• Hypertension: High blood pressure is very common and often requires medication to manage.
• Fatigue: A general feeling of tiredness or lack of energy.
• Proteinuria: The presence of excess protein in the urine, indicating potential kidney stress.

• Ophthalmic: Blurred vision, corneal edema (swelling of the clear front surface of the eye), and eye inflammation (iritis or vitritis).
• Oncologic: Stomatitis (sores in the mouth), headache, weight loss, and epistaxis (nosebleeds). Patients may also experience 'Hand-Foot Syndrome,' characterized by redness and peeling of the skin on the palms and soles.

• Endophthalmitis: A severe internal eye infection that can lead to permanent blindness if not treated immediately.
• Retinal Detachment: A medical emergency where the retina pulls away from the back of the eye.
• Gastrointestinal Perforation: A hole forming in the wall of the stomach or intestines (primarily with Zaltrap).
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): A rare brain disorder characterized by headache, seizures, and confusion.

> Warning: Stop taking Aflibercept (or contact your doctor immediately) if you experience any of the following symptoms. These may indicate a life-threatening reaction or a severe complication.

• Signs of Eye Infection: Sudden vision loss, severe eye pain, increasing redness, or extreme sensitivity to light. These may be signs of endophthalmitis.
• Signs of a Blood Blot (Arterial Thromboembolic Events): Sudden numbness or weakness (especially on one side of the body), sudden severe headache, confusion, or problems with speech or vision. These could indicate a stroke or heart attack.
• Severe Bleeding: Coughing up blood, blood in the stool (black or tarry stools), or unusual vaginal bleeding. Aflibercept can interfere with the body's ability to stop bleeding.
• Gastrointestinal Perforation: Severe abdominal pain, swelling of the stomach, fever, or chills.
• Compromised Wound Healing: If you have a surgical wound that will not heal. Aflibercept must be stopped before and after major surgery.
• Severe Hypertension: Symptoms include chest pain, severe headache, or blurred vision.

With prolonged use of ophthalmic Aflibercept, some patients may develop persistent changes in intraocular pressure or a higher risk of developing cataracts. For oncologic use, long-term exposure can lead to chronic kidney issues (proteinuria) or persistent high blood pressure. There is also a theoretical risk of geographic atrophy (thinning of the retina) with long-term VEGF inhibition in the eye, though this is a subject of ongoing clinical debate.

For Zaltrap (Intravenous Infusion):

Zaltrap carries significant risks that are highlighted in its prescribing information, though they are not always formatted as a formal 'Black Box' in every jurisdiction, they are considered 'Warnings and Precautions' of the highest level:

1. 1Hemorrhage: Severe and sometimes fatal bleeding, including GI bleeding, has occurred.
2. 2Gastrointestinal Perforation: This can be fatal and requires immediate discontinuation of the drug.
3. 3Compromised Wound Healing: Zaltrap impairs the body's ability to heal wounds. It should not be administered for at least 4 weeks prior to elective surgery and until the wound is fully healed following surgery.

Report any unusual symptoms to your healthcare provider immediately. Early intervention is key to managing these risks.

Aflibercept is a powerful medication that requires careful monitoring. Patients must be aware that while it is highly effective, it carries risks related to its mechanism of action—specifically its effect on blood vessels throughout the body. Whether you are receiving it for eye disease or cancer, your healthcare team will perform regular check-ups to ensure the drug is not causing unintended harm.

While Aflibercept (Eylea) for the eye does not carry an FDA Black Box Warning, Zaltrap (intravenous) has several major warnings that are critical to patient safety:

• Hemorrhage Risk: Increased risk of severe bleeding. Patients on anticoagulants (blood thinners) must be monitored with extreme caution.
• GI Perforation: A risk of developing holes in the digestive tract.
• Wound Healing: Significant interference with surgical recovery.

Allergic Reactions / Anaphylaxis Risk

As a protein-based biologic, Aflibercept can cause hypersensitivity reactions. Signs of an allergic reaction include rash, itching, swelling of the face or throat, and difficulty breathing. If these occur during or after an infusion, seek emergency care.

Cardiovascular Risks

There is a potential risk of arterial thromboembolic events (ATEs), including non-fatal stroke, non-fatal myocardial infarction (heart attack), or vascular death. This risk is slightly higher in patients with a history of heart disease or stroke.

Nephrotoxicity (Kidney Damage)

For patients receiving Zaltrap, Aflibercept can cause significant protein loss in the urine (proteinuria). In severe cases, this can lead to nephrotic syndrome, a serious kidney condition. Regular urine tests are mandatory during treatment.

Hypertension (High Blood Pressure)

VEGF inhibitors are notorious for raising blood pressure. This is because VEGF helps blood vessels relax; blocking it causes them to constrict. Blood pressure must be well-controlled before starting treatment and monitored weekly during therapy.

To ensure safety, the following monitoring is typically required:

• Eye Exams: For Eylea, your doctor will check your vision and intraocular pressure before and after each injection. They will also look for signs of infection or retinal detachment.
• Blood Pressure: Monitored at every visit, and often at home.
• Urinalysis: To check for protein in the urine (for Zaltrap).
• Complete Blood Count (CBC): To monitor white blood cell levels, as Zaltrap can cause neutropenia.
• Liver and Kidney Function: Periodic blood tests to ensure these organs are processing the medication and chemotherapy correctly.

After an intravitreal injection (Eylea), your vision may be temporarily blurred due to the injection itself or the dilating drops used during the exam. Do not drive or operate machinery until your vision has fully recovered. For Zaltrap, fatigue or dizziness may occur; assess your reaction to the medication before driving.

There are no direct chemical interactions between Aflibercept and alcohol. However, alcohol can worsen certain side effects like dehydration (from diarrhea) or high blood pressure. It is best to limit alcohol consumption during treatment, especially when combined with chemotherapy.

Do not stop Aflibercept treatment without consulting your doctor. In the eye, stopping treatment can lead to a rapid and irreversible loss of vision. In cancer treatment, discontinuation is usually only recommended if the disease progresses or if side effects (like a GI perforation or severe bleeding) become life-threatening.

> Important: Discuss all your medical conditions, including any history of stroke, heart disease, or bleeding disorders, with your healthcare provider before starting Aflibercept.

Because Aflibercept is a biologic protein, it does not have the same 'small molecule' drug-drug interactions as many pills (like those involving the CYP450 enzyme system). However, there are critical contraindications:

• Live Vaccines: While not a direct chemical interaction, patients receiving Zaltrap with chemotherapy are often immunocompromised. Live vaccines (like MMR or Yellow Fever) should be avoided as they could cause a severe infection.
• Other VEGF Inhibitors: Using Aflibercept simultaneously with other systemic VEGF inhibitors (like Bevacizumab or Sunitinib) is generally contraindicated due to the additive risk of severe hypertension and hemorrhage.

• Anticoagulants and Antiplatelets: Drugs like Warfarin, Heparin, Aspirin, or Clopidogrel significantly increase the risk of bleeding when used with systemic Aflibercept (Zaltrap). If you must take these, your doctor will monitor your 'INR' or clotting time very closely.
• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Medications like Ibuprofen or Naproxen can increase the risk of GI bleeding and stomach ulcers, which is particularly dangerous given Aflibercept’s risk of GI perforation.

• Antihypertensive Medications: Aflibercept often raises blood pressure, which may require your doctor to increase the dose of your blood pressure medications (e.g., Lisinopril, Amlodipine). This is a pharmacodynamic interaction where the drug reduces the efficacy of the blood pressure treatment.
• Corticosteroids: When used in the eye, the combination of Aflibercept and steroid injections can significantly increase the risk of high intraocular pressure and cataracts.

• Grapefruit: Unlike many drugs, Aflibercept is not metabolized by the CYP3A4 enzyme, so grapefruit does not typically interfere with its levels.
• High-Fat Meals: No known interaction for the intravenous form. For the eye injection, food intake is irrelevant.
• Caffeine: May slightly increase blood pressure, potentially compounding the hypertensive effects of Zaltrap.

• St. John’s Wort: While it mainly affects CYP enzymes, it is generally advised to avoid it during chemotherapy (FOLFIRI) used with Zaltrap.
• Garlic, Ginkgo Biloba, and Vitamin E: These supplements have mild blood-thinning properties and could theoretically increase the risk of bruising or bleeding during Aflibercept treatment.

• Urine Protein Tests: Aflibercept frequently causes false positives or elevated readings in dipstick protein tests. A 24-hour urine collection may be required for a more accurate assessment of kidney function.
• Coagulation Tests: It does not directly change PT/INR or aPTT levels, but the clinical risk of bleeding remains high regardless of lab values.

Mechanism of Interactions

Most interactions with Aflibercept are pharmacodynamic. This means the drugs don't necessarily change the concentration of Aflibercept in your blood, but they have 'overlapping' effects (like both increasing bleeding risk or both affecting the kidneys).

Management Strategy

Your healthcare provider will manage these interactions by:

1. 1Adjusting the doses of secondary medications (like blood pressure pills).
2. 2Increasing the frequency of monitoring (blood tests, eye exams).
3. 3Temporarily pausing Aflibercept before surgeries to allow for proper healing.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, including over-the-counter pain relievers.

Conditions where Aflibercept must NEVER be used include:

1. 1Ocular or Periocular Infection: For Eylea, the drug must not be injected if there is an active infection in or around the eye. This is because the injection procedure could push bacteria into the eye, leading to endophthalmitis (a devastating internal eye infection).
2. 2Active Intraocular Inflammation: If the eye is currently inflamed (e.g., uveitis), an injection could worsen the condition.
3. 3Known Hypersensitivity: If you have had a severe allergic reaction (anaphylaxis) to Aflibercept or any of its ingredients (like polysorbate 20), you cannot receive the drug.
4. 4Severe Hemorrhage: For Zaltrap, it should not be started in patients with active, severe bleeding.

These conditions require a careful risk-benefit analysis by your specialist:

• Recent Stroke or Heart Attack: Because VEGF inhibitors may slightly increase the risk of blood clots, patients who have had a cardiovascular event in the last 6 months must be treated with caution.
• Uncontrolled Hypertension: High blood pressure must be brought under control with medication before Aflibercept (especially Zaltrap) is administered.
• Planned Surgery: Aflibercept should be stopped at least 4 weeks before major elective surgery because it prevents the growth of new blood vessels needed for wound healing.
• Pregnancy: The risks to the fetus usually outweigh the benefits unless the mother's condition is life-threatening.

Patients who have had an allergic reaction to other VEGF inhibitors (like Bevacizumab/Avastin or Ranibizumab/Lucentis) may be at a higher risk of reacting to Aflibercept, although they are different proteins. Always inform your doctor of any previous reactions to 'biologic' or 'monoclonal antibody' treatments.

> Important: Your healthcare provider will evaluate your complete medical history, including any recent surgeries or infections, before prescribing Aflibercept.

FDA Pregnancy Category: Not formally assigned (current labeling uses descriptive risk).

Based on its mechanism of action, Aflibercept is likely to cause fetal harm. VEGF is essential for the development of the fetus's vascular system. Animal studies have shown that systemic exposure to Aflibercept leads to severe birth defects (teratogenicity) and fetal death.

• Intravitreal Use: While systemic absorption is low, it is still recommended that Aflibercept only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.
• Intravenous Use: Women of childbearing potential should use effective contraception during treatment and for at least 3 months after the last dose. It is generally not recommended during pregnancy.

It is not known if Aflibercept passes into human breast milk. Because many drugs and large proteins are excreted in milk, and because of the potential for serious adverse reactions in the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug. Most oncologists recommend against breastfeeding while on Zaltrap.

Aflibercept is approved for Retinopathy of Prematurity (ROP) in neonates. In this specific population, it helps prevent blindness caused by overgrowth of blood vessels in the developing eye. However, the long-term effects on the development of other organs in infants are still being studied. It is not approved for any other pediatric conditions.

A large percentage of patients receiving Eylea are over 65 (due to the nature of AMD). Clinical trials have shown that Aflibercept is effective and generally safe in this age group. However, elderly patients receiving the intravenous form (Zaltrap) may be more prone to diarrhea, dehydration, and hypertension. Doctors should monitor kidney function and blood pressure more frequently in patients over 75.

• Mild to Moderate: No dose adjustment is needed.
• Severe / End-Stage: Use with caution. Aflibercept is not cleared by dialysis because it is a large protein. Patients with severe kidney disease are at higher risk for proteinuria and hypertension.

• Mild to Moderate: No specific dose adjustment is required based on current data.
• Severe: Aflibercept has not been studied in patients with severe liver impairment (Child-Pugh C). It should be used with extreme caution as the liver is involved in the eventual clearance of the protein's breakdown products.

> Important: Special populations, particularly pregnant women and the elderly, require individualized medical assessment and frequent monitoring.

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. It acts as a soluble decoy receptor (often called a 'VEGF Trap'). Unlike other VEGF inhibitors like Ranibizumab, which only bind to VEGF-A, Aflibercept binds to all isoforms of VEGF-A, as well as VEGF-B and Placental Growth Factor (PlGF).

By binding these ligands with a much higher affinity than their natural receptors, Aflibercept prevents them from activating the VEGFR-1 and VEGFR-2 receptors on endothelial cells. This inhibition prevents the phosphorylation of these receptors and the subsequent downstream signaling cascades (such as the MAPK and PI3K pathways) that lead to endothelial cell proliferation, migration, and increased vascular permeability.

In the eye, Aflibercept reduces the thickness of the retina by decreasing the leakage from abnormal blood vessels. This effect is usually seen within 1 to 4 weeks after injection. Systemically, Aflibercept reduces the blood supply to tumors, leading to tumor shrinkage or stabilization. The duration of effect in the eye is typically 4 to 12 weeks, which is why repeated injections are necessary.

| Parameter | Value (Systemic/Zaltrap) |

|---|---|

| Bioavailability | 100% (IV); Minimal (Intravitreal) |

| Protein Binding | High affinity to VEGF ligands |

| Half-life | ~6 days (Free Aflibercept) |

| Tmax | End of infusion (IV) |

| Metabolism | Proteolysis (catabolism) |

| Excretion | Not renally excreted as intact protein |

• Molecular Formula: C6382H9854N1712O1942S44 (approximate for the protein monomer)
• Molecular Weight: Approximately 115 kDa (kilodaltons) for the glycosylated protein.
• Solubility: Soluble in aqueous buffers.
• Structure: A dimeric glycoprotein consisting of two identical polypeptide chains.

Aflibercept is a Vascular Endothelial Growth Factor (VEGF) Inhibitor. It is categorized as an 'Antineoplastic Agent' in oncology and an 'Ophthalmic Agent / Antineovascular Agent' in ophthalmology. Related medications include Bevacizumab (Avastin), Ranibizumab (Lucentis), and Brolucizumab (Beovu).