Drug information of Aflibercept


Aflibercept

Drug group:

Aflibercept is a recombinant protein composed of the binding domains of two human vascular endothelial growth factor (VEGF) receptors fused with the Fc region of human immunoglobulin gamma 1 (IgG1). Structurally, Aflibercept is a dimeric glycoprotein with a protein molecular weight of 96.9 kilo Daltons (kDa). It contains approximately 15% glycosylation to give a total molecular weight of 115 kDa.

Aflibercept, as an ophthalmic agent, is used in the treatment of macular edema following Central Retinal Vein Occlusion (CRVO) and neovascular Age-Related Macular Degeneration (AMD). Ziv-aflibercept was developed as an injection for treatment of metastatic colorectal cancer.

Mechanism of effect

Ablibercept is a recombinant fusion protein that acts as a decoy receptor for the ligands, vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PIGF). It prevents these ligands to binding to endothelial receptors, VEGFR-1 and VEGFR-2, to suppress neovascularization and decrease vascular permeability. This ultimately will slow vision loss or the progression of metastatic colorectal cancer.

Pharmacodynamic

Compared to other anti-VEGF drugs like bevacizumab and ranibizumab, aflibercept has a higher binding affinity to VEGF-A (Kd = 0.5 pM).

Pharmacokinetics

Peak plasma time: 1-3 days

Peak plasma concentration: 0.02 mcg/mL

Vd: 6 L

Half-life: 5-6 days

Dosage

Adult

Macular Degeneration

2 mg (0.05 mL) by intravitreal injection q4Week for the first 3 injections, followed by 2 mg q8Week (~ every 2 months)

Some patients may need to be dosed as frequently as 2 mg q4Weeks (~ every 25 days, monthly), additional efficacy was not demonstrated in most patients when dosed q4Weeks compared to q8Weeks

Although not as effective as the recommended q8Week dosing regimen, after 1 year of effective therapy, may treat with 1 dose q12Weeks

Macular Edema

2 mg (0.05 mL) by intravitreal injection q4Week (~ every 25 days, monthly)

Diabetic Macular Edema (DME)

2 mg (0.05 mL) administered by intravitreal injection q4Week for the first 5 injections, followed by 2 mg q8Week

May be dosed as frequently as 2 mg q4Week; however, additional efficacy was not demonstrated when dosed q4Week compared to q8Week

Some patients may need q4Week (monthly) dosing after first 20 weeks (5 months)

Diabetic Retinopathy

2 mg (0.05 mL) administered by intravitreal injection q4Week for the first 5 injections, followed by 2 mg q8Week

May be dosed as frequently as 2 mg q4Week; however, additional efficacy was not demonstrated when dosed q4Week compared to q8Week

Some patients may need q4Week (monthly) dosing after first 20 weeks (5 months)

Colorectal Cancer

4 mg/kg IV infused over 1 hr q2weeks; administer before any component of the FOLFIRI regimen on the day of treatment 

Continue until disease progression or unacceptable toxicity occurs

 

Pediatric

Safety and efficacy not established

Alerts

ophtalmic

Endophthalmitis and retinal detachments reported with intravitreal injections

Acute increases in intraocular pressure (IOP) observed within 60 minutes of intravitreal injection; sustained increases also reported after repeat dosing; monitor and manage IOP and perfusion of optic nerve head

Potential risk of arterial thromboembolic events (eg, nonfatal stroke, nonfatal myocardial infarction, or vascular death) following intravitreal use of VEGF inhibitors (incidence over 1 yr varies depending on the study ranging from 1.5-6.4%); no thromboembolic events reported within the first 6 months of RVO studies

Hypersensitivity reactions may present as severe intraocular inflammation

Females of reproductive potential should use effective contraception prior to initial dose, during treatment, and for at least 3 months after last intravitreal injection

IV

Increased risk of fistula formation involving GI and non-GI sites; discontinue if fistula develops

Increased risk of Grade 3-4 hypertension; monitor BP q2weeks or more frequently if indicated; treat with appropriate antihypertensive therapy; temporarily suspend if hypertension uncontrolled, and permanently reduce dose to 2 mg/kg for subsequent cycles once blood pressure normalizes; discontinue with hypertensive encephalopathy or hypertensive crisis

Increased risk of arterial thromboembolic events (eg, TIA, CVA, and angina pectoris); discontinue if thromboembolic event occurs

Increased risk of higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection; monitor CBC with differential count at baseline and prior to initiation of each cycle; delay if neutrophil count ≥1.5 x 10^9/L

Increased risk of severe diarrhea, especially in patients aged ≥65 years; monitor closely

Increased risk of RPLS (also known as posterior reversible leukoencephalopathy syndrome); confirm RPLS diagnosis with MRI and discontinue if present; RPLS may resolve or improve within days, but some patients have experienced ongoing neurologic sequelae or death

Proteinuria

  • Increased risk of severe proteinuria, nephrotic syndrome and thrombotic microangiopathy (TMA)
  • Monitor by urine dipstick analysis and urinary protein creatinine ratio (UPCR)
  • Obtain 24-hour urine collection in patients with UPCR ≥1; suspend if proteinuria is ≥2 g/24hr, and resume when ≤2 g/24hr; if reoccurs, suspend until ≤2 g/24hr and permanently reduce dose to 2 mg/kg for subsequent cycles; discontinue in patients who develop TMA or nephrotic syndrome 

Black Box Warnings (IV)

Increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events (eg, severe intracranial hemorrhage, pulmonary hemorrhage/hemoptysis); monitor for signs and symptoms of bleeding, and discontinue if needed; do not administer with severe hemorrhage

Increased risk of GI perforation including fatalities; monitor for signs and symptoms of bleeding, and discontinue if needed

Shown to impair wound healing; suspend therapy for ≥4 weeks prior to elective surgery; resume therapy ≥4 weeks following major surgery or until surgical wound has healed; for minor surgical procedures (eg, tooth extraction, biopsy, central venous access port placement), resume therapy once surgical wound has healed completely; discontinue in patients with compromised wound healing

Points of recommendation

ophtalmic

  • Tell all of your health care providers that you take aflibercept (ophthalmic). This includes your doctors, nurses, pharmacists, and dentists.
  • Use care when driving or doing other tasks that call for clear eyesight.
  • Have your eye pressure checked. Talk with your doctor.
  • This medicine may raise the chance of very bad and sometimes deadly health problems caused by blood clots, like heart attack and stroke. Talk with the doctor.
  • This medicine may cause harm to the unborn baby if you take it while you are pregnant.
  • Use birth control before starting aflibercept (ophthalmic), during treatment, and for 3 months after your last dose.
  • If you get pregnant while taking aflibercept (ophthalmic) or within 3 months after your last dose, call your doctor right away.

iv

  • It is not known whether ziv-aflibercept will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.
  • Use birth control to prevent pregnancy while you are receiving ziv-aflibercept, and for at least 3 months after your treatment ends, whether you are a man or a woman.
  • This medication may affect fertility (your ability to have children), whether you are a man or a woman.
  • It is not known whether ziv-aflibercept passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using ziv-aflibercept.
  • ziv-aflibercept can pass into body fluids (urine, feces, vomit). For at least 48 hours after you receive a dose, avoid allowing your body fluids to come into contact with your hands or other surfaces. Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Pregnancy level

Group c - Not adequate studies in pregnant women


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