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Aflibercept

Class: EENT Drugs, Miscellaneous
Chemical Name: Vascular endothelial growth factor receptor type VEGFR1 (synthetic human immunoglobulin domain 2 fragment) fusion protein with vascular endothelial growth factor receptor type VEGFR2 (synthetic human immunoglobulin domain 3 fragment) fusion protein with immunoglobulin G1 (synthetic Fc fragment), dimer
Molecular Formula: C4318H6788N1164O1304S32
CAS Number: 862111-32-8
Brands: Eylea

Introduction

Recombinant humanized fusion protein; a vascular endothelial growth factor A (VEGF-A) and placental growth factor (PlGF) antagonist.1 2 3

Uses for Aflibercept

Neovascular Age-related Macular Degeneration

Treatment of neovascular (wet) age-related macular degeneration.1 5 7 9 22

Clinically equivalent to ranibizumab.1 May provide some advantages (e.g., decreased treatment burden) over other agents (e.g., bevacizumab, ranibizumab) because of less frequent administration.5 6 7 8 (See Dosage under Dosage and Administration.)

Macular Edema Following Retinal Vein Occlusion

Treatment of macular edema following retinal vein occlusion.1 11 12 13 15 16 17 18 19 26

Diabetic Macular Edema

Treatment of diabetic macular edema.1 14 20

Diabetic Retinopathy in Patients with Diabetic Macular Edema

Treatment of diabetic retinopathy in patients with diabetic macular edema.1 14 20

Aflibercept Dosage and Administration

Administration

Ophthalmic

Administer by intravitreal injection only into the affected eye(s); must be administered only by a qualified physician.1

Prior to intravitreal administration, withdraw entire contents of aflibercept vial through a sterile 5-mcm, 19-gauge filter needle (provided by manufacturer) into a 1-mL syringe (provided by manufacturer) using aseptic technique.1 Prior to intravitreal injection, replace filter needle with a sterile 30-gauge, ½-inch needle (provided by manufacturer).1 To obtain appropriate dose (2 mg), expel contents in syringe until plunger tip is aligned with the line that marks 0.05 mL on the syringe.1

Inject under controlled aseptic conditions (including surgical hand disinfection and use of sterile gloves, sterile drape, and sterile eyelid speculum [or equivalent]) following adequate anesthesia and administration of a topical broad-spectrum anti-infective agent.1

Monitor patients for elevation of IOP immediately following intravitreal injection;1 monitoring may include evaluation of optic nerve head perfusion or tonometry.1 A sterile paracentesis needle should be available, if required.1

Use each vial only for treatment of a single eye; discard any unused portion.1 If contralateral eye requires treatment, use a new vial; change sterile field, syringe, gloves, drape, eyelid speculum, and filter and injection needles before administering to the other eye.1

Dosage

Adults

Neovascular Age-related Macular Degeneration
Ophthalmic

Intravitreal injection: 2 mg into the affected eye(s) once every 4 weeks for 12 weeks, then 2 mg once every 8 weeks.1

Additional efficacy not demonstrated following administration every 4 weeks compared with every 8 weeks.1

Macular Edema Following Retinal Vein Occlusion
Ophthalmic

Intravitreal injection: 2 mg into the affected eye(s) once every 4 weeks.1

Diabetic Macular Edema
Ophthalmic

Intravitreal injection: 2 mg into the affected eye(s) once every 4 weeks for the first 5 injections, followed by 2 mg once every 8 weeks.1

Additional efficacy not demonstrated following administration every 4 weeks compared with every 8 weeks.1

Diabetic Retinopathy in Patients with Diabetic Macular Edema
Ophthalmic

Intravitreal injection: 2 mg into the affected eye(s) once every 4 weeks for the first 5 injections, followed by 2 mg once every 8 weeks.1

Additional efficacy not demonstrated following administration every 4 weeks compared with every 8 weeks.1

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.1

Renal Impairment

No dosage adjustment required.1

Geriatric Patients

No dosage adjustment required.1

Cautions for Aflibercept

Contraindications

  • Ocular or periocular infections.1

  • Active intraocular inflammation.1

  • Known hypersensitivity (e.g., severe intraocular inflammation) to aflibercept or any ingredient in the formulation.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity reactions reported.1 (See Contraindications under Cautions.)

Endophthalmitis and Retinal Detachment

Intravitreal injections, including with aflibercept, associated with endophthalmitis and retinal detachment.1 Always use proper aseptic injection technique.1

If signs or symptoms of endophthalmitis or retinal detachment (e.g., redness, sensitivity to light, pain, changes in vision [including blurred vision]) occur, manage appropriately.1

Increased IOP

Acute increases in IOP observed within 60 minutes of intravitreal injection.1 Sustained increases in IOP also observed following repeated intravitreal injections of VEGF antagonists.1 Monitor IOP and perfusion of optic nerve head and manage appropriately.1

Thromboembolic Events

Potential risk of arterial thromboembolic events following intravitreal injection of VEGF antagonists, including aflibercept.1

Immunogenicity

Incidence of immunoreactivity to aflibercept was similar before and after 24–100 weeks of therapy.1 No differences in efficacy or safety between patients with or without immunoreactivity.1

Specific Populations

Pregnancy

Category C.1

No adequate and well-controlled studies in pregnant women.1 Animal studies suggest a possibility of adverse embryofetal effects.1

Use only if potential benefits justify potential risk to fetus.1 Women of childbearing potential should use effective contraception prior to initiating therapy, during treatment, and for ≥3 months after last intravitreal injection is administered.1

Lactation

Not known whether aflibercept is distributed into milk.1 Use not recommended in nursing women.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No substantial differences in safety or efficacy relative to younger adults.1

Renal Impairment

No differences in plasma concentrations observed with various degrees of renal impairment.1 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Conjunctival hemorrhage,1 2 3 eye pain,1 2 3 cataract,1 vitreous detachment,1 2 3 vitreous floaters,1 2 increased IOP.1 2 3

Interactions for Aflibercept

No formal drug interaction studies to date.1

Aflibercept Pharmacokinetics

Absorption

Bioavailability

Following intravitreal injection, mean peak plasma concentration attained in 1–3 days; peak plasma concentration estimated to be >100-fold lower than concentration required to half-maximally bind systemic VEGF.1

Free aflibercept undetectable in plasma 2 weeks after intravitreal injection.1

No accumulation observed following repeated intravitreal injections (i.e., once every 4 weeks).1

Special Populations

Following intravitreal injection every 4 or 8 weeks, no differences in free plasma aflibercept concentrations observed between patients with mild, moderate, or severe renal impairment.1

Distribution

Extent

Not known whether aflibercept is distributed into milk.1

Elimination

Metabolism

Expected to undergo elimination through both target-mediated disposition via binding to free endogenous VEGF and via proteolysis.1

Half-life

Approximately 5–6 days following IV administration of doses of 2–4 mg/kg.1

Stability

Storage

Ophthalmic

2–8°C.1 Do not freeze; protect from light.1 Store in original carton until use.1

Actions

  • Acts as a soluble decoy receptor that binds to VEGF-A and PlGF and inhibits their biologic activity.1 2 7

  • VEGF-A induces neovascularization (angiogenesis) and increases vascular permeability,1 which appear to play a role in the pathogenesis and progression of neovascular (wet) age-related macular degeneration, macular edema following retinal vein occlusion, diabetic macular edema, and diabetic retinopathy.2 3 4 5 7 8 25 27 28 29

  • Binding to VEGF-A and PlGF prevents these factors from binding to endogenous VEGF receptors (i.e., VEGFR-1, VEGFR-2), reducing endothelial cell proliferation, angiogenesis, and vascular permeability.

  • Binding affinity of aflibercept for VEGF-A isoforms is higher than that of endogenous receptors; aflibercept blocks VEGF binding and activation of VEGFR-1 and VEGFR-2 even at low concentrations.2 3 4

Advice to Patients

  • Possible temporary visual disturbances after intravitreal injection and associated eye examinations; importance of avoiding driving a vehicle or operating machinery until visual function has recovered sufficiently.1

  • Risk of endophthalmitis or retinal detachment; importance of immediately seeking care from an ophthalmologist if change in vision occurs or if the treated eye becomes red, sensitive to light, or painful.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

    Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Aflibercept (Recombinant)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Ophthalmic

Injection, for intravitreal use only

40 mg/mL (2 mg/0.05 mL)

Eylea (available as single-dose vial with syringe, filter needle, and injection needle)

Regeneron

AHFS DI Essentials. © Copyright 2016, Selected Revisions March 31, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Regeneron Pharmaceuticals, Inc. Eylea (aflibercept) injection prescribing information. Tarrytown, NY; 2015 Jul.

2. Heier JS, Boyer D, Nguyen QD et al. The 1-year results of CLEAR-IT 2, a phase 2 study of vascular endothelial growth factor trap-eye dosed as-needed after 12-week fixed dosing. Ophthalmology. 2011; 118:1098-106. [PubMed 21640258]

3. Brown DM, Heier JS, Ciulla T et al. Primary endpoint results of a phase II study of vascular endothelial growth factor trap-eye in wet age-related macular degeneration. Ophthalmology. 2011; 118:1089-97. [PubMed 21640257]

4. Dixon JA, Oliver SC, Olson JL et al. VEGF Trap-Eye for the treatment of neovascular age-related macular degeneration. Expert Opin Investig Drugs. 2009; 18:1573-80. [PubMed 19694600]

5. Lally DR, Gerstenblith AT, Regillo CD. Preferred therapies for neovascular age-related macular degeneration. Curr Opin Ophthalmol. 2012; 23:182-8. [PubMed 22450218]

6. Stewart MW. Aflibercept (VEGF Trap-eye): the newest anti-VEGF drug. Br J Ophthalmol. 2012; :. [PubMed 22446028]

7. . Aflibercept (eylea) for age-related macular degeneration. Med Lett Drugs Ther. 2012; 54:9-10. [PubMed 22354219]

8. Ohr M, Kaiser PK. Intravitreal aflibercept injection for neovascular (wet) age-related macular degeneration. Expert Opin Pharmacother. 2012; 13:585-91. [PubMed 22300011]

9. Heier JS, Brown DM, Chong V et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012; 119:2537-48. [PubMed 23084240]

10. Regeneron Pharmaceuticals, Inc. Managed Care Dossier: Eylea (aflibercept). Tarrytown, NY; 2015 Apr.

11. Campochiaro PA, Clark WL, Boyer DS et al. Intravitreal aflibercept for macular edema following branch retinal vein occlusion: the 24-week results of the VIBRANT study. Ophthalmology. 2015; 122:538-44. [PubMed 25315663]

12. Boyer D, Heier J, Brown DM et al. Vascular endothelial growth factor Trap-Eye for macular edema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology. 2012; 119:1024-32. [PubMed 22440275]

13. Holz FG, Roider J, Ogura Y et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol. 2013; 97:278-84. [PubMed 23298885]

14. Korobelnik JF, Do DV, Schmidt-Erfurth U et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014; 121:2247-54. [PubMed 25012934]

15. Brown DM, Heier JS, Clark WL et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. Am J Ophthalmol. 2013; 155:429-437.e7. [PubMed 23218699]

16. Korobelnik JF, Holz FG, Roider J et al. Intravitreal aflibercept injection for macular edema resulting from central retinal vein occlusion: one-year results of the phase 3 GALILEO study. Ophthalmology. 2014; 121:202-8. [PubMed 24084497]

17. Clark WL, Boyer DS, Heier JS et al. Intravitreal aflibercept for macular edema following branch retinal vein occlusion: 52-week results of the VIBRANT study. Ophthalmology. 2015; :. [PubMed 26522708]

18. Heier JS, Clark WL, Boyer DS et al. Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS study. Ophthalmology. 2014; 121:1414-1420.e1. [PubMed 24679444]

19. Ogura Y, Roider J, Korobelnik JF et al. Intravitreal aflibercept for macular edema secondary to central retinal vein occlusion: 18-month results of the phase 3 GALILEO study. Am J Ophthalmol. 2014; 158:1032-8. [PubMed 25068637]

20. Brown DM, Schmidt-Erfurth U, Do DV et al. Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies. Ophthalmology. 2015; 122:2044-52. [PubMed 26198808]

21. Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015; 372:1193-203. [PubMed 25692915]

22. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology. 2014; 121:193-201. [PubMed 24084500]

23. Chang AA, Hong T, Ewe SY et al. The role of aflibercept in the management of diabetic macular edema. Drug Des Devel Ther. 2015; 9:4389-96. [PubMed 26273198]

24. Martin DF, Maguire MG. Treatment choice for diabetic macular edema. N Engl J Med. 2015; 372:1260-1. [PubMed 25692914]

25. Palejwala NV, Lauer AK. Aflibercept: an update on recent milestones achieved. Drugs Today (Barc). 2014; 50:779-90. [PubMed 25588083]

26. Yang LP, McKeage K. Intravitreal aflibercept (Eylea): a review of its use in patients with macular oedema secondary to central retinal vein occlusion. Drugs Aging. 2014; 31:395-404. [PubMed 24740170]

27. Das A, Stroud S, Mehta A et al. New treatments for diabetic retinopathy. Diabetes Obes Metab. 2015; 17:219-30. [PubMed 25160598]

28. Stewart MW. The clinical utility of aflibercept for diabetic macular edema. Diabetes Metab Syndr Obes. 2015; 8:473-82. [PubMed 26425104]

29. Evoy KE, Abel SR. Aflibercept: newly approved for the treatment of macular edema following central retinal vein occlusion. Ann Pharmacother. 2013; 47:819-27. [PubMed 23673531]

30. Wells JA, Glassman AR, Ayala AR et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016; :1-9.

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