Vascular endothelial growth factors promote neovascularization and break the blood-retinal barrier. Anti-vascular endothelial growth factor (anti-VEGF) therapies block VEGF's actions, decreasing abnormal new blood vessel formation and retinal leakage/swelling. This stabilizes vision and may improve it. Bevacizumab, ranibizumab, and aflibercept are examples of anti-VEGF drugs used intravitreally to treat wet age-related macular degeneration, diabetic retinopathy, retinal vein occlusion and other conditions. While effective, anti-VEGF therapies require frequent injections and monitoring for side effects like increased intraocular pressure.

2.  Vasculo endothelial growth factors are
molecules produced by endothelial
cells,pericytes,RPE,muller cells and glial
cells to promote neovascularisation
 Also responsible for break in blood retinal
barrier
The future implications and indications of anti-vascular endothelial growth factor
therapy in ophthalmic practice IJO

3. HYPOXIA
VEGF ISOFORMS
VEGF PROTIENS
NEOVASCULARISATION
RETINA ANTERIOR SEGMENT
The future implications and indications of anti-vascular endothelial growth factor
therapy in ophthalmic practice IJO

4.  The antibodies which blocks the actions of VEGFs are
anti VEGFs
 thus benefit the patients by decreasing the abnormal
and harmful new blood vessels formation and by
decreasing the leakage and swelling of the retina.
 This leads to stabilization of vision and even
improvement in vision in many cases.
The future implications and indications of anti-vascular endothelial growth factor therapy in
ophthalmic practice IJO

5. ANTI VEGF
PEGABTANIB RANIBIZUMAB BEVACIZUMAB
MACUGEN LUCENTIS AVASTIN
The future implications and indications of anti-vascular endothelial growth factor
therapy in ophthalmic practice IJO

6.  Humanized monoclonal antibody
 Active against all isoforms of VEGFs
 Received its first approval in 2004
 Rosenfield et al were the first ones to describe &
publish the off label use of intravitreal
Bevacizumab in 2005.
 MECHANISM OF ACTION: Bevacizumab (Avastin)
binds directly to VEGF Forms protein complex
Incapable of further binding to VEGF receptor
sites which would initiate vessel growth
effectively reducing available VEGF
The future implications and indications of anti-vascular endothelial growth factor therapy in
ophthalmic practice IJO

7.  Off-label use as an intravitreal agent in the
treatment of proliferative (neovascular) eye
diseases Particularly for Choroidal neovascular
membrane (CNV) in AMD. (not currently
approved by the FDA for such use)
 The injection of 1.25-2.5 mg of –NO significant
intraocular toxicity.
 Noted impressive results in the setting of: 1. CNV
2. Proliferative diabetic retinopathy 3.
Neovascular glaucoma 4. Diabetic macular
edema 5. Retinopathy of prematurity 6. Macular
edema secondary to retinal vein occlusions.

8.  Typically given by transconjunctival intravitreal
injections.
 Intravitreal injections for retinal pathologies are
typically administered at 4-6 week intervals,
although this varies widely based on disease and
response.
 DOSE: Typical dose is 1.25mg in 0.05ml in adults,
and half that dose in babies.
 COMBINATION THERAPY: Photodynamic
Therapy Anti PDGF Intravitreal Triamcinolone
Triple Therapy Radiation
 BENEFITS: Reduces frequency of injections
Reduces recurrence

9.  1.High efficacy
 2. Longer half life upto
20 days & thus fewer
injections
 3. Lack of preservative
 4. Higher safety dose
Retinal toxicity occurs
at dosage > 3.5mg
 5. Lower cost
 6. Wide availability
 CNS: Headache,
Dizziness, Sensory
neuropath y
 CVS: HTN, Thrombo-
embolsim
 Dermat: Alopecia (32%)
 GI: Abdominal pain,
vomiting, anorexia
 Haemat: Bleeding,
leukopenia, neutropenia
 Genitourinary:
Proteinuria, vaginal
haemorrhage
 RS: URTI, epistaxis

10. RANIBIZUMAB
NON BINDING FRAGMENT Fab FRAGMENT
MAKES IT HUMANISED MOUSE DERIVED
LESS ANTIGENIC ACTIVE AGAINST ALL VEGF
ISOFORMS
HIGH AFFINITY BINDING SITE
The future implications and indications of anti-vascular endothelial growth factor
therapy in ophthalmic practice IJO

11.  Lucentis is an monoclonal antibody fragment
(Fab) developed from the identical parent
antibody as Avastin.
 Lucentis was approved for neovascular AMD
in the U.S. in 2006
 MECHANISM OF ACTION: Much smaller than
the parent molecule and has been affinity
stronger binding to VEGF-A.
 Anti-angiogenic property. Unlike the full
length antibody, it penetrates the ILM and
can gain access to the sub retinal space.

12.  Available as Injection, intravitreal 10 mg/mL
 Dose: 0.5 mg/0.05 ml once every month
 PHARMACOKINETICS: Vitreous t1/2 = 3 days
(animals) 9 days (humans) Serum concentrations
upto 2000x lower than in the vitreous.
 Reduction in Ranibizumab clearance in renal
impairment is considered clinically insignificant &
dose adjustment is not expected to be needed.
 DRUG INTERACTIONS: Have not been studied.
 SAFETY PROFILE: Serious ocular adverse events in 2
year MARINA study for ranibizumab 0.5 mg:
1. Endophthalmitis – 1.3% 2. Uveitis – 1.3% . 3. Retinal
tear – 0.4% 4. Lens damage – 0.4%
 Serious ocular adverse events in 1 year ANCHOR study for ranibizumab 0.5 mg : 1.
Endophthalmitis – 1.4 % 2. Uveitis – 0.7% There was no increase in systemic adverse effects such
as HTN, arterial thromboembolism in either study.

13. PEGABTANIN
FIRST ANTI ANGIOGENIC AGENT
28 BASE RNA APTAMER SELECTIVELY BIND VEGF 165
NON IMMUNOGENIC DOEST NOT AFFECT NORMAL
VASCULAR GROWTH

14.  Pegylated Aptamer Pegaptanib sodium
injection (brand name Macugen) is an anti-
angiogenic medicine for the treatment of
neovascular WET AMD.
 Discovered by Gilead Sciences and licensed in
2000 to EyeTech Pharmaceuticals.
 Approval was granted U.S.(FDA) in Dec 2004.
 MECHANISM OF ACTION: Specifically binds to
VEGF 165 ISOMER Protein that plays a critical
role in angiogenesis (the formation of new blood
vessels) Increased permeability (leakage from
blood vessels) Two primary pathological processes
responsible for vision loss associated with neovascular
AMD.

15.  ADMINISTRATION AND DOSAGE:
 Administered in a 0.3 mg dose once every six
weeks by intravitreal injection.
 Marketed as a pre-filled syringe.
 CONTRAINDICATED ocular or periocular
infections.
 PHARMACOKINETICS: (Not adequately studied in
humans) Absorption Very slow systemic
absorption Occurs within 1 to 4 days after 0.3
mg monocular dose. Metabolism & Excretion By
Endo & Exonucleases excreted by kidney.
 DRUG INTERACTIONS: Not affected by
Cytochrome P450 system.

16. BEVACIZUMAB RANIBIZUMAB
FULL SIZED ANTIBODY ANTIBODY FRAGMENT
148 KILODALTONS 48 KILODALTONS
HALF LIFE 20 DAYS HALF LIFE 3 DAYS
SLOW CLEARANCE 100 TIMES FASTER
COSTs LESS COSTLY
Comparative role of intravitreal ranibizumab versus bevacizumab in choroidal
neovascular membrane in age-related macular degeneration IJO

17.  Recombinant fusion protein consisting of VEGF- binding
portions from the extracellular domains of human VEGF
receptors 1 and 2, that are fused to the Fc portion of the
human IgG1 immunoglobulin.
 INDICATIONS :1. Neovascular (Wet) ARMD Recommended
dose for EYLEA 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).
 Macular Edema Following CRVO Recommended dose for
EYLEA is 2 mg (0.05 mL or 50 microliters). Administered
by intravitreal injection once every 4 weeks.
 CONTRAINDICATIONS: infections or active inflammations
of or near the eye
 AFLIBERCEPT is moving through clinical trials for further
intraocular and systemic indications.

18.  TOPICAL ANAESTHESIA GIVEN
 PAINTING WITH BETADINE WITH INSTILLATION OF
BETADINE IN CONJUNCTIVAL SAC
 DRUG TAKEN IN TUBERCULIN SYRINGE WITH 30G
NEEDLE (1.25MG/0.05ML)
 ASK PATIENT TO LOOK DOWN
 FROM SUPEROTEMPORAL QUADRANT 4mm AWAY
FROM LIMBUS NEEDLE IS INSERTED TOWARDS
CENTRE OF GLOBE AND DRUG INJECTED
 INJECTION SITE PRESSED WITH COTTON BUD
 Comparative role of intravitreal ranibizumab versus bevacizumab in choroidal
neovascular membrane in age-related macular degeneration IJO

19.  Injection volume : An injection volume of
0.05 mL is most commonly used.
 Safe volume to inject without preinjection
paracentesis is believed to be 0.1 mL to 0.2
mL.
 Larger injection volumes are uncommon,
exceptions: injection of gas for pneumatic
retinopexy
the injection of multiple intravitreal agents
in one session.

20.  Needle selection Needle size varies according to the substance injected, with 27-
gauge needles -triamcinolone acetonide and 30- gauge needles -anti-VEGF agents
ranibizumab, bevacizumab, and aflibercept.
 Studies suggest that smaller, sharper needles require less force for penetration and
result in less drug reflux. Needle length between 0.5 and 0.62 inches (12.7 to
15.75 mm) is recommended, as longer needles may increase risk of retinal injury if
the patient accidentally moves forward during the procedure.
 Injection site The patient should be instructed to direct his or her gaze away
from the site of needle entry. The injection is placed 3 to 3.5 mm posterior to the
limbus for an aphakic or pseudophakic eye, and 3.5 to 4 mm posterior to the limbus
for a phakic eye. Injection in the inferotemporal quadrant is common.
 Injection technique Some guidelines suggest pulling the conjunctiva over the
injection site with forceps or a sterile cotton swab to create a steplike entry path.
While this approach may, in theory, decrease reflux and risk of infection, a straight
injection path is most commonly employed. After the sclera is penetrated, the
needle is advanced toward the center of the globe and the solution is gently
injected into the midvitreous cavity.
 The needle is removed, and a sterile cotton swab is immediately placed over the
injection site to prevent reflux. IOP and CRA perfusion is assessed. Topical
Antibiotic is administered for one week.

22.  Wet Age-Related Macular Degeneration
 Proliferative Diabetic Retinopathy
 Retinal Vein Occlusion
 CNVM
 Neovascular Glaucoma
 Macular Edema
 Vitreous Hmg
 Comparative role of intravitreal ranibizumab versus bevacizumab in choroidal
neovascular membrane in age-related macular degeneration IJO

23.  POSTERIOR SEGMENT
 ROP
 EALES disease
 Refractory post surgical
CME.
 COATS disease
 ANTERIOR SEGMENT
 Iris neovascularization
 Before Keratoplasty to
reduce to reduce
corneal
neovascularization
(2.25mg IN 0.1ml near corneal
vasc.)
 Pterygium
(1.35mg/0.05m s/c)
 Trabeculectomy (to
modulate wound
healing

24.  Raised IOP (13-17.6%)
 Cataract (0.07%)
 Endophthal mitis (0.1- 1%)
 Risk of ATE(4.6%)( decrease the synthesis of
matrix metalloprote inases)
 Rebound macular edema Immunoreac
tivity(4.4- 6.3%)
 Retinal detatchment (0.08%)
 Central Retinal Artery Occlusion

25.  1.Fibrovascular proliferation threatening the
macula
 2. Active ocular or periocular inflammation
 3. Known hypersensitivity to drugs
 4. Uncontrolled hypertension 5.
Cardiovascular disease
 6. Pregnancy and lactation
 7. Pre pubescent children

26.  For the treatment of patients with wet
AMD, DME, RVO, or CNV due to PM,
bevacizumab is the preferred initial anti-
VEGF therapy, based on similar clinical
effectiveness and lower cost compared
with other anti-VEGF treatments.


27.  Ranibizumab or aflibercept can be used as
alternative treatment options in patients
who do not respond to bevacizumab or in
patients who experience
thromboembolism following the initiation
of bevacizumab treatment or who are at a
high risk of cardiovascular adverse events

28.  The frequency and dose of intravitreal
injections of the anti-VEGF drugs should be
determined by the treating ophthalmologist
 dose should not exceed that recommended
for a particular retinal condition by the
product monograph (if available) or that used
in randomized clinical trials.
 Comparative role of intravitreal ranibizumab versus bevacizumab in choroidal
neovascular membrane in age-related macular degeneration IJO

29.  Nowadays, anti-VEGF therapy has become
one of the more frequently applied
treatment modalities in ophthalmology.
The indications for its usage have become
wider and wider, but investigators still are
looking for new drugs with more
prolonged time of action or new forms of
drugs delivery.

30.  M. Rajappa, P. Saxena, and J. Kaur, “Ocular
angiogenesis: mechanisms and recent advances
in therapy,” Advances in Clinical Chemistry, vol.
50, pp. 103–121, 2010.
 PMLive, “Top Pharma list,” November 2014
 J. G. Arroyo, “Towards a rational approach to
combination therapy for neovascular age
related macular degeneration,” The British
Journal of Ophthalmology, vol. 91, no. 2, pp.
130–131, 2007.

31.  J. W. Miller, A. P. Adamis, D. T. Shima et al.,
“Vascular endothelial growth factor/vascular
permeability factor is temporally and
spatially correlated with ocular angiogenesis
in a primate model,” American Journal of
Pathology, vol. 145, no. 3, pp. 574–584, 1994
 L. P. Aiello, R. L. Avery, P. G. Arrigg et al.,
“Vascular endothelial growth factor in ocular
fluid of patients with diabetic retinopathy
and other retinal disorders,” The New
England Journal of Medicine, vol. 331, no.
22, pp. 1480–1487, 1994.

32.  M. S. Gordon, K. Margolin, M. Talpaz et al.,
“Phase I safety and pharmacokinetic study of
recombinant human anti-vascular endothelial
growth factor in patients with advanced
cancer,” Journal of Clinical Oncology, vol. 19,
no. 3, pp. 843–850, 2001
 E. S. Gragoudas, A. P. Adamis, E. T.
Cunningham Jr., M. Feinsod, and D. R. Guyer,
“Pegaptanib for neovascular age-related
macular degeneration,” The New England
Journal of Medicine, vol. 351, no. 27, pp.
2805–2816, 2004.

33.  The era of anti-vascular endothelial growth
factor (VEGF) drugs in ophthalmology, VEGF
and anti-VEGF therapy
 Dorota Pożarowska1 and Piotr Pożarowski2
 Author information ► Article
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