INTRAVITREAL INJECTIONS ARE A NEW MODALITY IN RETINAL DISEASES TREATMENT .

1. INTRAVITREAL
INJECTION AVASTIN
FACTS & MYTHS
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2. DR DINESH MITTAL DR SONALEE MITTAL
DRISHTI EYE HOSP INDORE INDIA

3. What is intravitreal inj AVASTIN
• Intravitreal inj are a effective mode of treatment of
many retinal vascular diseases like diabetic
maculopathy , age related macular degeneration
ARMD and retinal vascular occlusions .
• The development of vascular endothelial growth
factor VEGF inhibitors for the treatment of ocular
neovascularization and macular edema can be
regarded as the beginning of a new era in
ophthalmological therapy. Before the year 2000, the
treatment of any vascular abnormality in the macular
region was merely restricted to laser
photocoagulation

4. INJECTION dose of drug for DME
Intravitreal drug AVASTIN LUCENTIS TRIAMCINOLONE
Intravitreal dose 1.25 mg .3 mg 2 mg
strength in vial 25 mg / ml 10 mg / ml 40 mg / ml
Amt in cc injected .05 ml .03 ml .05 ml
To be repeated after 1 month 1 month 3 to 4 months
NUMBER OF INJ PER
VIAL
50 1 1
Cost per inj 6.5 thousand rs
(DOCTOR COST less
than 2000 )
25 thousand rs
(DOCTOR COST
18000 RS )
1000 rs
(DOCTOR COST less
than 200 RS )

5. HOW MANY AVASTIN INJ PER VIAL
• The 1.25 mg / .05 ml dosage is administered . AVASTIN
is prepared in pharmacy department aseptically .
They prepare a batch of syringes for use in a later
clinic with storage of such syringes for up to 14 days
in a refrigerator. One vial contains 4 ml and strength is
25 mg / ml . Each vial of Avastin® contains 100 mg of
bevacizumab, sufficient for 80 doses however it would
be difficult to extract this exact quantity.
• One method employed is to fill syringes with between
2.0 and 2.5 mg of bevacizumab (0.08 to 0.10 millilitre)
resulting in up to 50 doses per vial of Avastin®."

6. WHICH ANTI VEGF INHIBITOR
•BEVACIZUMAB ( AVASTIN ) &
RANIBIZUMAB ( LUCENTIS ) are
two of anti VEGF agents and both
are owned by GENTECH USA .
•Both are equally effective but
AVASTIN is not FDA approved .

7. DME
• One in every 25 diabetic patients of age 40 or older
experiences diabetic macular edema (DME).
Although there has been a paradigm shift in their
management with the advent of anti-VEGF agents,
a sizeable number of patients with DME are
resistant to these agents despite frequent
(monthly) intravitreal injections. Several recent
studies have shown incomplete response to such
agents despite rigorous study protocols, illustrating
the problem of persistent DME. The management of
these patients is challenging and frustrating

8. 1. nerve fiber layer ( hyper reflective )
2. ganglion cell layer ( hypo reflective )
3. internal limiting membrane ( hyper reflective )
4. inner plexiform layer ( hyper reflective )
5. inner nuclear layer ( hypo reflective )
6. outer plexiform layer ( hyper reflective )
7. outer nuclear layer ( hypo reflective )
8. external limiting membrane ( hyper reflective )
9. photoreceptors ( hyper reflective )
10.pigment epithelium ( hyper reflective )
Normal retina layers

9. MACULA layers

10. vitreous
internal limiting membranenerve fiber layer
ganglion cell layer & inner plexiform layer
inner nuclear layer & outer plexiform layer
photoreceptors
pigment epithelium
bruch’s membrane &
choriocapilaris
outer nuclear layer & external limiting
memmbrane
sclera
TEN RETINAL LAYERS

11. LAYERS OF RETINA ON OCT

12. Definition of Macular Edema
• Macular edema is defined as accumulation
of fluid in macula. Histologically, fluid
accumulation may occur in intercellular
space or may be intracellular, causing
cellular swelling. Clinically, ME can be
classified as diffuse, with generalized
leakage throughout the posterior pole, or
focal, if discrete areas of retinal thickening
are present (usually caused by leakage from
microaneurysms or dilated capillaries).

13. AETIOLOGY
MACULAR ODEMA

14. INNER BRB

15. OUTER BRB

16. Mechanisms in DR
Leading to DME
•For decades DR has been mainly considered
simply a microvascular disorder, caused by
endothelial cell damage, pericyte loss, and
secondary breakdown of the inner blood-
retinal barrier (BRB), leading to DME
formation. Other factors such as hypoxia,
altered blood flow, retinal ischemia, and
inflammation are also associated with the
progression of DR and DME .

17. Mediators in DME (VEGF)
• Vascular Endothelial Growth Factor (VEGF) is increased in
human ocular fluids and plays a crucial role in ischemic
retinal diseases, such as DR and retinal vein occlusions . The
VEGF family includes different isoforms: VEGF-A has been
shown to be upregulated in hypoxic tissues. In DR, the loss of
retinal capillaries is believed to lead to hypoxia, which is the
main stimulus for increased retinal expression of VEGF-A,
mediated through hypoxia-inducible factors. VEGF-A has an
angiogenic role that is responsible for the progression of DR
to the proliferative stage. Apart from its angiogenic role,
VEGF-A increases vascular permeability . Thus, the role of
VEGF-A may be central to DME pathogenesis. Moreover,
several studies have demonstrated the efficacy of anti-VEGF
treatment of DME, thus supporting the role of VEGF.

18. •Ranibizumab in 2012 & Aflibercept in 2014
were approved for treatment of DME by the
FDA . AVASTIN is still not approved by FDA .
•In the phase 3 RISE and RIDE studies that
compared ranibizumab 0.3 and 0.5 mg, the
higher dose was associated with more
deaths without providing any efficacy
advantage compared to the lower dose. As a
result of these studies, Ranibizumab 0.3 mg
is the approved dose for treating DME.

19. •As we know, corticosteroid agents are
not without attendant risks. IOP
elevation and cataract formation are
most notable side effects, for which we
regularly monitor our patients started on
steroids . In our experience, these side
effects, although common, are
effectively managed with topical
glaucoma medications and cataract
surgery, respectively .

20. Do you do laser
•Although laser usage has decreased, it has
not been totally eliminated. WE still use the
laser for high-risk, extra-foveal areas with
circinate exudates. Since the introduction of
anti-VEGF, our laser use has significantly
decreased. LASER is also used after anti
vegf and steroid therapy to supplement there
effect and to reduce the number of injections
. If DME is not invoving centre and pt is
asymptomatic then also we may apply laser .

21. INTRAVITREAL INJECTIONS
•Intravitreal injections and implants, most
often an office procedure, are a safe,
effective and common method of delivering
medication to the eye.
•Topical anesthesia usually sufficient
• Sterile technique with eyelid speculum used
• Small gauge needles 30-gauge can be used
for intravitreal injections

22. INTRAVITREAL INJECTIONS
•Effective method to deliver anti-vascular
endothelial growth factor (VEGF)
medications, corticosteroids, anti-
bacterials, anti-viral agents, air and gas
. For Anti VEGF 30 g needle and for
triamcinolone 27 g needle is used . For
dexamethasone implant 22 g inserter is
used .

23. Intravitreal Injections Introduction
•The office delivery of medication directly
into the vitreous cavity via injection or
implant has become commonplace in
ophthalmology. This method allows for higher
concentrations in the eye with less systemic
absorption compared to other methods of
medication administration.
•In 1911, the injection of air into the vitreous
cavity for retinal detachment (RD) repair was
initially reported.

24. INTRAVITREAL
INJECTION
TECHNIQUE
RECOMMENDA
TIONS

25. Intra
vitreal
injection
site

26. PRE-INJECTION PREPARATION
•Treatment of overt, active blepharitis
should be done prior to injection to attempt
to decrease bacterial load, which may
increase risk of infection. Patients with
bacterial or viral conjunctivitis should be
treated to manage infection and have their
injection rescheduled. As with any surgical
procedure all patients should sign an
informed consent after being explained the
risks, benefits, and alternatives to injection

27. INJECTION
•The needle used for injection should be 30 g
for a routine injection of medication or gas.
A smaller needle gauge may result in less
procedure discomfort for patients. The force
required to penetrate the sclera is almost
twice as much using a 27-gauge needle
compared to 30- or 31-gauge needles.
Needle length should be 1/2 to 5/8 inches to
prevent globe trauma.

28. INJECTION which gauge of needle
•The majority of retinal specialists
surveyed in 2010 used a 30-gauge
needle for BEVACIZUMAB and
RANIBIZUMAB, and a 27-gauge
needle for TRIAMCINOLONE.
Triamcinolone can precipitate
within the syringe and clog a needle
smaller than 27-gauge.

29. INJECTION dose of drug for dme
Intravitreal drug avastin lucentis triamcinolone
Intravitreal dose 1.25 mg .3 mg 2 mg
strength in vial 25 mg / ml 10 mg / ml 40 mg / ml
Amt in cc injected .05 ml .03 ml .05 ml
To be repeated after 1 month 1 month 3 to 4 months
NUMBER OF INJ PER
VIAL
50 1 1
Cost per inj 6.5 thousand rs
(DOCTOR COST less
than 2000 )
25 thousand rs
(DOCTOR COST
18000 RS )
1000 rs
(DOCTOR COST less
than 200 RS )

30. INJECTION
• Separate needles should be used to remove
medication from vial & to perform the
actual injection. This helps prevent both
contamination & dulling of the needle. The
injection is through pars plana and should
be performed approximately 3.5 mm from
the limbus in pseudophakic patients and 4.0
mm from the limbus in phakic patients.
Injections are commonly performed in
inferotemporal and superotemporal quadrants.

31. INJECTION
•Inserting needle perpendicular to eye is
preferred over other techniques .
•The injection should be done in a slow,
steady maneuver to prevent a sudden
flux through the vitreous cavity, as this
may disrupt vitreoretinal adhesions.
•A sterile cotton tip applicator may be
used to prevent reflux for injections

32. Injection Technique
• Confirm informed consent obtained
• Surgical time-out to confirm correct
medication and correct eye
•Place patient in near supine position; make
sure the headrest of the chair is stable
• Topical proparacaine (wait 10-15 seconds
before placing Betadine)
• 10% Betadine swab to inferior cul-de-sac, to
allow Betadine to start working; ask patient
to blink multiple times to spread Betadine .

33. Injection Technique
•Place 2% lidocaine jelly on the eye, focusing
on inferotemporal quadrant.
• (Note: Betadine placed prior to lidocaine
jelly to sterilize the globe prior to placing the
jelly so as not to have bacteria trapped in the
jelly and possibly increase risk of
endophthalmitis).
• Ask patient to close their eyes, and return in
2-5 minutes.

34. Injection Technique
•Apply Betadine swab again to inferotemporal
quadrant and inferior cul-de-sac, as well as to
eyelashes (do not manipulate much so as not
to liberate bacteria from the lashes)
• Place sterile closed-blade eyelid speculum
(careful not to cause corneal abrasion and
save yourself a phone call from the patient
with a painful corneal abrasion).
• Clean again with Betadine

35. Injection Technique
• Mark location of injection: 3-3.5mm for
pseudophakes, 3.5-4.0 mm for phakic
patients. Tip: Can use the end of a
TB syringe (without needle attached) to mark
3.5-4.0 mm. After marking and causing an
indentation with the TB syringe, you can
place Betadine again - Betadine will sit in
indentation ring and nicely highlight the
injection site. Careful with subconj
anesthesia so as not to cause too much
chemosis or subconj hemorrhage as this case

36. Injection Technique
•Have the patient look 180 degrees away from
the injection site. For example, if injecting
the right eye in the inferotemporal quadrant,
ask the patient to look up and to the left.
•Hold syringe in dominant hand, and a cotton
tip in the non-dominant hand
•Do not talk and ask patient not to talk during
the injection. Make sure the needle tip
(which is usually short 30g) is always kept
absolutely sterile
•Using your dominant hand, rest your wrist on
the patient's cheek for hand stabilization

37. Injection Technique
•Insert the needle at marked site in a smooth
and single motion, aiming for mid-vitreous cavity
•Insert the short 30g needle about 1/2 length
in (to make sure you are in the vitreous cavity
and not in subretinal space)
•Swing over with your non-dominant hand to
push down on the plunger in a smooth
fashion. (Note: some surgeons prefer to
inject with one-hand; the author feels that
using two hands is more stable).

38. Injection Technique
• Do not move the needle while inside
the eye so as to not cause traction on
the vitreous and potentially cause a
retinal tear / detachment.
•As you remove the needle out, cover
the injection site with a cotton tip
that is in your non-dominant hand
•Rinse the Betadine off of the patients
eye

39. Injection Technique
• Ensure optic nerve perfusion (patient
should be at least light
perception). Paracentesis is usually not
required, unless a large volume of
medication is injected. Some Retina
Specialists prefer to check and
document the IOP and not let the patient
leave until the IOP has reduced to an
acceptable level.

40. Bevacizumab AVASTIN
• Recombinant humanized monoclonal antibody that
blocks angiogenesis by inhibiting VEGF-A
• It received its first approval in 2004, for
combination use with standard chemotherapy for
metastatic colon cancer
• It has since been approved for use in
• Certain lung cancers,
• Renal cancers,
• Ovarian cancers
• Glioblastoma multiforme of the brain

41. ADMINISTRATION AND DOSING
•In ophthalmology, Bevacizumab is typically
given by transconjunctival intravitreal
injections into the posterior segment
• Intravitreal injections for retinal pathologies
are typically administered at 4-6 week
intervals, although this varies widely based
on disease and response.
•DOSE: The typical dose is 1.25mg in 0.05ml
in adults,and half that dose in babies.

42. RANIBIZUMAB
• Available as Injection, intravitreal 10 mg/mL
• Binds to and inhibits the biologic activity of VEGF-A
Pharmacokinetics:
• Absorption:
• C max is below the concentration thought necessary to inhibit
biological activity of VEGF-A by 50% (0.3 to 2.36 ng/mL).
• T max is 24 h.
• Elimination: Vitreous elimination half-life is
approximately 9 days.

43. threshold for starting anti- VEGF
injections in a patient?
•If my patient is symptomatic, I begin
treatment. But DME differs from AMD
in several ways. For one, you do not
have to treat a patient with DME
immediately. If a patient is 20/20 or
20/25 and asymptomatic, even with
350 to 400 μm of edema, I watch and
wait.

44. threshold for starting anti- VEGF
injections in a patient?
•Improving this patient’s condition
may require seven to eight ocular
injections during the first year, and
outcomes might not be discernable
to the patient.
•If a patient’s vision worsens within 2
or 3 months, I begin injections

45. If you choose to include steroids in
your treatment regimens, which one
do you use first
•I use triamcinolone suspension, 1 mg
to 2 mg as recommended by the
Protocol B and the SCORE studies. I
used to use a 4-mg dose, but now we
know that the same biologic effect
occurs with 1 mg, and that greatly
reduces the complication rate.

46. IST YEAR ANTI DME TREATMENT
• The great outcomes in RISE/RIDE,
VIVID/VISTA and Protocol I require a very
heavy burden, especially in that first year.
That is one of the real key points. In AMD, the
initiation phase/loading dose has usually
involved three injections . However, in DME,
there is a much heavier 9 OR 10 injection
burden in the first year. It is a very steady,
gradual improvement in both visual acuity and
OCT outcomes .

47. DRCR.net Protocol I
• DRCR.net Protocol I, patients were
started off with a loading dose of four
injections, but if patients did not have
20/20 vision and no edema, they were
given an additional two injections. So in
reality, it was a six-dose loading phase.
Comparatively speaking, in AMD it is
traditionally a three-dose loading
phase.

48. DRCR.net Protocol I
•Most of the AMD studies that utilized a p.r.n.
dosing strategy required six to seven
injections in the first year in comparison to
Protocol I and T, where the average was
higher with nine to 10 injections . Protocol I
was instrumental in showing us that monthly
treatment is not necessary to achieve vision
stabilization and letter gain comparable with
the more continuous treatment regimens in
RISE/RIDE .

49. TREATMENT OF DME VS ARMD
• It is important to distinguish wet AMD from
DME—these are, indeed, two very different
diseases. For patients with wet AMD, we are
treating choroidal neovascularization with
exudation. For patients with DME, we are
only treating edema, the source of which is
retinovascular incompetence. While we are
trying to get that macula to a satisfactory
dry status, the burden over time tends to fall
off in DME.

50. TREATMENT OF DME VS ARMD
•In wet AMD, there is more of a
continuous burden year after year for
an indefinite time frame in most
patients. In DME, studies with
discontinuous or P.R.N. style therapy
such as Protocol I and Protocol T,
many patients were eventually able to
cease therapy .

51. TREATMENT OF DME VS ARMD
•With wet AMD, whether it is P.R.N. or TREAT-
AND-EXTEND (TAE), the mean number of
treatments will typically reach a plateau after
the first year. It does not tend to decrease
much thereafter. But with DME, P.R.N.
studies that we have seen, Protocol I in
particular, started with a mean of eight to
nine injections in year 1, then three to four in
year 2, two to three in year 3 and by years 4
and 5, many had no further treatment .

52. How to reduce numer of injections
•Steroids can be used for reduced burden of
treatment as a combination therapy, but
probably not as a low-burden monotherapy
for most diabetic patients. There may be
special cases where steroids are best
choice as a monotherapy, such as in a newly
pseudophakic patient who develops macular
edema post-operatively, but results are simply
not as robust as with anti VEGF therapy.

53. Type of response to anti VEGF
•My patients typically fall into one of three
categories. The first is what we all want—a
patient who is exquisitely sensitive to anti-
VEGF therapy and needs only one injection to
have a very dramatic improvement. The
second group is what we dread—no
measurable response with anti-VEGFs after
three or four injections. The third group,
however, is what most of us see—people who
have some response to the anti-VEGF therapy.

54. final
• After all the studies, I think it is safe to say anti-VEGF is
our first-line defense. We have long-term outcomes from
the studies, and those results are extremely efficacious.
But it is a complex disease. Even when you look at the
results from Protocol T, the agent that worked the best
still left one-third of the patients with more than 250
microns of edema at 1 year. Most of us are using
bevacizumab, and many of our patients are going to have
persistent fluid even after 10 treatments in the first year. .
We don’t have large studies to dictate whether or not the
intravitreal triamcinolone should be our preferred
second-line agent.

56. HOW MANY AVASTIN INJ PER VIAL
• The 1.25 mg dosage is administered monthly "Another
consideration with bevacizumab is the preparation of
doses for intravitreal injection. A common approach
used in the clinical studies is for a pharmacy
department to aseptically prepare a batch of syringes
for use in a later clinic with one study reporting storage
of such syringes for up to 14 days in a refrigerator.
Each vial of Avastin® contains 100 mg of bevacizumab,
sufficient for 80 doses however it would be difficult to
extract this exact quantity.
• One method employed is to fill syringes with between
2.0 and 2.5 mg of bevacizumab (0.08 to 0.10 millilitre)
resulting in up to 50 doses per vial of Avastin®."

57. Pre-packaged syringes
• "Pre-packaged syringes of bevacizumab for
intravitreal use are available to purchase from
special manufacturing units. Moorfields
Pharmaceuticals, of Moorfields NHS hospital, can
supply syringes of 1.25 mg in 0.05 ml at £85 per
syringe, excluding VAT and delivery charges. The
syringes must be stored in a refrigerator and have
an expiry date of six weeks from the date of
manufacture, which would mean an effective expiry
of about two to four weeks from receipt of
delivery."

58. COMPOUNDING AVASTIN
• "Any compounding of a single vial of drug into
multiple dose units will carry some risk of
microbial and particulate cross contamination
beyond that associated with preparation of a single
dose. This risk can be minimised by performing the
procedure in an aseptic clean room using trained
staff and storing the finished product in a
refrigerator."

59. DME
• Our strategy in management of DME is as
follows – for cases of centre involving DME
with diffuse leak or leak close to the fovea,
intravitreal anti-VEGF
followed by laser is used.
.
.
In cases of DME where the leak is away from
macular centre without significant thickening
of fovea laser alone is preferred .

60. •The major problems with anti-VEGF therapy
are cost and frequency of administration. At
present, ranibizumab at a dose of 0.3 mg has
undergone the most rigorous testing, but due
to cost issues, worldwide, BEVACIZUMAB
1.25 mg is the drug of choice for DME . .
• Triamcinolone 2 mg is used to enhance or
to decrease number of required injections of
anti vegf drugs keeping in mind its
complications of cataract and glaucoma .
• Focal and grid laser should be used where
indicated

61. AVASTIN INDUCED ENDOPHTHALMITIS
• Vial itself may be adulterated and hence containing
toxins . So even if the vial is opened on the table and pt
given intravit injection pt. will develop symptoms like
TASS . In case of avastin symptoms will be localized in
posterior segment so this should be called TOXIN
POSTERIOR SEGMENT SYNDROME and not TOXIN
ANTERIOR SEGMENT SYNDROME ( TASS ) . These
symptoms will develop in few hours and are a type of
sterile reaction to toxins . And if the avastin gets
infected during compounding then infective endoph will
develop after some days .

62. AVASTIN INDUCED ENDOPHTHALMITIS
TOXIC INFECTIVE
TIME AFTER INJECTION WITH IN HOURS AFTER TWO THREE DAYS
REASON BECAUSE OF TOXINS IN
VIAL
BECAUSE OF BACTERIAL
CONTAMINATION
WHY IT HAPPENED BECAUSE OF SPURIOUS
VIAL
AT THE TIME OF
COMPOUNDINS OF VIAL
PREVENTION VIAL SHOULD BE
BROUGHT ONLY FROM A
RECOGNISED DEALER
AND THAT TOO WITH A
BILL
ALL STERILE
PRECAUTIONS SHOULD
BE TAKEN WHILE
COMPOUNDING THE VIAL
IN MULTIPLE SMALL
DOSES. THESE PREFILLED
INJECTIONS SHOULD BE
USED IN STIPULATED
TIME PERIOD

63. HOW TO PREVENT AVASTIN
INDUCED REACTIONS IN EYES
• 1 BEST IS FDA SHOULD APPROVE AVASTIN and
GENETECH should be persuaded to make available
avastin in small aliquots for intravitreal use .this
will help in three ways
• It will reduce price further .
• Spurious drugs will be knocked out and hence toxin
induced reactions will be avoided .
• Contamination of bacteria at the time of dispensing
AVASTIN will be avoided .

64. HOW TO PREVENT AVASTIN
INDUCED REACTIONS IN EYES
• 2. governments should appoint nodal agency in
country which will procure avastin directly from
genetech and it will dispense in small aliquots to
whole of country .
• It will again prevent us from spurious drugs and
also minimize the chances of bacterial
contamination .

65. HOW TO PREVENT AVASTIN
INDUCED REACTIONS IN EYES
• 3 . If above two steps are not feasible then is the
3rd step at the injecting surgeon level .
• MUST DO’S FOR INJECTING SURGEON
• 1 buy avastin vial from a well reputed and authrised
dealer and always insist for bill .it will save us from
spurios avastin vials .
• 2 dispense the vial in multiple preloaded injections
under asceptic conditions preferably in pharmacy
deptt.it will avoid bacterial contamination .

66. HOW TO PREVENT AVASTIN
INDUCED REACTIONS IN EYES
• 3. do not inject in all the pts together . Ist day
inject in two three eyes . Donot inject in both eyes
simultaneously .so that if disaster happens it will
happen only in one eye . See the response next day
and only then inject in other pts .
• 4 use all the prefilled intravitreal injections in
stipulated time period say two weeks .
• AVASTIN IS THERE TO HELP MAN TO REDUCE
BLINDNESS & MAN SHOULD ALSO USE IT
ACCORDINGLY TO DO THE SAME .

68. THANK
YOU
DR DINESH
DR SONALEE