INTRAVITREAL INJECTION AVASTIN

FACTS & MYTHS

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DR DINESH MITTAL DR SONALEE MITTALDRISHTI EYE HOSP INDORE INDIA

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

INJECTION dose of drug for DMEIntravitreal 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 )

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®."

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 .

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

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

MACULA layers

vitreousinternal limiting membranenerve fiber layer

ganglion cell layer & inner plexiform layer

inner nuclear layer & outer plexiform layer

photoreceptorspigment epitheliumbruch’s membrane &

choriocapilaris

outer nuclear layer & external limiting memmbrane

sclera

TEN RETINAL LAYERS

LAYERS OF RETINA ON OCT

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).

AETIOLOGY MACULAR ODEMA

INNER BRB

OUTER BRB

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 .

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.

•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.

•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 .

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 .

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

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 .

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.

INTRAVITREAL INJECTIONTECHNIQUE RECOMMENDATIONS

Intravitreal injection site

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

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.

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.

INJECTION dose of drug for dmeIntravitreal 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 )

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.

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

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 .

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.

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

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 affect your visibility of injection site mark.

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

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). 

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

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. 

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

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.

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.

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.

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

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.

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 .

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.

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 .

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.

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 .

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 .

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.

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.

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.

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®."

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."

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."

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 (Bevacizumab / Ranibizumab) followed by laser is used. Avastin is preferred over lucentis because of cost difference . Worldwide avastin is preferred over lucentis . In cases of DME where the leak is away from macular centre without significant thickening of fovea laser alone is preferred .

•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

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 .

AVASTIN INDUCED ENDOPHTHALMITIS

TOXIC INFECTIVETIME AFTER INJECTION WITH IN HOURS AFTER TWO THREE DAYSREASON BECAUSE OF TOXINS IN VIAL BECAUSE OF BACTERIAL

CONTAMINATIONWHY 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

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 .

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 .

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 .

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 .

THANK YOU

DR DINESHDR SONALEE