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Preferred practice pattern Intravitreal Injection Guidelines Ekta Rishi and Pramod Bhende

Shri Bhagwan Mahavir With an increase in the number of intravitreal 1 Check the authorization letter of the bevacizu- Vitreoretinal Services, injections especially intravitreal anti-vascular mab dealer and buy the drug from a certified Sankara Nethralaya endothelial growth factor (anti-VEGF) agents the Roche dealer. Since the use in the eye is off risk for is a potential concern. label, the dealers may not have the authoriza- 1 Correspondence to: A meta-analysis by Jager et al. shows that the tion for supply to the ophthalmologists. We Ekta Rishi, prevalence of endophthalmitis following intra- can inspect the authorization and bills from Senior Consultant, vitreal injections is low. They evaluated the Roche periodically. Shri Bhagwan Mahavir incidence of endophthalmitis into infectious and 2 Check the drug license of the dealer. Vitreoretinal Services, non-infectious categories and found that the Sankara Nethralaya. E-mail: [email protected] endophthalmitis rate was 0.9% (38/4382) per eye and 0.3% (38/14 866) per injection, when looking Cold chain lapse at both infectious and non-infectious cases. They can be stored at 2–8°C for 45 days. also found endophthalmitis rate of 1.4% per injec- Roche monitors the cold chain on its server till it tion for intravitreal and transports to the authorized dealer. The company 0.2% per injection for intravitreal . also monitors and maintains a log of cold chain The risk of endophthalmitis after intravitreal at the storage facility of the dealer. injection may vary with various drugs.2 The reported Our suggestions incidence of endophthalmitis per patient in multi- • Inspect the cold chain maintenance of the center clinical trials with anti-vascular endothelial dealer. growth factor (VEGF) therapy ranged from 0.019 to 1.6%.2–4 Although cases of acute endophthalmitis • Verify that the drug has not been kept in stock following intravitreal bevacizumab (IVB) have for a long period. occurred, the exact incidence rate remains unknown. • Check how long does the dealer stocks the The injection technique and compounding issues drug. of bevacizumab remains the major areas of concern. Ranibizumab comes as a single use vial so the concerns are limited to injection techniques. Storage These guidelines are framed to reduce the risk Once purchased, check that the drug is brought in of endophthalmitis by streamlining the com- a dry ice pack preferably with a temperature mon- pounding and injection techniques with special itoring device. reference to bevacizumab. It should be stored at the hospital refrigerator The risk for endophthalmitis following at 2–8°C in a dark place with temperature display, Intravitreal Injections could be: power backup, and a temperature log. Electronic data loggers are available in the market to 1 Drug related: monitor the temperature. a Counterfeit medication The drug should be kept under lock so that b Lapse in cold chain limited people have the access to it and refriger- ator is not opened again and again to avoid a 2 Procedure related lapse in cold chain. a Multiple use of multi-dose vial Injection procedure related b Injection technique How to use the multi-dose vial of 4 ml? c Aseptic precautions The study by Bakri et al. shows that the drug can be kept in capped disposable 1 ml syringes Drug related when stored at 2–8°C with minimal loss of effi- This concern is more with off label drugs like cacy over 1 month, but there is no level 1 evi- bevacizumab. dence for sterility.6 There are published articles for compounding the drug in aliquots for multiple use Counterfeit medication but there are reports of endophthalmitis resulting There are reports of counterfeit medications across from compounding issues. the world for bevacizumab. In 2010–11, the We suggest opening a vial and preparing the concern was raised in China and the USA.5 required number of injections under sterile con- How to address and make sure that the drug is ditions and storing in different sterile boxes to be not fake? used within few hours if it has to be used by

80 Sci J Med & Vis Res Foun June 2015 | volume XXXIII | number 2 | Preferred practice pattern different surgeons in different operation theatres 3 days of topical fluroquinolones or pulse dose on the same day within the same theatre complex. of fluroquinolone eye drops on the same day One box can be sent to each operation theatre of injection. with the required number of filled syringes. • We suggest that the injector has a proper scrub It is preferred to do the injection procedure in wears disposable mask, and gloves. If in oper- operation theater or a sterile room designated for ation theatre, cap is mandatory. such procedures.7,8 • The eye lids and lashes should be scrubbed with 10% povidone iodine solution and eye Preparation of multiple syringes for use on a should be draped. given day • Lid speculum should be used to avoid the • Note the batch number of the drug so that it contact of eye lashes with the injection site. can be helpful for tracking, in case of Use of lid speculum is reported to reduce the endophthalmitis. risk of endophthalmitis in the intravitreal • To check the bevacizumab vial for expiry date injection procedure. Contact of the needle with – and label by the technician. eyelashes should be avoided.13 15 • Opening of the vial and cleaning of rubber lid • Injection can be administered after the use of by alcohol wipes. sterile proparacaine eye drops. • 18/20 G needle is inserted in the rubber lid of • The needle used to cap the drug syringe for vial by a scrubbed paramedical staff in the storage should be replaced by a 30G needle for operation theatre with mask and cap with injection.16 minimal talking. Instead of using the 18/20G • Oblique scleral entry is preferred over perpen- needle for puncture an instrument called dicular injection to prevent reflux of vitreous mini-spike (Braun) can be used to prepare mul- and wick related endophthalmitis.16–19 tiple syringes to avoid contamination. • Any quadrant can be chosen for injection • The vial must be held upside down by non- (infero-temporal quadrant is preferred, particu- scrubbed personnel in the operation theater larly for opaque drugs which otherwise can wearing a cap and mask cause significant visual disturbance, e.g. triam- • The scrubbed staff can withdraw 0.2 cc of bev- cinolone). Sterile calipers can be used to acizumab in a 1 cc disposable syringe and cap measure 3–4 mm from limbus (depending on it with the needle. lens status) to mark the injection site. • Prepare the number of injections required for • Usage of mask is a must. Avoid talking while the day by withdrawing drug from a single giving the injection. Gram-positive cocci are puncture by 18/20G needle. the commonest infections following intra- vitreal injections and droplet infection may be • The prepared capped syringes with the drug the source.12,20,21 can be stored in separate boxes depending on the number of surgeons giving the injection on • The eye can be patched with povidone iodine the given day. The boxes can be kept in a 5% drops for 2 hours after injection. – refrigerator maintained at 2 8°C and should be • Patients should be examined on post injection used on the same day. day 1 and 3. We suggest a good examination • One syringe can be sent for bacterial culture of anterior segment using slit lamp and fundus sensitivity testing so that on follow-up of using indirect ophthalmoscopy. Also check these patients the report can help us to decide using Applanation tono- the next plan of action in case of infection. metry. It is preferable to see the patient on the third post injection day as most of the • Preparation of similar aliquots in a sterile envir- endophthalmitis after bevacizumab have onment under a laminar hood is also described. occurred between 2 and 5 days. • Patients should be instructed to avoid head Injection technique bath for 1 day post injection and swimming • The literature suggests that prophylactic anti- for 3 days post injection. biotics are not better than the use of povidone • Post injection prophylaxis should be iodine 5% drops for a contact period of reserved for one-eyed patients and patients 5 minutes in the conjunctival cul-de-sac.9–12 with doubtful hygiene or with iodine allergy. • Patients with doubtful hygiene, one eyed and Most of the studies suggest no role of antibio- with known povidone allergy, can have either tics in post injection period.

Sci J Med & Vis Res Foun June 2015 | volume XXXIII | number 2 | 81 Preferred practice pattern

• In case the patient is due for injection in both 8. Abell RG, Kerr NM, Allen P, Vote BJ. Intravitreal injections: is eyes, it should be done at an interval of 3 days there benefit for a theatre setting? Br J Ophthalmol. 2012;96 – to avoid an increased level of circulating drug (12):1474 8. 9. Cheung CY, Wong AT, Lui A, Kertes PJ, Devenyi RG, Lam WC. in the system. Some studies suggest that separ- Incidence of endophthalmitis and use of antibiotic prophylaxis ate batch number of the vials may be used for after intravitreal injections. . 2012;119 the two eyes in case bilateral injections are (8):1609–13. required on the same day. 10. Kim SJ, Toma HS. Ophthalmic and resistance: a randomized, controlled study of patients • Anti-VEGF injections should be deferred in undergoing intravitreal injections. Ophthalmology. pregnant ladies or people with uncontrolled 2011;118:1358–63. hypertension or increased risk of thrombo- 11. Bhat SB, Stepien KM, Joshi K. Prophylactic antibiotic use after embolic phenomenon or recent history of intravitreal injection: effect on endophthalmitis rate. . – stroke or myocardial infarction. 2011;31:2032 6. 12. Moss JM, Sanislo SR, Ta CN. A prospective randomized • Injections should be avoided in people with evaluation of topical gatifloxacin on conjunctival flora in uncontrolled blood sugar levels as it may in patients undergoing intravitreal injections. Ophthalmology. – turn increase the chances of endophthalmitis. 2009;116:1498 501. 13. Green-Simms AE, Ekdawi NS, Bakri SJ. Survey of intravitreal injection techniques among retinal specialists in the United Discarding the unused drug States. Am J Ophthalmol. 2011;151(2):329–32. It is preferable to discard the unused drug and 14. Fineman MS, Hsu J, Spirn MJ, Kaiser RS. Bimanual assisted eyelid retraction technique for intravitreal injections. Retina. destroy the label. 2013;33(9):1968–70. The bottle can be discarded as per the norms. 15. Ratnarajan G, Nath R, Appaswamy S, Watson SL. Intravitreal injections using a novel conjunctival mould: a comparison with a conventional technique. Br J Ophthalmol 2013;l(4):395–7. References 16. Rodrigues EB, Grumann A Jr, Penha FM, Shiroma H, Rossi E, 1. Jager RD, Aiello LP, Patel SC, Cunningham ET Jr. Risks of Meyer CH, Stefano V, Maia M, Magalhaes O Jr, Farah ME. intravitreous injection: a comprehensive review. Retina. Effect of needle type and injection technique on pain level and 2004;24:676–98. vitreal reflux in intravitreal injection. J Ocul Pharmacol Ther 2. Scott IU, Flynn HW Jr. Reducing the risk of endophthalmitis 2011;27(2):197–203. following intravitreal injections. Retina. 2007;27:10–12. 17. Rodrigues EB, Meyer CH, Grumann A Jr, Shiroma H, Aguni JS, 3. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Farah ME. Tunneled scleral incision to prevent vitreal reflux Chung CY, Kim RY, for the MARINA Study Group. Ranibizumab after intravitreal injection. Am J Ophthalmol. 2007;143 for neovascular age-related . N Engl J (6):1035–7. Med. 2006;355:1419–31. 18. Knecht PB, Michels S, Sturm V, Bosch MM, Menke MN. 4. Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Tunnelled versus straight intravitreal injection: intraocular Kim RY, Sy JP, Schneider S, for the ANCHOR Study Group. pressure changes, vitreous reflux, and patient discomfort. Ranibizumab versus verteporfin for neovascular age-related Retina. 2009;29(8):1175–81. macular degeneration. N Engl J Med. 2006;355:1432–44. 19. De Stefano VS, Abechain JJ, de Almeida LF, Verginassi DM, 5. Wykoff CC, Flynn HW Jr, Rosenfeld PJ. Prophylaxis for Rodrigues EB, Freymuller E, Maia M, Magalhaes O, Nguyen QD, endophthalmitis following intravitreal injection: antisepsis and Farah ME. Experimental investigation of needles, syringes and antibiotics. Am J Ophthalmol. 2011;152(5):717–9. techniques for intravitreal injections. Clin Experiment 6. Bakri SJ, Synder MR, Pulido JS, McCannel CA, Weiss WT, Ophthalmol. 2011;39(3):236–42. Singh RJ. Six month stability of Bevacizumab (Avastin) binding 20. McCannel CA. Meta-analysis of endophthalmitis after to vascular endothelial growth factor after withdrawal into a intravitreal injection of anti-vascular endothelial growth factor syringe and refrigeration or freezing. Retina. 2006;26:519–22. agents: causative organisms and possible prevention strategies. 7. Casparis H, Wolfensberger TJ, Becker M, Eich G, Graf N, Retina. 2011;31(4):654–61. Ambresin A, Mantel I, Michels S. Incidence of presumed 21. Wen JC, McCannel CA, Mochon AB, Garner OB. endophthalmitis after intravitreal injection performed in the Bacterial dispersal associated with speech in the setting of operating room: a retrospective multicenter study. Retina. intravitreous injections. Arch Ophthalmol. 2011;129(12): 2014;34(1):12–7. 1551–4.

How to cite this article Rishi E, Bhende P. Intravitreal Injection Guidelines, Sci J Med & Vis Res Foun 2015; XXXIII:80–82.

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