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47 Drugs used in ocular treatment
B.C.P. Polak
47 Drugs used in ocular treatment Intravitreal and parabulbar injection of drugs Both new angiostatic drugs and traditional glucocorticoids are currently undergoing evaluation in the treatment of diabetic retinopathy, diabetic macular edema, age-related macular degeneration (AMD), and other diseases of the posterior segment of the eye. New delivery techniques, such as intravitreal injections and intraocular sustained-release devices, facilitate high local concentrations of angiostatic and antipermeability drugs while minimizing intraocular and extraocular toxicity (1R –3R ). The risk of serious adverse events after intravitreal injection is low. Nevertheless, careful attention to injection technique and appropriate monitoring after injection are essential, because uncommon injection-related complications can be associated with permanent vision loss. A systematic research of the literature via PubMed from 1966 to 1 March 2004 was conducted to identify studies of the safety of intravitreal injection. Data submitted in New Drug Applications to the US Food and Drug Administration (FDA) for drugs administered into the vitreous were included where available. Serious adverse events reported in each study were included and risk per eye and risk per injection were calculated for the following serious adverse events: endophthalmitis, retinal detachment, iritis/uveitis, intraocular hemorrhage, ocular hypertension, cataract, and hypotony. Data from 14 866 intravitreal injections in 4382 eyes were analysed. There were 38 cases of endophthalmitis, a prevalence of 0.3% per injection and 0.9% per eye. Excluding cases reported specifically as pseudoendophSide Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29047-0 © 2007 Elsevier B.V. All rights reserved.
thalmitis, the prevalence of endophthalmitis was 0.2% per injection and 0.5% per eye. Retinal detachment, iritis/uveitis, ocular hypertension, cataract, intraocular hemorrhage, and hypotony were generally associated with intravitreal injection of specific compounds and were infrequently attributed by the investigators to the injection procedure itself. Retinal vascular occlusions were rare after intravitreal injection, and it was unclear in most cases whether these represented true injection-related complications or chance associations (4M ). Glucocorticoids are traditionally used in the eye for inflammatory disorders, such as keratitis and uveitis, because of their ability to diminish neutrophil transmigration, limit access to sites of inflammation, and reduce cytokine production. More recently investigators have focused on the angiostatic and antipermeability properties of glucocorticoids for posterior segment diseases, such as age related macular degeneration, diabetic retinopathy, and macular edema. Intravitreal glucocorticoid injections potently inhibit experimental choroidal neovascular membranes in primates and rats and have shown promise in some early human pilot trials. In proliferative diabetic retinopathy they may directly inhibit growth factors, such as vascular endothelial derived growth factor, and inhibit leukocytes, which play an important role in early microvascular alterations. In addition, the effect of glucocorticoids on vascular permeability has led to their use for macular edema from many causes, such as diabetes and venous occlusive disease. The apparent short-term success must be balanced by the fact that long-term safety and efficacy have yet to be determined for any of these approaches (5R ). Intravitreal triamcinolone In 15 patients with bilateral diabetic macular edema unresponsive to laser photocoagulation, one intravitreal injection of triamcinolone acetonide 4 mg was injected into one eye, under subconjunctival anesthesia, while the other eye served as a control. The main outcome measure was cen-
581
582 tral macular thickness at 1, 3, and 6 months, measured by optical coherence tomography. Secondary outcomes were Early Treatment Diabetic Retinopathy Study (ETDRS) scores, intraocular pressure, and cataract progression. Intravitreal injection of triamcinolone reduced macular thickening due to diffuse macular edema after 3 months. However, after 6 months the difference between the central macular thickness of injected and control eyes was no longer significant, because of recurrence of macular edema. In six of 12 injected eyes intraocular pressure exceeded 25 mmHg, and was controlled by topical medication (6c ). In another study, three patients developed a significant rise in intraocular pressure within 1 week after intravitreal injection of triamcinolone for refractory macular edema (7c ). In one patient a white material was found in the chamber angle on gonioscopy. All three patients required surgical intervention to reduce the intraocular pressure. Parabulbar triamcinolone Increased intraocular pressure has been reported after parabulbar triamcinolone. • A 53-year-old woman had been treated with glucocorticoid eye drops for continuous bilateral uveitis (8A ). For cystoid macular edema triamcinolone acetonide 32 mg was applied by bilateral subTenon’s capsule injection. Cystoid macular edema
Chapter 47
B.C.P. Polak
was reduced in both eyes 20 days after injection, but intraocular pressure was increased in both eyes (right eye 26 mmHg, left eye 37 mmHg). Because intraocular pressure continued to rise and visual field defects developed despite administration of antiglaucomatous medications, trabeculectomy was performed in both eyes. After surgery the intraocular pressure stabilized at about 10 mmHg.
In a double-blind, double-placebo study in 100 patients undergoing uncomplicated cataract surgery (phacoemulsification and intraocular posterior chamber lens implantation) intraoperative triamcinolone acetonide 40 mg by sub-Tenon’s capsule injection was compared with postoperative 1% prednisolone acetate eye drops (1 drop qds in week 1, tds in week 2, bd in week 3, and once daily in week 4) (9C ). Triamcinolone had anti-inflammatory efficacy equivalent to conventional 1% prednisolone eye drops in reducing intraocular inflammation and was as safe in terms of adverse effects, changes in visual acuity, and intraocular pressure. The intraocular pressure was significantly lower after triamcinolone than prednisolone.
Ocular dyes See Chapter 49 (p. 606).
References 1. Thompson MJ, Ip MS. Diabetic macular edema: a review of past, present and future therapies. Int Ophthalmol Clin 2004;44:51–67. 2. Kim RW, Heier JS. Innovative treatments for exudative age-related macular degeneration. Int Ophthalmol 2004;44:41–50. 3. Tranos PG, Wickremasinghe SS, Stangos NT, Topouzis F, Tsinopoulos I, Pavesio CE. Macular edema. Surv Ophthalmol 2004;49:470–90. 4. Jager RD, Aiello LP, Patel SC, Cunningham ET. Risks of intravitreous injection: a comprehensive review. Retina 2004;24:676–98. 5. Ciulla TA, Walker JD, Fong DS, Criswel MH. Corticosteroids in posterior segment disease: an update on new delivery systems and new indications. Curr Opin Ophthalmol 2004;15:211–20. 6. Massin P, Audren F, Haouchine B, Erginay A, Bergmann JF, Benosman R, Caulin C, Gau-
dric A. Intravitreal triamcinolone acetonide for diabetic diffuse macular edema: preliminary results of a prospective controlled trial. Ophthalmology 2004;111:218–24. 7. Singh IP, Ahmad SI, Yeh D, Challa P, Herndon LW, Allingham RR, Lee PP. Early rapid rise in intraocular pressure after intravitreal triamcinolone acetonide injection. Am J Ophthalmol 2004;138:286–7. 8. Konomi K, Nagasawa A, Mori A, Nomura M. A case of steroid-induced glaucoma caused by a sub-Tenon’s capsule injection of triamcinolone acetonide. Folia Ophthalmol Jap 2004;55:50–3. 9. Paganelli F, Cardillo JA, Melo LAS, Oliveira AG, Skaf M, Costa RA. A single intraoperative subTenon’s capsule triamcinolone acetonide injection for the treatment of post-cataract surgery inflammation. Ophthalmology 2004;111:2102–8.
47 Drugs used in ocular treatment Intravitreal and parabulbar injection of drugs Both new angiostatic drugs and traditional glucocorticoids are currently undergoing evaluation in the treatment of diabetic retinopathy, diabetic macular edema, age-related macular degeneration (AMD), and other diseases of the posterior segment of the eye. New delivery techniques, such as intravitreal injections and intraocular sustained-release devices, facilitate high local concentrations of angiostatic and antipermeability drugs while minimizing intraocular and extraocular toxicity (1R –3R ). The risk of serious adverse events after intravitreal injection is low. Nevertheless, careful attention to injection technique and appropriate monitoring after injection are essential, because uncommon injection-related complications can be associated with permanent vision loss. A systematic research of the literature via PubMed from 1966 to 1 March 2004 was conducted to identify studies of the safety of intravitreal injection. Data submitted in New Drug Applications to the US Food and Drug Administration (FDA) for drugs administered into the vitreous were included where available. Serious adverse events reported in each study were included and risk per eye and risk per injection were calculated for the following serious adverse events: endophthalmitis, retinal detachment, iritis/uveitis, intraocular hemorrhage, ocular hypertension, cataract, and hypotony. Data from 14 866 intravitreal injections in 4382 eyes were analysed. There were 38 cases of endophthalmitis, a prevalence of 0.3% per injection and 0.9% per eye. Excluding cases reported specifically as pseudoendophSide Effects of Drugs, Annual 29 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(06)29047-0 © 2007 Elsevier B.V. All rights reserved.
thalmitis, the prevalence of endophthalmitis was 0.2% per injection and 0.5% per eye. Retinal detachment, iritis/uveitis, ocular hypertension, cataract, intraocular hemorrhage, and hypotony were generally associated with intravitreal injection of specific compounds and were infrequently attributed by the investigators to the injection procedure itself. Retinal vascular occlusions were rare after intravitreal injection, and it was unclear in most cases whether these represented true injection-related complications or chance associations (4M ). Glucocorticoids are traditionally used in the eye for inflammatory disorders, such as keratitis and uveitis, because of their ability to diminish neutrophil transmigration, limit access to sites of inflammation, and reduce cytokine production. More recently investigators have focused on the angiostatic and antipermeability properties of glucocorticoids for posterior segment diseases, such as age related macular degeneration, diabetic retinopathy, and macular edema. Intravitreal glucocorticoid injections potently inhibit experimental choroidal neovascular membranes in primates and rats and have shown promise in some early human pilot trials. In proliferative diabetic retinopathy they may directly inhibit growth factors, such as vascular endothelial derived growth factor, and inhibit leukocytes, which play an important role in early microvascular alterations. In addition, the effect of glucocorticoids on vascular permeability has led to their use for macular edema from many causes, such as diabetes and venous occlusive disease. The apparent short-term success must be balanced by the fact that long-term safety and efficacy have yet to be determined for any of these approaches (5R ). Intravitreal triamcinolone In 15 patients with bilateral diabetic macular edema unresponsive to laser photocoagulation, one intravitreal injection of triamcinolone acetonide 4 mg was injected into one eye, under subconjunctival anesthesia, while the other eye served as a control. The main outcome measure was cen-
581
582 tral macular thickness at 1, 3, and 6 months, measured by optical coherence tomography. Secondary outcomes were Early Treatment Diabetic Retinopathy Study (ETDRS) scores, intraocular pressure, and cataract progression. Intravitreal injection of triamcinolone reduced macular thickening due to diffuse macular edema after 3 months. However, after 6 months the difference between the central macular thickness of injected and control eyes was no longer significant, because of recurrence of macular edema. In six of 12 injected eyes intraocular pressure exceeded 25 mmHg, and was controlled by topical medication (6c ). In another study, three patients developed a significant rise in intraocular pressure within 1 week after intravitreal injection of triamcinolone for refractory macular edema (7c ). In one patient a white material was found in the chamber angle on gonioscopy. All three patients required surgical intervention to reduce the intraocular pressure. Parabulbar triamcinolone Increased intraocular pressure has been reported after parabulbar triamcinolone. • A 53-year-old woman had been treated with glucocorticoid eye drops for continuous bilateral uveitis (8A ). For cystoid macular edema triamcinolone acetonide 32 mg was applied by bilateral subTenon’s capsule injection. Cystoid macular edema
Chapter 47
B.C.P. Polak
was reduced in both eyes 20 days after injection, but intraocular pressure was increased in both eyes (right eye 26 mmHg, left eye 37 mmHg). Because intraocular pressure continued to rise and visual field defects developed despite administration of antiglaucomatous medications, trabeculectomy was performed in both eyes. After surgery the intraocular pressure stabilized at about 10 mmHg.
In a double-blind, double-placebo study in 100 patients undergoing uncomplicated cataract surgery (phacoemulsification and intraocular posterior chamber lens implantation) intraoperative triamcinolone acetonide 40 mg by sub-Tenon’s capsule injection was compared with postoperative 1% prednisolone acetate eye drops (1 drop qds in week 1, tds in week 2, bd in week 3, and once daily in week 4) (9C ). Triamcinolone had anti-inflammatory efficacy equivalent to conventional 1% prednisolone eye drops in reducing intraocular inflammation and was as safe in terms of adverse effects, changes in visual acuity, and intraocular pressure. The intraocular pressure was significantly lower after triamcinolone than prednisolone.
Ocular dyes See Chapter 49 (p. 606).
References 1. Thompson MJ, Ip MS. Diabetic macular edema: a review of past, present and future therapies. Int Ophthalmol Clin 2004;44:51–67. 2. Kim RW, Heier JS. Innovative treatments for exudative age-related macular degeneration. Int Ophthalmol 2004;44:41–50. 3. Tranos PG, Wickremasinghe SS, Stangos NT, Topouzis F, Tsinopoulos I, Pavesio CE. Macular edema. Surv Ophthalmol 2004;49:470–90. 4. Jager RD, Aiello LP, Patel SC, Cunningham ET. Risks of intravitreous injection: a comprehensive review. Retina 2004;24:676–98. 5. Ciulla TA, Walker JD, Fong DS, Criswel MH. Corticosteroids in posterior segment disease: an update on new delivery systems and new indications. Curr Opin Ophthalmol 2004;15:211–20. 6. Massin P, Audren F, Haouchine B, Erginay A, Bergmann JF, Benosman R, Caulin C, Gau-
dric A. Intravitreal triamcinolone acetonide for diabetic diffuse macular edema: preliminary results of a prospective controlled trial. Ophthalmology 2004;111:218–24. 7. Singh IP, Ahmad SI, Yeh D, Challa P, Herndon LW, Allingham RR, Lee PP. Early rapid rise in intraocular pressure after intravitreal triamcinolone acetonide injection. Am J Ophthalmol 2004;138:286–7. 8. Konomi K, Nagasawa A, Mori A, Nomura M. A case of steroid-induced glaucoma caused by a sub-Tenon’s capsule injection of triamcinolone acetonide. Folia Ophthalmol Jap 2004;55:50–3. 9. Paganelli F, Cardillo JA, Melo LAS, Oliveira AG, Skaf M, Costa RA. A single intraoperative subTenon’s capsule triamcinolone acetonide injection for the treatment of post-cataract surgery inflammation. Ophthalmology 2004;111:2102–8.