Prophylaxis of Inflammation following Cataract Surgery

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Abstract and Introduction

Objective: To demonstrate the superiority of TobraDex® (tobramycin 3 mg/mL, dexamethasone 1 mg/mL) eye drops over Tobrex® (tobramycin 3 mg/mL)/vehicle (placebo) eye drops in the prophylaxis of inflammation after cataract surgery, and to provide additional safety data on TobraDex®.
Setting: Twenty-two ophthalmology clinics from Brazil, Belgium, Germany, Ireland, Portugal, Spain and Sweden.
Patients and methods: Prospective, randomised, double-masked, two-arm, parallel-group, placebo-controlled, multicentre study in 417 patients undergoing extracapsular cataract extraction with intraocular lens implantation. Patients were randomised (1:1) to TobraDex® or to Tobrex®/vehicle. One drop of TobraDex® or Tobrex® was instilled in the operative eye (four times daily) on the day before surgery (day -1), one drop immediately following surgery in the operated eye (day 0), and then treatment (four times daily) was continued until day 7 (inclusive). From day 8 through day 21, patients in the TobraDex® group continued with the same treatment, but patients in the Tobrex®/vehicle arm received the inactive ingredient only. Efficacy was assessed at 1, 3, 8, 14 and 21 days. The primary efficacy variable was the percentage of patients without post-surgical anterior chamber inflammation (i.e. with a sum of cells and flare scores of zero) on the day 8 visit.
Results: TobraDex® was significantly better (p < 0.05) than Tobrex®/vehicle in controlling post-surgical inflammation at day 8 as shown by the percentage of patients with an inflammation score of zero (51% vs 21%, respectively). The percentage of patients with treatment failure was 4% vs 16% (p < 0.001) in favour of TobraDex®. In the safety population (n = 415), 19% of patients reported a total of 52 adverse events while receiving TobraDex® and 35.3% patients reported 103 adverse events while receiving Tobrex®/vehicle. One patient receiving Tobrex®/vehicle discontinued the study due to an ocular allergic reaction. No patient experienced clinically relevant changes in visual acuity, fundus parameters, cup/disc ratio or intraocular pressure related to treatment following the day of surgery.
Conclusions: TobraDex® eye drops were superior to Tobrex®/vehicle in controlling post-surgical inflammation following cataract extraction. TobraDex® administered four times daily over 21 days post-surgery was safe and well tolerated in patients treated for the prevention of post-surgical inflammation following cataract extraction.

Inflammatory conditions of the anterior chamber of the eye are usually treated with eye drops containing a combination of anti-inflammatory and anti-infective drugs.^[1,2,3] Anti-infectives are given as a routine part of care in order to prevent the occurrence of a postoperative infection. In fact, the incidence of postoperative endophthalmitis has decreased substantially over the years.^[4] Therefore the combined use of anti-infective and anti-inflammatory agents is justified whenever the natural defence barriers of the eye are compromised, either accidentally or through a surgical procedure^[5,6,7] such as in patients undergoing cataract surgery.

The positive therapeutic effect on postoperative inflammation and prevention of postoperative infection following cataract surgery with standard formulations of corticosteroids, nonsteroidal anti-inflammatory drugs and antibiotics has been documented extensively in the literature.^{[8,9,10,11,12,13,14,15,16,17,18,19]} The concomitant administration of an anti-inflammatory and antibiotic agent in a single ophthalmic product overcomes any potential 'washout effect' that may be seen when separate medications are used. In addition, a single administration of a combination product leads to better compliance, patient comfort and safety.^[20] The reduced number of administrations needed for a combination product may be of particular benefit for elderly patients, who make up the majority of cataract surgery cases.

TobraDex® eye drops (Alcon Couvreur NV, Puurs, Belgium) is a combination of tobramycin 3 mg/mL and dexamethasone 1 mg/mL. The clinical development of TobraDex® was initiated in 1983 and results of various studies including a total of 1309 subjects have confirmed the efficacy of this ophthalmic suspension in controlling inflammation and preventing infection after cataract surgery.^[21] An extensive review of the postmarketing surveillance of this antibiotic-corticosteroid combination demonstrated that the occurrence of adverse events associated with the use of TobraDex® have been very rare and resolved quickly without sequelae, indicating that TobraDex® is safe and well tolerated for use in the treatment of inflammation and prophylaxis of infection following cataract surgery.^[21]

The present study was conducted with two objectives: (a) to demonstrate the superiority of TobraDex® to Tobrex®/vehicle, an anti-inflammatory 'placebo' in the prevention of post-surgical inflammation after cataract extraction, and (b) to provide additional safety data on TobraDex®. The model chosen was extracapsular cataract extraction, by phacoemulsification, with a posterior chamber intraocular lens (IOL) implantation.

Tobrex® (tobramycin 3 mg/mL) eye drops is a well accepted antibiotic ophthalmic solution used extensively as a standard treatment in the prevention of post-surgical infection.^[22] Tobramycin is an antibiotic that is active against most strains of bacteria that infect the eye and has been used in ophthalmology since the mid-1980s.^[5,14,23] The use of antibiotic agents as part of routine peri- and postoperative care is common practice and topical instillation of an antibiotic prior to surgery has been shown to reduce conjunctival colonisation and decrease the potential risk of post-surgical infection.^[24,25] Therefore, Tobrex® ophthalmic solution was used 1 day before and for 1 week following surgery to prevent post-surgical infection in patients randomised to the control group.

Cite this: Prophylactic Effectiveness of Tobramycin-Dexamethasone Eye Drops Compared with Tobramycin/Vehicle Eye Drops in Controlling Post-Surgical Inflammation in Cataract Patients - Medscape - Sep 01, 2004.

Table I. Study design
Parameters	Period 1 (day -1 to day 7)					Period 2 (day 8 to day 21)
Parameters	Screening^a	Day -1	Day 0 (surgery)	Day 1	Day 3 ± 1	Day 8 ± 1	Day 14 ± 2	Day 21 ± 2
General information; medical history	X
Informed consent	X
Pregnancy test, when applicable^b	X							X
Peri-operative medication			X
Ocular surgery			X
Visual acuity	X	X		X	X	X	X	X
Slit-lamp examination	X	X		X	X	X	X	X
Fundus examination (dilated)	X							X
Intraocular pressure measurements	X	X		X	X	X	X	X
Physician's follow-up impression of inflammatory response				X	X	X	X	X
Dispense study medication^c		X				X
Collect study medication^d						X		X
Record adverse events		X	X	X	X	X	X	X
Complete exit form^d								X

Table II. Demographic data of the intent-to-treat patients (n = 401)
	TobraDex®	Tobrex®/vehicle	Total	p-Value
Age (y)
Mean	69.76	68.97	69.37	0.4616^a
SD	10.53	10.91	10.71
n	203	198	401
Sex (no.)				0.0266^b
Male	96	72	168
Female	107	126	233
Race (no.)				0.6129^b
Caucasian	195	191	386
Black	7	7	14
Asian	1		1
Iris colour (n)				0.3611^b
Brown	104	118	222
Blue	63	48	111
Hazel	18	13	31
Green	8	10	18
Grey	10	7	17
Missing		2	2

Table III. Patients discontinued from the study
Reason	TobraDex® (n = 211)	Tobrex®/vehicle (n = 206)	All randomised (n = 417)
Adverse event (related and unrelated to the study medication)	2	11	13
Lost to follow-up	0	2	2
Patient's decision to postpone surgery day	2	5	7
Noncompliance	4	1	5
Treatment failure	9	32	41
Other	6	10	16
Total	23 (11%)	61 (30%)	84 (20%)

Table IV. Patients excluded from per-protocol (PP) data set
Reasons leading to a patient's exclusion^a	TobraDex® (n = 211)	Tobrex®/vehicle (n = 206)	All randomised (n = 417)
Not receiving study drug	0	2	2
Did not meet inclusion criteria^b	13	8	21
History or evidence of ocular or systemic disease that would preclude participation in this study	4	10	14
Use of concomitant anti-inflammatory drugs	8	10	18
Diabetes mellitus	3	1	4
Study medication wrongly dispensed	1	0	1
No follow-up visit available after surgery (day 0)	6	3	9
Total^a	35	34	69
Total^a number of patients excluded from PP	32	32	64

Table V. Results of secondary efficacy variables in the per-protocol data set (mean ± SD)
Parameters/treatment group	Day
Parameters/treatment group	1	3	8	14	21
Cells
TobraDex®	1.20 ± 0.76	0.91^a ± 0.67	0.56^a ± 0.82	0.31^a ± 0.76	0.18^a ± 0.68
Tobrex®/vehicle	1.27 ± 0.82	1.36 ± 1.02	1.25 ± 1.11	0.96 ± 1.13	0.75 ± 1.18
Flare
TobraDex®	0.73 ± 0.89	0.43^a ± 0.70	0.23^a ± 0.66	0.18^a ± 0.63	0.13^a ± 0.59
Tobrex®/vehicle	0.71 ± 0.82	0.72 ± 0.91	0.74 ± 0.97	0.58 ± 0.97	0.50 ± 0.97
Ocular pain
TobraDex®	0.60^a ± 0.74	0.37^a ± 0.67	0.26^a ± 0.64	0.16^a ± 0.59	0.11^a ± 0.57
Tobrex®/vehicle	0.80 ± 0.91	0.92 ± 1.08	0.92 ± 1.16	0.68 ± 1.04	0.54 ± 1.00
Physician's impression of inflammation
TobraDex®	2.40 ± 1.02	1.78^a ± 0.98	1.29^a ± 1.13	0.81^a ± 1.17	0.49^a ± 1.15
Tobrex®/vehicle	2.48 ± 0.98	2.49 ± 1.20	2.46 ± 1.44	2.00 ± 1.63	1.55 ± 1.84

Table III. Patients discontinued from the study
Reason	TobraDex® (n = 211)	Tobrex®/vehicle (n = 206)	All randomised (n = 417)
Adverse event (related and unrelated to the study medication)	2	11	13
Lost to follow-up	0	2	2
Patient's decision to postpone surgery day	2	5	7
Noncompliance	4	1	5
Treatment failure	9	32	41
Other	6	10	16
Total	23 (11%)	61 (30%)	84 (20%)

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Prophylactic Effectiveness of Tobramycin-Dexamethasone Eye Drops Compared with Tobramycin/Vehicle Eye Drops in Controlling Post-Surgical Inflammation in Cataract Patients

Abstract and Introduction

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