What safety and efficacy evidence is available for use of fluorescein-benoxinate?

Comment by InpharmD Researcher

Overall, there is limited high-quality evidence to support the safety and efficacy of fluorescein-benoxinate. For visualization (i.e., tonometry), the use of fluorescein-benoxinate has been found to result in similar intraocular pressure measurements compared to fluorexon-benoxinate, suggesting similar utility. However, fluorexon-benoxinate was found to lead to superior comfort and less burning/stinging compared to fluorescein-benoxinate in one study (see Table 1). In contrast, a separate study found fluorescein-benoxinate to result in less stinging compared to fluorescein-proparacaine. While there is limited data specifically for corneal anesthesia, fluorescein-benoxinate resulted in adequate corneal anesthesia as reported by patients in one study.

Background

A 2014 prospective, single-center study conducted in Sweden evaluated the effects of repeated measurements of intraocular pressure (IOP) using Goldmann applanation tonometry (GAT) and applanation resonance tonometry (ART) in six healthy volunteers. The study also investigated the impact of two topical anesthetics, oxybuprocaine/fluorescein and tetracaine, on IOP and anterior chamber volume (ACV). Participants underwent alternating IOP measurements in both eyes for one hour after instillation of either oxybuprocaine/fluorescein in the right eye or tetracaine in the left. Consecutive series of six IOP measurements per method were performed, and ACV was photographed periodically using Pentacam in the tetracaine-treated eyes. A separate trial was conducted on the same participants to isolate the effect of the anesthetics alone, with identical drop administration but without repeated IOP measurements. [1]

The study documented significant reductions in IOP during repeated applanation for both methods and anesthetics, with a greater effect observed in oxybuprocaine/fluorescein-treated eyes. IOP reductions of 4.4 mmHg (ART) and 3.8 mmHg (GAT) were noted with oxybuprocaine/fluorescein, compared to a 2.1 mmHg reduction (ART) with tetracaine. Furthermore, an immediate reduction of 12.6 μL in ACV was observed post-measurement, which recovered within two minutes, suggesting mechanical stress as a contributing factor rather than fluid displacement alone. Without mechanical applanation, oxybuprocaine alone decreased IOP by up to 3.1 mmHg, while tetracaine demonstrated no significant change. These findings indicate that both anesthetics and the repetitive mechanical indentation of the cornea contribute to IOP reduction, with oxybuprocaine exerting a more pronounced effect. The researchers highlighted the need to account for these factors in the design of studies utilizing repeated tonometry. [1]

A 2000 study compared the use of Fluorocaine (fluorescein sodium/proparacaine) and Fluorox (fluorescein sodium/benoxinate) ophthalmic solutions on the frequency and amount of corneal desquamation following Goldmann Applantation Tonometry (GAT). Patients (N= 30; 60 eyes) were randomized to receive one drop of Fluorocaine instilled into one eye, with one drop of Fluorox administered into the opposite eye of the same patient. Intraocular pressures (IOPs) were measured via GAT and tear-break up times (TBUTs) were collected; corneal integrity was evaluated via Cornea and Contact Lens Research Unit (CCLRU) standards at 0, 3, 7, 10, 15, and 20 minutes post-ophthalmic solution instillation. Average TBUTs were reportedly 6.87 seconds with Fluoracaine and 7.17 seconds with Fluorox; with fluorocaine producing both micro- and macropunctate keratitis of the superficial epithelium in 31% to 45% of the cornea. In comparison, Fluorox caused only superficial micropunctate keratitis in 16% to 30% of the cornea. Patients reported 47% greater corneal stinging with Fluorox use over Fluoracaine, with 23% reporting greater stinging with Fluoracaine over Fluorox use, and 30% reporting no difference between agents. CCLRU scoring at 20 minutes post-ophthalmic solution instillation showed that all eyes with Fluoracaine and all but one with Fluorox use had corneal desquamation present. Overall, fluorescein ophthalmic solution, when in combination with benoxinate, showed clinically significant lower rates of corneal desquamation following GAT procedure, but did not provide anesthetic effects superior to proparacaine combination product. [2]

References:

[1] Jóhannesson G, Hallberg P, Eklund A, Behndig A, Lindén C. Effects of topical anaesthetics and repeated tonometry on intraocular pressure. Acta Ophthalmol. 2014;92(2):111-115. doi:10.1111/aos.12058
[2] Yeung KK, Kageyama JY, Carnevali T. A comparison of Fluoracaine and Fluorox on corneal epithelial cell desquamation after Goldmann Applanation Tonometry. Optometry. 2000;71(1):49-54.
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What safety and efficacy evidence is available for use of fluorescein-benoxinate?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Table 1 for your response.

Validity of Fluorexon Disodium Versus Sodium Fluorescein for Use in Goldmann Tonometry
Design

Double-masked, randomized, crossover clinical trial

N= 67
Objective

To evaluate the safety, validity, and comfort of 0.35% fluorexon disodium and 0.4% benoxinate compared with 0.25% sodium fluorescein and 0.4% benoxinate for Goldmann applanation tonometry (GAT)
Study Groups

All patients (N= 67)
Inclusion Criteria

Age 18 years or older, any sex, any ethnicity, not currently wearing contact lens
Exclusion Criteria

Under 18 years of age, pregnant or breastfeeding, contact lens wearer, corneal epithelial abnormalities, concurrent topical ophthalmic medication use, highly anxious individuals, individuals requiring manual eyelid manipulation
Methods

Subjects received either the standard (0.25% sodium fluorescence/0.4% benoxinate) or study formulation (0.35% fluorexon disodium/0.4% benoxinate) for GAT on visit 1 and the other formulation 1 week later. One drop of the masked formulation was instilled into the patient's eyes, and 2 subsequent intraocular pressure (IOP) measurements were taken. Goldmann applanation tonometer attached to the Topcon slit-lamp biomicroscope was used to measure IOPs.
Duration

Each subject had two visits, with a 1-week washout period between visits.  
Outcome Measures

Primary: Validity of IOP with the study formulation versus the standard formulation

Secondary: Ease of use, ocular comfort, corneal compromise
Baseline Characteristics  

All patients (N= 67)

            
Male, n

35

    
Results

Endpoint

 Fluorexon/benoxinate (N= 67) Fluorescein/benoxinate (N= 67) p-value

IOP, mmHg

Right eye

Left eye

 

13.9 ± 2.7

14.0 ± 2.8

 

13.9 ± 2.8

13.9 ± 2.5

N/A

IOP range, mmHg

9 to 21

10 to 21

N/A

Patient symptom survey*

Clarity scale of mires

Fluorescence scale

Discomfort scale at 1 minute

Discomfort scale at 5 minutes

Soreness/irritation scale at 1 minute

Soreness/irritation scale at 5 minutes

Burning/stinging scale at 1 minute

 

4.582

4.530

0.657

0.1940

0.2836

0.1791

0.806

 

4.657

4.642

1.000

0.2687

0.3582

0.1940

1.284

 

0.490

0.309

0.039

0.414

0.472

0.859

0.014

The measurements with the 2 formulations were highly correlated for the right eye and left eye, and the differences between the 2 measurements were not clinically significant. The Pearson correlation coefficient was 0.79 (p<0.001) for all GAT readings in the right eye comparing IOP values taken with fluorexon versus fluorescein, suggesting a reasonably high correlation. Similar findings were found in the left eye (Pearson coefficient= 0.768, p<0.001).

In patient symptom surveys, 0 patients reported adequate anesthesia for fluorexon only, while 2 patients reported adequate anesthesia for fluorescein only. However, 65 patients reported adequate anesthesia for both formulas.

*Mean on a scale of 0-5
Adverse Events

More subjects reported post-GAT corneal damage with fluorescein (n= 11) compared to fluorexon (n= 4).  
Study Author Conclusions

Not only was the new fluorexon product accurate and effective in GAT, it was also statistically more comfortable and had a less stinging and burning effect at 1 minute after drop instillation than the traditional fluorescein formulation. Because fluorexon is less likely to stain soft contact lenses, this may be the dye-anesthetic formulation of choice for practices that routinely perform GAT.
Critique

The study was well-designed with a double-masked, randomized, crossover approach, reducing bias. However, the sample size was relatively small, and the study did not include subjects with glaucoma or ocular hypertension. The study's strength lies in its practical application for contact lens wearers, but further research is needed to confirm findings in a broader population and to evaluate the impact on soft lens staining.  
References:

Ng LT, Tong JW, De Land PN. Validity of fluorexon disodium versus sodium fluorescein for use in Goldmann tonometry. Cornea. 2006;25(6):679-686. doi:10.1097/01.ico.0000214233.74603.ce