TREATING DRY EYE

Treating Dry Eye With Hydroxypropyl Cellulose Ophthalmic Inserts

This article examines how ophthalmic insert use can benefit patients who have dry eye disease.

By Mile Brujic, OD

With approximately 5 million adults older than age 50 affected by dry eye disease (DED) in the United States (Schaumberg, 2003; Schaumberg, 2009), eyecare practitioners are likely to regularly encounter patients who have the disorder. In fact, data from a recent cohort study suggest that dry eye may occur even more often than originally thought. The 10-year incidence of patient-reported dry eye is more than 20 percent among adults aged 43 to 86 years (Moss, 2008).

Patients who have DED can suffer diminished quality of life (QoL), impaired activities of daily living (ADLs), and decreased visual function (DEWS, 2007b; Miljanovic, 2007; Nelson, 2000; Pflugfelder, 2000). Additional risks of DED include ocular fatigue, contact lens intolerance, and unfavorable outcomes following ocular surgeries including refractive surgical procedures (DEWS, 2007b; Lemp, 2008a).

Appropriate DED management necessitates recognition that the disease is a chronic condition with potentially serious effects, requiring patient education and appropriate treatment in a timely manner.

Although both signs and symptoms are important in managing dry eye patients, self-reported symptom severity and/or frequency rather than diagnostic testing may be a more useful guide for DED management decisions (Behrens, 2006; Lemp, 2008a; Nichols, 2004).

Tear supplementation represents first-line pharmacotherapy for dry eye (Behrens, 2006; DEWS, 2007a). For patients who have infrequent symptoms, sporadic reliance on artificial tears is appropriate. However, the inconvenience of repeated administration and safety concerns regarding frequent use of preservative-containing preparations, in particular those containing benzalkonium chloride (BAK) (Behrens, 2006; DEWS, 2007a; Lemp, 2008b), often require alternative management strategies including the use of hydroxypropyl cellulose ophthalmic inserts (Lacrisert; Aton Pharma, Inc.). Approved by the U.S. Food and Drug Administration (FDA) in 1981, the inserts are indicated for the treatment of moderate to severe dry eye syndromes.

Each preservative-free insert contains 5mg of hydroxypropyl cellulose, measures 1.27mm by 3.5mm, and is designed for placement in the inferior cul-de-sac of the eye (not in apposition to the cornea) using a reusable applicator (Figure 1). The inserts slowly dissolve to increase tear film stability and are designed to provide all-day lubrication (Breslin, 1977; Katz, 1978).

Figure 1. Hydroxypropyl cellulose ophthalmic insert (top) size and (bottom) placement location in the inferior cul-de-sac of the eye.

Real-World Effectiveness of Hydroxypropyl Cellulose Ophthalmic Inserts

Randomized, controlled clinical trials have demonstrated the efficacy of hydroxypropyl cellulose ophthalmic inserts (Breslin, 1977; Katz, 1978). A newly published retrospective study of patients who used the inserts, most for more than five years, showed that hydroxypropyl cellulose ophthalmic inserts are a relatively safe, tolerable, and effective long-term therapy for DED (Wander, 2009).

A recent multicenter, prospective, two-visit, four-week, open-label, patient registry study evaluated the effectiveness of hydroxypropyl cellulose ophthalmic inserts as monotherapy or in combination with existing therapies in patients who have DED (McDonald, 2009). Consistent with registry design, this study offered an unblended, uncontrolled look at clinical practice in action. Assessments focused on the severity and frequency of signs and symptoms, QoL measures, and ADL changes.

The study enrolled 520 patients (418 completed the study) who had bilateral DED and a history of artificial tear use or a desire to use artificial tears within the week prior to entering the study. Patients who had ocular infection, active inflammation, or recent ocular surgery were excluded from the registry while those using cyclosporine ophthalmic emulsion or those with punctal plugs were eligible for enrollment.

At a baseline visit, patients completed a questionnaire that assessed symptoms, daily living activities, and quality of life aspects. This patient-reported measure included the 12 items comprising the Ocular Surface Disease Index (OSDI), a valid and reliable measure of DED severity that contains questions regarding vision-related function, ocular symptoms, and environmental triggers (Schiffman, 2000). Patient reevaluations occurred after one month of treatment and demonstrated significant improvements in symptom severity (discomfort, burning, dryness, grittiness, sensitivity to light, and stinging), total OSDI scores, and multiple QoL and ADL items including difficulty reading, ability to watch television or movies, difficulty when driving at night, and performance of housework.

The most common adverse event associated with insert use leading to discontinuation was blurred vision, occurring in 8.7 percent of patients. Patients did not exhibit treatment-related corneal abrasions during the registry.

Use of Hydroxypropyl Cellulose Ophthalmic Inserts in Specific Patient Populations

Unlike most clinical trials, the hydroxypropyl cellulose ophthalmic insert registry previously described evaluated the safety and effectiveness of the inserts in a sample that closely mimics the patients encountered by clinicians in the “real world.” In other words, similar to the real world, these subjects represented a heterogeneous group with a wide spectrum of risk factors for DED. To deeper evaluate the effectiveness of hydroxypropyl cellulose ophthalmic inserts, Luchs and coworkers (in press) recently conducted additional analyses of different sub-samples within the registry. Specifically, analyses were performed on five subsets of patients who had DED: those who had concomitant glaucoma (n=15), those who had cataracts and had (n=52) or had not (n=79) undergone surgery, patients who had a history of laser-assisted in situ keratomileusis (LASIK) or refractive surgery (n=22), and contact lens wearers (n=86).

Similar to the overall study sample, subjects who had a history of LASIK, prior surgery for cataracts, and contact lens wear demonstrated significant improvements in total OSDI scores (Figure 2). Significant improvements in OSDI total scores were not observed in patients who had cataracts and had not undergone surgery or those who had glaucoma. Contact lens-wearing patients who had DED demonstrated significant reductions in the severity of most symptoms (discomfort, burning, and dryness) as well as most individual components of the OSDI and most ADLs assessed (ability to shop in retail stores and perform housework). Similar improvements were observed in patients who had undergone laser or refractive surgery.

Figure 2. Mean improvement in OSDI total score from baseline following one month of treatment with hydroxypropyl cellulose ophthalmic insert. Adapted from Luchs (in press).

Enrolled patients who had cataracts (and no history of surgery) or glaucoma did not demonstrate significant changes in individual OSDI components nor ADLs. In my experience, such patients may be less likely to recognize improvements in symptoms of DED given their coexisting disease which may, at least partially, account for the lack of significant improvement in most aspects of DED observed in these subgroups. It is also worth noting that the OSDI was not designed to discriminate between DED and other ocular abnormalities and has only been psychometrically evaluated as a tool comparing those who have DED to normal controls (Schiffman, 2000). In contrast, patients who had a history of cataracts and had undergone surgery demonstrated significant improvement in several components of the OSDI (i.e., discomfort, burning, dryness, and grittiness) and greater improvement in ADL measures compared to those who had not undergone surgery.

The benefit of hydroxypropyl cellulose ophthalmic inserts in contact lens wearers who have DED is worth noting. Contact lens-wearing patients should apply their lenses first and then place the inserts (Laurenzi, 2008). Some patients find it helpful to either precede or proceed placement of the inserts with a drop of artificial tears while others prefer to use the inserts at night (Laurenzi, 2008; Trattler, 2009). Simultaneous use of contact lenses and the inserts rarely results in expulsion of the insert. Furthermore, patients at ease with applying and removing contact lenses often quickly appear comfortable placing hydroxypropyl cellulose ophthalmic inserts.

Tolerability of Hydroxypropyl Cellulose Ophthalmic Inserts

Patients treated with hydroxypropyl cellulose ophthalmic inserts will at times report worsening of blurred vision, which likely occurs secondary to thickening of the tear film. This symptom is often transient and, blurred vision notwithstanding, patients frequently report improvements in ADLs that require considerable visual acuity (reading).

Patients who experience blurred vision may find it helpful to instill a drop of artificial tears prior to placement of the inserts. Another option is to have the patients remove the inserts–before they dissolve completely–if their vision is impacted. Although not an FDA-approved treatment schedule, some of my patients benefit from a less frequent insertion regimen (once every other day).

Clinician- Versus Patient-Reported Improvements

Although patient reports of DED symptoms are critical to the proper diagnosis and management of the disease, the potential value of physician-reported outcomes should not be overlooked. A recent analysis by McDonald and coworkers (in press), aimed to use data from the recent registry to determine the correlation between patient-reported ADLs and DED symptoms with physician-reported changes following treatment with hydroxypropyl cellulose ophthalmic inserts (as monotherapy or in conjunction with existing therapies).

In addition to patient questionnaires, investigators completed a Physician Questionnaire at the end of the study.

Patient reports of QoL (such as reading, watching TV, shopping, and performing housework) as well as symptoms (such as discomfort, burning, dryness, stinging, grittiness, and light sensitivity) significantly correlated with physician ratings of treatment adherence, DED symptoms, clinical signs, efficacy, and acceptability of the inserts as therapy for DED. While the degree of improvement perceived by patients was considerably greater than that observed by physicians, several patient factors remained predictive of a physician's likelihood to see improvement and recommend continued use.

The results of the analysis suggest that while routine completion of the validated measures such as the OSDI may be too time consuming in clinical practice, querying patients about specific symptoms of DED and ADLs is worthwhile and may serve as predictors of clinician-reported outcomes. In this analysis, these outcomes included physician ratings of patient compliance, change in DED symptoms, change in DED clinical signs, and physician perception of the efficacy of hydroxypropyl cellulose.

Whether such patient-reported measures should replace diagnostic testing is not clear, however, they are an essential element in any dry eye assessment (Nichols, 2000).

In practice, the importance of asking patients about symptoms of DED and its impact on their daily lives should not be underestimated. While some patients will offer such information without being prompted, many will not.

Role of Hydroxypropyl Cellulose Ophthalmic Inserts in Clinical Practice

Clinicians now recognize that dry eye is a chronic condition with potentially serious effects on patients’ QoL, visual functioning, and ADLs. Hydroxypropyl cellulose ophthalmic inserts represent an effective and generally well-tolerated option for treating moderate to severe DED. They can be used as monotherapy or in conjunction with other therapies such as cyclosporine ophthalmic suspension, ocular corticosteroids, punctal plugs, or artificial tears and have demonstrated short and long-term safety and effectiveness.

In a field in which the precise role of diagnostic testing remains unclear, patient-reported outcomes are considered paramount. Data from a recent open-label study demonstrate the effectiveness of hydroxypropyl cellulose ophthalmic inserts across a wide spectrum of outcomes including QoL, symptom severity, and measures of ADL as well as clinician ratings in a real-world environment. In these analyses, multiple subgroups of patients who had DED including contact lens wearers, post-refractive surgery patients, and patients who had a history of surgery for cataracts all benefited from treatment with hydroxypropyl cellulose ophthalmic inserts. Clinical experience also suggests that hydroxypropyl cellulose ophthalmic inserts may help patients who experience pain as a result of DED as well as those who have autoimmune or neurotrophic DED.

Taken together, recent clinical studies in conjunction with more than 25 years of post-marketing experience support the use of hydroxypropyl cellulose ophthalmic inserts in patients who have DED. CLS

The author would like to thank Aton Pharma Inc. as well as Adam Perahia, MD, and Donald Nelinson, PhD, for their help with this article.

For references, please visit www.clspectrum.com/references.asp and click on document #181.

Dr. Brujic is a partner of a four-location optometric practice in northwest Ohio. He practices full-scope optometry with special interest in contact lenses and ocular disease management of the anterior segment and glaucoma. He lectures on contemporary topics in eye care and has received honoraria for either writing, speaking, performing research, or acting in an advisory capacity from Alcon, Ciba Vision, CooperVision, Vistakon, Advanced Vision Research, Aton Pharma, Inspire Pharmaceuticals, and Ista Pharmaceuticals.