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Clinical White Paper
The following white
paper is intended
to provide
practicioners with
information on
the diagnosis and
treatment of dry
eye.
Lacrisert® is a
preservative-free
once-a-day*,
sustained release
prescription
insert made from
hydroxypropyl
cellulose that helps
to retain moisture,
stabilize the tear
film, and lubricate
the eye.
A review of
several Lacrisert
clinical studies are
presented in this
paper.
Introduction
Despite decades of research and advances in treatment, dry eye
syndrome remains one of the most common and confounding
issues clinicians deal with in clinical practice. Due to the great
variety among patient profiles, practicioners need to be armed
with as many effective treatment options as possible.
Lacrisert® (hydroxypropyl cellulose ophthalmic insert) is a prescription dry eye treatment and may help to fill the treatment
gap between artificial tears – which can be useful for those with
the mildest forms of dry eye – and more aggressive treatments
for those with severe dry eye. Studies have shown a retention
time of 3 to 10 minutes for artificial tears. 1 As a result, a leading
pharmaceutical company developed this polymeric insert that
dissolves slowly throughout the day. Lacrisert® received FDA
approval for the treatment of moderate to severe dry eye syndrome.
Lacrisert® is a therapeutically valuable alternative to repeated
applications of artificial tears. Many patients appreciate the convenience of a once-a-day*, preservative-free insert. Lacrisert®
may also make contact lenses more tolerable. In many patients
with severe dry eyes, Lacrisert® permits good functional vision
and controlled symptoms.6-12
Though valuable as an FDA approved prescription product for
dry eye, many doctors who wanted to use it had trouble finding
it or did not know that it was still manufactured. Aton Pharma
has obtained the rights to Lacrisert® to ensure this valuable
product’s availability and patient access. Given limited treatment choices for dry eye, particularly prescription products, it
is important that practitioners be aware of the availability of
Lacrisert® as a treatment option.
*Once daily is usually sufficient to relieve the symptoms associated with moderate to severe dry eye symptoms. Individual
patients may require more flexibility in the use of Lacrisert; some patients may require twice daily use for optimal results.
Page 1
Abstract
Dry eye disease is an increasingly common, yet frequently under-diagnosed clinical
condition, whose etiology and management can be challenging to ophthalmologists.
The effects of moderate to severe dry eye disease can be quite debilitating to patients
and may increase the likelihood of permanent damage and scarring to the front of the
eye. Lacrisert® is a preservative-free, once-a-day*, sustained release prescription
insert made from hydroxypropyl cellulose that helps to retain moisture, stabilize the
tear film and lubricate the eye. Several clinical studies, performed in patients with
moderate to severe dry eye syndrome, have demonstrated its ability to ameliorate
dry eye symptoms, increase tear film break-up time (TFBUT), and decrease rosebengal staining. This paper will provide a review of several clinical studies using
Lacrisert® and establish appropriate patient profiles for Lacrisert® based on
these data. Lacrisert® provides practitioners with an important addition to their
treatment armamentarium and has the potential to improve symptoms and lifestyles
for many dry eye patients.
Dry Eye Syndrome
The 2007 International Dry Eye Workshop defines dry eye as “a multifactorial disease of the
tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear
film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.”2 Dry eye syndrome has a number
of causes and patients exhibit a range of symptoms and clinical signs. In fact, one of the reasons
that dry eye can present such a challenge to the practitioner is that there has been no definitive
diagnostic test. A variety of patient questionnaires and clinical tests are used in practice, but
numerous studies have demonstrated that there is not necessarily a correlation between symptoms and clinical signs, or even among the many tests.3 The diagnosis of dry eye still depends a
great deal on obtaining a careful patient history and a patient’s report of symptoms.
Incidence and Prevalence of Dry Eye Syndrome
Establishing prevalence figures for dry eye is a challenge due to the variety of definitions and
multiple causes of the syndrome. Epidemiological studies have arrived at prevalence figures
ranging from 5% to 30% of the general population. In general, more restrictive definitions of the
syndrome yield lower numbers and vice versa. The 2007 DEWS report estimates that among
the population aged 50 and older, 3.2 million women and 1.6 million men experience dry eye
symptoms (Figure 1).
*Once daily is usually sufficient to relieve the symptoms associated with moderate to severe dry eye symptoms. Individual
patients may require more flexibility in the use of Lacrisert; some patients may require twice daily use for optimal results.
Page 2
Figure 1. Prevalence of Dry Eye Among US Population Age 50 and Above (By Sex)
Women
Men
3,200,000
1,600,000
Source: The epidemiology of dry eye disease: Report of the Epidemiology Subcommittee of the International Dry Eye Workshop (2007). The
Ocular Surface 2007;5(2):93-107.
As difficult as it may be to establish exact figures for the prevalence of dry eye, researchers and
practitioners alike agree that dry eye is one of the most common problems dealt with in clinical
practice and its incidence is on the rise. The primary risk factors for dry eye are female gender
and advanced age. The aging of the US population portends a growing pool of at-risk patients.
Dry eye is more than a nuisance. It can seriously affect the quality of life and ocular health of the
patient and is often progressively debilitating. A quality-of-life study published in 2007 suggests
that dry eye has a negative impact on “crucial daily activities of modern living such as reading,
computer use, professional work, driving, and watching television.”5 Moreover, traditional treatments for dry eye, such as the application of artificial tears throughout the day, can pose an
inconvenience for the patient.
Etiology of Dry Eye
Dry eye can result from a variety of causes, including the natural aging process. There are two
main classifications of dry eye syndrome: aqueous-deficient and evaporative. In aqueous-deficient
dry eye, the dry eye is caused by reduced lacrimal tear secretion or volume. Aqueous-deficient
dry eye patients fall into two main categories: Sjögren’s and non-Sjögren’s. Non-Sjögren’s aqueous deficient dry eye may be caused by lacrimal disease, lacrimal obstruction, reflex block, or
systemic drugs.2 Evaporative dry eye is characterized by a lack of ability to maintain a continuous tear film due to poor tear quality or dysfunction of the lids and other structures. It can be
caused by a number of intrinsic or extrinsic factors. Intrinsic factors include aging, low androgen
levels, meiobian gland deficiency, disorders of the lid (such as lagopthalmos), low blink rate, or
use of systemic drugs (such as antihistamines, beta blockers, antispasmodics, diuretics, and
psychotropics).2 Extrinsic factors include vitamin deficiencies, contact lens use, allergies, low humidity, high winds, and computer vision syndrome. Some LASIK and cosmetic surgery patients
may also be affected.
Page 3
Treatment of Dry Eye
The primary goals in the treatment of dry eye are to relieve the patient’s symptoms and to prevent damage to the cornea and other structures of the eye. Appropriate and aggressive treatment of dry eye can prevent damage caused by the disease.
In choosing an appropriate treatment plan, the practitioner is guided by such factors as the
severity level of the patient’s signs and symptoms, the probable etiology of the patient’s dry eye,
and patient tolerance of certain treatments. Published guidelines, such as the NEI/Industry
Workshop (1995), the Delphi Panel, and the DEWS Report, have helped to advance the awareness and understanding of dry eye. Clinicians may use these guidelines to aid in dry eye classification and potential treatment options.
The mildest forms of dry eye can often be effectively treated with non-prescription preserved or
unpreserved artificial tears. These are useful, but limited due to the brevity of effect. They may
also pose an inconvenience for the patient. Furthermore, studies show that the preservatives
used in artificial tears, such as benzalkonium chloride (BAK), pose a risk of epithelial toxicity.6-10
This risk is particularly high for patients with severe dry eye, reduced tear secretion, and punctual occlusion.11 If these patients are using other topical preparations containing BAK (such
as glaucoma medications), finding an alternative BAK-free dry eye treatment can help reduce
overall exposure.
Studies of another additive, disodium (EDTA), have yielded mixed results. Although one study in
rabbits found a formulation containing EDTA to be nontoxic, other studies found that preparations containing the additive increased corneal epithelial permeability.12-14 Advances have been
made in the use of “vanishing” preservatives. However, the authors of the DEWS report on management and therapy of dry eye caution that for patients with severe dry eye, “even vanishing
preservatives may not totally degrade, due to a decrease in tear volume, and may be irritating.”11
A variety of unpreserved artificial tear products exist. These obviously eliminate the risks associated with preservatives. However, unpreserved tears must be packaged in single unit-dose
containers to prevent bacterial contamination. For patients with moderate to severe dry eye
who must apply artificial tears multiple times throughout the day, the use of these products can
be inconvenient and expensive.11
In addition to artificial tears, there are several other therapies used to alleviate or treat the
symptoms of dry eye. Lid scrubs can be used to clean the lid margin; lid massaging promotes
fresh meibomian secretions to pass through the duct openings. Vitamins A, C, E, zinc, selenium
and molybdenum all play a part in the metabolism of tear production. Furthermore, a lack or
imbalance of essential fatty acids can affect lipid function. Nutritional supplements may alleviate
dry eye symptoms in some patients.
Patients with severe dry eyes may suffer from inflammation and neuronal impairment due to the
persistent irritation of the ocular surface. They may benefit from pharmacological interventions
including the use of tetracyclines, immunomodulators (such as cyclosporine), and anti-inflammatories (such as topical gluco-corticosteroids).
Page 4
SUMMARY SECTION
• Dry eye syndrome is an increasingly common disease due to the
aging of the population
• The causes and classification of dry eye vary widely and most
practitioners employ a multifactorial approach to treating the
disease
• Dry eye disease, especially the more moderate to severe cases, is a
serious condition, which if left untreated, can lead to corneal
scarring and irreversible damage to the eye
Lacrisert®
Lacrisert® is a preservative-free once-a-day* rod shaped, water soluble ophthalmic insert made
of hydroxypropyl cellulose available by prescription that helps to stabilize the tear film and lubricate the eye. Unlike artificial tear substitutes that have a residence time measured in minutes,
Lacrisert® acts to stabililize and thicken the precorneal tear film for all day lubrication and protection of the eye.
Lacrisert® is administered into the inferior cul-de-sac of the eye with the aid of a plastic applicator which is supplied with the inserts. Each Lacrisert® is 5mg of hydroxypropyl cellulose, which
is a physiologically inert substance that has been found to be safe in preclinical toxicity studies.15
It is 1.27mm in diameter and 3.5mm long. Its molecular structure is shown in Figure 2.
Figure 2. Molecular structure of Lacrisert®
H
H
OR
H
OR
H
O
CH2OR
H
H
O
CH2OR
O
H
OR
H
H
OR
O
H
n
R = CH2CHCH3
OH
Patients usually achieve relief from symptoms within 2 weeks of beginning treatment. However,
once Lacrisert® is inserted, it immediately absorbs fluid and begins to slowly dissolve and coats
the cornea, thereby providing the protection and lubrication that helps to ameliorate the symptoms of dry eye.
*Once daily is usually sufficient to relieve the symptoms associated with moderate to severe dry eye symptoms. Individual
patients may require more flexibility in the use of Lacrisert; some patients may require twice daily use for optimal results.
Page 5
Preclinical dissolution studies showed that Lacrisert® becomes soft within 1 hour after placed
in the conjunctival sac, and most inserts dissolved completely in 14 to 18 hours.15
Lacrisert® has been found to reduce the signs and symptoms of moderate to severe dry eye,
such as conjunctival hyperemia, corneal and conjunctival staining with rose bengal, exudation,
itching, smarting, burning, foreign body sensation, dryness, photophobia, and blurred or cloudy
vision. Lacrisert® is indicated in patients with moderate to severe dry eye syndromes, including
keratoconjunctivitis sicca. It is also indicated in patients with exposure keratitis, decreased corneal sensitivity, and recurrent corneal erosions. It is contraindicated in patients with hypersensitivity to hydroxypropyl cellulose. The following adverse reactions have been reported in patients
treated with Lacrisert®, but were in most instances mild and transient: blurring of vision, ocular
discomfort or irritation, matting or stickiness of eyelashes, and hyperemia.
Lacrisert® is placed in the inferior cul-de-sac using the plastic applicator that is supplied with the
product (Figure 4).
Figure 4. Insertion of Lacrisert® into eye
Patients should be advised to begin with clean hands and to follow insertion directions carefully.
Practitioners may want to coach their patients on proper insertion techniques or provide additional tips on how to facilitate insertion. Improper placement may result in corneal abrasion.
SUMMARY SECTION
• Lacrisert® is a preservative-free, prescription hydroxypropyl
cellulose insert that is administered once-a-day* to relieve the signs
and symptoms of moderate to severe dry eye
• Lacrisert® is placed into the inferior cul-de-sac by the patient and
slowly dissolves providing constant lubrication and thickening of
the corneal tear film
• Guidance regarding insertion is provided in the patient instructions,
though practitioners may want to augment these instructions with
helpful tips on the insertion process
*Once daily is usually sufficient to relieve the symptoms associated with moderate to severe dry eye symptoms. Individual
patients may require more flexibility in the use of Lacrisert; some patients may require twice daily use for optimal results.
Page 6
A History of Lacrisert® Clinical Trials
Several studies have shown Lacrisert® to be a safe and effective therapy for patients with moderate to severe dry eye syndrome. Clinical studies have demonstrated its ability to ameliorate
dry eye symptoms, increase TFBUT, and decrease rose bengal staining. In crossover studies
comparing Lacrisert® to artificial tears, most patients have reported a preference for Lacrisert®. Follow-up studies show that many patients benefit from long-term treatment with Lacrisert®, as symptoms continue to improve over time.
In a long-term follow-up study, Werblin, Rheinstrom, and Kaufman tested Lacrisert® (5mg) in 58
patients who had been experiencing keratoconjunctivitis sicca (KCS) symptoms of various etiologies for an average of 35 months prior to enrollment.16 As compared to previous treatments,
the majority of patients experienced improvement in both symptoms and clinical signs over
the course of treatment with Lacrisert®. As shown in Figure 5, after 52 weeks of Lacrisert®
use, patient symptoms (graded from 0 to 4, with 4 being most severe) were reduced from an
average grade of 2.09 to 0.24 (p < 0.02). No additional saline solution was required to aid in
dissolution of the insert. The authors indicate that the improvement in patients may be due to
the severity of their symptoms and signs prior to enrollment, with most enrolled patients having
failed a number of other treatments. It was suggested that long-term use (more than 10 weeks)
provided the greatest benefit.
Figure 5. Patient Symptom Score Over Time After Treatment With Lacrisert®
2.5
2.09
Symptom Score
2.0
1.5
1.01
1.0
0.41
0.5
0.40
0.13
0.0
0
3
6
12
32
0.24
52
Weeks
Source: Werblin TP, Rheinstrom SD, Kaufman HE. The use of slow-release artificial tears in the long-term management of keratitis sicca. Ophthalmol 1981;88(1):78-81.
A Norwegian study conducted by Høvding and Aasved designed to compare Lacrisert®
(5mg) with patients’ previous use of artificial tears began with 12 patients, all of whom had severe symptoms and had tried a variety of treatments prior to enrollment.17 Fifty-eight percent of
patients had reduced symptoms of burning, photophobia, and foreign body sensation with Lacrisert® compared to their previous use of artificial tears. An increased TFBUT and a decreased
rose bengal staining of the cornea were also recorded (p < 0.002). All patients continued to use
artificial tear substitutes, but those who preferred Lacrisert® reduced their usage.
Page 7
Breslin, Katz, Kaufman, and Katz conducted a 4-week crossover study to compare Lacrisert® with artificial tears in patients with moderate to severe symptoms.19 Eighteen patients
(90%) reported greater relief of their most distressing symptoms with Lacrisert® than with artificial tears or other previous treatments. They patients reported that their eyes looked and felt
better with Lacrisert® and that they obtained longer-lasting relief compared to artificial tears.
Fifteen patients also showed a decrease in corneal staining. Tear film meniscus was increased
in 11 patients. Thirteen patients continued use of Lacrisert® long-term and reported no adverse reactions in up to 22 weeks of use. Some patients removed Lacrisert in the afternoon to
avoid end of dose blurring of vision, therefore achieving the desired comfort and efficacy.
In a study of similar design by the same authors, 78% of patients in a 4-week crossover study
preferred Lacrisert® (12mg) to drops of artificial tears. 20
As shown in Table 1, Lacrisert® delivered greater benefits than artificial tears when it came to
symptoms of burning, foreign body sensation, itching, smarting, soreness, and dryness.
Table 1. Subjective Symptoms and Objective Signs of Patients after Treatment with Lacrisert® or Artificial Tear Drops (n=32)
Symptom
% Improved 2 or
% Improved One
% No Change or
More Levels
Level
Worsened
Artificial
Artificial
Artificial
Lacrisert® Tears Lacrisert® Tears Lacrisert® Tears
Burning (p<.05)
45
13
32
35
19
51
Foreign body (p<.01)
52
6
32
32
13
39
Itching (p<.01)
42
10
19
19
23
55
Smarting (p<.05)
48
19
9
16
13
42
Soreness (p<.05)
42
13
26
29
26
55
Dryness (p<.01)
48
6
32
29
16
61
Photophobia
No significant difference
Tearing
No significant difference
Blurred Vision
No significant difference
Objective Signs
Lacrisert® Artificial Lacrisert® Artificial Lacrisert® Artificial
Tears
Tears
Tears
Corneal staining
1% rose bengal
(p<.01)
Conjunctival staining
1% rose bengal
(p<.01)
23
6
39
23
15
58
19
0
31
19
46
81
Adapted from Katz JI, Kaufman HE, Breslin C, Katz IM. Slow-release artificial tears and the treatment of keratitis sicca. Ophthalmol. 1978;85:787793.
Page 8
No significant difference was found on the measures of photophobia, tearing, and blurred vision
between the Lacrisert® and artificial tear treatments or between each treatment and the baseline assessment. Lacrisert® outperformed artificial tears on the objective measures of corneal
and conjunctival staining. Precorneal tear thickness was improved with Lacrisert®, increasing
from the baseline average of 0.19mm to an average of 0.24mm, whereas thickness decreased
slightly to 0.17mm with the artificial tears (p<.01). Likewise, a significant increase in tear stability was noted. The precorneal tear film breakup time was increased from 4.1 seconds pretreatment to 6.9 seconds following 2 weeks of Lacrisert® treatment, compared to 3.4 seconds with
tears (p<.01). Forty-seven patients were followed long-term. They were given a smaller insert
(5mg or 8mg). The smaller doses of Lacrisert® reduced the amount of blurred vision and some
patients found the smaller rods easier to insert. The authors found that those with severe dry
eye benefited from the instillation of 1 to 2 drops of artificial tears upon insertion of Lacrisert®
to aid with the dissolution process. No patients used artificial tears more than 3 to 4 times during the day while using the insert.
Lamberts, Langston and Chu studied Lacrisert® in patients at the Cornea Service of the
Massachusetts Eye and Ear Infirmary.21 Forty dry eye patients were enrolled in a 4-week crossover study, 37 of whom had Sjögren’s syndrome. At the end of the initial study, 57% preferred
Lacrisert® to artificial tears. Thirty-seven enrolled in a long-term follow-up. The average tear
meniscus increased by 0.13mm with Lacrisert® compared to a decrease of 0.13 mm with the
drops (p<.05) (Figure 6).
Figure 6. Change in Tear Meniscus Height
Tear Meniscus Height (in mm)
0.35
0.30
Lacrisert
0.25
Drops
0.20
0.15
0.10
0.05
0.00
Pretreatment
Day 14
Source: Lamberts DW, Langston DP, Chu W. A clinical study of slow-releasing artificial tears. Ophthalmol 1978;85:794-800.
Six out of 16 patients had decreased corneal staining and 6 out of 19 had decreased conjunctival staining with Lacrisert®, but not with artificial tears (p<.05). It took 2-3 weeks of treatment
before these improvements occurred. No patients showed an improvement in corneal staining
while using artificial tears.
A Danish researcher performed the first double-masked, crossover study on Lacrisert®.22
Twenty-nine Sjögren’s syndrome (primary) patients were enrolled. Saccharose crystals were
Page 9
used as a placebo for Lacrisert®. The patients were randomly assigned to 2 treatment groups.
The first treatment group compared Lacrisert® and saline drops to the placebo and saline
drops. The second treatment group compared Lacrisert® and a tear substitute to the placebo
and a tear substitute. The researcher noted an improvement in TFBUT and rose bengal staining
in the Lacrisert® plus saline group over both placebo groups, Lacrisert® plus artificial tears, and
the pre-treatment assessment. It was suggested that Lacrisert® should be used in those with
moderate dry eye and should be supplemented with saline drops if necessary.
A crossover study was performed in patients with rheumatoid arthritis and moderate to
severe KCS.18 The purpose was to determine if patients with varying severity of hand deformity
and disabilities could still benefit from Lacrisert® compared to artificial tears despite any potential issues with insertion. Most patients reported no difficulty with insertion. Two patients who
initially had difficulty with insertion were able to do so after a few attempts. Moreover, 86% of the
patients found Lacrisert® to be an acceptable form of therapy and 64% preferred Lacrisert®
to other treatment regimens. All patients showed an improvement in conjunctival and corneal
staining (p=.0001 and .00001 respectively). As Figure 7 shows, Lacrisert® outperformed artificial tears on measures of burning, dryness, itching, soreness, and foreign body sensation. No
significant difference between Lacrisert® and drops was found on the measure of blurring. It
was concluded that decreased manual dexterity should not be considered a contraindication to
attempting Lacrisert® therapy.
Figure 7. Median Scores of Patient Symptoms and Clinical Signs
Corneal Staining (p=.00001)
Conjunctival Staining (p=.00001)
Foreign Body (p=.0003)
Lacrisert
Blurring (N.S.)
Drops
Soreness (p=.0013)
Itching (p=.0003)
Dryness (p=.0005)
Burning (p=.0005)
0
0.5
1
1.5
2
2.5
Severity (3=Most Severe)
Source: Hill JC. Slow-release artificial tear inserts in the treatment of dry eyes in patients with rheumatoid arthritis. Br J of Ophthalmol.
1989;73:151-154.
There appear to be some patients which may not have sufficient tear production to dissolve the
inserts, and who may experience blurred vision, a foreign body sensation or feeling of fullness in
the lower lid. These patients may find supplementation with artificial tears helpful.
Page 10
SUMMARY SECTION
• Lacrisert has been studied extensively and was found to be more
effective than artificial tears at ameliorating the signs and
symptoms of moderate to severe dry eye
• In some of these studies, patients who relied heavily upon artificial
tears for relief of symptoms found Lacrisert to be a more effective
treatment
• Lacrisert was found to be a safe treatment with no serious side
effects or safety concerns in any of the clinical trials performed
Summary
Lacrisert® can be an extremely valuable tool in the treatment of patients with moderate to severe dry eye. The constant tear film stabilization and lubrication may be useful in patients whose
symptoms are difficult to control with artificial tears alone. The continual bathing of the eye is
more akin to the normal physiologic benefits provided by natural tears. Lacrisert® might be the
logical next step for patients who benefit from artificial tears, but find that their dry eye has advanced to the point that they are using them too often. Likewise, it may also be helpful for those
patients whose dry eye is controlled by artificial tears, but either find it an inconvenience to instill
them repeatedly or who need help instilling them due to diminished manual dexterity. Lacrisert®
offers a once-a-day* alternative. And because Lacrisert® is biodegradable, there is no need to
remove it at the end of the day, although if desired, that is easily accomplished with the same
application tool used for insertion.
As demonstrated in several clinical studies, Lacrisert® can help to alleviate symptoms
in moderate to severe dry eye patients who may not be receiving adequate relief from artificial
tears or who may use preserved tears too often, risking potential corneal toxicity. Numerous
studies have demonstrated a patient preference for Lacrisert® over artificial tears.
While knowledge of dry eye increases, so too should the treatment options and regimens
for patients. Lacrisert® may provide practitioners with an important addition to their treatment
armamentarium, as well as give patients another therapeutic choice.
*Once daily is usually sufficient to relieve the symptoms associated with moderate to severe dry eye symptoms. Individual
patients may require more flexibility in the use of Lacrisert; some patients may require twice daily use for optimal results.
Page 11
References
1.
Krishna N, Brow, F. Polyvinyl alcohol as an ophthalmic vehicle. Am J of Ophthalmology 1964;
57:99
2.
The definition and classification of dry eye disease: Report of the Definition and Classification
Subcommittee of the International Dry Eye Workshop (2007). The Ocular Surface 2007;5(2):75-92.
3.
Methodologies to diagnose and monitor dry eye disease: Report of the Diagnostic Methodology Subcommittee of the International Dry Eye Workshop (2007). The Ocular Surface 2007:5(2):108152.
4.
The epidemiology of dry eye disease: Report of the Epidemiology Subcommittee of the International Dry Eye Workshop (2007). The Ocular Surface 2007;5(2):93-107.
5.
Miljanovic B, Dana R, Sullivan DA, Schaumberg DA. Impact of Dry Eye Syndrome on Vision-Related Quality of Life. Am J of Ophthalmology 2007;143(3):409-415.e402.
6. Gasset AR, Ishii Y, Kaufman H, Miller T. Cytotoxicity of ophthalmic preservatives. Am J
Ophthalmol 1974;78:98-105.
7. Wilson F. Adverse external effects of topical ophthalmic medications. Surv Ophthalmol
1979;24:57-88.
8. Burnstein N. Corneal cytotoxicity of topically applied drugs, vehicles and preservatives. Surv
Ophthalmol 1980;25:15-30.
9. Burnstein N. The effects of topical drugs and preservatives on the tears and corneal epithelium
in dry eye. Trans Ophthalmol Soc UK. 1985;104:402-9.
10. Smith L, George M, Berdy G, Abelson M. Comparative effects of preservative free tear
substitutes on the rabbit cornea: a scanning electron microscopic evaluation (ARVO abstract). Invest
Ophthalmol Vis Sci 1991;32(Suppl):733.
11. Management and therapy of dry eye disease: Report of the Management and Therapy
Subcommittee of the International Dry Eye Workshop (2007). The Ocular Surface 2007;5(2):163178.
12. Gilbard JP, Farris RL, Santamaria J 2nd. Osmolarity of tear microvolumes in
keratoconjunctivitis sicca. Arch Ophthalmol 1978;96:677-81.
13.
Lopez Bernal D, Ubels JL. Quantitative evaluation of the corneal epithelial barrier: Effect of
artificial tears and preservatives. Curr Eye Res 1991;1-:645-56.
14. Bernal DL, Ubels J. Artificial tear composition and promotion of recovery of the damaged
corneal epithelium. Cornea 1993;12:115-120.
15.
Lacrisert® [package insert]. Whitehouse Station, NJ: Merck &Co., Inc.; 2002.
16.
Werblin TP, Rheinstrom SD, Kaufman HE. The use of slow-release artificial tears in the long-term
management of keratitis sicca. Ophthalmol 1981;88(1):78-81.
17.
Høvding G, Aasved H. Slow-release artificial tears (SRAT) in dry eye disease: Report of a preliminary clinical trial. Acta Ophthalmol. 1981;59:842-846.
18.
Hill JC. Slow-release artificial tear inserts in the treatment of dry eyes in patients with rheumatoid arthritis. Br J of Ophthalmol. 1989;73:151-154.
19.
Breslin CW, Katz J, Kaufman HE, Katz IM. “Slow-ReleaseArtificial Tears”, Symposium on Ocular
Therapy 1977;10:77-83 (J. Wiley & Sons).
20.
Katz JI, Kaufman HE, Breslin C, Katz IM. Slow-release artificial tears and the
treatment of keratitis sicca. Ophthalmol. 1978;85:787-793.
21.
Lamberts DW, Langston DP, Chu W. A clinical study of slow-releasing artificial tears. Ophthalmol
1978;85:794-800.
22.
Prause JU. Treatment of keratoconjunctivitis sicca with Lacrisert®. Scand J Rheum
1986;61(suppl):261-263.
Page 12
LACRISERT® RESOURCES
www.Lacrisert.com
Customer Service: 1-877-ATON-549
Aton Pharma, Inc. is a global specialty pharmaceutical company providing
unique medicines to patients around the world. The mission of Aton Pharma
is to improve patient outcomes and quality of life worldwide by enhancing and
expanding access and availability of medically essential therapeutics through
improved distribution, customer education and product enhancement.
For more information about Aton please visit www.atonrx.com
Copyright Aton Pharma, Inc. 2007 LAC-001
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