`
`Published April 15, 2009
`
`Which Drop for Dry Eye?
`When it comes to treating dry eye, keep your
`armamentarium well stocked. No single artificial tear works
`well for every form of dry eye. Rather, each option has
`benefits in certain situations.
`Srihari Narayanan, O.D., Ph.D.
`
`Dry eye disease is observed often in our practice as primary eye care
`providers. In general, dry eye is characterized as a disease that occurs
`due to increased tear evaporation or decreased tear secretion that
`resulted in symptoms of ocular irritation.1
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`https://www.reviewofoptometry.com/article/which-drop-for-dry-eye
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`MYLAN - EXHIBIT 1086
`Mylan Pharmaceuticals Inc. et al. v. Allergan, Inc.
`IPR2016-01127, -01128, -01129, -01130, -01131, & -01132
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`The recent International Dry Eye WorkShop (DEWS) defined dry eye
`disease as follows: Dry eye is 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 As outlined in the DEWS
`definition, dry eye disease not only causes ocular irritation, but also
`affects the quality of the patients visual acuity and can affect the
`integrity of the ocular surface.
`
`Estimates of the prevalence of dry eye vary considerably between
`different populations of the world. In the United States, it is thought
`that dry eye occurs in 5% to 30% of the population.3 As practitioners, we
`are well aware that this disease affects women more than men and also
`increases in incidence in the older population.3
`
`Dry eye disease does cause significant economic burdens on the patient
`through the costs for obtaining treatment, follow-up visits, additional
`testing and loss of working hours.4 Furthermore, it has been shown that
`dry eye disease affects the quality of life of a patient.5
`
`A wide variety of therapeutic options are available for dry eye disease.
`Various treatment strategies, such as artificial tears or rewetting agents
`(henceforth called artificial tears), punctal plugs, anti-inflammatory
`agents (topical steroids or oral fatty acids), moisture goggles,
`secretogogues, autologous serum, prescription immunomodulatory
`drugs (topical and oral) as well as surgical options, are available for the
`treatment of dry eye disease.
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`Identification of the underlying cause of dry eye aids in successful
`treatment of this disease. However, its multifactorial nature makes it
`complicated to identify a single cause in a particular patient.
`
`The diagnostic challenge is further increased for dry eye disease
`because no single test is available to correctly diagnose its various
`forms. Current research suggests that inflammation at the ocular
`surface plays an important role in the pathogenesis of dry eye.6
`
`Among all therapeutic options for dry eye disease, artificial tears are
`still the mainstay in the initial management of a dry eye patient.7
`Ophthalmic physicians usually begin a newly-diagnosed dry eye patient
`on a regimen of topical artificial tears and then add to or modify the
`course of treatment from there.
`
`Currently, there are various artificial tears available over-the-counter;
`one brand (FreshKote, Focus Laboratories) is available by prescription
`only. Artificial tears are generally designed to lubricate the ocular
`surface and replace tear volume.
`
`Due to the complex nature of the tear film, it is difficult to design an
`artificial tear solution that is identical to human tears. However, many
`artificial tear brands try to improve their quality by altering the
`composition, viscosity and/or osmolarity of the solution.
`
`This article details some of the commonly available compositions of
`artificial tears and discusses their potential use in specific causes of dry
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`eye disease. There is no single brand of artificial tears that works well
`for every form of dry eye. Rather, each option (organized here by
`formulation composition) has benefits for certain clinical situations.
`
`CMC-Based Artificial Tears
`Carboxy methylcellulose (CMC, discussed below) and hydroxypropyl
`methylcellulose (discussed later) are polysaccharides known as
`mucilages.8 The methyl and hydroxpropyl cellulose derivatives are
`widely used in artificial tear formulations. They increase the residence
`time of tears as well as increase the viscosity of tears.8 Interestingly, the
`refractive index of 1% methylcellulose is 1.336, which closely matches
`that of human tears.8
`
`Commonly available CMC artificial tears include the Refresh brand of
`tears (Allergan) as well as TheraTears (Advanced Vision Research). CMC-
`based artificial tears may protect the integrity of the ocular surface.9
`
`Refresh is available in both preserved and non-preserved as well as in
`liquigel formulations. It has been shown that the mid-viscosity (1.0%
`CMC) Refresh Liquigel promotes significant reduction in the signs and
`symptoms of dry eye compared to lower viscosity agents.9 So, CMC-
`based artificial tears may be indicated in patients who demonstrate
`ocular surface staining with vital dyes. TheraTears has the added
`benefit of being a hypotonic solution. Hyperosmolarity is a common
`feature of most forms of dry eye disease.1 Therefore, the hypotonic
`TheraTears solution may provide comfort in dry eye patients.
`
`HMC-Based Artificial Tears
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`Several brands of artificial tears, such as Tears Naturale and Bion Tears
`(Alcon), GenTeal (Novartis) and Visine Tears (Pfizer) are hydroxypropyl
`methylcellulose (HMC) based. Tears Naturale is available both with and
`without preservatives. Bion Tears is preservative free and has been
`suggested for use in patients with severe dry eye.10 GenTeal is available
`in three different formulations, one each for mild, moderate or severe
`dry eye.11 Visine Tears is available with or without preservatives. HMC-
`based artificial tears work on the simple principle of lubricating the
`ocular surface in order to promote the integrity of the surface.10
`
`HP Guar-Based Artificial Tears
`Systane (Alcon) is formulated with hydroxypropyl guar (HP guar). The
`HP guar in this artificial tear brand is gel-forming and offers a unique
`mechanism to approach the problem. These properties of HP guar
`improve recovery of the ocular surface due to possible increased
`retention time of the artificial tear drop.12
`
`Also, the increased retention time may be responsible for the increase
`in tear film break-up times observed with HP guar-based artificial tears
`compared to CMC-based tears.13 Tear evaporation may be reduced by
`the use of HP guar containing artificial tears.14 So, HP guar-based
`artificial tears may be helpful in patients with conditions causing
`evaporative dry eye (e.g., meibomian gland disease) as well as patients
`demonstrating ocular surface staining.
`
`SH-Based Artificial Tears
`Blink Tears and Blink Contacts (Abbott Medical Optics) and AQuify
`comfort drops (CIBA Vision) are brands that include sodium hyaluronate
`(SH) as an inactive ingredient. Blink Tears and AQuify comfort drops
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`have been advertised for use in contact lens wearers. Blink Tears has a
`unique OcuPure preservative that dissipates upon exposure to light.
`Therefore, Blink Tears become preservative free upon instillation in the
`eye. AQuify comfort drops are blink-activated.15 Sodium hyaluronate in
`the AQuify comfort drops aids in a gradual release of water molecules,
`which increases the duration of wettability as well as relieves lens-
`related dryness.15
`
`Recent studies have shown that SH eye drops are useful in improving
`subjective symptoms (as well as the ocular health) of dry eye patients,
`treating lipid tear-deficient patients and managing Sjgrens syndrome
`patients.16-20 Sodium hyaluronate also seems to have protective effects
`on the corneal epithelium.21
`
`Based on the above evidence, it appears that SH-based artificial tears
`may be useful in a wide variety of patients with dry eye. Interestingly,
`Blink Tears may also provide relief to dry eye patients post-LASIK
`surgery or post-cataract surgery.22 So, this formulation appears to
`provide a wide range of beneficial effects for dry eye patients.
`
`PVA-Based Artificial Tears
`Polyvinyl alcohol (PVA) based artificial tears, such as Murine Tears
`(Murine Eye Care), Tears Again (Cynacon/Ocusoft) and HypoTears
`(Novartis), also work on the principle of lubricating the ocular surface.
`Tears Again is available in the eyedrop as well as the gel formulation.
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`HypoTears, as the name suggests, is a hypotonic solution. It is available
`with or without preservatives. So, HypoTears has the added advantage
`of addressing hyperosmolarity issues observed in dry eye patients
`(similar to TheraTears, which is CMC based).
`
`One recent article concluded that Murine Tears provided the drop
`volume closest to the volume of the natural tear fluid and was also the
`least expensive per year of treatment compared to artificial tears from
`seven other manufacturers.23
`
`Oil-Based Tears
`Refresh Endura (Allergan) and Soothe XP Emollient eye drops (Bausch &
`Lomb) are the two brands that use oils in their composition. Refresh
`Endura is a preservative-free castor oil-based formulation. Castor oil
`aids in the reformation of the lipid layer of the tear film and prevents
`evaporation of the existing tear film.24,25
`
`Castor oil-based eye drops also improve tear stability and aid in the
`treatment of meibomian gland disease.26 So, it is evident that the use of
`castor oil-based artificial tears is indicated in evaporative dry eyes.
`Unfortunately, the production of Refresh Endura was discontinued as of
`December 2008.
`
`Soothe XP Emollient eye drops, on the other hand, are mineral oil-
`based. This brand of artificial tears has been shown to increase the
`thickness of the lipid layer of the tear film.27 So, Soothe XP eye drops can
`also be considered for use in evaporative dry eye patients who have a
`poor quality of the lipid layer.27
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`https://www.reviewofoptometry.com/article/which-drop-for-dry-eye
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`Rx Tears
`FreshKote eyedrops (Focus Laboratories) are the only brand of artificial
`tears that require a prescription. The main ingredients of FreshKote
`include PVA as well as polyvinyl pyrrollidone. FreshKote also includes
`the companys proprietary Amisol Clear which is intended to stabilize
`the lipid layer of the tear film and prevent evaporation of the tear fluid.
`Because the manufacturer of FreshKote describes Amisol Clear as a
`phospholipid, FreshKote functions somewhat akin to the oil-based
`tears. Additionally, these eyedrops are designed to achieve better
`wetting by aiding the combination of all three layers of the tear film.
`FreshKote has a high oncotic pressure, which helps in increasing ocular
`surface integrity.28 And, FreshKote can be used daily on an as needed
`frequency.28
`
`No single artificial tear solution will work for all dry eye patients. Each
`patients symptoms, complaints and diagnosis will play a role in your
`selection of the best dry eyedrop for his or her needs.
`
`The different components of artificial tears offer distinct advantages,
`and it is your responsibility to choose the best formulation for your
`patients dry eye therapy.
`
`Dr. Narayanan is an Assistant Professor at the Pennsylvania College of
`Optometry at Salus University, Elkins Park, Pa.
`
`1. Lemp MA. Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes. CLAO J 1995;21(4):221-32.
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`2. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007).
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`Ocul Surf 2007;5(2):75-92.
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`Page 9 of 10
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`3. The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5(2):93-107.
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`lubricant eye drops. Cornea 2007;26(8):949-52.
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`14. Uchiyama E, Di Pascuale MA, Butovich IA, et al. Impact on ocular surface evaporation of an artificial tear solution containing hydroxypropyl guar. Eye Contact
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`15. CIBA Vision. AQuify. Available at: www.
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`aquify.com/html/drops.html (Accessed January 2009).
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`16. Brignole F, Pisella PJ, Dupas B, et al. Efficacy and safety of 0.18% sodium hyaluronate in patients with moderate dry eye syndrome and superficial keratitis.
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`18. McDonald CC, Kaye SB, Figueiredo FC, et al. A randomised, crossover, multicentre study to compare the performance of 0.1% (w/v) sodium hyaluronate with
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`1.4% (w/v) polyvinyl alcohol in the alleviation of symptoms associated with dry eye syndrome. Eye 2002;16(5):601-7.
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`controlled, exploratory study. Br J Ophthalmol 2007;91(1):47-50.
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`20. Aragona P, Di Stefano G, Ferreri F, et al. Sodium hyaluronate eye drops of different osmolarity for the treatment of dry eye in Sjogren"s syndrome patients. Br
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`J Ophthalmol 2002;86(8):879-84.
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`21. Choy EP, Cho P, Benzie IF, et al. Investigation of corneal effect of different types of artificial tears in a simulated dry eye condition using a novel porcine dry
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`eye model (pDEM). Cornea 2006;25(10):1200-4.
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`22. Donnenfeld ED, Holland EJ, McDonald MB, et al. New artificial tear developments. Rev Ophthalmol 2009 Jan;16(1 Suppl):8-15.
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`23. Enzenauer RW, Kao A, Williams T, et al. Relative costs of various preserved artificial tear solutions for the treatment of dry eye conditions. Eye Contact Lens
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`24. DiPascuale MA, Goto E, Tseng SC. Sequential changes of lipid tear film after the instillation of a single drop of a new emulsion eye drop in dry eye patients.
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`25. Khanal S, Tomlinson A, Pearce EI, et al. Effect of an oil-in-water emulsion on the tear physiology of patients with mild to moderate dry eye. Cornea 2007;26
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`26. Goto E, Shimazaki J, Monden Y, et al. Low-concentration homogenized castor oil eye drops for noninflamed obstructive meibomian gland dysfunction.
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`27. Korb DR, Scaffidi RC, Greiner JV, et al. The effect of two novel lubricant eye drops on tear film lipid layer thickness in subjects with dry eye symptoms. Optom
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`Vol. No: 146:04Issue: 4/15/2009
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