The Latest Uses of Restasis
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`Page 1 of 7
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`Michelle Stephenson, Contributing Editor
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`PUBLISHED 30 DECEMBER 2005
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`The Latest Uses of Restasis
`In addition to its FDA-approved indications for the treatment of dry eye, Restasis
`has many off-label uses.
`
`Although Restasis (0.05% cyclosporine A, Allergan) has only been approved by the Food and Drug Ad-
`ministration for the treatment of dry eye, ophthalmologists are using it off-label to treat many other
`conditions. Here are some the uses that clinicians and researchers are exploring.
`
`FDA Indications
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`Phase III studies have found cyclosporine A to be both safe and effective in the treatment of moderate to
`severe dry-eye disease.
`
`One Phase III study compared the efficacy and safety of cyclosporine A 0.05% and 0.1% ophthalmic
`1
`emulsions to vehicle in patients with moderate to severe dry-eye disease. This randomized, multicenter,
`double-masked study included 877 patients with moderate to severe dry-eye disease. Patients were
`treated twice daily with either cyclosporine A 0.05% or 0.1% or vehicle. Treatment with both
`concentrations of cyclosporine provided significant improvement compared to vehicle in corneal staining
`and categorized Schirmer values. Additionally, cyclosporine 0.05% treatment also provided significantly
`greater improvements in three subjective measures of dry-eye disease compared to vehicle: blurred
`vision, need for concomitant artificial tears, and the physician's evaluation of global response to
`treatment. There was no dose-response effect, and both cyclosporine A treatments exhibited an excellent
`safety profile, with no significant topical or systemic adverse safety findings.
`
`https://www.reviewofophthalmology.com/article/the-latest-uses-of-restasis
`
`11/29/2017
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`ALL 2114
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01127, -01128, -01129, -01130, -01131 & -01132
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`The Latest Uses of Restasis
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`Page 2 of 7
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`Figure 1. Fungal infection in a corneal transplant patient.
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`A separate Phase III study evaluated the safety of cyclosporine 0.1% ophthalmic emulsion over a one- to
`three-year period in moderate to severe dry-eye patients. This was a nonrandomized, multicenter, open-
`2
`label clinical trial that included 412 patients who were previously dosed for six to 12 months with
`cyclosporine 0.05% or 0.1% in prior Phase III trials. Patients instilled ophthalmic cyclosporine 0.1% twice
`daily into both eyes for up to three consecutive 12-month periods. The study found that cyclosporine
`0.1% ophthalmic emulsion taken for one to three years was safe and well-tolerated and was not
`associated with systemic side effects.
`
`"These results supplement the safety record of the commercially available cyclosporine 0.05%
`ophthalmic emulsion," says Stephen C. Pflugfelder, MD, one of the study's authors. Dr. Pflugfelder is a
`professor of ophthalmology at Baylor College of Medicine in Houston.
`
`Adds Eric D. Donnenfeld, MD, an associate professor of ophthalmology at New York University Medical
`Center, New York City, "The FDA studies have shown that this is an extraordinarily effective drug for
`treating patients who don't make enough quality tears. These studies showed that 15 percent of patients
`who were given Restasis had a tripling of their Schirmer scores."
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`Moreover, a study conducted by Karl Stonecipher, MD, and colleagues found that it is an effective
`3
`treatment for patients suffering from severe dry eye. The study included 4,504 ophthalmologists,
`optometrists and primary care physicians from across the United States. Data were obtained from patient
`surveys that included questions related to patients' experiences using topical cyclosporine A 0.05%
`ophthalmic emulsion. A total of 5,884 patients completed the study, and the vast majority of patients were
`women. Patients who completed the study achieved significant reductions of 30 percent in symptom
`severity and 31- to 36-percent reductions in activity impairments relative to baseline. Onset of relief was
`noted within one week by 32 percent of patients and within three weeks by 73 percent.
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`"These were mild to severe dry-eye patients who typically presented with dry-eye-related complaints,"
`says Dr. Stonecipher, who is in private practice at the TLC Eye Center in Greensboro, N.C. "The most
`notable difference between this study and the FDA studies is the rapidity of response. I attribute that to
`the fact that those patients who were initially enrolled in the FDA studies were the severe dry-eye patients
`in whom nothing else worked, as opposed to the general dry-eye patient seen in day-to-day practice."
`
`https://www.reviewofophthalmology.com/article/the-latest-uses-of-restasis
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`11/29/2017
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`ALL 2114
`MYLAN PHARMACEUTICALS V. ALLERGAN
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`The Latest Uses of Restasis
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`Page 3 of 7
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`Non-FDA Indications
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`One of the main off-label uses of Restasis is for the prevention and treatment of post-LASIK dry eye,
`according to Dr. Donnenfeld. He pretreats all patients with mild to moderate dry eye before LASIK.
`Restasis not only improves the symptoms of dry eye after LASIK, but it can also improve visual acuity
`results after LASIK. "The ocular surface is more regular, and patients achieve better quality of vision with
`reduced glare and halo," he says.
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`Figure 2. Various cases of meibomian gland dysfunction.
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`A recent masked study included 42 eyes of 21 myopic dry-eye patients who were considered poor
`candidates for LASIK. They were randomly divided into two treatment groups. One group received
`4
`unpreserved artificial tears, and the other group received Restasis. The drop was discontinued for 48
`hours postoperatively and was then resumed for three additional months. The eyes that received
`Restasis had significantly better postoperative uncorrected visual acuity at one month and in many cases
`at one year. Additionally, the one-week best-corrected visual acuity was better in the Restasis group, and
`it appeared that these eyes were recovering faster.
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`Dr. Stonecipher also recently reported that Restasis in LASIK patients with chronic dry eye produced im-
`provement in patient symptoms post-LASIK and decreased the impact of dry-eye symptoms on patients'
`daily activities. (Stonecipher KG, McMackin N. Onset of symptom relief in chronic dry-eye patients after
`treatment with cyclosporine 0.05% ophthalmic emulsion. Presented at the 2005 American Society of
`Cataract and Refractive Surgery Annual Meeting.) In this study, the majority of patients noted relief of
`their symptoms within three weeks and a reduction in concomitant artificial tear use.
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`According to Dr. Pflugfelder, one of the most effective off-label uses of Restasis is for the treatment of
`allergic-type conditions. "Patients with eczema or atopic dermatitis can get very severe conjunctival and
`corneal inflammation. Restasis works extremely well for these patients," he says.
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`A recent study found that topical cyclosporine A 0.05% is safe and effective in alleviating signs and
`5
`symptoms of severe atopic keratoconjunctivitis refractory to topical steroid treatment.
`In this study, 22
`patients with atopic keratoconjunctivitis were randomly assigned to receive topical 0.05% cyclosporine A
`
`https://www.reviewofophthalmology.com/article/the-latest-uses-of-restasis
`
`11/29/2017
`
`ALL 2114
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01127, -01128, -01129, -01130, -01131 & -01132
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`

`

`The Latest Uses of Restasis
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`Page 4 of 7
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`eyedrops or placebo for a period of 28 days six times daily during the first two weeks and then four times
`daily during the last two weeks. The study found that cyclosporine A had some effect in alleviating the
`signs and symptoms of severe atopic keratoconjunctivitis.
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`Figure 3. Restatis use may help a patient with Thygeson"s
`keratitis avoid corticosteriods and their attendant risk of
`cataract.
`
`Dr. Pflugfelder noted that Restasis is also effective in treating vernal keratoconjunctivitis. "This type of
`allergic and inflammatory-mediated keratoconjunctivitis typically occurs in young males. It can be severe
`and blinding," he says.
`
`He noted that Restasis is a better choice than steroids for treating both atopic keratoconjunctivitis and
`vernal keratoconjunctivitis because the conditions are chronic and may last for years. "These patients
`would require very frequent steroid drops, sometimes four times a day, to control the disease, so they are
`prone to developing steroid complications, such as cataract, glaucoma or infections. Restasis is an
`extremely safe medication that can be used chronically," he says.
`
`Another off-label use is the prevention of corneal transplant rejection. In these cases, Restasis is used as
`a steroid-sparing agent or as a supplement to steroids. "Transplant rejection is mediated in large part by
`T-lymphocytes, which are the master immune-regulating cells in the body. Cyclosporine is a potent
`inhibitor of T-lymphocytes, and it prevents their activation," Dr. Pflugfelder explains.
`
`It is also effective for managing post-corneal transplant glaucoma, according to Dr. Donnenfeld, who
`6
`published a paper on this topic. Many times, the glaucoma is induced by corticosteroids. "In patients who
`have glaucoma after a corneal transplant, if we take them off their steroid and put them on Restasis, they
`have a significant reduction in pressure," he says. In fact, these patients have a mean intraocular
`pressure decrease of 8.2 mmHg.
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`According to Henry D. Perry, MD, Restasis can also prevent a phakic corneal transplant recipient from
`developing cataracts. "This is especially useful in patients who are young and who have keratoconus,
`says Dr. Perry, an associate clinical professor at Weill Medical College. "Restasis protects their corneas
`and prevents the problems that can occur with long-term use of corticosteroids, in terms of cataracts and
`secondary glaucoma."
`
`https://www.reviewofophthalmology.com/article/the-latest-uses-of-restasis
`
`11/29/2017
`
`ALL 2114
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01127, -01128, -01129, -01130, -01131 & -01132
`
`

`

`The Latest Uses of Restasis
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`Page 5 of 7
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`Drs. Donnenfeld and Perry have also found Restasis to be helpful in the treatment of fungal infections in
`keratoplasty patients (See Figure 1). (Perry HD, Donnenfeld ED, Kornstein H, Kanellopoulos AJ. Topical
`cyclosporine A in the management of therapeutic keratoplasty for mycotic keratitis. Presented at the 1999
`American Academy of Ophthalmology Annual Meeting.)
`
`"We use it in conjunction with nonsteroidals in an effort to avoid corticosteroids postoperatively," Dr. Perry
`says. "This is important because steroids postoperatively potentiate fungal overgrowth and may enhance
`the likelihood of a fungal recurrence. Therefore, by avoiding corticosteroids, we improve the prognosis for
`our patients that the keratoplasty will be successful, both in terms of clarity and, most importantly,
`eradicating the fungal infection."
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`In addition to aqueous-deficient dry eye, Restasis also effectively treats meibomian gland dysfunction
`7
`(See Figure 2).
`In a prospective study, 33 patients with meibomian gland dysfunction were randomized
`to receive either Restasis or placebo twice daily for three months. They were evaluated at baseline and at
`the end of each month for subjective symptoms and objective signs, including meibomian gland
`inclusions, lid margin vascular injection, tarsal telangiectasis, fluorescein staining, tear breakup time, and
`Schirmer scores.
`
`The study found that, at the three-month visit, several objective examination findings were statistically
`significantly improved in the Restasis group compared to placebo. These differences included lid margin
`vascular injection, tarsal telangiectasis, and fluorescein staining. The most significant finding was the
`greater decrease in the number of meibomian gland inclusions in the Restasis group, Dr. Donnenfeld
`says.
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`He notes that Restasis is also effective for the treatment of inflammatory corneal ulceration, rheumatoid
`corneal ulcers, pauciarticular juvenile rheumatoid arthritis, iridocyclitis, and ligneous conjunctivitis.
`
`According to Dr. Pflugfelder, Restasis is also effective for certain types of superficial keratitis that typically
`occur after conjunctivitis. He says that superficial keratitis can occur as early as two weeks after the
`conjunctivitis and can last for months or years. Because it can be chronic, Restasis can be a better
`treatment choice than steroids.
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`Thygeson's superficial punctate keratitis has a similar appearance, and its cause is unknown (See Figure
`3). Restasis is a good choice for these patients because many are very young, and corticosteroids can
`cause a cataract if they are used often enough. Children are more at risk for cataracts just because of
`their age and their life expectancy.
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`Drs. Donnenfeld and Perry also published a study showing that Restasis is helpful as primary or
`8
`adjunctive therapy for superior limbic keratoconjunctivitis. "We use it as a treatment for these patients
`and also to help maintain them in a state of relative quiescence. In this way, we avoid the use of long-
`term corticosteroids," Dr. Perry says.
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`Their study included five patients diagnosed with Theodore's superior limbic keratoconjunctivitis. Topical
`cyclosporine A 0.5% drops were used four times daily in both eyes. All five patients had long-term
`improvement of irritation and foreign body sensation, as well as improvement of injection and filamentary
`keratitis. Except for burning on instillation, there were no complications related to this therapy.
`
`Dr. Pflugfelder also uses Restasis in patients with herpetic stromal keratitis.
`
`https://www.reviewofophthalmology.com/article/the-latest-uses-of-restasis
`
`11/29/2017
`
`ALL 2114
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01127, -01128, -01129, -01130, -01131 & -01132
`
`

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`The Latest Uses of Restasis
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`Page 6 of 7
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`"I also use it prophylactically in patients with Hashimoto's thyroiditis," Dr. Perry says. "These patients
`have a 20- to 45-percent chance of developing keratoconjunctivitis sicca. With this high likelihood, using
`Restasis in a prophylactic way is beneficial and justifiable," he says.
`The Future of Restasis
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`Because Restasis is a T-cell modulator, any patient with a T-cell-mediated disease will benefit from its
`use, and Restasis has several benefits over steroids:
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`• It inhibits T-lymphocytes.
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`• It causes no increase in IOP.
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`• It causes no decrease in wound healing.
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`• It does not inhibit the phagocytic system.
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`• It does not cause cataracts.
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`• It has no effect on viral replication.
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`• It improves tear function.
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`"There are opportunities for its use that we haven't even explored yet," Dr. Donnenfeld says. "As our
`comfort with cyclosporine increases, new indications for its use will be elucidated. Its unique combination
`of a high therapeutic efficacy and specific T-cell modulation without affecting the inflammatory pathways
`makes it a very low-risk drug for the treatment of these different diseases."
`
`1. Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized studies of the efficacy and
`safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study
`Group. Ophthalmology 2000;107:1220.
`2. Barber LD, Pflugfelder SC, Tauber J, Foulks GN. Phase III safety evaluation of cyclosporine 0.1%
`ophthalmic emulsion administered twice daily to dry eye disease patients for up to 3 years.
`Ophthalmology 2005;112:1790-1794.
`3. Stonecipher K, Perry HD, Gross RH, Kerney DL. The impact of topical cyclosporine A emulsion 0.05%
`on the outcomes of patients with keratoconjunctivitis sicca. Curr Med Res Opin 2005;21:1057-1063.
`4. Salib G, McDonald M, Smolek M. Safety and efficacy of cyclosporine 0.05% drops vs. unpreserved
`artificial tears in dry eye LASIK patients. J Cataract Refract Surg In press.
`5. Akpek EK, Dart JK, Watson S, et al. A randomized trial of topical cyclosporine 0.05% in topical steroid-
`resistant atopic keratoconjunctivitis. Ophthalmology 2004;111:476-482.
`6. Perry HD, Donnenfeld ED, Kanellopoulos AJ, Grossman GA. Topical cyclosporine A in the management
`of post-keratoplasty glaucoma. Cornea 1997;16:284-288.
`7. Perry HD, Doshi-Carnevale S, Donnenfeld ED, Solomon R, Biser SA, Bloom AH. Efficacy of
`commercially available topical cyclosporine A 0.05% in the treatment of meibomian gland dysfunction.
`Cornea In press.
`8. Perry HD, Doshi-Carnevale S, Donnenfeld ED, Kornstein HS. Topical cyclosporine A 0.5% as a possible
`new treatment for superior limbic keratoconjunctivitis. Ophthalmology 2003;110:1578-1581.
`
`https://www.reviewofophthalmology.com/article/the-latest-uses-of-restasis
`
`11/29/2017
`
`ALL 2114
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01127, -01128, -01129, -01130, -01131 & -01132
`
`

`

`The Latest Uses of Restasis
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`Page 7 of 7
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`Copyright © 2017 Jobson Medical Information LLC unless otherwise noted.
`All rights reserved. Reproduction in whole or in part without permission is prohibited.
`
`https://www.reviewofophthalmology.com/article/the-latest-uses-of-restasis
`
`11/29/2017
`
`ALL 2114
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01127, -01128, -01129, -01130, -01131 & -01132
`
`