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C U T T I N G - E D G E A D V A N C E M E N T S
By Nancy Groves; Reviewed by Jae Hee Kang, ScD
RECENT TOOTH LOSS—with or without periodontal disease—was associ-ated with a significantly increased risk of primary open-angle glaucoma (POAG), ac-cording to findings from a long-term pro-spective study of oral health in male health professionals.
“We observed that men who differed in number of natural teeth, in whether they had any periodontal disease, or in whether they had ever received root canal treatment, did not show differences in the risk of de-veloping POAG,” said Jae Hee Kang, ScD, co-author of the study recently published in Ophthalmology.1 “However, compared to men who reported no tooth loss, men who reported losing one or more teeth recently
(in the past 2 years) had a 45% increased risk of POAG (95% CI, 1.06-1.97) and men who reported having both periodontal dis-ease and had lost one or more teeth in the past 2 years had an 85% increased risk of POAG (95% CI, 1.07-3.18).”
This association did not differ by IOP at diagnosis, but other possible associations were identified, said Dr. Kang, assistant professor of medicine, Channing Division of Network Medicine, Department of Medi-cine, Brigham and Women’s Hospital and Harvard Medical School, Boston.
“We observed some suggestion that these relations were strongest in those whose para-central vision was primarily affected ver-sus those whose peripheral vision was pri-marily affected,” said Dr. Kang, adding that paracentral vision loss in POAG has been shown to be related to impaired blood flow.
CYCLOSPORINEFOR DRY EYE WITH ANTI-PD-1 THERAPY
IN THIS CASE, a 58-year-old man with metastatic melanoma from a primary nasal sinus tumor was referred for bi-lateral eye irritation. He was undergo-ing his sixth cycle of nivolumab (3 mg/kg) for treatment of melanoma, and his lesions had been regressing favor-ably in response. The patient was as-sessed to have dry eye syndrome for which he was started on drop therapy. He continued to experience persistent burning in both eyes and was referred to a cornea specialist.
( See story on page 6 : Resident Writer’s )
( Continues on page 12 : Oral health )
Poor oral health, POAG may be linkedStudy raises possibility of systemic adverse effects
January 2017 VOL. 42, NO. 1
FIVE ROADBLOCKS TO BEING HAPPIER IN OPHTHALMOLOGYSOME PHYSICIANS may have a pre-conceived notion that comparing them-selves with other physicians who may be better off will give them a state of contentment. This is but one example of how physicians may deprive them-selves of more contentment, said John S. Grande, CFP, Traudy F. Grande, CFP, and John J. Grande, CFP in this latest “Money Matters” column. Learn about some of the other stressors common to practicing ophthalmologists as they prepare for retirement.
( See story on page 37 : Happiness )
OphthalmologyTimes.com
WHAT IS IT LIKE WHEN AN ARTIST LOSES VISION? Individuals might express impact in unique way PAGE 4
increased risk of POAG in men who
reported losing one or more
teeth recently
increased risk of POAG in men who reported having both periodontal disease and
had lost one or more teeth in
the past 2 years
45%
85%
Advanced laser technology enables surgeons to perform a full range of anterior and posterior YAG laser procedures, as well as SLT. Surgeons can also toggle between on- and off-axis modes to better visualize � oaters and their position.(Image courtesy of Inder Paul Singh, MD)
READ THE ARTICLE ON PAGE 18
On- and off-axis visualization
C L I N I C A L D I A G N O S I S S U R G E R Y D R U G T H E R A P Y
Resident Writer's Award
Practice Management
SIIP SOME HOT COCOA
AND TAKE A PEEK INSIDE.
Marks designated ®�CPF�v�CTG�QYPGF�D[�5JKTG�QT�CP�CHƂNKCVGF�EQORCP[��������5JKTG�75�+PE��.GZKPIVQP��/#�������5������������
CHECK IIT OUTat Xiidra-ECP.com
C U T T I N G - E D G E A D V A N C E M E N T S
By Nancy Groves; Reviewed by Jae Hee Kang, ScD
RECENT TOOTH LOSS—with or
without periodontal disease—was associ-
ated with a significantly increased risk of
primary open-angle glaucoma (POAG), ac-
cording to findings from a long-term pro-
spective study of oral health in male health
professionals.
“We observed that men who differed in
number of natural teeth, in whether they
had any periodontal disease, or in whether
they had ever received root canal treatment,
did not show differences in the risk of de-
veloping POAG,” said Jae Hee Kang, ScD,
co-author of the study recently published
in Ophthalmology.1 “However, compared to
men who reported no tooth loss, men who
reported losing one or more teeth recently
(in the past 2 years) had a 45% increased
risk of POAG (95% CI, 1.06-1.97) and men
who reported having both periodontal dis-
ease and had lost one or more teeth in the
past 2 years had an 85% increased risk of
POAG (95% CI, 1.07-3.18).”
This association did not differ by IOP at
diagnosis, but other possible associations
were identified, said Dr. Kang, assistant
professor of medicine, Channing Division
of Network Medicine, Department of Medi-
cine, Brigham and Women’s Hospital and
Harvard Medical School, Boston.
“We observed some suggestion that these
relations were strongest in those whose para-
central vision was primarily affected ver-
sus those whose peripheral vision was pri-
marily affected,” said Dr. Kang, adding that
paracentral vision loss in POAG has been
shown to be related to impaired blood flow.
CYCLOSPORINEFOR DRY EYE WITH ANTI-PD-1 THERAPY
IN THIS CASE, a 58-year-old man with
metastatic melanoma from a primary
nasal sinus tumor was referred for bi-
lateral eye irritation. He was undergo-
ing his sixth cycle of nivolumab (3 mg/
kg) for treatment of melanoma, and
his lesions had been regressing favor-
ably in response. The patient was as-
sessed to have dry eye syndrome for
which he was started on drop therapy.
He continued to experience persistent
burning in both eyes and was referred
to a cornea specialist.
( See story on page 6 : Resident Writer’s )
( Continues on page 12 : Oral health )
Poor oral health, POAG may be linkedStudy raises possibility of systemic adverse effects
January 2017 VOL. 42, NO. 1
FIVE ROADBLOCKS TO BEING HAPPIER IN OPHTHALMOLOGYSOME PHYSICIANS may have a pre-
conceived notion that comparing them-
selves with other physicians who may
be better off will give them a state of
contentment. This is but one example
of how physicians may deprive them-
selves of more contentment, said John
S. Grande, CFP, Traudy F. Grande, CFP,
and John J. Grande, CFP in this latest
“Money Matters” column. Learn about
some of the other stressors common
to practicing ophthalmologists as they
prepare for retirement.
( See story on page 37 : Happiness )
OphthalmologyTimes.com
WHAT IS IT LIKE WHEN AN ARTIST LOSES VISION? Individuals might express impact in unique way PAGE 4
increased
risk of POAG
in men who
reported losing
one or more
teeth recently
increased risk
of POAG in men
who reported
having both
periodontal
disease and
had lost one or
more teeth in
the past 2 years
45%
85%
Advanced laser technology
enables surgeons to perform
a full range of anterior and
posterior YAG laser procedures,
as well as SLT. Surgeons can
also toggle between on- and off-
axis modes to better visualize
fl oaters and their position.
(Image courtesy of Inder Paul Singh, MD)
READ THE ARTICLE ON PAGE 18
On- and
off-axis
visualization
C L I N I C A L D I A G N O S I S S U R G E R Y D R U G T H E R A P Y
Resident Writer's Award
Practice Management
3JANUARY 2017 :: Ophthalmology Times
contentscontents
In Th is Issue 4 EDITORIAL 35 MARKETPLACE
Video
To see a new laser platform with
multiple treatment capabilities, go to
OphthalmologyTimes.com/LaserPlatform
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Introducing the
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app for iPad and
iPhone. Download
it for free today at
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See what the ophthalmic community
is reading on OphthalmologyTimes.com
What’s Trending
1 Top 16 stories of 2016OphthalmologyTimes.com/Top2016Stories
2 Drug therapies moving
beyond anti-VEGFsOphthalmologyTimes.com/BeyondAnti-VEGFs
3 News from pharmaceutical
forefront of cataract surgeryOphthalmologyTimes.com/Intracameral
4 How glucosamine supplements
may increase IOPOphthalmologyTimes.com/Glucosamine
Resident Writer’s Award
6 CYCLOSPORINE FOR DRY EYE WITH ANTI-PD-1 THERAPYIntense infl ammation treatment helpful
in dry eye disease, corneal perforation
Special Report
31 ADD-ON MODULE ENHANCES GLAUCOMA DIAGNOSTICSTechnology creates anatomic map
of eye by using two fi xed landmarks
Practice Management
37 TIPS TO BE A HAPPIER OPHTHALMOLOGISTChanging fi ve key lifestyle habits can
decrease stress, improve well-being
Find us on
4
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U.S.A.
JANUARY 2017 :: Ophthalmology Times
editorialeditorial
JANUARY 2017 ◾ VOL. 42, NO. 1
How gifted individuals may express impact of losing sight
VISION PROBLEMS have no doubt been
fairly common throughout history. However,
the difficulties of prominent artists—celebri-
ties that they are—often receive great attention.
Claude Monet’s difficulty with cataracts, Mary
Cassatt’s diabetes and cataracts that caused her
to give up painting, and Jules Chéret’s (creator
of those joyful posters of Parisian women) bi-
lateral angle-closure glaucoma are the subjects
of books.
Recently, I learned about three famous art-
ists who went blind in the 1700s. John Milton
(the English poet famous for writing Paradise
Lost) was born in 1674, 11 years before Johann
Sebastian Bach (who composed the Branden-
burg Concertos among other classical treasures)
and Georg Friedrich Handel (perhaps most fa-
mous for the choral work Messiah).
Bach’s blindness and subsequent death, both
at the age of 65, were reported to be “the un-
happy consequences of a very unsuccessful eye
operation” by British eye surgeon John Taylor
(who performed two operations a month apart).1
In 1751, at the age of 66, Handel developed a
cataract and was operated upon by “the great
charlatan Chevalier Taylor.”2 Again, the surgery
was unsuccessful and he was completely blind
for the last 7 years of his life.
H O W A R T I S T S
E X P E R I E N C E D L O S S
Not all famous artists of this time became blind
after failed surgery. Milton is thought to have
had either bilateral retinal detachments or glau-
coma, and he spent the last 20 years of life
without vision. He remained an acclaimed au-
thor, dictating his verse to scribes.3
Milton addressed the topic of his blindness
through the biblical character of Samson in the
poem Samson Agonistes. Samson, you may re-
call, was betrayed by the temptress Delilah, im-
prisoned, blinded by his captors, and chained
to giant columns.
The suffering Samson describes his blind-
ness as being similar to a solar eclipse: “O dark,
dark, dark, amid the blaze of noon,/Irrevocably
dark, total eclipse.”
Once his hair regrew, Samsom used his re-
gained strength to pull down the columns to
which he was chained, ending the lives of his
enemies as well as his own and his suffering
with blindness.
Handel, in his opera entitled “Samson,” has
his lead character describe his blindness using
a similar experience (a solar eclipse) and simi-
lar words: “Total eclipse! No sun, no moon!/All
dark amidst the blaze of noon!”
Bach, who only lived a few months following
his disastrous couching procedures, apparently
did not have the opportunity to use his art to
describe the experience of becoming blind.
Much has been written about these great art-
ists and their visual challenges. What to me is
less clear is the inner reaction of these gifted
individuals to the challenge of losing their
sight.
While a recent poll revealed the possibility of
losing sight to be the number one health-related
fear of Americans,4 my imagination causes me
to think that artists might experience that loss
in particularly dramatic fashion and might be
able express the impact in a special way. Q
When an artist loses vision
By Peter J. McDonnell, MD
director of the Wilmer Eye Institute,
Johns Hopkins University School of
Medicine, Baltimore, and chief medical
editor of Ophthalmology Times.
He can be reached at 727 Maumenee Building
600 N. Wolfe St. Baltimore, MD 21287-9278
Phone: 443/287-1511 Fax: 443/287-1514
E-mail: [email protected]
References1. David, Mendel, and Wolff. The New Bach Reader: A Life of
Johann Sebastian Bach in Letters and Documents. New
York; W.W. Norton and Company. 1998, p. 188.
2. Hicks, Anthony 2013. “Handel, Georg Frideric,” Groves
Music Online, Oxford University Press.
3. Sorsby A. The Nature of Milton’s Blindness. Br J
Ophthalmol. 1930;14:339-354.
4. Scott AW, Bressler NM, Ffolkes S, Wittenborn JS,
Jorkasky J. Public Attitudes About Eye and Vision Health.
JAMA Ophthalmol. 2016;134:1111-1118.
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advancements and analysis from around the world in surgery, drug therapy, technology, and
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JANUARY, 2014 :: Ophthalmology Times
editorial advisory boardeditorial advisory board5JANUARY 2017 :: Ophthalmology Times
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08-01720 Tearse5 Meibum Compression Forceps
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n Forceps
08-01719 Khouri2 Eyelid Squeegee
08-01716 Maskin3 Meibum Expresso
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08-01717 Hardten4 Eyelid Compression Forceps
-EIBUM%XPRESSORS
Hardten4
Tearse5
Batlle1
Khouri2
Maskin3
6
resident writer’s awardresident writer’s awardJANUARY 2017 :: Ophthalmology Times
sponsored by
A 58-YEAR-OLD MAN with metastatic
melanoma from a primary nasal sinus tumor
was referred to ophthalmology for bilateral eye
irritation. Around this time, he was undergo-
ing his sixth cycle of nivolumab (3 mg/kg) for
treatment of metastatic melanoma. His meta-
static lesions had been regressing favorably
in response to nivolumab, an immunomodu-
latory agent that upregulates host immunity.
The patient was assessed to have dry eye
syndrome for which he was started on pre-
servative-free artificial tears and lubricating
ointment at bedtime. For the next 2 weeks,
he continued to experience persistent burn-
ing in both eyes and was then referred to a
cornea specialist.
E X A M I N A T I O N
On presentation to the cornea service, his cor-
rected visual acuity was 20/30 in the right
eye and 20/25 in the left. His examination
was notable for a low tear meniscus and dif-
fusely distributed punctate epithelial erosions
in both eyes. A basic secretion test (Schirm-
er’s with anesthesia) was performed which
yielded values less than 4.0 mm from each eye.
T R E A T M E N T A N D
C L I N I C A L C O U R S E
The patient was recommended to intensify the
frequency of lubricant tear use to at least 6-8
times daily. Additionally, he received bilateral
lower eyelid punctum plugs and was started
on topical cyclosporine (0.05%) twice daily in
both eyes. However, due to overseas travel,
the patient reported difficulty adhering to this
medication regimen.
Two weeks later, he returned to the office
with a perforated cornea in the right eye. Ex-
amination of the right eye was notable then
for a 1.8- × 1.4-mm paracentral epithelial de-
fect within which there was variable corneal
thinning and a small focus of Seidel-positive
leakage. The chamber was shallow but with-
out iris plugging to the perforation site. This
was acutely managed with corneal glue and a
bandage contact lens. The left eye had a small
epithelial defect without associated stromal
thinning.
Further treatment with nivolumab was held
in light of this adverse event. In the weeks that
followed, the right eye was stabilized with ad-
herence to a regimen that included preserva-
tive-free artificial tears, daily topical lotepre-
dnol (0.5%), topical cyclosporine, autologous
serum tears, oral doxycycline, and vitamin C.
The left eye had exhibited areas of slight stro-
mal thinning (80-90% normal stromal thick-
ness) but it was similarly stabilized with lu-
bricating tears (artificial and serum), topical
cyclosporine, and a bandage contact lens. One
month after the cornea of the right eye was
glued, the full thickness defect had healed but
there remained a stromal scar with marked
corneal thinning (Figure 1 on Page 7).
One year after nivolumab was discontinued,
abdominal imaging revealed a pancreatic head
mass that was biopsy-positive for melanoma.
After additional imaging revealed further sites
Editor’s Note: Oph-
thalmology Times
is pleased to an-
nounce Alexander
T. Nguyen, MD,
and Jessica Chow,
MD, of Yale Univer-
sity School of Med-
icine, New Haven,
CT, as the second-
place winners of the
2016 Resident Writ-
er’s Award Program,
sponsored by Aller-
gan. Their entry is
featured here.
The Ophthalmol-
ogy Times Resident
Writer’s Award Program is a unique recog-
nition opportunity designed to promote ex-
cellence in ocular surface disease education.
It was created to acknowledge outstanding
case identification and written presentation
skills in ophthalmology residents.
This year’s third-place winners, Lekha
Mukkamala, MD, and Albert Khouri, MD,
of Rutgers New Jersey Medical School, New-
ark, NJ, submitted a case study, “Irritation
in a bottle: The intensity of glaucoma treat-
ment and ocular surface disease.”
Look for their case study submission in
a future issue of Ophthalmology Times.
PURPOSE: To present a clinical case of severe dry
eye associated with nivolumab (Opdivo, Bristol-Myers
Squibb) that progressed to corneal perforation.
BACKGROUND: Nivolumab is a PD-1 (programmed
cell death protein 1) antagonist that exerts its anti-tumor
effect by upregulating host T cell immunity.
CASE PRESENTATION: A 58-year-old man with
metastatic melanoma was referred for management
of severe bilateral dry eyes after undergoing his sixth
cycle of nivolumab. The right eye progressed to cor-
neal perforation that was acutely treated with corneal
gluing. Nivolumab therapy was subsequently discon-
tinued due to this adverse event. When the patient ex-
hibited evidence of recurrent metastases, nivolumab
was restarted. The patient’s ocular surface was able
to sustain continued therapy with nivolumab with an
intensive approach that included topical cyclosporine.
CONCLUSIONS: PD-1 antagonists can cause or worsen
dry eye disease to the point of corneal perforation.
Given that its anti-tumor effect is immune mediated,
therapies targeting ocular surface inflammation can
be effective for stabilizing dry eye disease in patients
who are treated with anti-PD-1 agents.
Abstract
Cyclosporine for dry eyewith anti-PD-1 therapyCase exemplifi es need of proper ophthalmic care for cancer patientsBy Alexander T. Nguyen, MD, and Jessica Chow, MD; Special to Ophthalmology Times
Dr. Nguyen
Dr. Chow
tR
ESI
DENT WRITER’S AW
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2nd
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7JANUARY 2017 :: Ophthalmology Times
resident writer’s award
of probable metastases, a decision was reached
to restart nivolumab.
In a recent clinic visit, the patient has cleared
all sites of metastases with several additional
treatment cycles. His ocular surface has been
maintained bilaterally with scleral lenses, topi-
cal cyclosporine, frequent surface lubrication,
and cautery of both upper and lower lid puncta.
D I S C U S S I O N
The programmed cell death protein 1 (PD-1)
is a membrane receptor that is involved in down-
regulating host immunity.1-3 Activation of this
pathway promotes the apoptosis of antigen-
specific T cells, which serves to promote host
tolerance for self-antigens. Nivolumab is an
antibody capable of disrupting this pathway;
in doing so, it exerts anti-tumor activity by up-
regulating host T cell immunity. Expectedly,
many of the adverse effects associated with
nivolumab are immune-mediated.1-4
While there is not much written about the
ocular side-effects of this drug class, we hypoth-
esized that the upregulation of T cell activity
could be the cause of worsening dry eye dis-
ease.4 If this were true, it follows that a thera-
peutic strategy targeting T cells may be of ben-
efit. The utility of controlling ocular surface
inflammation for the treatment of dry eye has
been demonstrated by prior studies investigat-
ing the use of topical cyclosporine for this end.5
Cyclosporine functions as a calcineurin inhibi-
tor. In doing so, it downregulates the transcrip-
tion of interleukin-2. The downstream effect of
this inhibition is a reduction in T cell activation.
Dry eye patients treated with cyclosporine
have been shown to have reduced levels of
pro-inflammatory cytokines on the ocular sur-
face,6 which is presumably responsible for the
improvement in symptoms, surface staining,7
and conjunctival goblet cell density.8
Because cyclosporine exerts its effect by in-
hibiting the activation of relatively naïve T cells,
its peak effect is delayed given the presence of
mature T lymphocytes that are already activated.
For this reason, bridging patients with a mild
topical corticosteroid can be helpful.
The patient’s poor compliance with the ini-
tial medication regimen may have contributed
to the progression towards perforation. Medi-
cation adherence, though, was improved after
the right eye required corneal gluing.
However, this adverse event led to the with-
drawal of nivolumab therapy, which had been
highly effective at resolving the patient’s meta-
static disease. When follow-up imaging showed
recurrent metastases, treatment with nivolumab
was reconsidered.
Ocular surface stability was a prerequisite
for receiving continued anti-PD-1 therapy. This
was achieved with an intensive approach that
includes topical cyclosporine, which provides
local inhibition of T cell activity on the ocu-
lar surface.
C O N C L U S I O N
Topical cyclosporine may be useful for treat-
ing dry eyes associated with immunomodula-
tory agents like nivolumab, which markedly
upregulate T cell activation.
In caring for patients with ocular side ef-
fects associated with cancer treatment, the de-
livery of proper ophthalmic care is critical. ■
References1. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and
activity of anti-PD-L1 antibody in patients with
advanced cancer. N Engl J Med. 2012;366:2455-
2465.
2. Rizvi NA, Mazieres J, Planchard D, et al. Activity and
safety of nivolumab, an anti-PD-1 immune checkpoint
inhibitor, for patients with advanced, refractory
squamous non-small-cell lung cancer (Checkmate
063): a phase 2, single-arm trial. Lancet Oncol.
2015;16:257-265.
3. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab
plus Ipilimumab in advanced melanoma. N Engl J
Med. 2013;369:122-133.
4. Nguyen AT, Elia M, Materin MA, et al. Cyclosporine
for dry eye associated with Nivolumab: a case
progressing to corneal perforation. Cornea.
2016;35:399-401.
5. Roberts CW, Carniglia PE, Brazzo BG. Comparison
of topical cyclosporine, punctal occlusion, and a
combination for the treatment of dry eye. Cornea.
2007;26:805-809.
6. Pflugfelder SC, Jones D, Ji Z, et al. Altered cytokine
balance in the tear fluid and conjunctiva of patients
with Sjogren’s syndrome keratoconjunctivitis sicca.
Curr Eye Res. 1999;19:201-211.
7. Chen M, Gong L, Sun X, et al. A comparison of
cyclosporine 0.05% ophthalmic emulsion versus
vehicle in Chinese patients with moderate to severe
dry eye disease: an eight-week, multicenter,
randomized, double-blind, parallel-group trial. J Ocul
Pharmacol Ther. 2010;26:361-366.
8. Kunert KS, Tisdale AS, Gipson IK. Goblet cell
numbers and epithelial proliferation in the conjunctiva
of patients with dry eye syndrome treated with
cyclosporine. Arch Ophthalmol. 2002;120:330-337.
Read the first-place entry 10 Tips for OSD-associated toxic epidermal necrolysis (TEN) at OphthalmologyTimes.com/10TipsForTEN
(FIGURE 1) Patient presented with severe dry eye after his sixth cycle of nivolumab for metastatic melanoma. Discontinuing nivolumab after corneal perforation
led to recurrent metastases. The anti-PD-1 agent was restarted successfully with a cyclosporine regimen, which stabilized the dry eye disease.
(Photos courtesy of Yale University School of Medicine)
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Take it all in at Xiidra-ECP.com
Proven to treat the signs of inferior corneal staining in 12 weeks and symptoms of eye dryness in 12, 6, and as little as 2.
(QWT�TCPFQOK\GF��FQWDNG�OCUMGF�����YGGM�VTKCNU�GXCNWCVGF�VJG�GHƂ�ECE[�CPF�UCHGV[�QH�:KKFTC�XGTUWU�XGJKENG�CU�CUUGUUGF�D[�KORTQXGOGPV�KP�VJG�UKIPU�OGCUWTGF�D[�+PHGTKQT�%QTPGCN�5VCKPKPI�5EQTG��
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what Dry Eye patients have been waiting forOVER
Indication Xiidra®�NKƂ�VGITCUV�QRJVJCNOKE�UQNWVKQP�����KU�KPFKECVGF�HQT�VJG�VTGCVOGPV�QH�UKIPU�CPF�U[ORVQOU�QH�FT[�G[G�FKUGCUG�&'&��
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BRIEF SUMMARY:Consult the Full Prescribing Information for complete product information.
INDICATIONS AND USAGE:KKFTCv�NKƂVGITCUV�QRJVJCNOKE�UQNWVKQP�����KU�KPFKECVGF�for the treatment of the signs and symptoms of dry eye FKUGCUG�&'&��
DOSAGE AND ADMINISTRATIONInstill one drop of Xiidra twice daily (approximately 12 JQWTU�CRCTV��KPVQ�GCEJ�G[G�WUKPI�C�UKPING�WUG�EQPVCKPGT��Discard the single use container immediately after using in each eye. Contact lenses should be removed prior to VJG�CFOKPKUVTCVKQP�QH�:KKFTC�CPF�OC[�DG�TGKPUGTVGF����minutes following administration.
ADVERSE REACTIONSClinical Trials ExperienceBecause clinical studies are conducted under widely varying conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may PQV�TGƃGEV�VJG�TCVGU�QDUGTXGF�KP�RTCEVKEG��+P�ƂXG�ENKPKECN�UVWFKGU�QH�FT[�G[G�FKUGCUG�EQPFWEVGF�YKVJ�NKƂVGITCUV�ophthalmic solution, 1401 patients received at least ��FQUG�QH�NKƂVGITCUV������QH�YJKEJ�TGEGKXGF�NKƂVGITCUV������6JG�OCLQTKV[�QH�RCVKGPVU������JCF�Ű��OQPVJU�QH�VTGCVOGPV�GZRQUWTG������RCVKGPVU�YGTG�GZRQUGF�VQ�NKƂVGITCUV�HQT�CRRTQZKOCVGN[����OQPVJU��6JG�OCLQTKV[�QH�VJG�VTGCVGF�RCVKGPVU�YGTG�HGOCNG�������6JG�OQUV�EQOOQP�CFXGTUG�TGCEVKQPU�TGRQTVGF�KP��������QH�RCVKGPVU�were instillation site irritation, dysgeusia and reduced XKUWCN�CEWKV[��1VJGT�CFXGTUG�TGCEVKQPU�TGRQTVGF�KP����VQ����QH�VJG�RCVKGPVU�YGTG�DNWTTGF�XKUKQP��EQPLWPEVKXCN�hyperemia, eye irritation, headache, increased lacrimation, eye discharge, eye discomfort, eye pruritus and sinusitis.
USE IN SPECIFIC POPULATIONSPregnancy6JGTG�CTG�PQ�CXCKNCDNG�FCVC�QP�:KKFTC�WUG�KP�RTGIPCPV�women to inform any drug associated risks. Intravenous +8��CFOKPKUVTCVKQP�QH�NKƂVGITCUV�VQ�RTGIPCPV�TCVU��HTQO�RTG�OCVKPI�VJTQWIJ�IGUVCVKQP�FC[�����FKF�PQV�RTQFWEG�teratogenicity at clinically relevant systemic exposures. +PVTCXGPQWU�CFOKPKUVTCVKQP�QH�NKƂVGITCUV�VQ�RTGIPCPV�rabbits during organogenesis produced an increased incidence of omphalocele at the lowest dose tested, ��OI�MI�FC[�����HQNF�VJG�JWOCP�RNCUOC�GZRQUWTG�CV�the recommended human ophthalmic dose [RHOD], DCUGF�QP�VJG�CTGC�WPFGT�VJG�EWTXG�=#7%?�NGXGN���5KPEG�JWOCP�U[UVGOKE�GZRQUWTG�VQ�NKƂVGITCUV�HQNNQYKPI�ocular administration of Xiidra at the RHOD is low, the CRRNKECDKNKV[�QH�CPKOCN�ƂPFKPIU�VQ�VJG�TKUM�QH�:KKFTC�WUG�KP�humans during pregnancy is unclear.
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Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger adult patients.
NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Animal studies have not been conducted VQ�FGVGTOKPG�VJG�ECTEKPQIGPKE�RQVGPVKCN�QH�NKƂVGITCUV� Mutagenesis: .KƂVGITCUV�YCU�PQV�OWVCIGPKE�KP�VJG�in vitro #OGU�CUUC[��.KƂVGITCUV�YCU�PQV�ENCUVQIGPKE�KP�VJG�in vivo mouse micronucleus assay. In an in vitro chromosomal aberration assay using mammalian cells (Chinese JCOUVGT�QXCT[�EGNNU���NKƂVGITCUV�YCU�RQUKVKXG�CV�VJG�JKIJGUV�concentration tested, without metabolic activation. Impairment of fertility: .KƂVGITCUV�CFOKPKUVGTGF�CV�KPVTCXGPQWU�+8��FQUGU�QH�WR�VQ����OI�MI�FC[� �����HQNF�VJG�JWOCP�RNCUOC�GZRQUWTG�CV�VJG�TGEQOOGPFGF�JWOCP�QRJVJCNOKE�FQUG�4*1&��QH�NKƂVGITCUV�QRJVJCNOKE�UQNWVKQP������JCF�PQ�GHHGEV�QP�fertility and reproductive performance in male and female treated rats.
latanoprost (Rhopressa, Aerie Pharmaceuti-
cals) show that netarsudil is additive to latano-
prost, he noted.
“In addition, there is evidence of additivity
when ripasudil, a rho kinase inhibitor that is
commercially available in Japan, is combined
with other glaucoma medications,” he said.
As ophthalmologists become more familiar
with the medication, they will probably begin
to consider using netarsudil as a standalone
agent, Dr. Bacharach said.
In the Mercury 1 trial, netarsudil demon-
strated non-inferiority to latanoprost in eyes
with baseline IOP ranging from >20 to <25
mm Hg.
W E L L T O L E R A T E D
The Rocket 4 study, which is still under way, was
designed to provide safety data for registration
filing with European regulatory authorities.
Data collected so far in Rocket 4 and other
clinical trials show that netarsudil has an ac-
ceptable safety profile in clinical trials.
So far, adverse events related to the medica-
tion have been limited to the eye. Erythema,
mostly mild, has been the most common ad-
verse event associated with netarsudil.
In addition, verticillata has developed in
some eyes, but these corneal deposits have not
interfered with vision and resolve when treat-
ment is discontinued, as does the erythema
“Most side effects in patients using netarsudil
during clinical trials were well-tolerated and
did not lead to treatment termination, and no
side effects were permanent in patients who
stopped the medication,” Dr. Bacharach said. ■
Rocket 4 randomly assigned about 700 pa-
tients 1:1 to once-daily netarsudil or twice-
daily timolol maleate 0.5%.
Netarsudil met the primary efficacy end-
point, achieving non-inferiority to timolol for
lowering IOP in eyes with baseline IOP rang-
ing from >20 to <25 mm Hg.
Netarsudil also met the secondary efficacy
endpoints by demonstrating non-inferiority to
timolol for lowering IOP in eyes with
baseline IOPs ranging from >20 to
<27 mm Hg and from >20 to <28
mm Hg.
“The 90-day topline efficacy re-
sults from Rocket 4 reiterated the
positive findings of Rocket 1 and
Rocket 2, the two phase III registra-
tion trials,” said Dr. Bacharach, who
was an investigator in the Rocket 2
and Rocket 4 trials and a glaucoma
specialist in private practice in So-
noma County, CA.
Collectively, the phase III clinical
trial program for netarsudil includes
a robust number of treated patients, with nearly
2,000 patients dosed, he noted.
“Approval of this rho kinase/norepineph-
rine transporter inhibitor would be an excit-
ing and welcome development considering
that it would be the first new class of IOP-
lowering agents to become available in over
20 years,” Dr. Bacharach said. “Based on the
clinical trial experience, I expect netarsudil
will be an important part of our armamen-
tarium, and I am looking forward to using it
in the clinical practice.”
Dr. Bacharach observed that in Rocket 4,
netarsudil performed better for lowering IOP
in eyes with the higher baseline levels than it
did in the Rocket 1 and Rocket 2 trials.
In addition, its activity for reducing IOP in
eyes with lower starting IOPs distinguishes it
from available ocular hypotensive
agents. Netarsudil’s broad efficacy
is probably explained by its multi-
modal mechanism of action that in-
volves increased trabecular outflow
facility and likely also reduction of
episcleral venous pressure, he said.
E X P L O R I N G
C L I N I C A L R O L E
Dr. Bacharach foresees that if net-
arsudil is approved, it likely will be
first adopted for use as an add-on
to a prostaglandin analogue in pa-
tients needing combination therapy.
“The fact that about 50% of patients with
glaucoma are on two IOP-lowering medications
clearly speaks to the need for having multi-
ple therapeutic options with different mecha-
nisms of action that can be used in combina-
tion therapy,” Dr. Bacharach said.
Results from a phase II study of netarsudil
and the phase III Mercury 1 trial investigat-
ing the fixed combination of netarsudil and
Topline results from data collected after 90 days in
the 6-month Rocket 4 phase III clinical trial confirm
that netarsudil ophthalmic solution 0.02% (formerly
AR-13324; Rhopressa, Aerie Pharmaceuticals) safely
and effectively lowers elevated IOP in eyes with ocu-
lar hypertension or open-angle glaucoma, said Jason
Bacharach, MD.
NOVEL OCULAR HYPOTENSIVE DRUG MEETS ENDPOINTSThird phase III trial findings add evidence of efficacy, safetyBy Cheryl Guttman Krader; Reviewed by Jason Bacharach, MD
take-home Netarsudil
ophthalmic solution
0.02% met its primary
and secondary
efficacy endpoints in
a third phase III trial
investigating its non-
inferiority to timolol
maleate 0.05% for IOP
lowering.
JASON BACHARACH, MD
Dr. Bacharach is a consultant to Aerie Pharmaceuticals and to other companies that
market and are developing medications for treatment of glaucoma.
1111EVOLVING CLINICAL STRATEGIES IN
GLAUCOMASpecial Report )
JANUARY 2017 :: Ophthalmology Times
ADVANCES CONTINUE TO PROGRESS FOR PHYSICIANS, RESEARCHERS IN FINDING A CURE FOR THIS BLINDING DISEASE
To investigate the hypothesis that poor oral
health may have systemic effects on the eye, the
researchers analyzed 26 years of data from the
Health Professionals Follow-up Study (HPFS),
which was designed to determine what factors
contribute to long-term health in men. They
reviewed data of 40,536 participants who were
followed biennially from 1986 to 2012.
Using information from the 2-year updates,
such as reports of periodontal dis-
ease, the participants could be cat-
egorized as having good oral health
versus poor oral health. Research-
ers could then compare the rates of
development of POAG in the two
groups over time.
“We also had a wealth of informa-
tion on additional health variables,
such as body mass index, smoking,
and diabetes so that we could ac-
count for these factors in our analy-
ses,” Dr. Kang said.
The 485 cases of POAG that were confirmed
with medical records were classified into sub-
types defined by IOP ≥ or < 22 mm Hg and vi-
sual field loss pattern at diagnosis (peripheral
loss only or early paracentral loss). Multi variate
rate ratios adjusted for key covariates with 95%
confidence intervals were estimated.
Although a modest increased risk of POAG
was observed in this study, observational epide-
miologic studies alone cannot establish causal
relations, and any clinical recommendations are
inappropriate at this time, Dr. Kang said.
“Nevertheless, the findings of the study raise
the possibility that systemic adverse effects of
poor oral health may also impact eye health,
and more confirmatory studies are warranted,”
she said.
E A R L I E R R E S E A R C H
This study follows earlier published studies by
several of the co-authors of this paper (Les-
lie Hyman, PhD, and John Danias, MD, PhD),
which found that individuals with glaucoma
had higher bacterial loads and fewer teeth than
those without glaucoma. Because the earlier
work had a small sample size and was con-
ducted in a clinic-based rather than a popu-
lation-based study sample, the authors were
interested in collaborating on a
larger study using the HPFS data.
The proposed association be-
tween poor oral health and POAG
derives from the shared factors of
impaired blood flow and endothe-
lial dysfunction, as well as the ob-
servation that treatment of peri-
odontal disease has been shown to
improve systemic blood flow and
endothelial function, Dr. Kang said.
“Therefore, we hypothesized that
poor oral health, manifesting as peri-
odontal disease and tooth loss, may be associated
with POAG,” she said.
Although studies often evaluate both women
and men, the investigators decided to use data
from the male-only HPFS since oral health ques-
tions were asked much less frequently in a simi-
lar study in women (the Nurse’s Health Study).
“We speculate that there may not be large
differences by gender, as periodontal disease
has been associated with various systemic dis-
eases, such as diabetes, cardiovascular dis-
ease, rheumatoid arthritis, certain cancers,
and neuro degenerative diseases in a similar
manner for men and women,” Dr. Kang said.
She added that some prior small studies have
not observed any differences by gender. ■
Reference1. Pasquale LR et al. Ophthalmology. 2016;123:2318-
2327. Epub 2016 Aug 20.
ORAL HEALTH( Continued from page 1 )
WEIGHING ROLE OF IOP FLUCTUATION IN PROGRESSIONAVAILABLE EVIDENCE INDICATES that
long-term IOP fluctuation is an important
factor in glaucoma progression, said Joseph
Caprioli, MD. Based on this information he
encouraged ophthalmologists to consider
IOP “modulation” rather than “reduction.”
“This relates to the quality of IOP control,”
said Dr. Caprioli, professor of ophthalmology,
University of California, Los Angeles. “The
target for patients with progressing primary
open-angle glaucoma at high risk should
be a low mean IOP and fewer excursions of
pressures into a range that may be damaging.
Go to OphthalmologyTimes.com/FluctuatingIOP
OphthalmologyTimes.comOnline Exclusive
take-home Recent tooth loss
and periodontal
disease have been
linked to primary
open-angle glaucoma
in a large prospective
study of male health
professionals.
JAE HEE KANG, SCD
This article was adapted from a study published in Ophthalmology as well as a
presentation by principal investigator Louis Pasquale, MD, at the 2016 meeting of the
American Glaucoma Society. Dr. Kang did not report any relevant disclosures.
Biosensors in contact lenses advancing to monitor IOP, diabetesBy Laird Harrison
CONTACT LENSES that can monitor
biomarkers in tear film for IOP and diabetes
mellitus are continuing to advance.
“The widespread use of contact lens sen-
sors could provide a paradigm shift in clinical
management of a variety of diseases,” wrote
Chau-Minh Phan, BSc, MSc, and colleagues of
the Centre for Contact Lens Research, School
of Optometery and Vision Science, Waterloo,
Canada, in Optometry and Vision Science.
Sensimed launched the Triggerfish IOP-mon-
itoring contact lens, which has CE approval in
Europe, but has not yet been FDA approved.
It uses four circular strain gauges capable
of sensing circumferential changes at the lim-
bus, Phan and colleagues noted.
An embedded microprocessor and antenna in
the contact lens sensor transfer the data wire-
lessly to an external eyepiece, and the data are
stored on a portable unit worn on the waist.
In clinical trials, the results proved highly
reproducible, and because no force is needed
on the cornea, they are independent of the in-
vestigator and patient, the authors said.
However, validation between the contact
lens sensor and tonometry has proved diffi-
cult because of the impossibility of simultane-
ous measurement using the contact lens sen-
sor and tonometry on the same eye.
Despite its technological obstacles, the de-
vice may prove useful over a 24-hour period
to glean information about fluctuation in IOP,
the researchers noted. ■
12 JANUARY 2017 :: Ophthalmology Times
Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA
GLUCOSAMINE SULFATE supplements
widely used as an osteoarthritis treatment ap-
pear to increase IOP, according to H. Esfandi-
ari, MD, of the University of Medical Sciences,
Tehran, Iran, and colleagues in the journal Eye
(http://go.nature.com/2igYKFX).
Though the study did not have enough glau-
coma patients to evaluate the effects of glucos-
amine in this population, “it’s a wise
practice that ophthalmologists di-
rectly ask patients about its usage
and carry out medication discontinu-
ation trial[s] in uncontrolled cases,”
the researchers wrote.
An amino monosccharide, glucos-
amine is an essential constituent of
cartilage. Though evidence is lack-
ing that it can improve symptoms
of osteoarthritis, radiographic stud-
ies have shown that it slows joint
space width loss. Since it appears to be safe, it
is popular as a treatment.
However, glucosamine is also abundant in
corneal stroma and plays a role in the mor-
phology and function of the trabecular mesh-
work. One small retrospective study showed an
association between glucosamine supplement
usage and IOP.
Other researchers have proposed that glucos-
amine could restore the extracellular matrix of
cartilage or halt additional cartilage degrada-
tion. “It’s no surprise” if changing glycosami-
noglycans could lead to changes in IOP or IOP
measurement, the authors wrote.
D I V I N G D E E P E R
To investigate this finding further, Dr. Esfandi-
ari and colleagues recruited 88 patients with os-
teoarthritis who attended a rheumatology clinic
from July 2014 to March 2015. They excluded
patients with ophthalmic diseases that might
affect the biomechanics of the cornea.
They randomly assigned 44 patients to take 750
mg glucosamine three times a day for 3 months
and 44 patients to take gelatinous capsules filled
with sugar as a placebo on the same schedule.
Sixty-seven of the patients were female and
21 were male. Their mean age was 57.7 years.
The mean IOP of the glucosamine group was
12.4 mm Hg at baseline and 13.0 mm Hg in the
placebo group, differences that were not statis-
tically significant (p = 0.329).
At month 1, IOP rose to 12.6 mm Hg in the
glucosamine group and fell to 12.9 mm Hg in
the placebo group. The differences were still not
statistically significant (p = 0.868).
At month 3, IOP rose to 13.5 mm Hg in the
glucosamine group and 13.0 mm Hg
in the placebo group. At that point,
the differences reached statistical sig-
nificance (p = 0.023). In the glucos-
amine group, 34% of patients had
an increase of more than 2 mm Hg
compared with 23.5% of patients in
the placebo group.
There were no significant differ-
ences between the groups in ocular
response analyser Goldmann-corre-
lated IOP, cornea-compensated IOP,
corneal hysteresis or corneal resistance factor.
The mean age in those with increases of 2
mm Hg IOP or more was 66 years, compared
with 57.7 years in patients who had increases
of <2 mm Hg.
A B O U T T H E F I N D I N G S
“The results of this study show that while glu-
cosamine causes statistically significant in-
crease in IOP in patients with [osteoarthritis],
corneal biomechanics remain unchanged within
3 months of glucosamine supplement therapy,”
the authors wrote.
Their results suggest that glucosamine sup-
plementation could be “pathological” in the tra-
becular meshwork after 3 months, they wrote.
Glycosaminoglycans constitute the ground
substance for the outermost part of the trabec-
ular meshwork. Long, flexible chains of glycos-
aminoglycans interact with each other to form
a system of entangled polyanionic macromole-
cules which act like a gel and contribute to out-
flow resistance.
Accumulated glycosaminoglycans in the ground
substance of the trabecular meshwork outflow
pathways, and increased constriction of the tra-
becular spaces could explain the rises in IOP
seen with even short courses of steroid treat-
ment, the authors wrote. ■
CyPass® Micro-StentIMPORTANT PRODUCT INFORMATION
CAUTION: FEDERAL (USA) LAW
RESTRICTS THIS DEVICE TO SALE BY OR
ON THE ORDER OF A PHYSICIAN.
INDICATION: The CyPass® Micro-Stent is indicated for use in conjunction with cataract surgery for the reduction of intraocular pressure (IOP) in adult patients with mild to moderate primary open-angle glaucoma (POAG).
CONTRAINDICATIONS: Use of the CyPass Mi-cro-Stent is contraindicated in the following circum-stances or conditions: (1) in eyes with angle-closure glaucoma; and (2) in eyes with traumatic, malignant, uveitic, or neovascular glaucoma or discernible con-genital anomalies of the anterior chamber angle.
MRI INFORMATION: The CyPass Micro-Stent is magnetic resonance (MR) Safe: the implant is constructed of polyimide material, a non-conducting, non-metallic, non-magnetic polymer that poses no known hazards in all magnetic resonance imaging environments.
WARNINGS: Gonioscopy should be performed prior to surgery to exclude peripheral anterior synechiae (PAS), rubeosis, and other angle abnormalities or conditions that would prohibit adequate visualization of the angle that could lead to improper placement of the stent and pose a hazard.
PRECAUTIONS: The surgeon should monitor the patient postoperatively for proper maintenance of intraocular pressure. The safety and effectiveness of the CyPass Micro-Stent has not been established as an alternative to the primary treatment of glaucoma with medications, in patients 21 years or younger, in eyes with significant prior trauma, chronic inflammation, eyes with an abnormal anterior segment, eyes with chronic inflammation, eyes with glaucoma associated with vascular disorders, pseudophakic eyes with glaucoma, eyes with uveitic glaucoma, eyes with pseudoexfoliative or pigmentary glaucoma, eyes with other secondary open-angle glaucomas, eyes that have undergone prior incisional glaucoma surgery or cilioablative procedures, eyes with laser trabeculoplasty performed ≤ 3 months prior to the surgical screening visit, eyes with unmedicated IOP less than 21 mmHg or greater than 33 mmHg, eyes with medicated IOP greater than 25 mmHg, in the setting of complicated cataract surgery with iatrogenic injury to the anterior or posterior segment, and when implantation is without concomitant cataract surgery with IOL implantation for visually significant cataract. The safety and effectiveness of use of more than a single CyPass Micro-Stent has not been established.
ADVERSE EVENTS: In a randomized, multicenter clinical trial comparing cataract surgery with the CyPass Micro-Stent to cataract surgery alone, the most common postoperative adverse events included: BCVA loss of 10 or more letters at 3 months after surgery (8.8% for the CyPass Micro-Stent vs. 15.3% for cataract surgery only); anterior chamber cell and flare requiring steroid treatment 30 or more days after surgery (8.6% vs. 3.8%); worsening of visual field mean deviation by 2.5 or more decibels (6.7% vs. 9.9%); IOP increase of 10 or more mmHg 30 or more days after surgery (4.3% vs. 2.3%); and corneal edema 30 or more days after surgery, or severe in nature (3.5% vs. 1.5%).
ATTENTION: PLEASE REFER TO THE
INSTRUCTIONS FOR A COMPLETE LIST
OF CONTRAINDICATIONS, WARNINGS,
PRECAUTIONS, AND ADVERSE EVENTS.
© 2016 Novartis 08/16 US-CYP-16-E-3239
Glucosamine supplements may increase IOPFinding raises questions about possible role in glaucomaBy Laird Harrison
take-home A study investigated
the ocular hypertensive
effect of exogenous
glucosamine in
comparison with
placebo in patients
with osteoarthritis.
JANUARY 2017 :: Ophthalmology Times
Special Report ) EVOLVING CLINICAL STRATEGIES IN
GLAUCOMA
Intracameral prostaglandin analogue therapy delivers durable benefitAnalysis: Nine months after single dose in ongoing trial, potential for once-a-year therapyBy Cheryl Guttman Krader; Reviewed by Thomas Walters, MD
AN EXTENDED-RELEASE intracam-
eral implant loaded with travoprost (travoprost
XR; ENV515, Envisia Therapeutics) was found
to be well tolerated and effective for providing
sustained IOP-lowering, according to 9-month
interim analysis findings in an ongoing phase
II trial.
The study included 5 patients with bilateral
ocular hypertension or open-angle glaucoma
previously treated with a topical prostaglandin
analogue (PGA). They received a single dose
of a low-dose formulation of the travoprost XR
implant in one eye and used
topical timolol maleate oph-
thalmic solution 0.5% contra-
laterally, twice daily.
In October 2016, Envisia
Therapeutics announced that
in an interim analysis, the in-
vestigational product provided
clinically meaningful reduction in IOP through-
out 9 months of follow-up.
The magnitude of the effect was comparable
to that achieved prior to the study with topical
prostaglandin treatment and during the study
with topical timolol treatment in the fellow eye
of the same patients.
Anecdotally, the IOP-lowering effect with
the travoprost intracameral implant
has been maintained beyond the
9-month assessment and with-
out loss of clinical efficacy, noted
Thomas Walters, MD, study inves-
tigator and medical director, Key-
stone Research, Austin, TX.
“The ongoing efficacy of this
intracameral implant is quite re-
markable, and safety data indi-
cate that it minimizes or avoids
several of the side effects associ-
ated with the topical administra-
tion of a prostaglandin,” he said.
“Namely, hyperemia seems to be
reduced compared to daily topi-
cal PGA therapy.
“The experience is still very preliminary,
but suggests this product has the potential to
be a big game-changer in medical therapy for
ocular hypertension and glaucoma by taking
patient compliance with daily drops out of the
equation,” he added.
Prior to washout of existing IOP-lowering
medications, the 5 patients included in the
study were using topical latanoprost 0.005%
or travoprost 0.004%.
Their mean IOP mea-
sured at 8 a.m. while
on pre-study medica-
tion was 19.7 mm Hg
and was 26.1 mm Hg
after washout.
The travoprost XR
implant was already
observed to have an
IOP-lowering effect
when the first mea-
surement was taken on Day 3. At 9 months,
mean IOP was reduced by 6.7 ± 3.8 mm Hg
(-26%) from the post-washout level.
“Because of the steady release of travoprost
from the delivery system, the intracameral im-
plant also controls diurnal fluctuations in IOP
better than topical therapy,” Dr. Walters said.
Dr. Walters noted there is some anterior
chamber inflammation for about 2 days after
the implantation procedure, which is due in
part to the use of povidone-iodine for sterile
preparation.
“After that resolves, the eyes have
been very white and the anterior
chamber quiet,” he said. “Prob-
lems that patients had in associ-
ation with topical prostaglandin
use prestudy, such as blurred vi-
sion and conjunctival hyperemia,
largely abated.”
M O R E A B O U T
T H E P R O C E D U R E
The procedure for placing the in-
tracameral implant is easily done
under topical anesthesia. In addi-
tion to the povidone-iodine prepa-
ration, the lashes and lids are isolated with a
speculum and a surgical drape placed.
Placement of the implant is similar to in-
serting a paracentesis port. The device is in-
troduced into the anterior chamber in front of
the iris and settles itself down into the inferior
angle. The biodegradable device is rectilinear
in shape, but becomes more amorphous and
conforms to the angle as it dissolves over time,
Dr. Walters said.
Monitoring is ongoing to determine the lon-
gevity of the IOP-lowering benefit, although
variation among patients is expected consid-
ering the potential for the kinetics of the im-
plant’s degradation to differ in the eyes of dif-
ferent patients.
A third cohort of the ongoing clinical trial
investigating the travoprost XR implant was re-
cently launched in which a high dose of ENV515
is being studied with the expectation of provid-
ing an IOP-lowering treatment effect that will
extend beyond 12 months after a single dose.
“In patients, the low dose demonstrated 9
months of IOP lowering efficacy after a single
dose,” Dr. Walters said. “The high dose demon-
strated 3-month-longer IOP duration versus the
low dose in preclinical evaluations in Beagle
dogs, thus, supporting its potential for once-
a-year therapy.” ■
take-home Five patients
receiving an extended-
release travoprost
delivery system
(ENV515, Envisia
Therapeutics) in the
anterior chamber have
ongoing IOP-lowering
with follow-up to 9
months in an ongoing
study.
THOMAS WALTERS, MD
Dr. Walters is an investigator and consultant for Envisia Therapeutics and multiple other
companies with products for IOP lowering.
Dr. Walters
‘The experience is still very preliminary, but suggests this product has the potential to be a big game-changer.’ — Thomas Walters, MD
15JANUARY 2017 :: Ophthalmology Times
Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA
Exploring risk/reward in trabecular bypass, suprachoroidal devicesAdditions will provide more surgical options, allow surgeons to individualize treatmentsBy John Berdahl, MD, Special to Ophthalmology Times
MICROINVASIVE GLAUCOMA sur-
gery (MIGS) has revolutionized the treatment
of glaucoma. With compliance concerns re-
garding topical medications, the benefits of
MIGS may even outweigh those of medical
therapies in patients with pressures adequately
controlled on medications.
Several companies are currently striving to
add more tools to the MIGS armamentarium
(including Glaukos with the iStent Trabecular
Micro-Bypass device).
Past focus for stents has been in the tra-
becular meshwork. However, companies are
currently developing suprachoroidal devices,
which are in various stages of FDA review.
These include the iStent SUPRA (Glaukos), the
CyPass Micro-Stent (Alcon Laboratories), and
the Solx Gold Shunt (Solx). These additions
will provide more surgical options and allow
surgeons to individualize treatments to pa-
tients more effectively.
T R A B E C U L A R B Y P A S S S T E N T S
The eye has two outflow pathways: the tra-
becular outflow and the uveoscleral outflow
pathway. The trabecular outflow pathway is
more pressure dependent and is where 75% of
the aqueous humor outflow occurs,1 making
this area a logical place to insert a stent to
restore natural physiologic aqueous outflow.
The episcleral venous pressure present is in
the range of 6 to 12 mm Hg, and while distal
outflow resistance adds a few mm Hg to the
IOP,2 trabecular bypass stents are still capable
of producing effective IOP lowering. The es-
sential benefit of the episcleral venous pres-
sure is that it virtually ensures no hypotony
will occur.
The iStent has a strong safety and efficacy
profile, as proven in the pivotal FDA trial.3
Results have only improved with time as sur-
geons continually become more experienced
with the procedure.
In a recently published study,4 a single stent
in combination with cataract surgery resulted
in a post-treatment mean IOP of 14.9 mm Hg ±
2.3 mm Hg at 3 years, a 36% reduction in IOP
from medicated baseline and an 86% reduc-
tion in the mean number of medications. This
was accomplished with no cases of hypotony,
IOP spikes, or hyphema within 1 month. Simi-
lar studies have shown corroborating results.5
Further studies demonstrate the efficacy of
multiple stents in reducing IOP and medica-
tions, illustrating the possibility of titrating
treatment with the stent.5-7
Optimizing patient benefit-to-risk is the cor-
nerstone of every glaucoma clinician’s man-
agement of glaucoma disease and iStent has
arguably demonstrated the highest benefit-to-
risk profile of any MIGS device to date.
S U P R A C H O R O I D A L S H U N T S
Suprachoroidal devices bypass the episcleral
venous pressure system and shunt fluid directly
into the suprachoroidal space to be reabsorbed
into the body. The intrinsic pressure differ-
ential between the anterior chamber and the
suprachoroidal space may aid in transferring
(FIGURE 1)
The iStent
Micro-Bypass
(Glaukos) is
implanted
through the
trabecular
meshwork
and into the
Schlemm’s
canal. (Images
courtesy of
Glaukos)
(FIGURE 3) The iStent SUPRA (Glaukos) is
designed to reduce IOP by accessing the
suprachoroidal space.
(FIGURE 2) The iStent
is designed with a
self-trephinating tip
and retention arches.
The device is 1 mm
long and 0.33 mm
tall.
16 JANUARY 2017 :: Ophthalmology Times
Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA
aqueous from the anterior chamber.10 How-
ever, without the episcleral venous pressure
back-stop there may be a greater risk of hy-
potony. A 2-year study of the CyPass demon-
strated hypotony prior to 1 month in 15.4%
of patients and hypotony after 1
month in 1.9% of patients.9 With
suprachoroidal stents there is also
potential for corneal edema10 as
well as hyphema.10-12
Published clinical evidence on
suprachoroidal shunts has at best
shown comparable efficacy to a
single trabecular bypass stent. Ini-
tial data for a CyPass inserted at
the time of cataract surgery in
patients with an IOP of > 21 mm
Hg show a reduction from a base-
line mean IOP of 25.5 mm Hg to a
mean of 15.8 mm Hg at 24 months
which is meaningful10 and it is possible that
safety and efficacy rates will improve over
time as surgeons gain experience but further
long-term study will be needed.
Like trabecular stents, implanting supracho-
roidal shunts requires a good understanding
of the anatomy. Surgeons should be deliberate
about placing a shunt in such a highly vascu-
larized space as it does present the possibil-
ity of serious intraoperative complications.
Risks can include bleeding from the highly
vascular iris and ciliary body and from the
anterior ciliary arteries while unintended cy-
clodialysis clefts may result from implanta-
tion of suprachoroidal shunts.
Other possible complications include pe-
ripheral anterior sequelae (PAS), small areas
of scarring around the device, which could
impair long-term efficacy. The creation of pas-
sageways in the suprachoroidal space could
cause abrupt closures of the cleft, resulting in
high-pressure spikes. The CyCLE trial showed
PAS formation at 10%,10 while the COMPASS
trial showed PAS formation reducing to 3.1%
over a 2-year period.12
However, suprachoroidal shunts
may be a valuable tool, especially as
an adjunct to a trabecular outflow
procedure in cases where disease
progression required additional pres-
sure lowering. I would like to see a
diagnostic that could easily deter-
mine episcleral venous pressure.
For low episcleral venous pres-
sures, a trabecular meshwork stent
would be more logical, while higher
episcleral venous pressures might
yield better results with supracho-
roidal stents. Perhaps in the future
that technology will be available.
Our collective experience and the accu-
mulation of data will determine the best use
for suprachoroidal and trabecular stents. Ex-
ploiting both the conventional and uveoscleral
pathways will enable enhanced treatment of
patients with progressive glaucoma disease
who require lower target pressures than can
be obtained by trabecular bypass treatment
alone. ■
References 1. Grant WM. Further studies on facility of flow through
the trabecular meshwork. AMA Arch Ophthalmol.
1958;60(4 Part 1):523-533.
2. Rosenquist R, Epstein D, Melamed S, Johnson M,
Grant WM. Outflow resistance of enucleated human
eyes at two different perfusion pressures and
different extents of trabeculotomy. Curr Eye Res.
1989;8:1233-1240.
3. Samuelson TW, Katz LJ, Wells JM, Duh Y-J,
Giamporcaro JE. Randomized evaluation
of the trabecular micro-bypass stent with
phacoemulsification in patients with glaucoma and
cataract. Ophthalmology. 2011;118:459-467.
4. Neuhann TH. Trabecular micro-bypass stent
implantation during small-incision cataract surgery
for open-angle glaucoma or ocular hypertension:
Long-term results. J Cataract Refract Surg.
2015;41:2664–2671.
5. Katz LJ, Erb C, Carceller Guillamet AC, Fea
AM, Voskanyan L, Wells JM, Giamporcaro JE.
Prospective, randomized study of one, two, or three
trabecular bypass stents in open-angle glaucoma
subjects on topical hypotensive medication. Clinical
Ophthalmology. 2015;9:2313-2320.
6. Donnenfeld ED, Solomon KD, Voskanyan L, Chang
DF, et al. A prospective 3-year follow-up trial of
implantation of two trabecular microbypass stents
in open-angle glaucoma. Clinical Ophthalmology.
2015;9:2057–2065.
7. Ahmed II, Katz LJ, Chang DF, Donnenfeld ED,
Solomon KD, Voskanyan L, Samuelson TW.
Prospective evaluation of microinvasive glaucoma
surgery with trabecular microbypass stents and
prostaglandin in open-angle glaucoma. J Cataract
Refract Surg. 2014;40:1295–1300.
8. Emi K, Pederson JE, Toris CB. Hydrostatic pressure of
the suprachoroidal space. IOVS. 1989;30:233-238.
9. Höh H, Grisanti S, Grisanti S, Rau M, Ianchulev
S. Two-year clinical experience with the CyPass
micro-stent: safety and surgical outcomes of a novel
supraciliary micro-stent. Klin Monbl Augenheilkd,
2014. Vol. 231(4), pp. 377-81.
10. Grisanti et al. [Supraciliary microstent for open-angle
glaucoma: clinical results of a prospective multicenter
study]. Ophthalmology. 2014;111:548-552.
11. Brown R. Minimally invasive supraciliary microstent
for IOP control in combined POAG-Cataract surgery:
2-year COMPASS RCT results. Presented at the ASCRS
Symposium and Congress. May 7, 2016. New Orleans.
12. García-Feijoo J, Rau M, Grisanti S, Grisanti S, Höh H,
Erb C, Guguchkova P, Ahmed I, Grabner G, Reitsamer
H, Shaarawy T, Ianchulev T. Supraciliary Micro-stent
Implantation for Open-Angle Glaucoma Failing Topical
Therapy: 1-Year Results of a Multicenter Study. Am J
Ophthalmol. 2015;159:1075-1081.
take-home Though much focus
for stents has been
in the trabecular
meshwork, many
companies are
currently developing
suprachoroidal devices,
which are in various
stages of FDA review.
MANAGING THE GROWING BURDEN OF GLAUCOMATHE NUMBERS OF PATIENTS with glaucoma
will rise dramatically in the future because of
growth in both the size of the aged population
and in demographic groups at high risk for
the disease.
Ophthalmology, however, is not equipped to
handle the increasing demand for services
considering workforce projections and current
models of care.
Delivering the Robert N. Shaffer Lecture at
AAO 2016, George A. Cioffi, MD, proposed
potential solutions and offered some testable
hypotheses aimed at addressing the problem
of glaucoma population management.
Go to OphthalmologyTimes.com/GlaucomaBurden
OphthalmologyTimes.comOnline Exclusive
JOHN BERDAHL, MD
Dr. Berdahl is an ophthalmologist at Vance Thompson Vision, Sioux
Falls, SD. He is a consultant for Glaukos.
‘I would like to see a diagnostic that could easily determine episcleral venous pressure.’
‘Exploiting both the conventional and uveoscleral pathways will enable enhanced
treatment of patients with progressive glaucoma disease.’ — John Berdahl, MD
17JANUARY 2017 :: Ophthalmology Times
Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA
Laser technology offers multiple treatments in single deviceSystem designed to perform full range of anterior, posterior YAG laser procedures, plus SLTBy Laird Harrison; Reviewed by Inder Paul Singh, MD
NEW LASER TECHNOLOGY (Tango
Reflex, Ellex) combines specialized Nd:YAG
vitreolysis settings for floaters, with settings
for trabeculoplasty, capsulotomy, and iridotomy
in one unit.
“It’s an exciting time, because for so long
floaters have been ignored,” said Inder Paul
Singh, MD, glaucoma specialist, Eye Centers of
Racine and Kenosha, WI. “It is one of the most
common patient complaints I see in my office.”
In its YAG mode, the platform delivers a
truncated, ultra-Gaussian energy beam that can
vaporize floaters with less energy and it uses a
coaxial illumination configuration to maximize
visualization of the floaters, Dr. Singh said.
Though some clinicians fear a higher dose
of energy will cause damage to nearby struc-
tures in the eye, dispersion of energy does not
increase in proportion to the increase in in-
tensity, he said.
“I realized early on how much of
a misperception some people have
about the physics behind the YAG
laser,” Dr. Singh said. For exam-
ple, 1 mJ of laser energy disperses
in a convergence zone of 100 μm,
while the convergence zone of 5
mJ is 150 μm.
In addition, the platform features
a truncated energy beam. Since it
has a sharper rise and fall, 30% to
40% less energy is needed to treat
floaters when compared with stan-
dard lasers. It can vaporize floaters at 3 to 4
mJ, but Dr. Singh said he often uses settings
in the 5 to 6 mJ range.
He uses 200 to 800 shots per floater depend-
ing on the size and density of the floater. Since
the laser delivers a 4-nanosecond pulse, the
energy dissipates before the next shot is fired,
therefore preventing a build up of energy.
C O A X I A L I L L U M I N A T I O N
The system also situates the slit lamp light,
aiming beam, and laser all on the same opti-
cal pathway.
This allows the clinician to more effectively
visualize posterior floaters in relationship to
the retina, Dr. Singh said.
By contrast, the light source on most lasers
is inferior, superior, or to one side of the laser.
The coaxial position allows for a red reflex
and maximizes visualization of floaters in the
middle and posterior vitreous, he said.
Without this coaxial illumination, it is not
possible to identify many of the symptomatic
floaters and more importantly, provide spatial
context with the retina, he explained.
“If the floater is in focus and the retina is
in focus, that tells me it is not okay to fire,” he
said. “If the floater is in focus and the retina
is not, that tells me it is okay to fire.”
The clinician can also fire with the slit lamp
off-axis.
“When the slit lamp is in the oblique posi-
tion, it gives us an understanding of where the
floater is in relation to the posterior capsule,”
Dr. Singh said. “You lose the red reflex and
thus the floaters appear white behind a black
background.”
Because the illumination level
provided with Reflex Technology is
adjustable, it is possible to precisely
titrate the amount of coaxial illu-
mination as needed, Dr. Singh said.
For example, a floater in the mid-
dle-to-posterior vitreous requires
use of coaxial illumination for spa-
tial context with the retina.
However, if a surgeon finds the
lighting too bright and the floater
gets lost in the red reflex, it is pos-
sible to incrementally adjust the amount of co-
axial illumination by slowly moving the slit
lamp into the oblique position. This can be
done until the perfect level of lighting needed
to maximize the contrast of the floater—yet
keep the spatial context in relation to the ret-
ina—is achieved.
O T H E R I N N O V A T I O N S
A third advantage of the platform over some
other lasers is that the light source is a light-
emitting diode instead of a halogen globe.
“That allows for fewer and less intense back
reflections for the doctor,” Dr. Singh said. “An-
other benefit is that the light runs cool and
can be left on indefinitely without warming
the environment and putting strain on sur-
rounding components.”
The platform uses a green aiming beam for
YAG treatments, which improves contrast sen-
sitivity and visualization against the red reflex
of the retina, and differentiates from the red
aiming beam of the SLT mode, Dr. Singh said.
The increased possibilities with vitreoly-
sis have awakened interest in treating float-
ers, with a new international floater society,
the International Ophthalmic Floater Society,
launched at the 2016 meeting of the European
Society of Cataract and Refractive Surgeons,
Dr. Singh said.
This group has begun work on classifying
floaters, developing standardized protocols,
and creating a customized floater question-
naire. Their goal is to raise awareness and
push technology forward in this space.
Until now, clinicians have often dismissed pa-
tient’s complaints about floaters, Dr. Singh said.
“We told them, ‘Deal with it, it’s normal
part of life.’ Now we’re realizing it does have
an impact on their daily life,” he said. “If you
have a large clump of vitreous, how can it not
affect vision?”
O U T C O M E S M E A S U R E D
To quantify the effectiveness of the laser, Dr.
Singh and colleagues asked 362 patients whether
the procedure made a difference. Ninety-three
take-home New laser technology
in a single device offers
multiple treatment
platforms, including
SLT for glaucoma, laser
vitreolysis for floaters,
capsulotomy, and
iridotomy.
VIDEO Watch how coaxial position
allows for a red reflex and maximizes visualization
of floaters in the middle and posterior vitreous.
(Video courtesy of Inder Paul Singh, MD)
Go to OphthalmologyTimes.com/LaserPlatform
ON- AND OFF-AXIS
18 JANUARY 2017 :: Ophthalmology Times
Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA
percent said it did. Asked to rate the improve-
ment on a scale of 1 to 10, the patients gave it
a 7.2 on average after 1 session and a 8.9 after
multiple sessions.
The best results were with solitary Weiss
rings. These required an average of 1.3 sessions,
while “amorphous clouds” typically required
about 3 sessions to satisfy patients.
In addition, the researchers used a wave-
front aberrometer and corneal topographer
(iTrace, Tracey Technologies) to measure vi-
sion changes in the patients.
The device distinguishes between the contri-
butions of the corneal and internal aberrations
(including the lens, posterior cornea, macula,
and vitreous) and calculates a dysfunctional
lens index based on multiple factors, including
higher-order aberrations, analysis of contrast
sensitivity, and pupil size dynamics.
In one example, before vitreolysis, a patient
reported “blurry” vision, and had a dysfunc-
tional lens index score of 3.79 on a scale of zero
to 10. After vitreolysis, the patient’s score im-
proved to 10, which is the best possible score,
and the patient was “very happy.”
“They were saying, ‘Doc, I can see better,’
and ‘Doc, I can read now,’” Dr. Singh said. “We
knew patients were seeing with better quality
of vision, and now, with the aberrometer, we
can objectively demonstrate this improvement.”
Still, Dr. Singh does not recommend the pro-
cedure for all floaters, since there are risks and
not all floaters are amenable to this procedure.
Patients with floaters right behind the pha-
kic lens, or near the retina/optic nerve are not
good candidates, Dr. Singh said.
Those with asteroid hyalonosis and other
diffuse floaters also may not respond well.
“Some people do neuroadapt,” he said. “And
we don’t advocate this procedure for people
without symptoms.”
In more than 1,400 cases, Dr. Singh said,
1 patient had a peripheral retinal hemorrhage,
7 patients had spikes in IOP, and 2 patients’
lenses were affected. There were no retinal
detachments, anterior chamber or vitreous
reactions, and no vitreous hemorrhages. The
lenses were hit before Dr. Singh discovered
the importance of using both coaxial and off-
axis illumination, he said.
“I have not seen a detachment or tear,” he
said. “In fact, in a few patients with vitreo-
macular traction, we have seen improvement
in macular contour on optical coherence to-
mography and release of the traction because
the laser severed strands of adhesion.”
The IOP spikes are most common in pseu-
dophakic patients who have had previous pos-
terior YAG capsuloptomies, where the floaters
are very close to the capsule, Dr. Singh said.
“It might be the gas bubbles floating into
anterior chamber or debris blocking outflow,”
he speculated. “I limit the number of shots in
those patients because we have seen a corre-
lation with number of shots and IOP spikes in
these subset of patients.”
C L I N I C A L P E A R L S
The best candidates are pseudophakic because
“you have a clear view into the vitreous and
retina and you don’t have to worry about hit-
ting the lens,” Dr. Singh said.
And those with Weiss rings make ideal can-
didates because it is relatively easy to see a
floater that correlates with patients’ symptoms.
Weiss rings require fewer shots and sessions
to improve patients’ symptoms.
Dr. Singh recommends that clinicians prac-
tice visualizing a floater before the procedure.
Visualizing can be made easier with the use
of a specialized lens such as one of the vitre-
olysis lenses made by Ocular Instruments or
the Singh Midvitreous Lens, which Volk Op-
tical designed with Dr. Singh’s help (though
he does not have a financial interest in the
product), he said.
He also recommends waiting 4 to 6 months
after first examining patients with new symp-
toms to see if the condition improves through
neuroadaptation and to make sure there are
no tears or holes that might have been missed
or develop later.
“It’s important to involve retina specialists,”
Dr. Singh added. “If I’m concerned about the
retina, I’ll send them to the retina specialist to
make sure everything is okay preoperatively.”
Also, if the laser cannot sufficiently remove
the floaters, a vitrectomy is an option, he noted.
(FIGURE 1) On-axis picture of a Weiss ring—nice red reflex, no retina in focus,
so okay to fire.
(FIGURE 3) Off-axis floater. Phakic patient—
no red reflex, but the floater appears white
behind a dark background and can help
determine distance from posterior capsule.
(Images courtesy of Inder Paul Singh, MD)
(FIGURE 2) Partial off-axis—still see some red reflex, but partially off-axis to
decrease the amount of the red reflex more anteriorly and therefore increase
contrast.
19JANUARY 2017 :: Ophthalmology Times
Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA
Continues on page 25 : Options
Microstent demonstrates lowered IOP, use of fewer drugs in European studyData focus on patients with combined cataract surgery and device implantationBy Vanessa Caceres; Reviewed by Steven R. Sarkisian Jr., MD
THREE-YEAR RESULTS with the mi-
croinvasive glaucoma surgery (MIGS) device
(CyPass Micro-Stent, Alcon Laboratories) com-
bined with cataract surgery showed sustained
IOP control and a lower need for glaucoma
medications, said Steven R. Sarkisian Jr., MD.
The device is placed in the supraciliary space
and is implanted in an ab interno fashion via a
clear cornea incision. This approach spares the
conjunctiva, sclera, and trabecular meshwork.
T W O C O H O R T S
European data presented by Dr. Sarkisian from
the multicenter prospective CyCLE study fo-
cused on two patient cohorts (245 eyes) that
both had combined small-incision cataract sur-
gery and device implantation. In one cohort
(93 eyes), the patients had uncontrolled IOP
(21 mm Hg or greater) at baseline.
“The goal with this group was to lower the
IOP,” said Dr. Sarkisian, clinical professor and
Glaucoma Fellowship Director, Dean McGee
Eye Institute, University of Oklahoma, Okla-
homa City, OK.
In a second cohort of 152 eyes, the IOP was
controlled (21 mm Hg or lower), and the goal
was to lower the number of medications used.
The mean baseline IOP in cohort 1 was 25.3
mm Hg versus 16.4 mm Hg in cohort 2. At
baseline, both groups used about 2.1 medica-
tions on average.
Thirty-two patients in the study
had previous glaucoma surgery, Dr.
Sarkisian said
After implantation of the device,
the mean IOP in cohort 1 lowered
from 25.3 mm Hg to 17.2 mm Hg
at 3 years. At 12 and 24 months,
the mean IOP in cohort 1 had low-
ered by 34% and 30%, respectively,
he said.
In cohort 2, the mean IOP stayed
the same postoperatively. However, by month
36, the mean number of medications used had
dropped to 1.
“Of note, we see that the percentage of pa-
tients on 1 or fewer medications at baseline
was only 31.6% and then increased to 64.1%
by 36 months,” Dr. Sarkisian said. “If you sep-
arate out the patients in cohort 2 who were on
zero medications at 36 months, it was 45%.”
The most commonly seen adverse event was
device obstruction (9.4%).
“There were 2 reports of transient device
obstruction by blood within the first postop-
erative week,” Dr. Sarkisian said. “However,
in the vast majority of cases (n = 19), obstruc-
tion appeared to have been related to intra-
operative device positioning that
was more posterior than optimal
and, over time, iris tissue over-
grew some portion of the device
lumen, which was resolved by use
of a YAG laser.
“Also, retinal complications oc-
curred in 4.1% of patients, but only
one case was related to the [de-
vice], and was due to hypotony
that resolved after device explan-
tation,” he said.
Although visual loss occurred in some pa-
tients, none of it was related to the implant.
“The 3-year safety profile gives long-term
evidence of compatibility with cataract sur-
gery and the potential to employ this therapy
earlier in the glaucoma treatment paradigm,”
Dr. Sarkisian said. ■
take-home Patients with
cataract surgery and
microstent implantation
had a lowered IOP and
a reduced number of
medications used at 3
years postoperatively.
STEVEN R. SARKISIAN JR., MD
This article was adapted from Dr. Sarkisian’s presentation at the 2016 meeting of
the American Academy of Ophthalmology. Dr. Sarkisian is a consultant for Alcon
Laboratories.
S E L E C T I V E L A S E R
T R A B E C U L O P L A S T Y
Combining YAG and selective laser trabeculo-
plasty (SLT) functions into one unit can make it
feasible for small ophthalmology offices to offer
both services, said Savak “Sev” Teymoorian,
MD, MBA, of Harvard Eye Associates in Or-
ange County, CA.
If that encourages more practitioners to offer
SLT to their patients, then everyone will ben-
efit, he noted.
“In our treatments for glaucoma we are al-
ways looking for medication, and the new hot
things is microinvasive glaucoma surgery, but
we’re really underutilizing the SLT,” he said.
Patients often opt to try eye drops first be-
cause it sounds like a more conservative ap-
proach, but after they realize the challenge
of applying drops every day and especially if
they experience adverse reactions, they be-
come more interested in SLT, he said.
The treatment is particularly helpful in pa-
tients who have difficulty putting in their eye
drops, he said.
And despite patients’ concerns, adverse events
are rare with SLT, he said.
“I haven’t come up with any of them, but
in the literature, in those who have heavy pig-
ment, such as pigment dispersion syndrome
and pseudoexfoliation glaucoma, their IOP can
be elevated.”
In these patients, clinicians should use fewer
doses or less energy, Dr. Teymoorian said.
Some patients need repeat treatments, and
it can be used in both eyes, he pointed out. ■
INDER PAUL SINGH, MD
Dr. Singh is a speaker and consultant for Ellex.
SAVAK “SEV” TEYMOORIAN, MD, MBA
Dr. Teymoorian is a consultant to Ellex.
25JANUARY 2017 :: Ophthalmology Times
Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA
OPTIONS( Continued from page 19 )
Pelvic organ prolapse may be clue to presence of exfoliation syndromeInvestigators hypothesize that LOXL1 dysregulation may be contributing factorBy Lynda Charters; Reviewed by Barbara M. Wirostko, MD
RESEARCHERS HAVE identified a link
between exfoliation syndrome, an inherited
systemic disorder of elastin and extracellu-
lar matrix (ECM) associated with the LOXL1
gene locus, and pelvic organ prolapse, a com-
monly diagnosed connective tissue disorder in
women. The identified association was highly
statistically significant and thus, unlikely to
be a chance finding.
The recent investigation found that women
in the study population with
a history of pelvic organ pro-
lapse had an increased risk of
about 50% of receiving a diag-
nosis of exfoliation syndrome.
In exfoliation syndrome,
noted Barbara M. Wirostko,
MD, lead author of the Utah
Project on Exfoliation Syndrome Study, exfo-
liative material is deposited in the anterior
ocular segment (which can result in exfolia-
tion glaucoma) as well as in the
heart, brain, lungs, and skin, with
the potential for the development
of cardiovascular and cerebrovas-
cular diseases and hearing loss,
among other conditions.
Pelvic organ prolapse is consid-
ered a major health issue for women,
noted Dr. Wirostko, clinical ad-
junct associate professor, Depart-
ment of Ophthalmology and Vi-
sual Sciences, John A. Moran Eye
Center, University of Utah School of Medicine,
Moran Eye Center, Salt Lake City.
Study investigators noted the prevalence es-
timates of symptomatic pelvic organ prolapse
have been reported to range between 3% and
11%. In addition, 11% to 19% of women have
been reported to need surgical intervention to
repair the pelvic organ prolapse during their
lifetimes.
“Pelvic organ prolapse is believed to be as-
sociated with defects produced by elastin and
connective tissue injury in conjunction with
abnormalities in pathways for ECM tissue re-
pair,” the investigators said.
The study team explained in their report
(JAMA Ophthalmol 2016;134:1-8; doi:10.1001/
jamaophthalmol.2016.3411; published online
Sept. 15, 2016) that “because both exfoliation
syndrome and pelvic organ prolapse are char-
acterized by changes in elastin-containing ECM
tissue, we hypothesized that women with pel-
vic organ prolapse are more likely to develop
exfoliation syndrome during their lifetime.”
S T U D Y D E S I G N ,
R E S U L T S
Using the Utah Population Database (http://
bit.ly/1xuTosW)—a research resource at the
University of Utah that contains medical, de-
mographic, and genealogical records—a two-
pronged approach of a cross-sectional analy-
sis in Medicare patients and a retrospective
cohort study in patients in the University of
Utah Healthcare system of hospitals and clin-
ics was employed.
Investigators first performed a cross-sectional
analysis (substudy A) of 132,772
Utah women aged more than 65
years, who were Medicare recipi-
ents for more than 3 consecutive
years from 1992 to 2009, to deter-
mine the association between pel-
vic organ prolapse and the exfolia-
tion syndrome.
Then, investigators estimated
the longitudinal risk of an incident
diagnosis of exfoliation syndrome
from Jan. 1, 1995, to Dec. 31, 2014,
in 5,130 women aged between 30 and 65 years
at baseline who had been diagnosed with pel-
vic organ prolapse compared with 15,338 age-
matched female controls—women who had not
ever received a diagnosis of pelvic organ pro-
lapse (substudy B), Dr. Wirostko noted.
The mean age of the women in substudy A
was 82 years during the last year of follow-up
in the respective Medicare record. In substudy
A, investigators reported that pelvic organ pro-
lapse was associated with a 56% increased risk
of a diagnosis history of exfoliation syndrome
in Medicare beneficiaries (odds ratio, 1.56; 95%
confidence interval [CI], 1.4-1.7)
In substudy B, the results showed a 48% in-
creased incident risk of receiving a subsequent
exfoliation syndrome diagnosis in women who
were aged 30 to 65 years at baseline when
they had been diagnosed with a pelvic organ
prolapse compared with age-matched controls
during 20 years of follow-up (hazard ratio,
1.48; 95% CI, 1.1-1.9).
“Systemic conditions with altered ECM me-
tabolism, such as pelvic organ prolapse, might
share common biological pathways with the
exfoliation syndrome,” Dr. Wirostko said. “It is
possible that the LOXL1 dysregulation, thought
to occur in the exfoliation syndrome, is a com-
mon contributing factor.”
She added that a better understanding of the
shared pathways will ultimately impact clini-
cal diagnosis, management, and treatments. ■
take-home Women with pelvic
organ prolapse were
diagnosed more
frequently with
exfoliation syndrome
in the Utah Population
Database.
Dr. Wirostko
Increased risk of receiving a
diagnosis of exfoliation syndrome,
in women with a history of pelvic
organ prolapse
50%
26 JANUARY 2017 :: Ophthalmology Times
Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA
BARBARA M. WIROSTKO, MD
Dr. Wirostko has no financial interest in any aspect of this report. She was joined in
this study by Karen Curtin, PhD, Samuel Thomas, MD, Kristina Allen-Brady, PhD, Gregory
S. Hageman, PhD, and Ken R. Smith, PhD, from the University of Utah, Salt Lake City;
Robert Ritch, MD, New York Eye and Ear Infirmary of Mount Sinai, NY, and R. Rand
Allingham MD, Duke University, Durham, NC.
Tracking treatment, adherence in cases of newly diagnosed OAGClaims data point to significant gap between diagnosis, medical/surgical therapiesBy Lynda Charters; Reviewed by Gail F. Schwartz, MD
A SIGNIFICANT NUMBER of patients
(17%) remained untreated 4 years after their
initial open-angle glaucoma (OAG) diagnosis,
according to U.S. claims data that follow the
prescription of IOP-lowering medications and
performance of glaucoma procedures.
“For this patient population, IOP-lowering eye
drops are the most common initial therapy for
OAG,” said Gail F. Schwartz, MD. “The avail-
ability of ophthalmic fixed combinations has
simplified topical dosing regimens for many
patients.
“For selected patients, laser trabeculoplasty
is frequently an alternative first-line treatment,”
added Dr. Schwartz,
who is in private prac-
tice and assistant pro-
fessor, Wilmer Eye In-
stitute, Johns Hopkins
University School of
Medicine, Baltimore.
Despite this, little is
known about the treat-
ment numbers and the
sequence/ timing used
to manage these pa-
tients. Having this in-
formation available would facilitate more accu-
rate assessment of the patient burden and the
unmet need for innovative therapies, she noted.
C L A I M S A N A L Y S I S
Considering the need for specific prescribing
data, Dr. Schwartz and her colleagues con-
ducted a retrospective claims analysis using
the Truven MarketScan Commercial Claims
and Medicare Supplemental databases that
covered July 2007 to December 2014.
Patients were included if they had a mini-
mum of two diagnoses of OAG 7 or more days
apart and within 1 year, with the first diagno-
sis in 2010; 30 or more months of continuous
enrollment before the index diagnosis with
no OAG diagnosis or OAG medication (un-
less with an accompanying pre-index ocu-
lar hypertension diagnosis); and 48 or more
months of continuous enrollment after the
index diagnosis.
During the 4-year study period, investiga-
tors evaluated the use of glaucoma medications
and the procedures performed, the time from
diagnosis to first therapy with medication or
laser trabeculoplasty, the sequence of thera-
pies implemented, and the use of adjunctive
medications after laser trabeculoplasty.
The glaucoma procedures included laser tra-
beculoplasty, trabeculectomy, implantation of
glaucoma drainage device, and a small num-
ber of minimally invasive glaucoma surgeries.
Further analysis of the surgical procedures
is planned.
A total of 6,172 patients (53% women, 47%
men) met the study inclusion criteria. The mean
patient age was 64.1 years.
During the 4 years after the index OAG di-
agnosis, Dr. Schwartz noted that 5,120 (83.0%)
patients with OAG were treated medically, by
laser trabeculoplasty or surgically. This left a
take-home An analysis of U.S.
claims data reveals a
substantial proportion
of patients (17%)
remained untreated 4
years after their initial
diagnosis of open-angle
glaucoma (OAG).
Number of other medication classes used before this
drug/procedure
Number of medication classes used subsequently
(including this medication)
MEDICATION OR PROCEDURE N (%) MEAN (SD) MEDIAN MEAN (SD) MEDIAN
Prostaglandin analogue3885
(75.88)0.2 (0.5) 0 1.7 (1.0) 1
Laser trabeculoplasty1292
(25.23)0.9 (1.1) 0 1.0 (1.2) 1
Sympathomimetic 1 (0.2) 0 (0) 0 1 (0) 1
Beta-blocker1336
(26.09)0.7 (0.8) 1 2.1 (1.0) 2
Alpha agonist800
(15.63)1.0 (1.0) 1 2.4 (1.1) 2
Fixed-combination alpha
agonist—beta-blocker
(Combigan)
673
(13.14)0.9 (0.9) 1 2.4 (1.1) 2
Topical CAI520
(10.16)1.4 (1.1) 1 2.6 (1.1) 2
Fixed-combination
CAI–beta-blocker (generic)479 (9.36) 1.4 (1.1) 1 2.4 (1.1) 2
Cholinergic agent 47 (0.92) 1.9 (1.4) 2 2.8 (1.3) 3
Fixed-combination
CAI–alpha-agonist (Simbrinza)47 (0.92) 2.3 (1.2) 2 1.7 (0.7) 2
Fixed-combination
CAI–beta-blocker (Cosopt)45 (0.88) 2.3 (1.3) 2 2.2 (1.1) 2
CAI, carbonic anhydrase inhibitor; OAG, open-angle glaucoma
(Figure courtesy of Gail F. Schwartz, MD)
(FIGURE 1) Sequence of use of medications and laser trabeculoplasty in 48 months after initial OAG diagnosis
28 JANUARY 2017 :: Ophthalmology Times
Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA
Continues on page 30 : Analysis
NS
95 (18%)
G
79 <1%
N
69 (12%)
T
51 (2%)
NI
95 (18%)
TS
92 (2%)
TI
129 (7%)
substantial percentage (17%) of patients who
had not been treated by 4 years after they ini-
tially received the OAG diagnosis.
“The most common medical treatments
were a prostaglandin analogue prescribed in
75.9% of patients and a beta-blocker in 26.1%,”
she said. “Laser trabeculoplasty was the most
common procedure and used in 25.2% as the
first line.”
Patients who underwent laser trabeculoplasty
did so less than 5 months after receiving the
diagnosis of OAG.
Data also showed that 3,592 (70.2%) patients
who underwent treatment during the 4 years
after the initial diagnosis were treated with
anti-glaucoma medications eye drops only. Of
that group of patients, 58.7% had insurance
claims for only one class of medication dur-
ing that time.
In addition, of 4,332 (85%) treated-patients
received topical medications as their first ther-
apy, and in more than half (54%), the therapy
was not changes during the course of the study.
Of that last group of patients, only about 25%
continued to refill their prescriptions through
the end of the 4-year study.
The most frequently prescribed, second-line
medications were beta-blockers, alpha agonists,
and fixed combinations of these medications
(brimonidine–timolol) with a median of one
previously prescribed medication.
The median times from the initial OAG diag-
nosis to the first prescriptions of those medica-
tions were 184, 299, and 241 days, respectively,
according to Dr. Schwartz.
Study limitations were those that are often
associated with insurance claims data analy-
ses, such as whether patients received pre-
scriptions but did not fill them, or whether
they used their medications as prescribed,
she noted.
Regarding the large percentage of patients
who were untreated at the 4-year time point,
another study limitation was that the current
analysis does not include data from office vis-
its, and it is unknown whether the 17% of pa-
tients who were untreated missed visits or did
not pick up their medications, or if other fac-
tors played a role in their lack of treatment.
Future analysis will incorporate office visit
data and further characterize the untreated
patients, Dr. Schwartz noted.
“Even in the setting of continuous insur-
ance coverage, adherence with topical therapy
remained limited, which was consistent with
previous data,” Dr. Schwartz said. “Forty-five
percent of patients undergoing initial laser tra-
beculoplasty were not prescribed additional
topical medication.”
This study lends further data to support
the need for long-acting medication and/or
alternative procedures that reduce or elimi-
nate the adherence component, Dr. Schwartz
concluded. ■
GAIL F. SCHWARTZ, MD
Dr. Schwartz has received speaker honoraria and consulting fees from Allergan. This
study was sponsored by Allergan plc, Dublin, Ireland. Dr. Schwartz was joined in this
study by Degang Wang, Guo Li, and Hitesh Chandwani, who were employees of Allergan
at the time of the study.
(FIGURE 2) Median time from index OAG diagnosis to fi rst use of medication or laser trabeculoplasty
Median time to fi rst prescription fi ll or laser (days)CAI, carbonic anhydrase inhibitor; OAG, open-angle glaucomaaFDA approved in April 2013
Prostaglandin analogue
Laser trabeculoplasty
Beta-blocker
Sympathomimetic
Fixed-combination alpha agonist—beta-blocker (Combigan)
Alpha agonist
Fixed-combination CAI–beta-blocker (generic)
Topical CAI
Cholinergic agent
Fixed-combination CAI–beta-blocker (Cosopt)
Fixed-combination CAI–alpha-agonist (Simbrinza)a
were prescribed
prostaglandin analogue
were prescribed
a beta-blocker
had laser trabeculoplasty
as the fi rst-line treatment
75.9%
26.1%
25.2%
MOST COMMON MEDICAL TREATMENTS
BY THE NUMBERS
MOST COMMON PROCEDURE
did not have claims for IOP-lowering medication or a glaucoma procedure during the 4 years after initial OAG diagnosis17%
(Figure courtesy of Gail F. Schwartz, MD)
(in days)
30 JANUARY 2017 :: Ophthalmology Times
Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA
ANALYSIS( Continued from page 28 )
Add-on technology module enhances accuracy in glaucoma diagnosticsSystem creates patients’ anatomic map using center of fovea, Bruch’s membrane openingBy Nancy Groves; Reviewed by Donald C. Hood, PhD
GLAUCOMA SPECIALISTS have a
new tool in their clinical armamentarium via an
add-on module designed to improve diagnostic
accuracy through a comprehensive analysis of
the optic nerve head, retinal nerve fiber layer,
and ganglion cell layer, as well as the use of
an extensive reference database.
The technology (SPECTRALIS Glaucoma
Module Premium Edition, Heidelberg Engi-
neering) received FDA 510(k) clearance last
fall. The add-on module, which has been on the
market internationally for a number of years,
has several distinctive features, said Kester
Nahen, PhD, managing director, Heidelberg
Engineering.
“One is that for the first time we are cus-
tomizing or individualizing the scan proto-
col to the anatomy of the patient,” Dr. Nahen
said. “There’s quite a variation from patient
to patient in the way that the optic nerve
head is oriented, relative to the fovea, what
we call the fovea-to-Bruch’s membrane open-
ing angle.
“And the Bruch’s membrane opening center
is the center of the optic nerve head,” Dr. Nahen
added. “With the optical coherence tomography
(OCT), we’re able to identify those landmarks,
and we are then able to place any subsequent
OCT scan according to these coordinates.”
I N D I V I D U A L I Z E D M E D I C I N E
The glaucoma module’s anatomic positioning
system (APS) technology creates the
anatomic map based on the two fixed
landmarks.
“This is quite a unique feature
that we have on our OCT system,”
Dr. Nahen said. “This is individu-
alized medicine in glaucoma care.
We’re taking the anatomy of the in-
dividual patient into consideration,
and then we’re using optimized scan
protocols for the different anatomic
structures that we’re studying.”
One of the options in the new glau-
coma model is a star-pattern or ra-
dial scan that looks at the thickness
of the neuroretinal rim.
“We’re not using a standard pro-
tocol that could also be used in the
retina,” Dr. Nahen said. “We have
come up with a scan pattern that is specific
to glaucoma.”
The star-pattern scan is focused on the cen-
ter of the Bruch’s membrane opening, and the
end of the membrane opening is also identi-
fied on every scan, as it is a stable anatomic
structure that can then be used to take cross-
sectional measurements of the minimum rim
width of the neuronal tissue that
exits the eye.
Deterioration of the Bruch’s
membrane opening minimum rim
width is important in monitor-
ing glaucoma progression, and
the measurements from the scan
can be compared with a refer-
ence database included in the
module. In the United States,
this age- and disc-size adjusted
reference represents the racial
and ethnic mix of the popula-
tion, making it more valuable
to local clinicians.
The series of scan patterns in-
cluded in the module will provide
extensive information with mul-
tiple applications, said Donald C.
Hood, PhD, the James F. Bender Professor of
Psychology and Professor of Visual Sciences
take-home Heidelberg
Engineering has
launched the Spectralis
OCT Glaucoma Module
Premium Edition in the
United States, which
has the capability of
creating an anatomic
map of each patient’s
eye by using two
fixed landmarks. The
module also includes
an extensive reference
database.
The glaucoma module enables precise
examination of relevant structures and ensures
accurate comparisons with reference data.
(Images courtesy of Heidelberg Engineering)Analysis of the Bruch’s membrane opening-based minimum rim width (BMO-MRW) with the glaucoma
diagnostics technology (Glaucoma Module Premium Edition), including a color-coded classification chart.
31JANUARY 2017 :: Ophthalmology Times
Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA
Continues on page 32 : Module
Titrate therapy to master efficacy, maintain safetyConsider glaucoma severity, eye pigmentation, medication useBy Vanessa Caceres; Reviewed by Nathan Radcliffe, MD
THOUGH TECHNOLOGY (MicroPulse
P3 Glaucoma Device, Iridex) allows surgeons to
personalize glaucoma therapy and reduce IOP,
there are ways to work the laser effectively de-
pending on several patient factors, said Nathan
Radcliffe, MD.
The device is used in conjunction with the
CYCLO G6 Glaucoma Laser System (Iridex) in
the office or the operating room. This cyclo-
photocoagulation device controls thermal eleva-
tion by chopping a continuous-wave beam into
repetitive microsecond pulses (micropulses),
which allow the tissue to cool between pulses,
Dr. Radcliffe said.
The treatment is efficient, non-incisional, re-
peatable, titratable, and can help address com-
mon concerns about medication compliance.
“The laser itself is powerful enough to cause
side effects and risks and powerful enough to
induce profound IOP lowering,” said Dr. Rad-
cliffe, glaucoma surgeon, New York Eye Surgery
Center, New York.
“That’s where personalizing and appropriately
titrating it comes into play,” he added.
With use of the MicroPulse, the mean IOP
reduced from 38.1 mm Hg to 23.2 mm Hg in a
study reported at the American Glaucoma Society
meeting in 2015 from Marlene Moster, MD, Phil-
adelphia, according to Dr. Radcliffe. That same
study found that the mean number of medica-
tions used dropped from 2.54 to 1.77.
A 2014 study reported a 45% reduction in IOP
with use of the P3 and a 75% success rate at 12
months, with no cases of hypotony.1
With the 200 cases that Dr. Radcliffe has treated,
there has been a 30% to 80% reduction in IOP
with no cystoid macular edema or phthisis. There
has been one case of worsening cataract. Post-
operative inflammation can occur and mydri-
atic pupil has also been reported.
P E A R L S T O M A X I M I Z E U S E
> Titrate according to glaucoma severity. For ex-
ample, if Dr. Radcliffe sees a glaucoma patient
with 20/20 vision who is on one or two glaucoma
drops, he’ll treat with 2,000 mW delivered for
100 seconds—50 seconds to the top half of the
eye and 50 seconds to the bottom half (sparing
the neurovascular bundles at 3:00 and 9:00).
“You get a 30% pressure reduction and a very
good safety profile,” he said.
However, if a patient is using four or five eye
drops and has had failed surgeries and 20/200
visual acuity, he will likely increase the device’s
power setting. The strongest setting Dr. Radcliffe
uses is 2,500 mW, so he may select that power
setting in such a patient and deliver the energy
for the same amount of time.
> Consider eye pigmentation. As the laser is bet-
ter absorbed in eyes with a lot of pigment, Dr.
Radcliffe will use a lower setting, at least for
starters, in eyes that are dark brown. In a pa-
tient with very blue eyes, he may use 2,200 mW
for the initial treatment depending on other pa-
tient factors. Assess the patient’s willingness to
undergo a repeat procedure and treat conserva-
tively until you understand the laser–pigment
interaction.
> Go aggressive to reduce medication use. If a
patient uses three or four medications, includ-
ing oral Diamox, Dr. Radcliffe is more likely to
start them at 2,250 or 2,500 mW. “There’s more
room to go down in terms of IOP,” he said. “If
a patient is on four medications, the likelihood
of overtreating and inducing hypotony is low.
We can be more aggressive with laser power in
eyes that have worse visual acuity.”
In contrast, if a patient does not use any medi-
cations and has MicroPulse treatment, surgeons
would be more cautious with laser settings, typi-
cally starting with a power of 2,000 mW. For pa-
tients with an IOP of 55 or 60 mm Hg, Dr. Rad-
cliffe may treat in the 2,300 or 2,500 mW range
and be able to lower their IOP to the mid-teens. ■
Reference1. Aquino MC, Barton K, Tan AM, et al. Micropulse
versus continuous wave trans-scleral diode
cyclophotocoagulation in refractory glaucoma:
A randomised exploratory study. Clin Exp
Ophthalmol. 2015;43:40-46.
NATHAN RADCLIFFE, MD
This article was adapted from an Iridex booth presentation by Dr. Radcliffe during the
2016 meeting of the American Academy of Ophthalmology. Dr. Radcliffe is a consultant
for Iridex and other ophthalmic companies.
(Ophthalmology), Columbia Univer-
sity, New York.
“If you complete the full package on
a patient from a clinical research or
clinical diagnosis point of view, you
have a lot of information as well as
high-quality scans,” he said.
“By having radial scans within the
disc, it allows you to take a close look
at the damaged regions around and
in the disc,” he added. “It also will
help differentiate damage due to glau-
coma from damage due to other optic
neuropathies.”
Dr. Hood tests patients and inter-
prets OCT images in his lab and also
conducts clinical research. His lab
uses different OCT systems and soft-
ware packages, including those from
Heidelberg Engineering, with the goal
of improving the use of this technol-
ogy for diagnosing and understand-
ing glaucomatous damage.
F I L L I N G T H E G A P
The new glaucoma module for the
Spectralis OCT may help eradicate
what Dr. Hood sees as a shortcom-
ing in glaucoma diagnosis.
“Glaucoma specialists, in general,
are underutilizing the OCT,” he ex-
plained. “They tend to look at sum-
mary statistics on commercial reports.
What I’ve been trying to do is get them
away from these summary statistics
and get them to look instead at the
scan images and thickness maps.”
The module for the Spectralis OCT
is set up so that users can both view
reports and look at individual scans.
However, Dr. Hood is also work-
ing with Heidelberg Engineering to
design an improved format for a one-
page summary in the glaucoma mod-
ule that will describe the key features
from an imaging session for the cli-
nicians who prefer to view a single
report. It will be included in the mod-
ule in the near future. ■
32 JANUARY 2017 :: Ophthalmology Times
Special Report ) EVOLVING CLINICAL STRATEGIES IN GLAUCOMA
DONALD C. HOOD, PHD
Dr. Hood has received grants from Heidelberg Engineering of equip-
ment and support for his laboratory at Columbia University.
MODULE( Continued from page 31 )
A new 0.075% formulation of
brom fenac ophthalmic solu-
tion (BromSite, Sun Pharma)
could provide relief from pain
and inflammation associated
with cataract surgery, according
to Sheri Rowen, MD, of Nvision
Eye Centers, Newport Beach, CA.
Last April, the FDA approved
the nonsteroidal anti-inflam-
matory drug (NSAID) to pre-
vent pain and treat inflam-
mation associated with cat-
aract surgery, Sun Pharma
announced.
“According to the study data,
it has good aqueous concentrations of the mol-
ecule after 1 drop,” Dr. Rowen said. “So that is
an encouraging sign.”
Sun Pharma’s U.S. subsidiary, Sun Ophthal-
mics, began marketing BromSite in the United
States last fall.
H O W I T W O R K S
The agent delivers bromfenac in a synthetic
polymer of crosslinked polyacrylic acid devel-
oped as DuraSite by InSite Vision. DuraSite
is also the vehicle for Bausch + Lomb’s be-
sifloxacin ophthalmic suspen-
sion (Besivance) and Akorn’s
azithromycin ophthalmic so-
lution (AzaSite).
DuraSite is mucoadhesive and
“can be used to improve solubil-
ity, absorption, bioavailability
and residence time as compared
to conventional topical thera-
pies,” according to Sun Pharma.
Sun Pharma of Mumbai, India,
purchased InSite Vision of Al-
ameda, CA, in November 2015.
The active ingredient is sus-
pended in the DuraSite and is released in small
doses each time the patient blinks, Dr. Rowen
explained. The label calls for twice-daily dos-
ing, morning and evening, beginning 1 day
before surgery and ending 14 days after.
Bromfenac, the active ingredient of Brom-
Site, inhibits cyclooxygenase (cox) 1 and 2, en-
zymes responsible for forming prostaglandins.
P H A S E I I I S T U D I E S
In two multicenter phase III, randomized clini-
cal trials, a higher proportion of patients treated
with BromSite were pain-free a day after surgery
than patients treated with the vehicle alone,
according to Sun Pharma.
In one study, 77% of the BromSite group
was pain free versus 48% of the vehicle group.
In the other, 82% of the BromSite group was
pain free versus 62% of the vehicle group.
The differences were statistically significant
(p < 0.001).
Likewise, a higher proportion of subjects ad-
ministered BromSite were inflammation-free
15 days after cataract surgery compared to a
vehicle control.
The proportions were 57% versus 19% in
the first study (p < 0.001) and 38% versus
22% in the second study (p = 0.035).
Adverse reactions listed on the BromSite
label include slow or delayed healing, an ef-
fect common to all NSAIDS.
Dr. Rowen has just begun treating patients
with the product, but so far has a good im-
pression, she said.
“It’s very comfortable and
interestingly enough it doesn’t
have a prolonged blur, which
was one of our concerns,” she
said. “Vision seems to clear
within a few blinks.”
Bromfenac is already avail-
able in a more standard vehicle
in Bausch + Lomb’s Prolensa,
which is approved to reduce (as
opposed to prevent) ocular pain
and treat inflammation associ-
ated with cataract surgery.
Other alternatives include nepafenac ophthal-
mic suspensions by Alcon Laboratories in two
concentrations: 0.1% (Nevanac, which is dosed
three times daily) and 0.3% (Ilevro, which is
dosed once daily).
Ketorolac is available as a generic for the
same indication.
“You have to use it 4 times a day,” Dr. Rowen
said. “It can cause corneal toxicity. It can sting
quite a bit so patients end up not wanting to
take it.”
BromSite comes in a 5 cc bottle, which is
larger than the bottle size for most competing
medications, Dr. Rowen said.
L O O K I N G A H E A D
Other medications in Sun Pharma’s pipeline in-
clude latanoprost ophthalmic solution 0.005%
(Xelpros) for the reduction of elevated IOP in
patients with open-angle glaucoma or ocular
hypertension, cyclosporine A 0.09% ophthal-
mic solution (Seciera) for the treatment of dry
eye disease, and dexamethasone 0.1% (Dexa-
Site) for the treatment of blepharitis. ■
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Clinicians, patients welcome pain-preventing NSAIDMultiple clinical studies demonstrate drug’s efficacy in cataract surgeryBy Laird Harrison; Reviewed by Sheri Rowen, MD
SHERI ROWEN, MD
Dr. Rowen is a consultant for Sun Pharma.
Dr. Rowen
‘Vision seems to clear within a few blinks.’ — Sheri Rowen, MD
The recent approval
of bromfenac
ophthalmic solution
0.075% marks the
first NSAID approved
for the prevention
of ocular pain in
patients undergoing
cataract surgery.
TAKE-HOME
drug therapydrug therapy34 JANUARY 2017 :: Ophthalmology Times
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After working with ophthal-mologists across the country for more than 20 years, we have heard from hundreds of physicians about what stresses them out and de-tracts from their happiness.
Here are five ways physicians deprive them-selves of more contentment.
1 ) C O M P A R I N G A N O T H E R ’ S‘ P E R C E I V E D N E T W O R T H '
Physicians have a preconceived notion that comparing themselves with other physicians who may be better off will give them a state of contentment. Ironically, most physicians who claim they are poor could not be more wrong.
Ophthalmologists are close in net worth and, in some instances, physicians who worry about not having enough success ac-tually have more than the average physi-cian. We frequently hear, “If only I had twice what I have now, I’d be okay.” There are some physicians who do have twice that amount saying exactly the same thing.
These are the same ophthalmologists whose short-, intermediate-, and long-term goals have been met—or will be met with a high probability of success. Yet, they insist on focusing on what they don’t have. What happened to living in appreciation and ac-knowledging oneself for “a job well-done”?
2 ) R E T I R I N G T O O Y O U N GWe cannot tell you how many physicians have fretted over the thought that they may run out of money if they retire at age 62.
Hundreds of clients in their 40s or 50s who insisted they would retire at age 62 started pushing retirement out year after year when the age of 62 drew near.
Overall, ophthalmologists love what they do. They love their specialty. They have at-tachments to their patients and colleagues. They do not want to retire at the age of 62.
We suggest physicians be realistic when
targeting a retirement age. Why save a lot of money to meet that target, then give up a rewarding working life? Seventy is the new 62. Don’t retire too early, then find yourself saying, “I feel like I don’t count anymore.”
3 ) L A M E N T I N G O V E RI N V E S T M E N T S
The best advice we can give to avoid this habit is to have a written plan. This includes a investment policy statement, a description of your goals and aspirations, a realistic ex-pectation for a rate of return on your invest-ment portfolio, and an analysis tracking the probability of success of your plan.
Ask—and have the answers to—the fol-lowing questions: How will I educate my children? Can I have a second home? How much will I need in retirement? How can I plan for long-term care? Am I taking suf-ficient risk in my portfolio? Is it diversi-fied properly? Am I saving too much or too little? Do I have a will? Is my estate set up properly?
Physicians don’t need to add another worry to their life. To avoid such worry, or-ganize your financial life. A month-long ef-fort should give a lifetime of security and peace of mind.
4 ) N O T S P E N D I N G T I M E O N P E R S O N A L D E V E L O P M E N T
We know physicians are busy, but there is nothing wrong with taking time to read material that is uplifting and inspirational. There are countless books and seminars that address how to live a full, enriched life.
Suffering is caused many times by only a thought or idea held in one’s head. Learn to be the author of these thoughts rather than “being thought” by your mind and think-ing these thoughts are who you are. Living a happy life is more of a learned art than something that just unfolds naturally.
Of our ophthalmology clients with the exact circumstances—money, success, fam-
Akorn Pharmaceuticals CV4267/483-4010www.akorn.com
Alcon Laboratories 13-14, 38, CV3800/862-5266www.alcon.com
Ellex 27855/767-5784www.ellex.com/tango-reflex
Glaukos CV2949/367-9600www.glaukos.com
Heidelberg Engineering 29800/931-2230www.HeidelbergEngineering.com
Rhein Medical 5727/209-2244www.RheinMedical.com
Shire Ophthalmic CVTIP, 8-10800/828-2088www.shire-eyes.com
This index is provided as an additional service.The publisher does not assume any liabilityfor errors or omissions.
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OPHTHALMOLOGY TIMES (Print ISSN 0193-032X, Digital ISSN 2150-7333) is published semimonthly except for one issue in Jan, May, Aug and Dec (20 issues yearly) by UBM Medica, 131 W First Street, Duluth, MN 55802-2065. Subscription rates: $200 for one year in the United States & Possessions, Canada and Mexico; all other countries $263 for one year. Pricing includes air-expedited service. Single copies (prepaid only): $13 in the United States & Possessions, Canada and Mexico; $20 all other countries. Back issues, if available are $25 in the U.S. $ Possessions; $30 in Canada and Mexico; $35 in all other countries. Include $6.50 per order plus $2 per additional copy for U.S. postage and handling. If shipping outside the U.S., include an additional $10 per order plus $5 per additional copy. Periodicals postage paid at Duluth, MN 55806 and additional mailing offices. POSTMASTER: Please send address changes to OPHTHALMOLOGY TIMES, P.O. Box 6009, Duluth, MN 55806-6009. Canadian G.S.T. number: R-124213133RT001, Publications Mail Agreement Number 40612608. Return undeliverable Canadian addresses to: IMEX Global Solutions, PO Box 25542 London, ON N6C 6B2 CANADA. Printed in the U.S.A.
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5 roadblocks from being happierMost common stressors: money, retirement planning, healthMoney Matters By John S. Grande, CFP, Traudy F. Grande, CFP, and John J. Grande, CFP
Continues on page 38 : Happier
37JANUARY 2017 :: Ophthalmology Times
practice managementpractice management
ily, etc.—some are very happy, and some are
so unhappy that it manifests in their ill health.
What is the difference between the happy
and the unhappy? Happy physicians are cel-
ebrating life and appreciating everything they
have. They are uplifting to be around, and you
can see the joy on their faces.
5 ) N E G L E C T I N G O N E ' S H E A L T H
We visited a wealthy client in Florida many
years ago for a financial review. This physi-
cian, in his mid-70s, showed us his fishing
rods, bike, and golf clubs. He then turned to
us and said: “I am going to give you the only
wisdom that I have learned in life that mat-
ters. See these wonderful toys I have to play
with? Well, I can’t ride my bike, golf, or fish.
I never took care of my body and now I am a
HAPPIER( Continued from page 37 )
This article was written by Wells Fargo Advisors and
provided courtesy of John S., Traudy F., and John J.
Grande, CFPs, editors of the Money Matters column.
They are owners and principals of Grande Financial
Services Inc., Oakhurst, NJ, (www.grandefs.com) and registered principals of Wells Fargo
and Co., member of SIPC. The Grandes advise physicians across the country on a diverse
range of investment and financial matters. Readers may submit their financial questions to
them at [email protected] or call 800/722-1258.
The views expressed in the Money Matters column are the views of Grande Financial
Services, and should not be considered as investment advice. Grande Financial Services
does not provide tax or legal advice. All information is believed to be from reliable sources;
however, Grande Financial Services make no representation as to its completeness or
accuracy. Past performance does not guarantee future results. Investing involves risk
including the potential loss of principal.
Wells Fargo Advisors and its Financial Advisors provide non-fiduciary services only. They do
not provide investment advice [as defined under the Employee Retirement Income Security
Act of 1974 as amended (“ERISA”)], have any discretionary authority with respect to the
plan, make any investment or other decisions on behalf of the plan, or otherwise take any
action that would make them fiduciaries to the plan under ERISA.
Wells Fargo Advisors does not provide legal or tax advice. Be sure to consult with your tax
and legal advisors before taking any action that could have tax consequences.
Wells Fargo Advisors Financial Network, LLC, Member SIPC, is a registered broker-dealer and
a separate non-bank affiliate of Wells Fargo & Company.
Investments in securities and insurance products are: NOT FDIC-INSURED/NOT BANK-
GUARANTEED/MAY LOSE VALUE. Investment products and services are offered through Wells
Fargo Advisors Financial Network, LLC (WFAFN), Member SIPC. Grande Financial Services,
Inc. is a separate entity from WFAFN.
©2017 Wells Fargo Advisors, LLC. All rights reserved. 1015-05666 [86913-v6] 1115
e6830
prisoner here after earning my retirement.
Please, don’t do this to yourselves.”
You have one body. Many physicians
take better care of their cars, which they
can replace at will. We know firsthand
how busy physicians are, but even 20 min-
utes a day, five days a week will reduce
muscle atrophy and the aging process.
Today, we have healthy clients traveling
the world in their late 80s, exploring and
enjoying life like they did when they were
teenagers. We wish you all happiness and
health that life has to give. It is not about
how much money you have or don’t have.
Our quote is: “Those who are happiest in
life, win!” You deserve to win as you have
spent your life helping others see. Happiness
is a decision of sorts. Choose to be happy! ■
JANUARY 2017 :: Ophthalmology Times38
practice management
BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE
SIMBRINZA® (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2% is a fixed combination of a carbonic anhydrase inhibitor and an alpha 2 adrenergic receptor agonist indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. DOSAGE AND ADMINISTRATION The recommended dose is one drop of SIMBRINZA® Suspension in the affected eye(s) three times daily. Shake well before use. SIMBRINZA® Suspension may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. DOSAGE FORMS AND STRENGTHS Suspension containing 10 mg/mL brinzolamide and 2 mg/mL brimonidine tartrate. CONTRAINDICATIONS Hypersensitivity - SIMBRINZA® Suspension is contraindicated in patients who are hypersensitive to any component of this product. Neonates and Infants (under the age of 2 years) - SIMBRINZA® Suspension is contraindicated in neonates and infants (under the age of 2 years) [see Use in Specific Populations]. WARNINGS AND PRECAUTIONS Sulfonamide Hypersensitivity Reactions - SIMBRINZA® Suspension contains brinzolamide, a sulfonamide, and although administered topically is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration of SIMBRINZA® Suspension. Fatalities have occurred due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may recur when a sulfonamide is re-administered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation [see Patient Counseling Information]. Corneal Endothelium - Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma membranes of the corneal endothelium. There is an increased potential for developing corneal edema in patients with low endothelial cell counts. Caution should be used when prescribing SIMBRINZA® Suspension to this group of patients.Severe Renal Impairment - SIMBRINZA® Suspension has not been specifically studied in patients with severe renal impairment (CrCl < 30 mL/min). Since brinzolamide and its metabolite are excreted predominantly by the kidney, SIMBRINZA® Suspension is not recommended in such patients.Acute Angle-Closure Glaucoma - The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. SIMBRINZA® Suspension has not been studied in patients with acute angle-closure glaucoma.Contact Lens Wear - The preservative in SIMBRINZA® Suspension, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of SIMBRINZA® Suspension but may be reinserted 15 minutes after instillation [see Patient Counseling Information].Severe Cardiovascular Disease - Brimonidine tartrate, a component of SIMBRINZA® Suspension, has a less than 5% mean decrease in blood pressure 2 hours after dosing in clinical studies; caution should be exercised in treating patients with severe cardiovascular disease. Severe Hepatic Impairment - Because brimonidine tartrate, a component of SIMBRINZA® Suspension, has not been studied in patients with hepatic impairment, caution should be exercised in such patients.Potentiation of Vascular Insufficiency - Brimonidine tartrate, a component of SIMBRINZA® Suspension, may potentiate syndromes associated with vascular insufficiency. SIMBRINZA® Suspension should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangiitis obliterans.Contamination of Topical Ophthalmic Products After Use - There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers have been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface [see Patient Counseling Information].ADVERSE REACTIONS Clinical Studies Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice.SIMBRINZA® Suspension - In two clinical trials of 3 months duration 435 patients were treated with SIMBRINZA® Suspension, and 915 were treated with the two individual components. The most frequently reported adverse reactions in patients treated with SIMBRINZA® Suspension occurring in approximately 3 to 5% of patients in descending order of incidence were blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy. Rates of adverse reactions reported with the individual components were comparable. Treatment discontinuation, mainly due to adverse reactions, was reported in 11% of SIMBRINZA® Suspension patients. Other adverse reactions that have been reported with the individual components during clinical trials are listed below.Brinzolamide 1% - In clinical studies of brinzolamide ophthalmic suspension 1%, the most frequently reported adverse reactions reported in 5 to 10% of patients were blurred vision and bitter, sour or unusual taste. Adverse reactions occurring in 1 to 5% of patients were blepharitis, dermatitis, dry eye, foreign body sensation, headache, hyperemia, ocular discharge, ocular discomfort, ocular keratitis, ocular pain, ocular pruritus and rhinitis.The following adverse reactions were reported at an incidence below 1%: allergic reactions, alopecia, chest pain, conjunctivitis, diarrhea, diplopia, dizziness, dry mouth, dyspnea, dyspepsia, eye fatigue, hypertonia, keratoconjunctivitis, keratopathy, kidney pain, lid margin crusting or sticky sensation, nausea, pharyngitis, tearing and urticaria.Brimonidine Tartrate 0.2% - In clinical studies of brimonidine tartrate 0.2%, adverse reactions occurring in approximately 10 to 30% of the subjects, in descending order of incidence, included oral dryness, ocular hyperemia, burning and stinging, headache, blurring, foreign body sensation, fatigue/drowsiness, conjunctival follicles, ocular allergic reactions, and ocular pruritus.Reactions occurring in approximately 3 to 9% of the subjects, in descending order included corneal staining/erosion, photophobia, eyelid erythema, ocular ache/pain, ocular dryness, tearing, upper respiratory symptoms, eyelid edema, conjunctival edema, dizziness, blepharitis, ocular irritation, gastrointestinal symptoms, asthenia, conjunctival blanching, abnormal vision and muscular pain.The following adverse reactions were reported in less than 3% of the patients: lid crusting, conjunctival hemorrhage, abnormal taste, insomnia, conjunctival discharge, depression, hypertension, anxiety, palpitations/arrhythmias, nasal dryness and syncope.Postmarketing Experience - The following reactions have been identified during postmarketing use of brimonidine tartrate ophthalmic solutions in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to brimonidine tartrate ophthalmic solutions, or a combination of these factors, include: bradycardia, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, eyelid pruritus, rash, and vasodilation), and tachycardia. Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine tartrate ophthalmic solutions [see Contraindications].DRUG INTERACTIONS Oral Carbonic Anhydrase Inhibitors - There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and brinzolamide ophthalmic suspension 1%, a component of SIMBRINZA® Suspension. The concomitant administration of SIMBRINZA® Suspension and oral carbonic anhydrase inhibitors is not recommended.High-Dose Salicylate Therapy - Carbonic anhydrase inhibitors may produce acid-base and electrolyte alterations. These alterations were not reported in the clinical trials with brinzolamide ophthalmic suspension 1%. However, in patients treated with oral carbonic anhydrase inhibitors, rare instances of acid-base alterations have occurred with high-dose salicylate therapy. Therefore, the potential for such drug interactions should be considered in patients receiving SIMBRINZA® Suspension.CNS Depressants - Although specific drug interaction studies have not been conducted with SIMBRINZA® Suspension, the possibility of an additive or potentiating effect with CNS depressants (alcohol, opiates, barbiturates, sedatives, or anesthetics) should be considered.Antihypertensives/Cardiac Glycosides - Because brimonidine tartrate, a component of SIMBRINZA® Suspension, may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with SIMBRINZA® Suspension is advised.
Tricyclic Antidepressants - Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not known whether the concurrent use of these agents with SIMBRINZA® Suspension in humans can lead to resulting interference with the IOP lowering effect. Caution is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.Monoamine Oxidase Inhibitors - Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine tartrate and potentially result in an increased systemic side-effect such as hypotension. Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines. USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category C: Developmental toxicity studies with brinzolamide in rabbits at oral doses of 1, 3, and 6 mg/kg/day (20, 60, and 120 times the recommended human ophthalmic dose) produced maternal toxicity at 6 mg/kg/day and a significant increase in the number of fetal variations, such as accessory skull bones, which was only slightly higher than the historic value at 1 and 6 mg/kg. In rats, statistically decreased body weights of fetuses from dams receiving oral doses of 18 mg/kg/day (180 times the recommended human ophthalmic dose) during gestation were proportional to the reduced maternal weight gain, with no statistically significant effects on organ or tissue development. Increases in unossified sternebrae, reduced ossification of the skull, and unossified hyoid that occurred at 6 and 18 mg/kg were not statistically significant. No treatment-related malformations were seen. Following oral administration of 14C-brinzolamide to pregnant rats, radioactivity was found to cross the placenta and was present in the fetal tissues and blood. Developmental toxicity studies performed in rats with oral doses of 0.66 mg brimonidine base/kg revealed no evidence of harm to the fetus. Dosing at this level resulted in a plasma drug concentration approximately 100 times higher than that seen in humans at the recommended human ophthalmic dose. In animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent.There are no adequate and well-controlled studies in pregnant women. SIMBRINZA® Suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Nursing Mothers - In a study of brinzolamide in lactating rats, decreases in body weight gain in offspring at an oral dose of 15 mg/kg/day (150 times the recommended human ophthalmic dose) were observed during lactation. No other effects were observed. However, following oral administration of 14C-brinzolamide to lactating rats, radioactivity was found in milk at concentrations below those in the blood and plasma. In animal studies, brimonidine was excreted in breast milk.It is not known whether brinzolamide and brimonidine tartrate are excreted in human milk following topical ocular administration. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from SIMBRINZA® (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2%, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.Pediatric Use - The individual component, brinzolamide, has been studied in pediatric glaucoma patients 4 weeks to 5 years of age. The individual component, brimonidine tartrate, has been studied in pediatric patients 2 to 7 years old. Somnolence (50-83%) and decreased alertness was seen in patients 2 to 6 years old. SIMBRINZA® Suspension is contraindicated in children under the age of 2 years [see Contraindications].Geriatric Use - No overall differences in safety or effectiveness have been observed between elderly and adult patients.OVERDOSAGE Although no human data are available, electrolyte imbalance, development of an acidotic state, and possible nervous system effects may occur following an oral overdose of brinzolamide. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. Very limited information exists on accidental ingestion of brimonidine in adults; the only adverse event reported to date has been hypotension. Symptoms of brimonidine overdose have been reported in neonates, infants, and children receiving brimonidine as part of medical treatment of congenital glaucoma or by accidental oral ingestion. Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained.NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of Fertility - Brinzolamide caused urinary bladder tumors in female mice at oral doses of 10 mg/kg/day and in male rats at oral doses of 8 mg/kg/day in 2 year studies. Brinzolamide was not carcinogenic in male mice or female rats dosed orally for up to 2 years. The carcinogenicity appears secondary to kidney and urinary bladder toxicity. These levels of exposure cannot be achieved with topical ophthalmic dosing in humans.The following tests for mutagenic potential of brinzolamide were negative: (1) in vivo mouse micronucleus assay; (2) in vivo sister chromatid exchange assay; and (3) Ames E. coli test. The in vitro mouse lymphoma forward mutation assay was negative in the absence of activation, but positive in the presence of microsomal activation. In this assay, there was no consistent dose-response relationship to the increased mutation frequency and cytotoxicity likely contributed to the high mutation frequency. Carbonic anhydrase inhibitors, as a class, are not mutagenic and the weight of evidence supports that brinzolamide is consistent with the class. In reproduction studies of brinzolamide in rats, there were no adverse effects on the fertility or reproductive capacity of males or females at doses up to 18 mg/kg/day (180 times the recommended human ophthalmic dose).Brimonidine tartrate was not carcinogenic in either a 21-month mouse or 24-month rat study. In these studies, dietary administration of brimonidine tartrate at doses up to 2.5 mg/kg/day in mice and 1 mg/kg/day in rats resulted in plasma drug concentrations 80 and 120 times higher than the human plasma drug level at the recommended clinical dose, respectively. Brimonidine tartrate was not mutagenic or cytogenic in a series of in vitro and in vivo studies including the Ames test, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, a host-mediated assay and cytogenic studies in mice, and a dominant lethal assay. In reproductive studies performed in rats with oral doses of 0.66 mg brimonidine base/kg (approximately 100 times the plasma drug concentration level seen in humans following multiple ophthalmic doses), fertility was not impaired.PATIENT COUNSELING INFORMATION Sulfonamide Reactions - Advise patients that if serious or unusual ocular or systemic reactions or signs of hypersensitivity occur, they should discontinue the use of the product and consult their physician.Temporary Blurred Vision - Vision may be temporarily blurred following dosing with SIMBRINZA® Suspension. Care should be exercised in operating machinery or driving a motor vehicle.Effect on Ability to Drive and Use Machinery - As with other drugs in this class, SIMBRINZA® Suspension may cause fatigue and/or drowsiness in some patients. Caution patients who engage in hazardous activities of the potential for a decrease in mental alertness.Avoiding Contamination of the Product - Instruct patients that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions [see Warnings and Precautions ]. Always replace the cap after using. If solution changes color or becomes cloudy, do not use. Do not use the product after the expiration date marked on the bottle.Intercurrent Ocular Conditions - Advise patients that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician’s advice concerning the continued use of the present multidose container.Concomitant Topical Ocular Therapy - If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.Contact Lens Wear - The preservative in SIMBRINZA® Suspension, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of SIMBRINZA® Suspension, but may be reinserted 15 minutes after instillation.©2013-2016 Novartis U.S. Patent No: 6,316,441
ALCON LABORATORIES, INC. Fort Worth, Texas 76134 USA1-800-757-9195 [email protected]
© 2016 Novartis 6/16 US-SMB-16-E-2215
INDICATIONS AND USAGESIMBRINZA® (brinzolamide/brimonidine tartrate ophthalmic suspension)
1%/0.2% is a fi xed combination indicated in the reduction of elevated intraocular
pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.
Dosage and Administration The recommended dose is one drop of SIMBRINZA® Suspension in the affected
eye(s) three times daily. Shake well before use. SIMBRINZA® Suspension may
be used concomitantly with other topical ophthalmic drug products to lower intraoc-
ular pressure. If more than one topical ophthalmic drug is being used,
the drugs should be administered at least fi ve (5) minutes apart.
IMPORTANT SAFETY INFORMATION Contraindications SIMBRINZA® Suspension is contraindicated in patients who are hypersensitive
to any component of this product and neonates and infants under the age
of 2 years.
Warnings and PrecautionsSulfonamide Hypersensitivity Reactions—Brinzolamide is a sulfonamide, and
although administered topically, is absorbed systemically. Sulfonamide attributable
adverse reactions may occur. Fatalities have occurred due to severe reactions to
sulfonamides. Sensitization may recur when a sulfonamide is readministered irre-
spective of the route of administration. If signs of serious reactions or hypersensi-
tivity occur, discontinue the use of this preparation.
Corneal Endothelium—There is an increased potential for developing corneal
edema in patients with low endothelial cell counts.
Severe Hepatic or Renal Impairment (CrCl <30 mL/min)—SIMBRINZA® Suspension
has not been specifi cally studied in these patients and is not recommended.
Contact Lens Wear—The preservative in SIMBRINZA® Suspension, benzalkonium
chloride, may be absorbed by soft contact lenses. Contact lenses should
be removed during instillation of SIMBRINZA® Suspension but may be reinserted
15 minutes after instillation.
Severe Cardiovascular Disease—Brimonidine tartrate, a component of SIMBRINZA®
Suspension, had a less than 5% mean decrease in blood pressure 2 hours after
dosing in clinical studies; caution should be exercised in treating patients with severe
cardiovascular disease.
Adverse ReactionsSIMBRINZA® Suspension In two clinical trials of 3 months’ duration with SIMBRINZA® Suspension, the most
frequent reactions associated with its use occurring in approximately 3-5%
of patients in descending order of incidence included: blurred vision, eye irritation,
dysgeusia (bad taste), dry mouth, and eye allergy. Adverse reaction rates with
SIMBRINZA® Suspension were comparable to those of the individual components.
Treatment discontinuation, mainly due to adverse reactions, was reported
in 11% of SIMBRINZA® Suspension patients.
Drug InteractionsConsider the following when prescribing SIMBRINZA® Suspension:
Concomitant administration with oral carbonic anhydrase inhibitors is not recom-
mended due to the potential additive effect. Use with high-dose salicylate
may result in acid-base and electrolyte alterations. Use with CNS depressants may
result in an additive or potentiating effect. Use with antihypertensives/cardiac glyco-
sides may result in additive or potentiating effect on lowering blood
pressure. Use with tricyclic antidepressants may blunt the hypotensive effect
of systemic clonidine and it is unknown if use with this class of drugs interferes
with IOP lowering. Use with monoamine oxidase inhibitors may result
in increased hypotension.
References: 1. Data on fi le, 2014. 2. SIMBRINZA® Suspension Package Insert.
24-hour IOP-lowering coverage, including the night — nocturnal effi cacy established through an 8 AM time point2
© 2016 Novartis 4/16 US-SMB-16-E-1229
Aim for Target IOPConsider Adding SIMBRINZA® Suspension to a PGASIMBRINZA® Suspension should be taken at least fi ve (5) minutes apart from other topical ophthalmic drugs
Up to 7.1 mm Hg additional IOP reduction from baseline when
added to a PGA1
5.6 mm Hg* additional mean diurnal IOP lowering observed from baseline when added to a PGA1
* Treatment difference (mm Hg) and P value at Week 6 was -3.7, P<0.0001.
Learn more at myalcon.com/simbrinza
For additional information about SIMBRINZA® Suspension, please refer to the brief summary of the full Prescribing Information on the following page.
Treatment Arm 8 AM 10 AM 3 PM 5 PM
PGA + SIMBRINZA®
Suspension (N=88)
PGA + Vehicle (N=94)
Baseline‡ 24.5 22.9 21.7 21.6Week 6 19.4 15.8 17.2 15.6
Baseline‡ 24.3 22.6 21.3 21.2
Week 6 21.5 20.3 20.0 20.1
† Differences (mm Hg) and P values at Week 6 time points between treatment groups
were -2.14, P=0.0002; -4.56, P<0.0001; -2.84, P<0.0001; -4.42, P<0.0001.‡Baseline (PGA Monotherapy).
Baseline|| 22.7Week 6 17.1
Baseline|| 22.4
Week 6 20.5
Treatment Arm
PGA + SIMBRINZA®
Suspension (N=83)
PGA + Vehicle (N=92)
§ Difference (mm Hg) and P value at Week 6 between treatment groups
were -3.44, P<0.0001.||Baseline (PGA Monotherapy).
IOP Daily Time Points (mm Hg)1† Mean Diurnal IOP (mm Hg)1§
Study Design: A prospective, randomized, multicenter, double-blind, parallel-group study of 189 patients with open-angle glaucoma and/or ocular hypertension receiving treatment
with a PGA. PGA treatment consisted of either travoprost, latanoprost, or bimatoprost. Patients in the study were randomized to adjunctive treatment with SIMBRINZA® Suspension
(N=88) or vehicle (N=94). The primary effi cacy endpoint was mean diurnal IOP (IOP averaged over all daily time points) at Week 6 between treatment groups. Key secondary
endpoints included IOP at Week 6 for each daily time point (8 AM, 10 AM, 3 PM, and 5 PM) and mean diurnal IOP change from baseline to Week 6 between treatment groups.1
PGA=prostaglandin analog.
ZIOPTAN is licensed by Santen Pharmaceutical Co., Ltd.
©2016 Akorn, Inc. All rights reserved. P641 Rev 09/16 (a)
Cosopt is a registered trademark of Merck Sharp & Dohme Corp and is used under license. ZIOPTAN is a registered trademark of Merck Sharp & Dohme Corp and is used under license.
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