Download Topical Corticosteroids: Making Sense of the Options

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ISSUE 3
Topical Corticosteroids: Making Sense
of the Options
ERIC D. DONNENFELD, MD Topical corticosteroid
prescribing decisions are based on differences in
potency, formulation, side-effect profile, patient
factors, and the intended use. Here we will review
what distinguishes currently available agents and how
prescribing patterns are evolving based on new options
and new understandings of the importance of treating
inflammation.
Topical ophthalmic corticosteroids are frequently used to
prevent or control ocular inflammation resulting from surgery,
disease, or trauma. All surgical manipulation damages cellular
membranes, releasing inflammatory mediators and triggering a cascade of events that can culminate in vasodilation,
edema, and pain. In other parts of the body, this inflammatory
response can be tolerated as a normal part of healing, but in
the eye, uncontrolled or inadequately controlled inflammation
can result in temporary or permanent vision loss.
By binding glucocorticoid receptors within cells, corticosteroids block the expression of proinflammatory proteins
and activate the expression of antiinflammatory proteins.
Steroids inhibit phospholipase A2, the enzyme that initiates
the arachidonic acid cascade; steroids also stabilize cell membranes, limit capillary dilation, and inhibit the proliferation
of leukocytes and fibroblasts.1
But everything comes at a price: this broad antiinflammatory activity—especially when continued for long periods
of time—may be accompanied by unwanted side effects. For
topical ophthalmic steroids, these may include increased in-
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traocular pressure (IOP), cataractogenesis, impaired wound
healing, and reduced response to infection.1 In the great
majority of cases, however, the risk from unchecked ocular
inflammation far outweighs the risks associated with carefully
monitored and appropriate corticosteroid use.
STEROID POTENCY
A number of factors interact to determine the activity
of individual topical corticosteroid agents. While the antiinflammatory potency of the active molecule is critical, its
influence is modified by the drug’s bioavailability, which is
determined by factors such as the agent’s intrinsic potency,
solubility, ocular surface contact time, and corneal penetration. In systemic application, dexamethasone is five to seven
times more potent than prednisolone; but because drug from
prednisolone acetate 1% suspension penetrates the cornea
readily and achieves higher anterior chamber concentrations
than dexamethasone (alcohol 0.1% solution or phosphate 0.1%
suspension), prednisolone is regarded as a more potent topical
ophthalmic steroid.2,3
See INSIDE for:
Complications of Topical Antiinflammatory Agents
by John R. Wittpenn, MD
Punctate keratopathy associated with topical NSAID use.
Topics in
ANTIINFLAMMATORIES
Supported by an unrestricted educationalOCULAR
grant from
Bausch + Lomb, Inc. 1
Less potent steroids available to
US ophthalmologists include fluorometholone 0.1% ophthalmic suspension,
rimexolone 1.0% ophthalmic suspension, and loteprednol etabonate 0.2%
ophthalmic suspension. While less
suited to treating or preventing massive inflammatory insult, these agents
are useful for treating inflammatory
conditions of the ocular surface, such
as allergic conjunctivitis.4 Fluorometholone, for instance, penetrates the cornea
but appears to have little activity in the
anterior chamber.4 Its greatest utility is
in ocular surface inflammation, where it
can be effective without as pronounced
a tendency to induce IOP elevation or
cataract formation as stronger steroids.
Loteprednol etabonate 0.2% is FDA
approved for the treatment of seasonal
allergic conjunctivitis and has been
found superior to placebo and to the
antihistamine olopatadine 0.1% in
reducing bulbar conjunctival injection
and itching in affected patients.1 Because allergic conjunctivitis tends to be
chronic and recurring, corticosteroids,
while extremely effective, should be used
cautiously for this indication, typically
for a short period to quell inflammation
until topical antihistamines can be used
for long term management. Patients
should be educated about risks associated with long-term use.
“STRONG” STEROIDS
A higher (0.5%) concentration of
loteprednol etabonate is available in
several forms: a suspension, an ointment, and, most recently, a gel. A
product of retrometabolic drug design,
loteprednol etabonate was engineered
from the prednisolone backbone. The
substitution at the C-20 position of an
ester group for the ketone found in all
other topical corticosteroids (including prednisolone and dexamethasone)
allows endogenous tissue esterases to
break loteprednol down to inactive
metabolites. (Other steroids have active
metabolites.) The result is a moderately
potent steroid with less propensity to
increase IOP than prednisolone acetate,
dexamethasone, or even fluorometholone.5
The strongest ophthalmic cortico2
Topics in OCULAR ANTIINFLAMMATORIES
TOPICS IN OCULAR ANTIINFLAMMATORIES, ISSUE 3
STATEMENT OF NEED
The indications for topical ophthalmic antiinflammatory
drugs (both steroidal and nonsteroidal) are evolving
rapidly, as new agents and new applications emerge.
Many of these are novel—eg, the perioperative use of
nonsteroidal antiinflammatory drugs (NSAIDs) to prevent
cystoid macular edema—and/or fly in the face of older
thinking—eg, the use of steroids to calm inflammation
and reduce the risk of melting or scarring from infection.
Neither of these important applications is on-label.
In addition, new steroidal and nonsteroidal agents
continue to come to market, expanding the utility of
both classes. Antiinflammatory drugs are now used
for: the treatment of ocular surface disease and allergic
conjunctivitis; prevention of perioperative pain and
inflammation in ocular surgery; infection management;
cystoid macular edema prophylaxis following cataract
surgery; haze prevention in PRK; and much more.
What has regrettably not followed this expansion of
indications, formulations, and new molecular entities
are protocols for drug selection and use.1 These are vital
because significant differences in safety, tolerability, and
efficacy exist between and within both antiinflammatory
drug classes. C-20 ester steroids, for example, have a
demonstrated lower risk of intraocular pressure (IOP)
elevation than ketone steroids.2,3 Since a range of steroid
formulations and concentrations is available, clinicians
need up-to-date information about the indications and
optimum uses for each.3
Although topical NSAID formulations have been
associated with significant adverse events (keratopathy
ranging from superficial punctate keratitis to corneal
melt), recent work shows these to be uncommon and less
severe with newer formulations.4 Indeed, novel NSAIDs
make use of lower concentrations and less frequent
dosing, potentially impacting safety profiles and reducing
risk from long-term use.5
Although both are “antiinflammatory,” steroids and
NSAIDs act at different points in the inflammatory
cascade, and thus offer opportunities for physicians
to fine-tune their drug selection. And although they
are frequently used together, whether or not the two
drug classes can act synergistically is controversial. In
the context of recent clinical data, a clear mechanistic
understanding of each drug class generally—and of
newer formulations specifically—will equip clinicians
to make effective, evidence-based prescribing
decisions across the many situations that call for ocular
inflammation control.
REFERENCES
1. Dua HS, Attre R. Treatment of post-operative
inflammation following cataract surgery—a review.
European Ophthalmic Review. 2012;6(2):98-103.
2. Comstock TL, DeCory H. Advances in corticosteroid
therapy for ocular inflammation: loteprednol
etabonate. International Journal of Inflammation. 2012;
doi:10.1155/2012/789623.
3. Fong R, Leitritz M, Siou-Mermet R, Erb T. Loteprednol
etabonate gel 0.5% for postoperative pain and
inflammation after cataract surgery: results of a
multicenter trial. Clin Ophthalmol. 2012;6:1113-24.
4. Singer M, Cid MD, Luth J, et al. Incidence of corneal melt
in clinical practice: our experience vs a meta-analysis of
the literature. Clin Exp Ophthalmol. 2012;S1:003.
5. Cable M. Comparison of bromfenac 0.09% QD to
nepafenac 0.1% TID after cataract surgery: pilot
evaluation of visual acuity, macular volume, and retinal
thickness at a single site. Clin Ophthalmol. 2012;6:9971004.
OFFLABEL USE STATEMENT This work discusses offlabel uses of antiinflammatory medications.
GENERAL INFORMATION This CME activity is
sponsored by the University of Florida College of
Medicine and is supported by an unrestricted educational
grant from Bausch + Lomb, Inc.
Directions: Select one answer to each question in the
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Physicians should only claim the credit commensurate
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FACULTY AND DISCLOSURE STATEMENTS
Lisa B. Arbisser, MD (Faculty Advisor), is an adjunct
associate professor at the University of Utah Moran Eye
Center in Salt Lake City, UT, and an ophthalmologist at Eye
Surgeons Associates PC in Bettendorf, IA. She states that
in the past 12 months, she has participated in a standalone Bausch + Lomb advisory board meeting.
Penny A. Asbell, MD, FACS, MBA (Faculty Advisor), is a
professor of ophthalmology and director of the cornea
and refractive services at Icahn School of Medicine at
Mount Sinai. She states that in the past 12 months, she
has been a consultant for R-tech, Senju, and Bausch +
Lomb, has given CME lectures for Merck, and has received
a research grant from Alcon.
William E. Smiddy, MD (Faculty Advisor), is a professor
of ophthalmology at the Bascom Palmer Eye Institute,
University of Miami Miller School of Medicine. He states
that in the past 12 months, he has attended a steering
committee meeting of Alimera Scientific.
Eric D. Donnenfeld, MD, practices at Ophthalmic
Consultants of Long Island and is a clinical professor of
ophthalmology at New York University. He states that in
the past 12 months, he has consulted for Allergan, Alcon,
Bausch + Lomb, and Kala.
John R. Wittpenn, MD, is a partner in Ophthalmic
Consultants of Long Island and a clinical associate
professor of ophthalmology at the State University of
New York at Stony Brook. He is a consultant for and a
member of the speaker’s bureau for Bausch + Lomb.
DISCLAIMER Participants have an implied responsibility
to use the newly acquired information to enhance
patient outcomes and professional development. The
information presented in this activity is not meant
to serve as a guideline for patient care. Procedures,
medications, and other courses of diagnosis and
treatment discussed or suggested in this activity should
not be used by clinicians without evaluation of their
patients’ conditions and possible contraindications
or dangers in use, applicable manufacturer’s product
information, and comparison with recommendations of
other authorities.
COMMERCIAL SUPPORTERS This activity is supported
by an unrestricted educational grant from Bausch +
Lomb, Inc.
To obtain CME credit for this activity, go to http://cme.ufl.edu/toai
steroid currently available is difluprednate 0.05% ophthalmic
emulsion. Structurally similar to prednisolone, difluprednate
is distinguished by the addition of two fluorine atoms (at the
C-6 and C-9 positions) and a butyrate ester group at the C-17
position that increase the molecule’s affinity for the glucocorticoid receptor.6,7 An acetate ester at the C-21 position further
boosts potency by facilitating tissue penetration.6,7
Using a strong corticosteroid, such as prednisolone acetate
or difluprednate, can be of particular advantage in the period
before and after cataract or refractive surgery. Pretreatment,
aggressive management, and rapid tapering may promote
faster visual rehabilitation and reduce the need for long-term
corticosteroid use.
FORMULATION
Formulation is an important consideration in ophthalmic
steroid selection, as it can affect dose uniformity, ocular surface
residence time, and corneal penetration. Lipophilic molecules
like prednisolone acetate penetrate the lipid-rich corneal epithelial cells more readily than hydrophilic derivatives such as
prednisolone phosphate. However, formulating a hydrophobic/
lipophilic molecule as a topical eyedrop is challenging. So in
addition to steroid solutions like dexamethasone sodium phosphate 0.1% and prednisolone sodium phosphate 1.0%, many
important ophthalmic steroids are formulated as suspensions.
Because the particles in a suspension settle, suspensions
must be shaken vigorously prior to use—a barrier to patient
adherence and to consistent dosing. Even when ophthalmic
steroid suspensions are shaken, laboratory studies show significant variability in actual drug concentration delivered: when
branded and generic prednisolone acetate 1.0% suspensions
were stored upright, shaken, and dosed to simulate patient usage, actual drop concentrations fell within 10% of the declared
value only 23% and 6% of the time, respectively.8
It is therefore encouraging to see newer steroids in emulsion and gel formulations, which ensure drop-to-drop consistency of drug concentration without the need for shaking.
Difluprednate 0.05% is formulated as a stable oil-in-water
emulsion, in which surfactant molecules keep the oil-dissolved
drug particles suspended in an aqueous phase. In the same
study mentioned above, difluprednate drops were within 10%
of declared concentration nearly 100% of the time, regardless
of shaking or bottle orientation during storage.8
A newly available non-settling gel formulation of loteprednol etabonate 0.5% also offers improved dose uniformity and
ocular surface residence time over the suspension preparation.5
And while ophthalmic steroids are generally well-tolerated
by patients, this formulation, which also contains the ocular
lubricants propylene glycol and glycerin, as well as a lower
concentration of benzalkonium chloride than the suspension,
may also offer improved comfort over the suspension.5
SAFETY: CHANGING PATTERNS OF USE
In general, the risk of steroid side effects correlates directly
with the potency of the drug. To minimize the risks associated
with high drug concentrations, prescribers often favored modTo obtain CME credit for this activity, go to http://cme.ufl.edu/toai
CORE CONCEPTS
✦ Topical corticosteroid potency depends multiple factors,
including the active molecule, its solubility, ocular surface
retention, and corneal penetration.
✦ Degree of inflammation, anticipated duration of therapy,
target tissue, and associated patient risk factors can help
determine the selection of a “strong” vs a “soft” steroid.
✦ Less potent ophthalmic steroids, including
fluorometholone, rimexolone, and loteprednol etabonate
0.2%, are well suited to treating conditions of the ocular
surface.
✦ In general, the more potent the steroid, the greater
the risk of side effects, including IOP increase,
cataractogenesis, delayed wound healing, and secondary
infection.
✦ Formulation can significantly affect the degree of
certainty over the drug concentration dosed.
erate doses for longer periods of time, with the goal of quelling
an existing inflammatory response. Today, particularly in
surgical applications, the aim of corticosteroid prescribing is
first of all to prevent, rather than suppress, inflammation. The
thought here is that side effects can be effectively minimized
by reducing not the concentration of drug but the duration
of therapy.
To inhibit inflammation in cataract surgery patients, we
begin dosing non-steroidal antiinflammatory drugs (NSAIDs)
3 days before surgery to reduce the level of endogenous prostaglandins in the tissue. We begin corticosteroid dosing just
two hours prior to surgery, in a pulse of three or four doses.
We then instruct patients to use their steroid drops 2 times per
day postoperatively for 2 weeks and then taper to one drop a
day for the third week.
In addition to a history of glaucoma, ocular hypertension,
or IOP elevation in response to prior topical steroid use, Chang
and colleagues have identified younger age and high axial
myopia as risk factors for steroid response in cataract surgery
patients.9 Indeed, their retrospective case control study found
that cataract patients younger than 65 with an axial length of >
29.0 mm had a 35-fold increased risk of having steroid-induced
IOP spike to over 34 mmHg.9 Patients with any of these risk
factors for elevated IOP during corticosteroid therapy should
be monitored closely, particularly if a potent steroid such as
difluprednate is used.
When patients are expected to be on topical steroid therapy
for an extended period of time, eg, in order to prevent graft
rejection after keratoplasty, less potent steroids with fewer side
effects, such as 0.1% fluorometholone and loteprednol, can be
effective long-term.10 In cases of corneal infection, steroid use
is more controversial. It has been argued that adding steroid
to antimicrobial therapy for infectious keratitis, for example,
could improve the visual outcome by inhibiting the immune
response that leads to scarring. Physicians have been hesitant
Topics in OCULAR ANTIINFLAMMATORIES
3
to employ this reasoning because the immunosuppressive effects of steroids also risk worsening an infection, particularly
in the absence of effective antimicrobial therapy.
A recent large-scale, randomized, double-masked,
placebo-controlled trial of adjunctive steroids in the treatment of bacterial corneal ulcers did not demonstrate either
significant benefit (measured by best corrected visual acuity
or size of scar) or detriment of adjunctive steroid treatment.11
Subgroup analyses and future studies may identify factors (eg,
size of corneal defect, virulence of infecting agent, frequency
of steroid dosing) that can guide adjunctive steroid treatment.
This applies only to treatment of bacterial infections: viral,
fungal, or Acanthamoeba etiologies should be ruled out before
initiating adjunctive steroid treatment for an epithelial corneal
infection. The most important factor is that the antimicrobial
therapy control the infection if corticosteroids are going to
be employed.
CHALLENGES
All of the thought physicians put into prescribing topical
steroids can be compromised if substitutions are made at the
pharmacy. Generic drugs are required to be “bioequivalent”
to their branded counterparts—that is, generics must have
the same active ingredients in the same concentration, as well
as identical dosage, route of administration, indications, and
labeling. But while bioequivalence theoretically correlates with
therapeutic equivalence (and it often does in reality), generic
drugs are not typically required to prove this by undergoing
clinical evaluation prior to approval.12 In the case of prednisolone acetate 1%, investigations have found larger and less
consistent particle sizes in generic vs branded suspensions,
which leads to observed reductions in dose uniformity and
the formation of clogging precipitates.12
More worrisome than generics are substitutions of different entities entirely, such as prednisolone acetate for
loteprednol etabonate. Specifying “dispense as written” or
similar clear instructions for pharmacists can help prevent
such substitutions; but patient education is also essential. We
make a practice of including an image of the prescribed drug
along with dosing instructions for patients, and we explain why
it is important to us that they obtain the correct medication.
The cost of medication must always be weighed in prescribing decisions. When we prescribe a generic drug to a
cost-conscious patient, we ensure the patient understands the
issues involved. When appropriate, we let patients know that
the characteristics of their case and the differences between
the branded and generic drug formulations merit serious
consideration of the branded original, despite its cost.
NEW DIRECTIONS
Much has changed over the last two decades in topical
ophthalmic steroid therapy. We now not only have more agents
to choose from but also, increasingly, more sophisticated
agents engineered for greater potency and lower associated
risks. There remain areas of clinical application, however, in
which steroids are underutilized, perhaps because of caution
4
Topics in OCULAR ANTIINFLAMMATORIES
or longtime habits on the part of clinicians.
Though they tend to be chronic and/or recurring in nature,
ocular allergy and dry eye disease are two key therapeutic areas
for which brief topical steroid therapy can be quite beneficial.
Steroids suppress the proliferation of mast cells and block the
prostaglandins, leukotrienes, and other inflammatory mediators involved in the allergic response. A pulse of steroid therapy
can help curtail signs and symptoms of inflammation during
an acute episode of allergic conjunctivitis and allow patients
to be better managed on antihistamines, mast-cell stabilizers,
or combination agents.4
Likewise, short-term pulse therapy with steroids can help
to hasten relief for dry eye patients beginning therapy with
cyclosporine ophthalmic emulsion 0.05%, which may take a
period of weeks or months to produce clinical improvement.13
In addition to reducing inflammation and improving patient
symptoms, steroids may help increase goblet cell density. For
acutely inflammatory meibomian gland dysfunction, and for
the marginal keratitis that may accompany this condition, a
brief course of topical steroid may also be of benefit.14
On the horizon, we have a new class of agents that also
work by binding glucocorticoid receptors. These selective
glucocorticoid receptor agonists (SEGRAs) operate with
antiinflammatory activity similar to corticosteroids, but
with a more limited scope of gene activation and thus, fewer
unwanted side effects.15
Mapracorat, a SEGRA currently under investigation as an
ophthalmic suspension for the treatment of allergic conjunctivitis and post-cataract surgery pain and inflammation, has
shown promise in preclinical studies.15 In a rabbit model of dry
eye, mapracorat was found to be as effective as dexamethasone
sodium phosphate solution 0.1% at maintaining tear volume
and tear-film breakup time but without the significant IOP
elevations seen in dexamethasone-treated eyes.15 SEGRAs
thus represent a very exciting area of development in topical
ophthalmic antiinflammatory therapy.
CONCLUSION
Topical ophthalmic steroids continue to be an essential
component of postsurgical inflammation management. But
their short-term use can meaningfully benefit other ocular
surface and anterior segment inflammatory conditions where
they may be less frequently used. Careful monitoring of steroid
treatment is warranted, but steroids should not be avoided
simply because they may carry significant risks—the sequelae
of ocular inflammation are very commonly worse than the side
effects of steroid use, which, if detected promptly, can typically
be managed without impairing vision. Taking advantage of
newer formulations and prescribing aggressive, short-term
dosing regimens with rapid tapering can help minimize risk
and maximize benefit.
Eric D. Donnenfeld, MD, practices at Ophthalmic Consultants of Long Island
and is a clinical professor of ophthalmology at New York University. He states that
in the past 12 months, he has consulted for Allergan, Alcon, Bausch + Lomb, and
Kala. Managing editor Jennifer Zweibel assisted in the preparation of this article.
To obtain CME credit for this activity, go to http://cme.ufl.edu/toai
REFERENCES
1. Comstock TL, DeCory HH. Advances in corticosteroid therapy for ocular
inflammation: loteprednol etabonate. Int J Inflamm. 2012;Article ID 789623.
2. Cunningham ET, Wender JD. Practical approach to the use of corticosteroids
in patients with uveitis. Can J Ophthalmol. 2010;45;352-8.
3. McGhee CNJ. Pharmacokinetics of ophthalmic corticosteroids. Br J Ophthalmol. 1992;76:681-4.
4. Friedlaender MH. The current and future therapy of allergic conjunctivitis.
Curr Opin Ophthalmol. 1998;9(4):54-8.
5. Lyseng-Williamson KA. Loteprednol etabonate ophthalmic gel 0.5%: a review
of its use in post-operative inflammation and pain following ocular surgery.
Drugs. 2013;73:949-58.
6. Donnenfeld ED. Difluprednate for the prevention of ocular inflammation
postsurgery: an update. Clin Ophthalmol. 2011;5:811-6.
7. Bikowski J, Pillai R, Shroot B. The position not the presence of the halogen
in corticosteroids influences potency and side effects. J Drug Dermatol.
2006;5(2):125-30.
8. Stringer W, Bryant R. Dose uniformity of topical corticosteroid preparations:
difluprednate ophthalmic emulsion 0.05% versus branded and generic pred-
nisolone acetate ophthalmic suspension 1%. Clin Ophthalmol. 2010;4:119-24.
9. Chang DF, Tan JJ, Tripodis Y. Risk factors for steroid response among cataract
patients. J Cataract Refract Surg. 2011;37:675-81.
10. Shimazaki J, Iseda A, Satake Y, Shimazaki-Den S. Efficacy and safety of longterm corticosteroid eye drops after penetrating keratoplasty. Ophthalmology.
2012;119:668-73.
11. Srinivasan M, Mascarenhas J, Rajaraman R, et al. The steroids for corneal
ulcers trial. Arch Ophthalmol. 2012;130(2):151-7.
12. Zore M, Harris A, Tobe LA, et al. Generic medications in ophthalmology.
Br J Ophthalmol. 2013;97:253-7.
13. Pflugfelder SC. Antiinflammatory therapy for dry eye. Am J Ophthalmol.
2004;137:337-42.
14. Geerling G, Tauber J, Baudouin C, et al. The international workshop on
meibomian gland dysfunction: report of the subcommittee on management
and treatment of meibomian gland dysfunction. Invest Ophthalmol Vis Sci.
2011;52(4):2050-64.
15. Shafiee A, Bucolo C, Budzynski E, et al. In vivo ocular efficacy profile of
mapracorat, a novel selective glucocorticoid receptor agonist, in rabbit models
of ocular disease. Invest Ophthalmol Vis Sci. 2011;52:1422-30.
Complications of Topical
Antiinflammatory Agents
JOHN R. WITTPENN, MD Although they carry the
potential for serious side effects, topical antiinflammatory
agents are typically well tolerated and have become
integral to ophthalmologic practice. Conscientious
prescribing and follow up can mitigate their risks.
duration of treatment required against the drug’s potential to
cause harmful side effects.
Some commonly prescribed corticosteroids, including
prednisolone acetate and difluprednate, are very effective at
suppressing inflammation but place patients at a substantial
risk for IOP elevation within weeks to months. In my experience, difluprednate offers excellent antiinflammatory potency
with less frequent dosing but can produce IOP elevation in
many patients within a matter of 2 to 3 weeks.
An indispensible part of eyecare practice, topical antiinflammatory agents are effective across a range of preventive
and therapeutic indications. Although each topical
antiinflammatory drug is a unique combination
of active and inactive molecules that carries a
unique set of risks (and benefits), we often tend
✦ In assessing antiinflammatory risk, look beyond drug class. The active
to think of risk in terms of drug class rather than
agent, inactive ingredients, dosage, duration, and patient factors may
individual agent. Because their side effect profiles
all affect drug-related complications.
differ, there are some significant advantages to
✦ Corticosteroids differ significantly in their propensity to cause IOP
selecting antiinflammatory agents not by class but
elevation.
by individual drug.
CORE CONCEPTS
✦ Loteprednol etabonate, an ester steroid, is associated with fewer
CORTICOSTEROIDS AND INTRAOCULAR
PRESSURE
When using topical corticosteroids the risk
that typically comes first to mind is intraocular
pressure (IOP) elevation. This is particularly an
issue in treating patients with chronic conditions
such as iritis and ocular surface inflammatory
problems, including common conditions like dry
eye and blepharitis. These conditions often require
prolonged antiinflammatory treatment, making it
critical to balance the corticosteroid potency and
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IOP and cataract side effects than more potent steroids such as
dexamethasone, prednisolone, and difluprednate.
✦ Elevated IOP is thought to relate to excess unmetabolized drug that
impedes outflow through the trabecular meshwork.
✦ Corticosteroids should be avoided if active ocular herpes cannot be
ruled out.
✦ The risk of NSAID-related corneal surface problems increases in patients
with underlying corneal abnormalities but may occur in any patient.
✦ NSAID selection should be approached thoughtfully; generic
formulations may not be exact replicas of their branded counterparts.
Topics in OCULAR ANTIINFLAMMATORIES
5
The mechanism for pressure increase is thought to involve
an accumulation of corticosteroid within epithelial cells of the
trabecular meshwork and interference with their filtering capacity.1 One strategy for reducing risk is to switch patients who
require chronic inflammation suppression, such as post-graft
patients, from a maximally potent steroid like prednisolone
acetate or difluprednate to a corticosteroid with less tendency
to cause IOP elevation (eg, fluorometholone, rimexolone, or
loteprednol etabonate) as soon as it is safe to do so.2
PATIENT COMMUNICATION
Regardless of the indication, the specific corticosteroid
prescribed, or the intended duration, the need for clear patient
communication and education when prescribing topical ocular
corticosteroids cannot be overemphasized. This is particularly true for patients with chronic or potentially recurrent
conditions. A complete discussion includes not only when to
return for follow-up, but also why. Explaining corticosteroidassociated risks using the words “cataracts” and “glaucoma”
may help patients take the risks seriously.
SAFE PRESCRIBING OF CORTICOSTEROIDS
■ Use the lowest dose of corticosteroid for the shortest
period that will achieve the antiinflammatory aim.
■ Minimize risk by choosing a lower potency agent or
an ester steroid whenever possible for corticosteroid
treatment of longer than 2 weeks.
■ When prescribing both a corticosteroid and an NSAID (eg,
for cystoid macular edema prophylaxis following cataract
surgery), use the least toxic agents available.
■ Never prescribe a corticosteroid or corticosteroid/
antibiotic combination without a full ophthalmic
examination, including a documented examination of the
cornea by slit lamp.
■ Monitor patients on ocular corticosteroids closely for
increased IOP and for development of infection.
■ Tell patients the when, why, and who to see for follow up;
emphasize the need to return to the eyecare provider for a
full ocular exam should the condition recur.
■ Institute an appointment reminder/missed appointment
system to get patients on corticosteroids back for
follow-up.
Patients should also receive clear instruction to follow
up with an eyecare practitioner. In the case of topical corticosteroids, it is critical to follow up with a physician who
knows—and has the ability—to monitor IOP. Some years
ago, a patient I had treated for blepharoconjunctivitis with
combination tobramycin/dexamethasone presented more than
a year after her last visit with an IOP of 38 mmHg. She had
initially responded to treatment but failed to come back for
her follow-up appointment at 2 to 3 weeks. Over the ensuing
months, her condition recurred periodically, but instead of
6
Topics in OCULAR ANTIINFLAMMATORIES
returning to our office she went to her primary care physician,
who had simply refilled the original prescription without ever
checking the patient’s pressure.
Fortunately, the patient’s optic nerve was undamaged
and she responded to IOP-lowering treatment. But it was a
significant and alarming steroid response, and it illustrates
something about patients’ perception of doctors’ roles. Some
patients associate their eyecare provider with matters related
to vision (eg, for glasses or visual complaints like blurriness)
and think of their primary care physician as the person to call
regarding disease, even diseases of the eye. After an initial referral, these patients may disappear from your practice, going
back to the doctor they see as the person who treats “disease.”
Careful communication about risks and necessary follow up
may prevent such mishaps.
CATARACT RISK
Exposure to corticosteroids—including topical or intravitreal ocular corticosteroids and inhaled nasal or systemic
steroids—can contribute to the development of posterior
subcapsular cataracts. The mechanism is unclear but may
involve glucocorticoid-induced gene transcription in lens
epithelial cells and intralenticular glucocorticoid-protein adduct formation.3-5
In patients who develop cataracts in their 60s or 70s, it
may be difficult to tease out the contribution of corticosteroid
medication, since they may have had multiple risk factors—including their age and the intraocular inflammatory condition
for which they received corticosteroid treatment. Naturally,
though, it is important to limit corticosteroid exposure whenever possible to minimize cataract risk, especially in younger
patients who may not otherwise be at risk.
In addition to using the lowest dose and duration of
corticosteroid, an ester steroid (eg, loteprednol etabonate)
may reduce risk of cataractogenesis.6 While the reasons are
not fully understood, it is known that loteprednol is rapidly
transformed by naturally occurring esterases to inactive metabolites. In addition, the absence of a ketone at the C20 position in loteprednol etabonate prevents formation of adducts
with lens proteins, the reported first step in cataract formation
with ketone steroids.6
INFECTION
Broad suppression of inflammation by corticosteroids also
suppresses aspects of the body’s natural immune response to
bacteria and other pathogens, creating an opportunity for
infections that might be smoldering on the ocular surface to
effloresce. This was brought home to me by a patient I examined with a permanent corneal scar from a herpetic infection
that was exacerbated by treatment with a topical steroid. The
patient, a nurse, awoke on a Monday with a red eye, diagnosed
herself with pink eye, and, keen to have it resolved before her
wedding that weekend, asked a physician friend to give her
“something” for it.
The physician prescribed a topical antibiotic/steroid com-
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bination, and by Thursday the nurse was photophobic and experiencing blurred vision. Examination by an ophthalmologist
on Friday revealed a large herpetic corneal dendrite. A taper
of the steroid was started along with antiviral treatment. The
patient spent her rehearsal dinner, wedding, and honeymoon
wearing dark sunglasses and was very uncomfortable. She
was left with a permanent corneal scar, ongoing symptoms
of glare, and a small drop in vision to 20/25 from 20/20. The
lesson is simple: Corticosteroids should not be prescribed
without a full eye exam.
TOPICAL NSAIDS
Topical ophthalmic NSAIDs are prescribed for their
antiinflammatory effect mediated by blocking prostaglandin
synthesis, thereby avoiding steroid-associated side effects.
However, NSAIDs have their own risks, ranging from minor
corneal surface irritation and punctate keratopathy—which
is common with generic NSAID formulations—to frank corneal melting, which is rare (Figure 1). Although the number
of significant corneal events has decreased since the removal
of generic diclofenac from the market, care that the corneal
surface is not compromised through use of topical NSAIDs
remains important.7
of corneal nerves. It is well known that diminished ocular
surface sensation—whether due to diabetes, herpetic infection,
or surgical trauma—can cause the corneal epithelium to break
down, presumably due to loss of the feedback mechanism that
signals damage to the ocular surface (and the need for repair).
Blocking the corneal “sensing” mechanism with NSAIDs
could, in theory, have a similar effect. Indeed, the vast preponderance of patients who suffered serious adverse corneal
effects from NSAIDs had significant ocular surface problems
prior to NSAID use.9
SAFE PRESCRIBING OF NSAIDS
■ Be cautious when prescribing generic NSAIDs; educate
patients about the possibility of corneal side effects.
■ When prescribing both a steroid and an NSAID (eg, for
CME prophylaxis), use the least toxic agents that provide
appropriate efficacy.
■ Use of NSAIDs requires more frequent examination of
patients with corneal anesthesia at baseline; these include
patients with dry eye, recurrent ocular surface herpetic
disease, diabetes, or multiple ocular surgeries.
■ Educate patients regarding the early signs of corneal side
effects. Tell them to call if they have increased burning
following application of the drug. See these patients and
stop the NSAID if exam reveals any corneal epithelial
pathology.
The one subgroup without prior corneal compromise
consisted of patients treated with a particular generic formulation of diclofenac that was later removed from the market.9
Current commonly prescribed NSAID options available in the
US include diclofenac, branded and generic ketorolac, branded
and generic bromfenac, and branded nepafenac.8
GENERIC NSAIDS
FIGURE 1 Punctate keratopathy associated with topical NSAID use.
(Image courtesy of John R. Wittpenn, MD.)
Topical NSAIDs represent a chemically heterogeneous
group of molecules. As a class, they are useful for perisurgical
antiinflammatory prophylaxis, because they suppress prostaglandin production, which reduces vascular permeability
and the risk for cystoid macular edema (CME). NSAIDs can
be started a few days prior to surgery for maximal efficacy. In
addition, NSAIDs augment analgesia and maintain pupillary
dilation during surgery.8
NSAID RISKS
The mechanism of NSAID corneal toxicity is not entirely
clear. Research in the 1990s, when severe events were first
starting to be reported, showed that diclofenac and ketorolac
caused not only analgesia but anesthesia via a direct blockade
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All available NSAIDs have the potential to create a punctate
keratopathy.7 But the rate at which they do it varies greatly. One
widely prescribed ocular NSAID, generic ketorolac, is concerning for several reasons. One is that the active agent (ketorolac)
was associated with high rates of punctate keratopathy, even in
its original branded form. Furthermore, generic agents pose
a higher risk for idiopathic adverse effects since the complete
formulation does not have to be scrutinized in clinical trials
in the same way that branded agents have been. Unpublished
data shows that up to 30% of healthy cataract surgery patients
treated with generic ketorolac develop symptomatic punctate
keratopathy by 3 to 4 weeks.
Although, in my view, branded agents are safer because
they have been more rigorously tested, any NSAID—including
the branded formulations—may contribute to corneal damage.
The jury is out regarding which among the branded NSAIDs is
safest. Bromfenac was recently reformulated with a pH closer
to that of the tear film, which enhances corneal penetration
Topics in OCULAR ANTIINFLAMMATORIES
7
and should allow for greater effect with lower concentration
of drug; this could serve to improve safety even over older
bromfenac formulations.
Nepafenac has also recently been reformulated and is the
first prodrug NSAID.7 Nepafenac has been associated with
toxicity when dropped on bare stroma in conjunction with
PRK.10,11 Also, in order to reduce the dosing frequency to once
per day, the latest formulation of nepafenac uses a higher concentration of active ingredient and a formulation that increases
the contact time of active molecule against the ocular surface.
The effect of these features on corneal safety is not yet known.
With any NSAID, it is good practice to limit use to 14 days
for patients with baseline corneal abnormalities, including
dry eye.
OTHER NSAID CONCERNS
All NSAIDs, including topical NSAIDs, carry a warning
that they can potentiate bleeding on their label. This, however,
is a far more serious concern with systemic agents than topical,
and rarely is it an issue with ocular NSAIDs.
Patients with sulfite allergy should avoid branded bromfenac, which contains a sulfite.12 Sulfites are present in certain
food products such as wines and cured meats; allergy to sulfites
is rare but can be severe. Sulfite allergy is not to be confused
with sulfate allergy, which is much more common. Patients
with sulfate allergy react to sulfa drugs such as sulfamethoxazole but not to NSAIDs.
CONCLUSION
Safety profiles of antiinflammatory agents depend on the
drug class, the individual molecule, and the inactive ingredients in the formulation. Safety may vary between branded
and generic versions. Efforts to minimize risk have resulted in
improved drugs in both corticosteroid and NSAID categories.
Attention to potential side effects and good staff and patient
8
Topics in OCULAR ANTIINFLAMMATORIES
communication are essential to all clinical efforts to control
ocular inflammation.
John R. Wittpenn, MD, is a partner in Ophthalmic Consultants of Long Island
and a clinical associate professor of ophthalmology at the State University of
New York at Stony Brook. He is a consultant for and a member of the speaker’s
bureau for Bausch + Lomb. Medical writer Noelle Lake, MD, assisted in the
preparation of this article.
REFERENCES
1. Jones R 3rd, Rhee DJ. Corticosteroid-induced ocular hypertension and
glaucoma: a brief review and update of the literature. Curr Opin Ophthalmol.
2006;17:163-7.
2. Bhattacherjee P, Paterson CA, Spellman JM, et al. Pharmacological validation
of a feline model of steroid-induced ocular hypertension. Arch Ophthalmol.
1999 Mar;117(3):361-4.
3. James ER. The etiology of steroid cataract. J Ocul Pharmacol Ther.
2007;23:403-20.
4. Amon M, Busin M. Loteprednol etabonate ophthalmic suspension 0.5 %:
efficacy and safety for postoperative anti-inflammatory use. Int Ophthalmol.
2012;32:507-17.
5. Manabe S, Bucala R, Cerami A. Nonenzymatic addition of glucocorticoids
to lens proteins in steroid-induced cataracts. J Clin Invest. 1984 November;74(5):1803-10.
6. Comstock DL, DeCory HH. Advances in corticosteroid therapy for ocular
inflammation: loteprednol etabonate. Int J Inflam. 2012;2012:789623.
doi:10.1155/2012/789623.
7. Gaynes BI, Onyekwuluje A. Topcal ophthalmic NSAIDs: a discussion with
focus on nepafenac ophthalmic suspension. Clin Ophthalmol. 2008;2:355-68.
8. Cho H, Wolf KJ, Wolf EJ. Management of ocular inflammation and pain
following cataract surgery: focus on Bromfenac ophthalmic solution. Clin
Ophthalmol. 2009;3:199-201.
9. Congdon NG, Schein OD, Kulajta PV, et al. Corneal complications associated with topical ophthalmic use of nonsteroidal antiinflammatory drugs. J
Cataract Refract Surg. 2001;27:622-31.
10. Feiz V, Oberg TJ, Kurz CJ, et al. Nepafenac-associated bilateral corneal melt
after photorefractive keratectomy. Cornea. 2009;28:948-50.
11. Trattler W, McDonald M. Double-masked comparison of ketorolac tromethamine 0.4% versus nepafenac sodium 0.1% for postoperative healing rates and
pain control in eyes undergoing surface ablation. Cornea. 2007;26:665-9.
12. Prolensa® (bromfenac ophthalmic solution) 0.07% product information.
Tampa, FL: Bausch and Lomb; 2013.
To obtain CME credit for this activity, go to http://cme.ufl.edu/toai
EXAMINATION QUESTIONS
TOPICS IN OCULAR ANTIINFLAMMATORIES | ISSUE 3
This CME program is sponsored by the University of Florida College of Medicine and supported by an unrestricted educational grant from Bausch + Lomb, Inc.
Directions: Select the one best answer to each question in the exam (Questions 1–10) and in the evaluation (Questions 11–16) below by circling one letter for each
answer. Participants must score at least 80% on the questions and complete the entire Evaluation section on the form below. The University of Florida College of
Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. There is no fee to participate in this activity. You can take the test
online at http://cme.ufl.edu/toai.
1. Difluprednate is distinguished by the
presence of:
A. Two chlorine atoms at the C-6 and
C-9 positions
B. A ketone group at the C-20
position
C. Two fluorine atoms at the C-6 and
C-9 positions
D. None of the above
2. Which of the following topical
corticosteroids is associated with both
high potency and high risk for classic
steroid side effects?
A. Rimexolone
B. Fluorometholone
C. Difluprednate
D. Loteprednol etabonate
3. Which of the following is true about
generic formulations of prednisolone
acetate 1%?
A. Drug particle sizes may be more
variable than in branded drug
B. Mucoadhesive vehicle may clog
dropper tips
C. They contain a lower
concentration of benzalkonium
chloride
D. They contain propylene glycol
EXAMINATION ANSWER SHEET
1. A B C D
6. A B C D
2. A B C D
7. A B C D
3. A B C D
8. A B C D
4. A B C D
9. A B C D
5. A B C D
10. A B C D
5. Which of the following is an NSAID
prodrug?
A. Nepafenac
B. Bromfenac
C. Ketorolac
D. Diclofenac
6. Which of the following has
been shown to correlate with a
predisposition to a stronger steroid
IOP response?
A. Darkly colored irides
B. Age > 80
C. Anterior chamber depth > 3 mm
D. Axial length > 28 mm
7. NSAID use has been most frequently
associated with:
A. Cataract formation
B. Punctate keratopathy
C. IOP elevation
D. Iris color change
8. Which of the following should be
discussed when prescribing an
antiinflammatory agent?
A. Potential side effects and their
early signs
B. Where and when to follow up
C. Which physician to see if the
condition returns
D. All of the above
9. Ocular corticosteroids should not be
prescribed without:
A. A baseline IOP measurement
B. Careful corneal examination to
rule out preexisting infection
C. Examination of the peripheral
retina
D. Both A and B are correct
10. SEGRAs:
A. Are being studied for adjunctive
use alongside steroids
B. Have steroid-like activity but are
not suitable for topical application
C. May have antiinflammatory
potency similar to steroids with
fewer side effects
D. Both A and C are true
TOPICS IN OCULAR ANTIINFLAMMATORIES | ISSUE 3
This CME activity is jointly sponsored by the University
of Florida and Candeo Clinical/Science Communications,
LLC, and supported by an unrestricted educational grant
from Bausch + Lomb, Inc. Mail to: University of Florida
CME Office, PO Box 100233, Gainesville, FL 32610-0233.
DIRECTIONS: Select the one best answer for each question in the exam above (Questions 1–10). Participants
must score at least 80% on the questions and complete
the entire Evaluation (Questions 11–16) to receive CME
credit. CME exam expires September 30, 2014.
ANSWERS:
4. FDA approval of a generic steroid
formulation requires demonstration
of:
A. Noninferior clinical efficacy
B. Bioequivalence
C. Noninferior clinical safety
D. All of the above
EVALUATION:
1=Poor 2=Fair 3=Satisfactory 4=Good 5=Outstanding
PLEASE PRINT CLEARLY
11. Extent to which the activity met the identified
Objective 1: 1 2 3 4 5
Objective 2: 1 2 3 4 5
12. Rate the overall effectiveness of how the activity:
Related to my practice:
1 2 3 4
Will influence how I practice:
1 2 3 4
Will help me improve patient care: 1 2 3 4
Stimulated my intellectual curiosity: 1 2 3 4
Overall quality of material:
1 2 3 4
Overall met my expectations:
1 2 3 4
Avoided commercial bias/influence: 1 2 3 4
5
5
5
5
5
5
5
13. Will the information presented cause you to make any
changes in your practice?
Yes No
14. If yes, please describe: __________________________
________________________________________________
15. How committed are you to making these changes?
1 2 3 4 5
16. Are future activities on this topic important to you?
Yes No
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If you wish to receive credit for this activity, please fill in the
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