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OPHTHALMIC
DRUGS
20th
h Anniversary
Edition
Sincerely,
A PEER-REVIEWED
Disclosure: Drs. Melton and Thomas are consultants to, but have no financial
SUPPLEMENT
interests in, the following companies: Bausch + Lomb/Valeant and Icare.
Note: The authors present unapproved and off-label uses of specific drugs in this guide.
ALLERGY TREATMENT:
QUELLING THE ITCH
D
octor, my eyes just
Though the itch and burn all
the time, the pa-
condition may tient says. How
many hundreds of
be the most times have we heard this lament?
harmless one However, this common complaint
brings us front and center to the prover-
we see, our bial fork in the road. The first question is
basic. Ask the patient, So, think about
ocular allergy this: Is the burning or the itching your
main symptom? Most patients can give
patients are a clear answer to this fundamental ques-
among our tion.
For the few patients who feel the symp-
most grateful. toms of burning and itching are about
equal, or who cant decide which symp-
tom is most bothersome, treatment with A woman experiencing a severe ocular
a topical corticosteroid will usually quell allergic reaction.
both complaints. Dont forget our time-
honored advice in these cases: When in
doubt, use a steroid. SYMPTOMS ONLY
If itching is the predominant symptom, If there are minimal associated signs of
our approach to drug selection takes one allergysuch as chemosis, conjunctival
of the following two routes. injection and/or eyelid edemaan anti-
histamine/mast cell stabilizer is an Olopatadine (Patanol/Pataday/ has been available generically and
excellent clinical approach. Within Pazeo, Alcon) over the counter. There are several
this class, there are six drugs from Notwithstanding fine differences, brand name OTC ketotifen prep-
which to choose: all the antihistamine subtype 1 re- arations, such as Alaway (Bausch
Alcaftadine (Lastacaft, Allergan) ceptor blockers nicely suppress ocu- + Lomb), among others. All come
Azelastine (Optivar, Meda Phar- lar itching. Most are dosed initially in 5ml bottles except for Alaway,
maceuticals; generic available) BID (except Pataday, Pazeo and which comes in a 10ml bottle. In-
Bepotastine (Bepreve, Bausch + Lastacaft, which are dosed once dai- terestingly, our casual observations
Lomb) ly). After two weeks at BID, ask the in a variety of pharmacies reveal
Epinastine (Elestat, Allergan; patient to try to reduce the drop to that the cost of the 10ml Alaway is
generic available) once-daily maintenance therapy. In very near (and occasionally cheaper
Ketotifen (Zaditor, Novartis; our experience, once symptomatic than) the price of its 5ml competi-
many generics available. This itching has been brought under con- tors. Thus, OTC Alaway is the most
drop is OTC.) trol, it takes less pharmacological cost-effective way to suppress ocular
intervention to itch.
maintain. How- When a prescription medication
ever, some pa- is preferred, perhaps a 10ml bottle
tients may have of Bepreve (using a standard copay)
to continue BID would be of greatest value to the pa-
therapy. tient, especially with insurance cov-
Perhaps the erage or coupons.
best news for
the consumer is SYMPTOMS PLUS SIGNS
the loss of patent The other route of allergy presen-
protection for tation is represented by the patient
Zaditor. Since who presents with predominant
2007, ketotifen itching along with one or more
Aminoglycosides
Tobrex tobramycin 0.3% Alcon, and generic sol./oint. > 2 mos. 5ml/3.5g
Garamycin gentamicin 0.3% Perrigo, and generic sol./oint. N/A 5ml/3.5g
Polymyxin B Combinations
Polytrim polymyxin B/trimethoprim Allergan, and generic solution > 2 mos. 10ml
Polysporin polymyxin B/bacitracin generic ointment N/A 3.5g
Neosporin polymyxin B/neomycin/ generic solution N/A 10ml
gramicidin
polymyxin B/neomycin/ generic ointment N/A 3.5g
bacitracin
Other Antibiotics
AzaSite azithromycin 1% Akorn solution > 1 yr. 2.5ml
Ilotycin erythromycin 0.5% Perrigo, and generic ointment > 2 mos. 3.5g
Bacitracin bacitracin 500u/g Perrigo ointment N/A 3.5g
CONQUERING BLEPHARITIS
Chronic anterior eyelid margin disease is most commonly caused by chronic, low-grade infection of Staphylococcus aureus
and Staphylococcus epidermidis bacteria. These bacteria produce exotoxins, creating secondary inflammation to the adja-
cent eyelid marginal tissues. (This is distinct from meibomian gland disease, which has a wholly different pathophysiology.)
Occasionally, these exotoxins can cause inferior corneal epithelial compromise.
Understanding the cascade of tissue compromise resulting from unchecked Staph. populations residing on the ante-
rior eyelid tissues perfectly provides the rationale for using a good antibiotic/corticosteroid combination drug as the
treatment of choice for symptomatic blepharitis. No other drug or drug class even approximates the efficacy of such
therapeutic intervention.
Any of the available combination drugs would work well short term (less than two weeks), but given that blepharitis is
a chronic, recurrent disease, the drug we find best suited for treating blepharitis is a combination of tobramycin (excellent
anti-Staph. action) with loteprednol (excellent, safe, anti-inflammatory action) known by the popular brand name Zylet.
Initiate treatment with Zylet four times daily for two weeks, depending upon the severity of the clinical disease, then just
pulse dose four times a day for a week if or when breakthrough symptoms occur. Such pulse dosing is an effective and
steroid-sparing therapeutic approach and one that we embrace for almost any chronic, recurrent ocular surface disease.
The combination drugs TobraDex and Maxitrol are both generic and relatively inexpensive, but contain dexamethasone,
which limits their usefulness beyond a couple of weeks. One would rarely ever employ dexamethasone for a chronic
condition because of its propensity to increase intraocular pressure. All three of these drugs are suspensions and, as such,
need to be shaken well.
However, blepharitis is not treated exclusively with any eye drop. Concurrent
use of eyelid scrubs is an essential component to not only help control the
infectious/inflammatory disease, but as ongoing hygiene to maintain eyelid
health. Avenova (hypochlorous acid 0.01%, NovaBay Pharmaceuticals) eyelid
and eyelash cleanser has become quite popular, and does seem to help main-
tain healthy tissues in our patients. Further, with diminution of Staph. popula-
tions, there is a decreased risk of secondary styes and internal hordeola.
In summary, the combined use of an effective, safe antibiotic/steroid and
meticulous eyelid hygiene perfectly embodies rational care for patients with
anterior eyelid margin disease.
clinical practice, we have seen only reason they are rarely, if ever, used eye that one would treat with a combi-
half a dozen such events, mostly with systemically. Any drug actively or pas- nation drug almost invariably requires
neomycin exposure of greater than a sively reserved for only topical use is treatment for no more than a week.
week, and often prescribed by prima- relatively protected from resistance, These medicines are highly effective,
ry care practitioners. thus enabling it to be a powerful che- cheap, and they remain workhorse
When neomycin is packaged (along motherapeutic agent for many decades. drugs in contemporary eye care.
with polymyxin B) with a steroid, For example, bacitracin was brought Last, we stress that bacterial infec-
such as generic Maxitrol, whatever to market in the 1940s and remains a tions are characterized by a mucopuru-
expression of a hypersensitivity reac- superb, exclusively gram-positive anti- lent discharge. Sometimes this is gross-
tion that may be occurring typically biotic into the 21st century. ly visible; other times, the discharge is
remains subthreshold, or subdued, In summary, neomycin remains an more subtle and is only found via slit
courtesy of the concurrent corticoste- excellent antibiotic in combination lamp observation of microparticulate
roid suppression. with other antibiotics, such as Neospo- debris in the lacrimal lake.
The aminoglycosides, used systemi- rin and/or dexamethasone, and when Both the aqueous humor and lac-
cally, can cause ototoxicity. For this used for about a week. The acute red rimal lake should be optically empty.
FROM THE
LITERATURE hence some blanks are present. Also, we did not list meth-
icillin-sensitive Staphylococcus species because a clinician
NEW BENCHMARKS ON does not know the nature (i.e., methicillin sensitive vs.
methicillin resistant) of the causative pathogen at clinical
ANTIBIOTIC RESISTANCE
presentation, so we need to treat based on a most difficult
The five-year Antibiotic Resistance Monitoring in Ocular
to kill approach. If we treat a presumed Staphylococcus
Microorganisms (ARMOR) study data was recently pub-
infection, and in reality it is methicillin sensitive, it will be
lished in JAMA Ophthalmology (December 2015). This
quickly eradicated if we are assuming (and treating for)
is reportedly the most robust evaluation of nationwide
methicillin-resistant species.
antibacterial susceptibility of common ocular pathogens
Interestingly, MRSA organisms are more common
to date. Thankfully, resistance rates have remained stable
among the elderly and those who reside in the southern
over the past five years of this study.
portions of the United States. Note that the drug of choice
About half of Staphylococcus species are methicillin
for culture-proven Pseudomonas is ciprofloxacin, although
resistant, meaning they are more difficult to kill than the
the fluoroquinolones and tobramycin performed quite well.
methicillin-sensitive bacterial pathogens. Minimal inhibi-
A summary statement says: Until rapid diagnostic meth-
tory concentration90 (MIC90) represents how effective a
ods are available to guide treatment choices, clinicians
drug is at eradicating a bacterial speciesi.e., the lowest
should consider these data to guide the empirical treat-
concentration of a drug that will inhibit 90% of bacterial
ment of ocular infections.
isolates. To interpret these results: the lower the MIC90, the
more effective the drug. Focusing on the most commonly Asbell PA, Sanfilippo CM, Pillar CM, et al. Antibiotic Resistance Among
Ocular Pathogens in the United States: Five-Year Results From the
prescribed drugs, the findings are as follows: Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR)
Some drugs were not tested against all pathogens, Surveillance Study. JAMA Ophthalmol. 2015 Dec;133(12):1445-54.
Note that besifloxacin and vancomycin share superb MIC90 levels, which would portend high clinical efficiacy.
ALL ABOUT
DRY EYE
D
onald Korb, OD, and Caro-
We hope line Blackie, OD, PhD, and
their research team, along
that some with other researchers around
intervention the world, have now shown
that the root of all evil in dry eye disease
will soon be is dysfunction of the meibomian glands.1
Said differently, if we can find ways to
found to help embellish and restore normal meibomian
gland function, most dry eye disease likely
the masses would resolve or not occur at all. This patients lid, imaged with meibography
technology, displays severe meibomian gland
who suffer Following along this foundational
dysfunction.
pathophysiologic pathway, it makes sense
from dry eye. that a dysfunction of the lipid layer needs
to be secondarily addressed. With this cas- ease is comparable. Obviously, the earlier
For now, cade of deterioration of the precorneal tear we can intervene in these pathophysiologi-
film, hyperosmolarity occurs because of cal processes, the better. Different thera-
several rational increased evaporation, which then causes pies are employed at these different stages.
approaches, ocular surface inflammation. Such inflam- Until meibography comes into wide-
mation has been consistently characterized spread clinical use, which will allow us to
properly as the epicenter of the pathogenesis of clin- stratify proper interventions, we will con-
ically symptomatic dry eye disease. tinue to encounter patients at secondary
applied, can Lets try a complex analogous compari- and tertiary levels of dry eye expression.
help most son of meibomian gland disease (MGD) Interventions could include: inclusion of
to vascular disease: Many factors, such dietary omega-3 essential fatty acids, such
patients. as diet, lifestyle and genetics, determine as fish oils or flaxseed oil; use of lipid-
ones risk for hypercholesterolemia. Such based artificial tears to augment the de-
pathological blood chemistry leads to ath- ficient lipid layer; and/or a short course
eromatous plaquing of the intimal lining of a topical ester-based corticosteroid to
of arteries. If subsequent cholesterol levels address the inflammatory component. A
are not stabilized, the risk of arterial oc- clear target for intervening at the earliest
clusion occurs, which can result in a heart stages of meibomian gland compromise
attack or stroke. has yet to be fully elucidated, but it is ob-
The cascade of evaporative dry eye dis- vious that supporting meibomian gland
* Loteprednol (Lotemax) therapy for inflammation due to dry eye disease is consid-
ered an off-label use. All mentions of such use herein reflects the views of the authors.
function early on is the key to ulti- symptoms with which patients pres-
mate prevention of dry eye disease. ent. Interventions such as LipiFlow
Aggressive use of warm compresses and intense pulsed light can be intro-
combined with physical expression of duced earlier in the pathway to hope-
the meibomian glands can go a long fully obviate the need for downstream
way in enhancing proper function. interventions.
While these maneuvers are indeed We think that as meibography be-
helpful, wouldnt it be grand if there comes a standard diagnostic tool in
were some sort of side effect-free pill the office, and as technology becomes
we could give patients to prevent more refined and affordable, meibo-
MGD and to maintain a youthful, vi- mian gland disease can be detected
brant precorneal tear film? earlier, and preventive or enhance-
The current reality is that patients ment techniques can be employed to
present to us with the downstream massively decrease the clinical presen- A reduced lacrimal lake and meibomian
symptoms of dry, gritty, burning tation of symptomatic dry eye. gland dysfunction, as is seen in this
eyes. So, at least for the time being, patient, suggests a poor tear film lipid
we are left having to intervene at these CASCADE OF EVENTS layer.
more advanced levels of disease. This IN DRY EYE DISEASE
is why we commonly use lipid-based We know that dessicatory stress initi-
artificial tears and pulse-dosing of ates the cascade of events leading to mented with fish oil and/or punctal
loteprednol used off-label, along with dry eye disease. Clinically, therapeu- plugs.
punctal plugs to address these dry eye tic intervention is relatively straight- Although treatment is compara-
symptoms. forward: Suppress the ocular surface tively basic, the biochemical mecha-
We are hopeful that potential FDA inflammation and augment the pre- nism is complexbut here is a simpli-
approval of a new drug for dry eye corneal tear film (especially the lipid fied version:
disease, lifitegrast, will be helpful layer) with lipid-based artificial tears. Intracellular adhesion molecules
in the amelioration of the signs and This latter portion can be further aug- (ICAM) are found on the surface of
epithelial cells, and they are over- cells as the ligand to antigen, setting try, then this inflammatory process
expressed in the face of dessica- in motion degranulation, release of and its treatment makes perfect sense.
tory stress. T-lymphocytes abound histamines and the start to the allergic
throughout the body, and their acti- cascade. PROPER DIAGNOSIS
vation results in inflammation. When Topical steroids potently inhibit AND TREATMENT
T-lymphocyte cells are activated, they this process and subdue the inflam- The genesis of most cases of dry eye
release pro-inflammatory cytokines. mation. NSAIDs and Restasis (cyclo- disease lies in the meibomian glands.
These cytokines lead to the develop- sporine 0.05%, Allergan) also inhibit Perhaps it is our diets and lifestyles
ment of tissue inflammation. On the this process, but in a more attenuated that set the stage for altered meibum
surface of T-lymphocytes are recep- manner.3-4 This is why we initiate function; the pathophysiology has not
tors called lymphocyte functional as- anti-inflammatory therapy with the been fully elucidated.
sociated antigen (LFA). ICAM binds most efficacious suppressor of inflam- Not all meibomian gland disease
(ligands) to the LFA, thus activating mation: a topical corticosteroid. As is immediately evident. We can test
the T-cell lymphocytes, setting the in- per our algorithm, we use Lotemax* for non-obvious meibomian gland
flammatory cascade in motion. QID for two weeks, then BID for disease by pressing on the meibomian
Investigational data shows that li- two more weeks. Should lifitegrast glands to qualify and quantify their
fitegrast blocks recruitment and acti- gain FDA approval, we plan to try secretions. This is a diagnostic maneu-
vation of T-lymphocytes to the ocular using this agent concurrently at the ver that needs to be a routine part of
surface by binding to LFA on the sur- time we reduce Lotemax to BID. The the comprehensive eye examination.
face of T-lymphocytes and preventing drugs Phase III OPUS-1 trial showed Performing meibography could/
LFA from interacting with ICAM on improvement in corneal and conjunc- should be entertained as well. Just
the surface of the corneal epithelial tival staining associated with ocular as OCT has revolutionized posterior
cells and on other immune cells resid- inflammation.5 pole evaluation, so will meibography
ing in the ocular surface tissue.2 When you understand the basic for MGD. Unfortunately, just as with
Think of IgE receptors on mast biochemistry and medicinal chemis- asymptomatic glaucoma, it is difficult
THIS DEVICE IS A REAL TEAR-JERKER 180 days.2 Specific neurological pathways are crucial to
It is well said that necessity is the mother of invention, maintenance of a healthy ocular surface. Delivery of low
and herein we share just how true this is. levels of intranasal neuronal stimulation activates these
Most chronic conditions present a management chal- pathways, which stimulates tear production.
lenge. Dry eye is a perfect example. The precorneal tear film has three
Photo: Allergan
Certainly, we have essential fatty acids sub-layers, and it is yet to be fully deter-
to help meibomian gland disease.1 We mined if there is an effect on mucin
have good quality lipid-based artifi- and/or lipid layers in addition to aque-
cial tears and good anti-inflammatory ous layer enhancement. A 2016 ARVO
medicines. While these can be helpful abstract, however, does show con-
to many patients, there is always a junctival goblet cell degranulation and
need for other beneficial interventions. increased mucin level after ILN.3
Enter a new idea currently in clinical We foresee a definite, but not yet
trials called intranasal lacrimal neuro- quantified, role for this device, but we
stimulation (ILN). A battery-powered will not know the exact stage of disease
device generates a low-grade electri- or optimum frequency of application
cal current that stimulates lacrimation until widespread clinical application. We
when applied to the interior aspect are excited to see the potential of intra-
of the nosenot copious tearing, nasal lacrimal neurostimulation for dry
but rather more of a physiological eye treatment.
enhancement of natural tear produc- Trials are ongoing. Hopefully, we will
tion. This genius concept seems to have more to write on this device next
truly help many patients suffering from year, pending FDA approval.
dry eye disease.
Allergan acquired this technology from the original 1. Malhotra C, Singh S, Chakma P, et al. Effect of oral omega-3 Fatty Acid supplemen-
tation on contrast sensitivity in patients with moderate meibomian gland dysfunc-
research and development company Oculeve, and plans to tion: a prospective placebo-controlled study. Cornea. 2015 Jun;34(6):637-43.
commercialize such a device in the event of FDA approval. 2. Chayet A. Evaluation of the effect of intranasal lacrimal neurostimulation on tear
production in subjects with dry eye: nonrandomized open-label study. ASCRS 2016
In one study, this handheld instrument, self-administered paper session 3-A.
by patients four times a day, showed increased tear pro- 3. Gumus K, Schuetzle K, Loudin JD, Pflugfelder SC. Randomized, controlled,
crossover trial comparing the impact of sham or intranasal neurostimulation on
duction and reduced corneal/conjunctival staining out to conjunctival goblet cell degranulation ARVO 2016 abstract 2864.
to get patient cooperation in the treat- not wholly practical at this time. integrity of the epithelial tissue, and
ment of asymptomatic dry eye disease. Regarding diagnosis of dry eye measure the tear film breakup time.
Success in getting patients to consis- disease, the approach we use is pro- As part of our diagnostic protocol
tently use warm soaks, eyelid massage foundly simple: for dry eye disease, these three steps
(including LipiFlow, etc.) and fish oil 1. First, take a history of the pa- offer us the information needed to
supplementation at these pre-symp- tients symptoms make the diagnosis and provide su-
tomatic stages of dry eye/meibomian 2. Next, assess the height and vol- perb patient care.
gland disease is a challenge. The real- ume of the lacrimal lake When patients do present with
ity is, early intervention in meibomian 3. Stain the cornea with fluorescein symptomatic dry eye disease, we have
gland disease may be ideal, but it is or lissamine green dye to assess the quite a few options for resolution.
FROM THE
LITERATURE genesis, various anti-inflammatory agents were used to
treat this syndrome. In particular, there is a type I level of
SUPPRESS INFLAMMATION evidence on corticosteroids efficacy. Among these, 0.5%
loteprednol etabonate was effective in reducing signs and
TO TREAT DED
symptoms of dry eye Modulating the expression of proin-
Dry eye is a complex, multifactorial condition of the ocular
flammatory and proapoptotic molecules may have a thera-
surface whose pathogenesis can be attributed to two dif-
peutic potential for the treatment of the corneal epithelial
ferent mechanisms, namely reduced tear production and
disease that develops in dry eye.
increased tear evaporation, both inducing increased tear
osmolarity and inflammation, according to a recent study in Aragona P, Aguennouz M, Rania L, et al. Matrix metalloproteinase 9 and transgluta-
Ophthalmology: minase 2 expression at the ocular surface in patients with different forms of dry eye
disease. Ophthalmology. 2015 Jan; 122(1):62-71.
Given the importance of inflammation in dry eye patho-
Because almost all dry eye disease is ment is achieved. The omega-3 essen- um-quality fish oil. It is our opinion
expressed as a result of meibomian tial fatty acids found in fish (or flax- that a pharmacist should know more
gland disease, evidence exists that seed) oil enhance meibomian gland about the nuances of fish oil than
there is a lipid-deficient dry eye state; function, and this therapy is likely most clinicians.
so we should, at the very least, start enhanced with warm soaks. For patients with a history of dif-
the patient on a lipid-based artificial We guide the patient to consult ficulty swallowing large capsules, rec-
tear, such as Soothe XP (Bausch + with a pharmacist regarding a premi- ommend either Coromega Omega-3
Lomb) or Systane Balance (Alcon).
For those rare patients we encoun- FROM THE
LITERATURE
ter who need a preservative-free tear,
Retaine MGD (OcuSoft) or Refresh
Optive Advanced Preservative Free EFFICACY OF LOTEMAX GEL
(Allergan) are excellent. Gel formula- FOR EVAPORATIVE DED & MGD
tions, such as Systane Gel (Alcon) or In some big news for treatment of patients with evaporative dry eye (EDE)
GenTeal Gel (Novartis) can be used disease and meibomian gland dysfunction (MGD), a study presented at a
at bedtime if needed, which is not all poster session at the annual American Academy of Optometry meeting in
that often. October 2015 on the efficacy of off-label use of loteprednol etabonate oph-
If there is concurrent blepharitis, thalmic gel 0.5% for treating evaporative DED and MGD found:
warm soaks followed by meticulous When used twice a day, loteprednol etabonate ophthalmic gel
eyelid hygiene can be quite helpful. 0.5% significantly improved the clinical signs associated with EDE
Hypochlorous acid in solution is an resulting from MGD.
efficient antimicrobial agent, report- Loteprednol etabonate ophthalmic gel 0.5% showed significant
ed to have a >99.99% kill for many reduction in severity of symptoms associated with EDE resulting
pathogens.6,7 Anecdotally, it appears from MGD.
Results indicate that loteprednol etabonate gel is a safe and
the newer hypochlorus acid scrubs
effective treatment option for EDE and MGD.
(e.g., NovaBay, Ocusoft, etc.) work
In this open-label, prospective, multi-centered study, patients
well. The main drawback to these is
with meibomian gland dysfunction were treated bilaterally with
the necessity for the patient to pur-
loteprenol gel 0.5% twice a day for 30 days. After treatment, all
chase cotton pads at the pharmacy objective parameters evaluated showed a statistically significant improve-
on which to spray the hypochlorus ment, except for Schirmer II and tear osmolarity. Results also showed a sig-
acid solution prior to performing lid nificant reduction of patient symptoms as measured by the OSDI and SPEED.
scrubs. IOP and visual acuity were unchanged, and no adverse events took place.
We start almost all of our patients
on 2,000mg of fish oil daily, telling Opitz, DL, Evola C, Paradesi A, et al. (2015, October). Efficacy of loteprednol etabonate ophthalmic gel 0.5%
for the treatment of evaporative dry eye and meibomian gland dysfunction. Poster presented at the meeting
them that it may be four to six months of the American Academy of Optometry, New Orleans, LA.
before the full benefit of the supple-
FROM THE
LITERATURE as a public health problem, the long-term course of
the disease is not yet well characterized.
LONG-TERM PERSPECTIVE One of the most consistent correlates of worsening
ON DRY EYE DISEASE was a record of past severe symptoms. This finding
A study following about 700 patients over a decade of is in line with the idea that patients who present with
dry eye care suggests that DED is not necessarily pro- more severe symptoms early in the course of their
gressive over the long-term, and most men and women disease are the ones who are most likely to experi-
report no change or some level of improvement. ence a worsening, usually despite therapy.
Clinical tests in dry eye disease tend to have We fervently hope that some sort of intervention
poor reproducibility, and symptoms and signs will soon be discovered or invented to help the masses
may fluctuate. Newer technologies such as in vivo who suffer with DED. In the meantime, there are rational
confocal microscopy and tear osmolarity also have approaches as outlined in this drug guide, that when
limitations. properly applied, can be of significant help to many.
Even with therapy, dry eye disease tends to persist, Lienert JP, Tarko L, Uchino M, et al. Long-term natural history of dry eye disease
but despite data supporting the importance of DED from the patients perspective. Ophthalmology. 2016 Feb;123(2):425-33.
CLINICAL UPDATE
ON THE NSAIDs
T
While oral he field of nonsteroidal anti- PHARMACOLOGY OF NSAIDS
inflammatory drugs has many Lets first understand the pharmacology
nonsteroidals players. Older drugs have been of NSAIDs. First of all, they dont directly
reformulated and new drugs reduce inflammation. Rather, they inhibit
are heavily have come to market. The an enzyme along the synthetic pathway to
newest editions, Prolensa (bromfenac so- the production of prostaglandins, which
used in dium 0.07%, Bausch + Lomb) and Ilevro are powerful mediators of inflammation.
systemic (nepafenac 0.3%, Alcon), are the super- As doctors, it is vital that we have knowl-
stars of this class and need to be used only edge of this particular pathwaythe ara-
medicine, once daily. This should be a blessing to chidonic acid cascade.
post-op cataract patients by reducing the As you can see in the diagram (The
topical intensity of their eye drop regimen. Arachidonic Acid Pathway, page 21),
ophthalmic While oral NSAIDs are heavily used the origin substrate for inflammatory
in systemic medicine, topical ophthalmic mediators is phospholipids released from
NSAIDs have NSAID use within nonsurgical eye care cell membranes as a generic response to
is relatively limited. The foundational multiple causes of cellular microtrauma.
limited use in perspective on this class of drugs is the Corticosteroids inhibit the conversion of
acknowledgement that steroids reign su- these phospholipids to arachidonic acid
nonsurgical preme in inflammation control; topical (AA) by inhibiting the catalytic enzyme
eye care. NSAIDs are never an appropriate substi- phospholipase A2 early in this synthetic
tute when the clinical condition merits a cascade.
topical corticosteroid. Once AA is formed, two different en-
NSAID use has much more applicabil- zymes convert it to either prostaglandin or
ity in perioperative care than in primary leukotriene. Cyclooxygenase converts AA
eye care; however, several clinical circum- to prostaglandins, and lipoxygenase con-
stances merit use of such a drug in order verts AA to leukotrienes. The key point
to enhance patient care. here is that while NSAIDs inhibit the en-
NONSTEROIDAL ANTI-INFLAMMATORIES
BRAND NAME GENERIC NAME MANUFACTURER DOSAGE PEDIATRIC USE BOTTLE SIZE(S)
Acular LS ketorolac tromethamine 0.4% Allergan, and generic QID 3 years 5ml
Acuvail bromfenac 0.075% Allergan BID N/A unit-dose
Bromsite bromfenac 0.075% Sun Pharma N/A N/A 5ml
Ilevro nepafenac 0.3% Alcon QD 10 years 1.7ml
Nevanac nepafenac 0.1% Alcon TID 10 years 3ml
Prolensa bromfenac 0.07% Bausch + Lomb QD N/A 1.6ml, 3ml
Voltaren diclofenac sodium 0.1% Novartis, and generic QID N/A 2.5ml, 5ml
Trauma
Membrane Phospholipids
Phospholipase A2 Inhibited by
corticosteroids
Arachidonic Acid
Inhibited by
Cyclo-oxygenase Lipoxygenase
NSAIDs
Endoperoxides Hydroperoxides
zymatic activity of cyclooxygenase, oxygenase and lipoxygenase, thus in- frequency). However, this synergy is
they have no effect on lipoxygenase, hibiting production of prostaglandins difficult to reconcile based on the dy-
thereby allowing the production of and leukotrienes. namics of the AA cascade previously
leukotrienes to go unchecked. The AA pathway is more eas- discussed. Perhaps the rapidity of
For clinical perspective, remember ily grasped by studying the diagram, onset and/or the degree of enzymatic
the early days of photorefractive kera- which illustrates the processes we inhibition may be considerations for
tectomy where NSAIDs were initially have just described. Once you have a explanation.
used postoperatively? Patients experi- clear understanding of the AA path- Contrarily, we find no literature
enced problems with white blood cell way, then you can prescribe with supporting the use of both drug
(leukocytic) corneal infiltrates until it enhanced clinical authority and pre- groups in the standard initial treat-
was realized that steroids prevented cision. ment of anterior uveitis. A great deal
their formation. Why? Because leu- Steroids and NSAIDs are thought remains to be understood in how
kotrienes are chemotactic for leuko- to demonstrate some synergy, and these drug classes modify tissue re-
cytes, for which NSAIDs do noth- therefore, might be beneficial used sponses.
ingthey only inhibit the synthesis concurrently. For example, standard-
of prostaglandins and have no activ- of-care treatment of postoperative ROLE OF TOPICAL NSAIDS
ity against lipoxygenase-catalyzed cystoid macular edema is usually Compared to topical corticosteroids,
production of leukotrienes. Because treated with a potent corticosteroid, NSAIDs play a limited role in prima-
steroids work higher up in the AA such as Durezol, and a topical NSAID ry eye care. Nonetheless, several situ-
synthetic pathway, they inhibit cyclo- (dosed at its FDA-approved dosing ations demonstrate where NSAIDs
FROM THE
LITERATURE NSAIDs significantly reduced the odds of developing cys-
toid macular edema, as compared to topical corticosteroids.
UPDATE ON NSAIDs FOR CME Approximately 0% to 6% of non-diabetic subjects
Cystoid macular edema, known academically as Irvine-Gass develop visual complaints and suffer from clinically signifi-
syndrome, is the most common cause of post-cataract sur- cant macular edema. In contrast, incidence rates of clini-
gery visual impairment. Are topical NSAIDs of clinically sig- cally significant macular edema are up to 56% in diabetic
nificant value in managing the small subset of postoperative patients with mild to moderate nonproliferative diabetic
patients who develop cystoid macular edema? retinopathy and no cystoid macular edema preoperatively.
A seminal work addressing this issue appeared in Results of this meta-analysis show that topical NSAIDs
Ophthalmology (November 2015).1 Below are excerpts: significantly reduced the odds of developing CME, as com-
Because many cases of CME are mild and resolve spon- pared to topical corticosteroids in non-diabetic and mixed
taneously, it remains unknown whether prophylactic NSAID populations. Furthermore, a combination of topical NSAIDs
treatment improves long-term visual outcomes. It also and corticosteroids significantly reduced the odds of devel-
remains unclear whether prophylactic treatment prevents oping cystoid macular edema in non-diabetic and diabetic
the onset of chronic CME (present >six months after sur- patients, as compared to topical corticosteroids in a single
gery) or in some way decreases its severity. drug treatment. Based on an indirect treatment comparison,
In conclusion, there is a lack of level I evidence that sup- no difference could be found between topical combination
ports the long-term visual benefit of NSAID therapy when treatment and topical NSAIDs in non-diabetic patients.
applied solely or in combination with corticosteroid therapy As can be seen from these articles, there is no defini-
to prevent vision loss resulting from CME after cataract tive consensus yet on the best therapeutic intervention to
surgery. The implication that the combined effect of NSAID diminish or prevent cystoid macular edema. We anticipate
and corticosteroid exceeds the additive effect of these that use of NSAIDs and steroids in contemporary cataract
drugs is not supported by the literature. Dosing of NSAIDs care will continue unabated for the foreseeable future.
before surgery seems to hasten visual recovery after cata- 1. Kim SJ, Schoenberger SD, Thorne JE, et al. Topical nonsteroidal
ract surgery, but does not affect long-term visual outcomes. anti-inflammatory drugs and cataract surgery. Ophthalmology. 2015
Nov;122(11):2159-68.
Another article, from the American Journal of
2. Wielders LHP, Lambermont VA, Schouten J, et al. Prevention of cys-
Ophthalmology (November 2015), gave these observations:2 toid macular edema after cataract surgery in nondiabetic and diabetic
In non-diabetic patients, it was found that topical patients: A systematic review and meta-analysis. Am J Ophthalmol. 2015
Nov;160(5):968-981.
can be beneficial. (See Consider an what in effect. Systemic NSAIDs are their fort in ocular surface pain ame-
NSAID For..., page 23.) true to their name and do indeed ren- lioration and provide only limited ac-
However, be aware that topical der a significant anti-inflammatory tivity against inflammation.
and systemic NSAIDs differ some- effect, whereas topical NSAIDs have Diclofenac (Voltaren 0.1%, No-
vartis) and ketorolac (Acular LS
NEW NSAID APPROVED WITH 0.4%, Allergan) have historically
CATARACT SURGERY INDICATION been the standard bearers of topical
In early April 2016, the FDA approved BromSite (bromfenac 0.075% oph- NSAID care. Both are used QID and
thalmic solution, Sun Pharma), the first NSAID with the specific indication for are largely clinical equivalents. One
preventing ocular pain in patients undergoing cataract surgery. Like other study that compared ketorolac and
NSAIDs, its also indicated for treating postoperative inflammation. diclofenac head to head concluded:
BromSite achieves its low 0.075% concentration due to its DuraSite deliv- The decrease in corneal sensitivity
ery vehicle (developed by InSite Vision), which is believed to extend the in normal human corneas is more
drugs residence time on the ocular surface. (Sun Pharma acquired InSite pronounced and longer lasting with
Vision in November 2015.) diclofenac than with ketorolac.1
In two Phase III clinical trials, a greater number of patients treated with A modification of ketorolac is the
BromSite were pain-free at one day post-op (77% and 82%) compared development of a 0.45% concentra-
with those given only the vehicle (48% and 62%). Also, more patients given tion: Acuvail (Allergan) comes as a
BromSite were free of inflammation at 15 days post-cataract surgery com- preservative-free unit-dose indicated
pared with patients given only the vehicle. Sun Pharma expects BromSite to for perioperative use BID one day
come to market in the second half of 2016. prior to cataract surgery, and is con-
tinued for two weeks postoperatively.
InSite Vision Announces FDA Acceptance of NDA Filing for BromSite (0.075% bromfenac). Avail-
able at: www.businesswire.com/news/home/20150817006205/en/InSite-Vision-Announces-FDA- The original formulation of oph-
Acceptance-NDA-Filing (last accessed April 25, 2016).
thalmic ketorolac (Acular) was a 0.5%
FROM THE
LITERATURE reported that concurrent administration of NSAIDs and corti-
costeroids results in additive effects.
ESSENTIAL LITERATURE ON NSAIDs At present, there is no evidence to suggest one topical
If you want the ultimate review of NSAIDs, we urge NSAID treatment is better than another in controlling post-
you to read Nonsteroidal Anti-inflammatory Drugs in operative inflammation.
Ophthalmology, by Stephen J. Kim, MD, Allan J. Flach, MD, CME remains the most common cause of vision loss
and Lee M. Jampol, MD, in Survey of Ophthalmology, March- after cataract surgery. Despite its significance, the patho-
April 2010. It is excellent. Some quotes (or in-context para- genesis of this syndrome, and its relationship to and its
phrases) from this article, and our commentary (indicated in associations with CME in other diseases, is not completely
purple), follow: understood.
NSAIDs do not inhibit lipoxygenase (LPO) and thus do Systemic NSAIDs provide insufficient drug levels to
not typically prevent generation of leukotrienes. This may inhibit prostaglandin production in the anterior segment,
explain, in part, their decreased anti-inflammatory effects especially when compared to topical administration.
compared to corticosteroids, which inhibit both LPO and The true incidence of CME following cataract surgery
COX (cyclooxygenase). However, celicoxib (Celebrex) and is not precisely known. Despite this continued uncertainty,
diclofenac (Voltaren) are notable exceptions and inhibit recent studies have reported incidences following small-inci-
LPO by direct and indirect means, respectively. In addition, sion cataract surgery as high as 9% to 19% using fluorescein
NSAIDs appear to have anti-inflammatory and anti-angio- angiography, and 41% as measured by OCT.
genic effects independent of their inhibition of COX. Several It has long been recognized that the natural history of
reports suggest that ketorolac is the most potent inhibitor of CME usually includes spontaneous resolution.
COX-1, while both bromfenac and amfenac have staked the Although there is no FDA-approved treatment for the
claim as being the most potent inhibitors of COX-2. prevention or treatment of CME following cataract surgery,
The clinical importance of selective COX-1 and COX-2 an extensive review of the world literature concluded that
inhibition for ocular disease remains to be established. prevention and treatment of CME with NSAIDs is beneficial
The prostaglandins produced via COX-1 are physiologic in Available evidence suggests that topical NSAIDs may pre-
their action, whereas the prostaglandins produced from the vent and treat CME when used alone or concurrently with
upregulation of COX-2 result in pathologic expression of pain corticosteroids.
and inflammation. This is another example of where the scientific litera-
There is good evidence that topical NSAIDs may be ture trumps FDA guidelines. Off-label use of medicines is
used in place of, or in addition to, topical corticosteroids becoming more and more commonplace, so dont let other
after cataract surgery to avoid excessive inflammation considerations override sound, rational and prudent use of a
and to improve visual acuity. Although none of the studies helpful drug.
reviewed by the FDA used topical NSAIDs more than 24 Although no other topical NSAID has been approved
hours before cataract surgery, well-designed studies sug- for allergic conjunctivitis besides ketorolac, there are studies
gest potential benefit from preoperative dosing regimens of suggesting that 0.1% diclofenac and 0.09% bromfenac may
up to three days. Furthermore, several clinical studies have also be effective.
as hourly for a few days, we recom- inducible enzyme, which is primarily appears to be less likely to cause such
mend that NSAID use not exceed the activated during inflammatory tissue untoward events. All three of these
FDA-approved dosing frequency. assaults. As a result, COX-2 inhibitors drugs were FDA-approved around the
created great excitement when they year 2000.
NOTES ON ORAL NSAIDs came to market years ago because they We rarely prescribe oral NSAIDs,
Cyclooxygenase (COX) is the enzyme were purported to address inflamma- but do occasionally use Celebrex
by which arachidonic acid is metabo- tion while sparing the physiological 100mg or 200mg BID to help our
lized into prostaglandins. Two sub- prostaglandins, specifically sparing the patients in whom we have difficulty
species of cyclooxygenase are: COX- GI tract from NSAID toxicity. tapering off oral prednisone when
1 and COX-2. Unfortunately, a couple of these treating orbital pseudotumor, stub-
COX-1 is a constitutive enzyme that products, Vioxx (rofecoxib) and Bex- born uveitis or scleritis. For example,
synthesizes prostaglandins, which reg- tra (valdecoxib), were thought to sig- if the anterior uveitis tends to rebound
ulate physiological functions such as nificantly increase the risk of heart when the oral prednisone is tapered
in the GI tract, kidneys, platelets and attack and stroke, and were removed below 20mg per day, we have been
vascular endothelium. from the market.2 Celebrex (celecoxib) successful using Celebrex along with
COX-2, on the other hand, is an is now used more conservatively, but prednisolone 20mg for a week, then
10mg for a week or two, while con- (cimetadine) similarly protects the primary eye care. Their main use is in
currently using Celebrex for four to gastrointestinal tissues. the prevention or treatment of cata-
six weeks to facilitate the discontinu- With most oral NSAIDs, clinicians ract surgery-related cystoid macular
ation of the oral prednisone. Aggres- should pay heed to the black box edema concurrent with a potent cor-
sive use of Durezol and therapeutic warning of cardiovascular risk. The ticosteroid. Topical formulations
cycloplegia is foundational to these FDA is strengthening its existing are far more commonly used in
oral supplementary therapies. warning in prescription drug labels eye care than orals, but the latter
Risk of peptic ulcer disease is in- and OTC drug facts labels to indicate do play an important role in taper-
creased when using both oral pred- that oral NSAIDs can increase the ing patients off oral steroid therapy
nisone and an oral NSAID (including chance of a heart attack or stroke. when needed.
Celebrex), so we would likely also As well, oral NSAIDs can produce
1. Seitz B, Sorken K, LaBree LD, et al. Corneal sen-
prescribe a proton pump inhibitor, hypoglycemia in type 2 diabetics by sitivity and burning sensation: comparing topical
ketorolac and diclofenac. Arch Ophthalmol. 1996
such as OTC Prilosec or Prevacid drug interaction and can decrease re- Aug;114(8):921-4.
20mg once daily when we are using nal function in susceptible patients. 2. US FDA website. FDA Strengthens Warning of
Heart Attack and Stroke Risk for Non-Steroidal
such dual therapy. A histamine H2 In summary, NSAIDs have several Anti-Inflammatory Drugs. 2015 July 21. Available at:
www.fda.gov/ForConsumers/ConsumerUpdates/
receptor blocker such as Tagamet off-label uses within the context of ucm453610.htm (accessed April 7, 2016).
FROM THE
LITERATURE recent clinical trial was not only to assess the clinical effi-
cacy of a three-week fluorometholone 0.1% therapy in DED
TOPICAL STEROIDS TREAT patients, but more importantly, to determine if this therapy
DRY EYE DISEASE could ameliorate the expected worsening of the ocular
In our 2015 Drug Guide, we reported on a study showing surface after exposure to a desiccating stress set in a con-
the benefit of topical loteprednol (used off label) in caring trolled environmental laboratory.
for patients with dry eye disease (DED). Another study, Patients randomly received one drop four times daily of
published in Ophthalmology (January 2016), found, unsur- either topical 0.1% fluorometholone (FML group) or topical
prisingly, a similar effect using fluorometholone 0.1%.1 The polyvinyl alcohol (PA group) for 22 days Liquifilm Tears
following are excerpts from this randomized clinical trial: was selected as the control treatment because it is the
An important factor contributing to the increased vehicle used in fluorometholone.
prevalence of DED, and certainly making it a worse prob- No adverse events or treatment-related adverse reac-
lem, is the growing proportion of the population exposed tions were observed throughout the study In particular,
to so-called adverse environments or desiccating stress there were no significant changes in IOP and no signs of
conditions. We are currently staying longer within artificially corneal epithelial healing-related problems or secondary
created environments, such as office buildings, shopping infections as potential side effects from steroid use.
malls, air-conditioned vehicles and even households. These The FML group, at the end of the study, experienced
environments are characterized by low humidity, high significant improvement in high- and low-contrast best-
temperatures and draftinessall conditions that cause tear corrected visual acuity. In contrast, the control group expe-
film alterations that usually worsen DED. For many DED rienced no change.
patients, these conditions are unbearable. In addition, the This clinical trial evaluated the efficacy of topical fluoro-
number of users of visual display terminals (including tablets metholone 0.1% in preventing the exacerbation of DED signs
and smart phones) and the amount and symptoms that patients expe-
of time spent using them also have rience when exposed to adverse
increased dramatically. These infor- environmental desiccating stress
mation technology devices reduce ... Findings confirm the efficacy of
blink rate, causing tear film evapora- topical corticosteroids as a short-
tion that can worsen DED signs and term (4 weeks) DED treatment, as
symptoms further. previously shown by other research
Even at low severity level two, groups.
anti-inflammatory therapy is indi- Corticosteroids are among the
cated, including topical steroids that most effective agents used to treat
have been shown to be effective in noninfectious inflammatory diseases,
several studies and clinical trials ... Note the scant tear lake in this patient. especially those mediated by the
Consequently, the main goal of the immune system. They reduce cel-
in the setting of advanced iritis and (Flarex and Alcon). The acetate moiety comfortable using it long-term as we
episcleritis, as discussed above. gives the fluorometholone molecules are with the ester-based loteprednol.
some additional anti-inflammatory ef- FML Forte (fluorometholone 0.25%,
MODERATE EFFICACY fectiveness over the alcohol moiety.7 Allergan) is not recommended because
CORTICOSTEROIDS Fluorometholone is available ge- fluorometholone 0.1% represents the
Moderate efficacy steroids in common nerically and is thus reasonably inex- top of the dose response curvemean-
use are fluorometholone 0.1% suspen- pensive. (However, there have been ing that the 0.25% formulation is no
sion and Alrex (loteprednol 0.2%, sporadic reports of fluorometholone more efficacious than the 0.1%. More-
Bausch + Lomb) suspension, both of being temporarily unavailable in vari- over, the 0.25% concentration has a
which must be shaken prior to instil- ous parts of the country. When pre- greater tendency to raise IOP.8
lation. scribing, be sure to check with your Alrex. For allergic eye disease, pre-
Fluorometholone 0.1%. There are pharmacy for availability.) While fluo- scribe a steroid when itching is accom-
two derivatives of fluorometholone rometholone has less tendency to in- panied by clinical signs of conjunctival
0.1% suspensionthe alcohol (FML, crease intraocular pressure than other injection, chemosis or eyelid swell-
Allergan and generic) and the acetate ketone steroids, we are not nearly as ing. In these instances, Alrex (or even
Lotemax gel) is our answer. We typi- Lotemax ointment. The only FML ointment. FML ophthalmic
cally dose Alrex (or Lotemax gel) QID ester-based steroid ointment avail- ointment (fluorometholone 0.1%,
for one week, then BID for one month. able is Lotemax ophthalmic ointment Allergan) is used much the same as
Beyond awareness of the various de- (loteprednol 0.5%, Bausch + Lomb). It Lotemax ointment. It is indicated for
livery systems (suspensions, solutions, is indicated for postoperative inflam- inflammation of the palpebral and bul-
emulsions, gels and ointments), know- mation and pain, but also has many bar conjunctiva, cornea and anterior
ing the clinical efficacy of these drugs off-label clinical uses: dry eye, al- segment of the globe, and any of the
is important. lergy, corneal transplant protection, off-label uses mentioned above. The
blepharitis, giant papillary conjuncti- only very minor difference is to keep a
STEROID OINTMENTS vitis, chronic uveitis, stromal immune little bit closer watch on the patient for
The ophthalmic ointments enjoy a herpetic keratitis, Thygesons SPK, steroid-related adverse effects since it is
wide array of clinical indications. RCE, augmentation of steroid eye a ketone steroid.
Three corticosteroid medicines that drop therapy in acute advanced uveitis Triamcinolone 0.1% cream. This
merit frequent clinical use in the oint- or episcleritis, contact dermatitis and is a dermatologic preparation that
ment formulation include: other inflammatory conditions. works well for periocular dermati-
1. Foster CS, Davanzo R, Flynn TE, et al. Durezol Sheppard JD, Comstock TL, Cavet ME. Impact of the topical ophthalmic corticosteroid loteprednol
(Difluprednate Ophthalmic Emulsion 0.05%) com- etabonate on intraocular pressure. Adv Ther. 2016; Mar 17. [Epub ahead of print].
pared with Pred Forte 1% ophthalmic suspension
in the treatment of endogenous anterior uveitis. J
Ocul Pharmacol Ther. 2010 Oct;26(5):475-83.
2. Slabaugh MA, Herlihy E, Ongchin S, van Gelder
RN. Efficacy and potential complications of diflu-
prednate use for pediatric uveitis. Am J Ophthal-
STEROIDS FOR DRY EYE DISEASE mol. 2012 May;153(5):932-8.
3. Leibowitz HM, Ryan WJ Jr, Kupferman A. Com-
EFFECTIVE AND SAFE LONG-TERM TREATMENT parative anti-inflammatory efficacy of topical cor-
ticosteroids with low glaucoma-inducing potential.
Topical administration of methylprednisolone 1% ophthalmic solution for Arch Ophthalmol. 1992 Jan;110(1):118-20.
several weeks provides moderate to complete relief of DES symptoms and 4. Roberts CW, Nelson PL. Comparative analysis of
reduces corneal fluorescein staining in patients with SS-related DES, sug- prednisolone acetate suspensions. J Ocul Pharma-
col Ther. 2007 Apr;23(2):182-7.
gests research. Pulse treatment with methylprednisolone for two weeks fol- 5. US Food and Drug Administration. Center for
lowed by a taper led to improvement in symptoms starting at two weeks, Drug Evaluation and Research. Deputy Division
Director Review for NDA 202-872. 2012 Sep 27.
followed by improved TBUT and Schirmer test scores by the end of taper. Available at: www.accessdata.fda. gov/drugsatf-
After the first pulse treatment, mean drug-free remission time was 56.6 da_docs/nda/2012/202872Orig1s000MedR.pdf.
6. Lane SS, Holland EJ. Loteprednol etabonate
weeks; after the second, it increased to 72.4 weeks. No serious complica- 0.5% versus prednisolone acetate 1.0% for the
tions, including IOP elevation and cataract formation, occurred during the treatment of inflammation after cataract surgery. J
Cataract Refract Surg. 2013 Feb;39(2):168-73.
entire follow-up period. 7. Leibowitz HM, Hyndiuk RA, Lindsey C, Rosenthal
Again, short-term use of topical corticosteroids (used off-label) should AL. Fluorometholone acetate: clinical evaluation in
the treatment of external ocular inflammation. Ann
be standard-of-care in most symptomatic dry eye patients. Ophthalmol. 1984 Dec;16(12):1110-5.
8. Kass M, Cheetham J, Duzman E, Burke PJ. The
Hong S, Kim T, Chung S-H, et al. Recurrence after topical nonpreserved methylprednisolone thera- ocular hypertensive effect of 0.25% fluorometho-
py for keratoconjunctivitis sicca in Sjgrens syndrome. J Ocul Pharmacol Ther. 2007;23(1):78-82. lone in corticosteroid responders. Am J Ophthal-
mol. 1986 Aug 15;102(2):159-63.
KID GLOVES:
PEARLS FOR PEDIATRIC EYE CARE
By Kathleen Foster Elliott, OD
N
Learn ew doors are opening every
day for general optometric
some of the practitioners to increase their
knowledge and skill set in pro-
foundational viding pediatric comprehen-
sive care. This article explores ophthalmic
and alternative indications for pediatric treatment, along
pharmacologic with strategies, dosages and side effects.
For non-complicated corneal abrasion,
strategies erythromycin ophthalmic ointment is
frequently used in pediatric ophthalmol-
for treating ogy and optometry clinics. Gentle on the
Drop instillation is challenging in pediatric
cornea, easily accessible, affordable and
your pediatric boasting a 50-year track record of broad- patients; ophthalmic gel administered at a
lower frequency dose can aid in administration
patientsan spectrum, gram-positive and chlamydial
in some cases.
coverage, the macrolide comes in 0.5%
increasingly ointment and is safe for all ages down to
newborn. It is also used in neonates for pro- rigation. We educate the parent to lavage
important phylaxis against gonococcal ophthalmia several times a day before instillation of the
segment of neonatorum. It is essential to cycloplege the medication. Additionally, check for pseu-
patient and recommend acetaminophen or domembranes on the initial slit lamp exam
your patient ibuprofen for discomfort. and remove any with a surgical sponge, wet
For pediatric bacterial conjunctivitis, cotton swab, blunt forceps or Alger brush.
population. the most commonly prescribed medication Corneal ulcers need fast, viable ther-
is Polytrim (polymyxin B sulfate and trime- apy. Besivance (besifloxacin, Bausch +
thoprim ophthalmic solution, Allergan; and Lomb) is a newer fluoroquinolone, avail-
generic), active against a variety of aerobic able in 0.6% ophthalmic suspension, that is
gram-positive and gram-negative ophthal- highly effective against MRSE and MRSA,
mic pathogens. Safety and effectiveness in according to the ARMOR study (although
children below the age of two months have topical vancomycin is rapidly becoming the
not been established.1 Instill one drop in drug of choice to target MRSA).2,3
the affected eye every three hours (up to six This potent, dual-halogenated chloroflu-
doses per day) for seven to 10 days.1 A rea- oroquinolone is also highly effective against
sonable response time is three to five days. Pseudomonas aeruginosa.4 Children are at
For mucopurulent conjunctivitis, a increased risk for this invasive microbe if
preservative-free rinsing solution is rec- they have corneal hypoxia, are immuno-
ommended. We use Unisol because the compromised or are diagnosed with diabe-
design of the bottle lends itself to easy ir- tes. Pediatric microbial keratitis treatment
should be coupled with a cycloplegic look for the Hutchison signpresence acyclovir users with pediatricians so
agent, such as cyclopentolate 1% BID of a vesicle on the tip of the nosesig- proper blood tests and drug interac-
or homatrapine 5% QD. nifying greater risk of corneal involve- tions can be monitored.
Besifloxacin is safe for use in infants ment secondary to herpes zoster. Shin- Preseptal cellulitis is a common pe-
to toddlers one year of age. Dosage gles occasionally manifests in pediatric diatric condition that requires an oral
is three times a day, four to 12 hours patients. Treatment options for prima- agent. It is common clinical procedure
apart for seven days. Around 2% of ry ocular herpes infection include: to rely on the patients pediatrician
treated patients will have adverse re- Oral acyclovir (Zovirax, Glaxo or a pharmacist in determining oral
actions (e.g., conjunctival redness, SmithKline) 200mg capsules or antibiotics dosage for children. Close
blurred vision, eye pain, eye irritation, 200mg/5ml (teaspoon) suspension monitoring is crucial to avoid orbital
eye pruritus and headache).4 No sys- Ganciclovir ophthalmic gel cellulitis, which requires hospitaliza-
temic side effects have been reported 0.15% (Zirgan, Bausch + Lomb): five tion with IV antibiotics. Periorbital
with besifloxacin on weight-bearing times daily cellulitis usually is caused by Staphylo-
joints, although systemic administra- Trifluridine 1% ophthalmic solu- coccus aureus, Streptococcus pyogenes
tion of some quinolones has been tion (Viroptic, Pfizer): seven to nine or Streptococcus pneumoniae. Hae-
shown to cause arthropathy in imma- times daily mophilus influenzae B is becoming a
ture animals, according to the Adverse Vidarabine 3% ophthalmic oint- rare cause because of the prevalence of
Event Reporting System study.5 ment: five times daily (must be com- H. influenzae vaccinations.11
Treatment of pediatric microbial pounded by an ophthalmic specialty Common antibiotic treatments for
keratitis involves an initial applica- pharmacy) preseptal cellulitis in pediatrics include
tion of antimicrobial agents followed Oral dosing guidelines for acyclovir Augmentin (amoxicillin clavulanate,
by anti-inflammatory agents. Pediatric are as follows: In patients over two GlaxoSmithKline) or clindamycin.
cases are rare but devastating if not years old, 20mg/kg every eight hours Augmentin has good broad-spectrum
treated properly or quickly. for five to seven days, not to exceed 1g and gram-negative coverage against
For herpes simplex with skin or PO every eight hours. For older teens Haemophilus influenza. In patients less
ocular involvement, oral antiviral ther- of adult size, the adult dose of 400mg than 90 pounds, dosage is 35mg/kg per
apy with acyclovir is highly effective five times daily for 10 days can be ad- day to 40mg/kg per day with three di-
more effective than ophthalmic antivi- ministered. vided doses every eight hours for 10
ral agents in treating herpetic corneal With pediatrics, putting anything days. If the patient weighs more than
keratitis.6 Oral acyclovir reaches ther- in the eye can be challenging; there- 90 pounds, dose is 250mg to 500mg
apeutic levels in aqueous and tears, fore, an ophthalmic gel five times daily every eight hours, or 875mg every 12
virtually eliminating the need for con- makes more sense than drops needed hours, for seven to 10 days. Maximum
current use of topical antivirals. It is seven to nine times a day. Compared dosage should not exceed 2g per day.
highly effective for treatment and pro- with the standard treatment of triflu- Clindamycin is a broad-spectrum
phylaxis of herpes simplex epithelial ridine, ganciclovir is equally effective alternative to the penicillin-allergic
keratitis, and immune stromal keratitis but less toxic.8 Ganciclovir ophthal- patient. Adverse effects may include
in conjunction with Lotemax, and for mic gel has low corneal toxicity and nausea and vomiting, diarrhea and ab-
prevention of recurrent infectious epi- less frequent applications. Trifluridine dominal pain. (Bactrim is also a good
thelial keratitis. solution and vidarabine ointment are choice for patients allergic to penicil-
Ocular manifestations of herpes also effective in treating HSV kera- lin, although it does not cover Group
simplex virus or herpes zoster virus titis; however, epithelial toxicity is a A Streptococcusa likely etiology
typically occur later in life, but dis- frequent adverse effect, especially with of preseptal cellulitis in pediatric pa-
ease in pediatric patients is often sys- prolonged use.9 tients.) Clindamycin dosing is as fol-
temic and accompanied by more ocu- The Herpetic Eye Disease Study lows: 30mg/kg per day to 40mg/kg per
lar inflammation and amblyopia risk; Group (HEDS) demonstrated in pa- day divided TID or QID for 10 days.
quick and effective therapeutic dosing tients 12 years or older that long-term Bactrim dosage is 8mg per day to 12
is imperative.7 Adding a cycloplegic suppressive oral acyclovir therapy at mg per day divided BID for 10 days.
agent such as cyclopentolate 1% BID 400mg BID reduces risk of recurrent If the patient is less than one year old,
will help heal and debride the corneal HSV epithelial (9% vs. 14%) and stro- parenteral antibiotics and/or hospital-
epithelium affected by a dendrite. A mal (14% vs. 28%) keratitis.10 So, for ization is recommended. For patients
moistened surgical sponge, cotton patients at risk of developing herpetic allergic to penicillin, the broad mac-
swab or Alger brush can help debride eye disease, long-term antiviral therapy rolides azithromycin (10mg/kg per
necrotic tissue. is a common approach. In our clinic, day for three days) and clarithromycin
When evaluating for zoster disease, we typically comanage these long-term (7.5mg/kg BID) are safe and effective.
Prostaglandin Analogs
Bimatoprost bimatoprost generic 0.03% 2.5ml, 5ml, 7.5ml
Lumigan bimatoprost Allergan 0.01% 2.5ml, 5ml, 7.5ml
Travatan Z travoprost Alcon 0.004% 2.5ml, 5ml
Travoprost travoprost generic 0.004% 2.5ml, 5ml
Xalatan latanoprost Pfizer, + generic 0.005% 2.5ml
Zioptan tafluprost Akorn 0.0015% unit-dose
Alpha Agonists
Alphagan P brimonidine Allergan 0.1%, 0.15% 5ml, 10ml, 15ml
Brimonidine brimonidine generic 0.15%, 0.2% 5ml, 10ml, 15ml
ral and/or superotemporal rim tissues. high-risk glaucoma suspect or who sure, which can exacerbate glaucoma-
This is because of relatively sparse has the disease, we strongly urge them tous progression.1 We find ourselves
glial support tissues in these regions. to recommend to their siblings that more and more often writing letters
The ISNT rule (inferior > superior > they seek an optometric glaucoma to primary care physicians explain-
nasal > temporal) speaks to this ana- evaluation in the area where they live. ing this relatively new knowledge and
tomic reality, in that in a normal optic Such screening has been shown to asking them to consider having pa-
nerve head the inferior tissues are usu- have a quite high yield, and to posi- tients take blood pressure medicines
ally the thickest, followed by slightly tively impact public health. in the morning time. Once the PCPs
less thick superior rim tissues, then Check blood pressure in-office. have this scientific explanation, good
slightly less thick nasal rim, with the Carefully assess the patients systemic cooperation is generally the rule.
temporal rim being the thinnest. This conditions, especially treatment for Along this same line, many pa-
is not a bulletproof concept, but it is a systemic hypertension. It has been tients with asthma can use a topical
good general guide. found, particularly in low-tension beta blocker very successfully. How-
Talk about family history. Be- glaucoma patients, that when blood ever, we never prescribe a topical beta
cause glaucoma tends to run in fami- pressure medicines are taken in the blocker for such patients without first
lies, we always ask about siblings. evening or at bedtime, they can patho- writing to the primary care physi-
When we have a patient who is a logically lower nocturnal blood pres- cian for clearance, and having a let-
ter (i.e., written documentation) from hydroxychloroquine.) Sending a copy explain progression of glaucoma,
that doctor to place in our medical of the EMR is an extremely poor sub- despite achievement of target intra-
records attesting to such. We have, stitute for a brief letter. ocular pressure. The small, forearm
with proper consultative advice, used The optometric measurement of (radial) devices for measuring blood
topical beta blockers for a handful of systemic blood pressure can accom- pressure are inexpensive, simple to
patients with asthma without inci- plish two key goals: screening for the use by ancillary personnel and can be
dent and successfully obtained target epidemic of uncontrolled (or under- of enormous value to human health
intraocular pressure. (As an aside, controlled) systemic hypertension, and to glaucoma assessment.
we also find ourselves communicat- and fine-tuning our understanding Analyze retinal nerve fiber layer,
ing more often with rheumatologists, of low-tension glaucoma, as many if available. Additional assessment
since many of these specialists have a of these patients have blood pres- with retinal nerve fiber layer analysis
proclivity to overdose patients taking sure that is too low, which can often can be extremely helpful in under-
FROM THE
LITERATURE Our findings indicate that aging in healthy control
subjects leads to a significant reduction of neuroreti-
AGING ALONE CAN EXACERBATE nal parameters and may explain a large proportion
of the deterioration observed in patients with treated
PROGRESSION IN GLAUCOMA
glaucoma. Furthermore, both cross-sectional and
PATIENTS
longitudinal studies of healthy subjects show pat-
It stands to reason that natural quantitative loss of optic
terns of regional loss similar to those in patients with
nerve fibers over time can contribute to glaucomatous
glaucoma, suggesting that age-related regional sus-
optic neuropathy. An article in Ophthalmology (December
ceptibility may be accelerated in glaucoma. Because
2015) gives important insights into the impact of natural
several previous longitudinal studies of structural
aging on visual field compromise in the setting of glau-
progression of glaucoma lacked a control population,
coma progression, per these excerpts:
the observed changes were attributed to glaucoma,
Age-related loss of neuroretinal parameters may
perhaps overestimating the rate of change in treated
explain a large proportion of the deterioration
glaucoma. Therefore, without an understanding of
observed in treated patients with glaucoma and
the significant normal age-related changes, there
should be carefully considered in estimating rates of
could be errors in rate estimates and the diagnostic
changes.
accuracy of glaucoma-related progression.
Because there is accumulating evidence that aging
Thankfully, there are many other metrics and param-
in otherwise healthy subjects also results in statisti-
eters to guide us in clinical decision making than just the
cally significant change, often with patterns resem-
visual fields. However, this article does serve to make us
bling those in glaucoma, the clinical assessment of
more analytical in changes in the visual fields. Remember,
glaucomatous progression can be challenging.
in order to establish true progression, we would have to
The effect of IOP variability on ONH parameters is
do three or four fields about every six to 12 months. This is
probably related to changes in laminar position and
why it is so challenging and minimally productive to micro-
prelaminar tissue compression.
manage the visual field component of the comprehensive
Because mean deviation (MD) is age adjusted, it is
glaucoma assessment.
likely that the absence of normal aging effects with
this parameter allows better estimates of glaucoma- Vianna JR, Danthurebandara VM, Sharpe GP, et. al. Importance of normal
related damage than with the neuroretinal param- aging in estimating the rate of glaucomatous neuroretinal rim and retinal
nerve fiber layer loss. Ophthalmology; 2015;122(12):2392-8.
eters.
both of these factors limit their clini- uniqueness is that, unlike Cosopt and
cal usefulness. CAIs inhibit aqueous Combigan, it does not contain a beta
production. Although they have a sul- blocker. Thus, for a patient with asth-
fa side chain, we have observed little ma, or one who is nonresponsive to
or no cross-reactivity in those people beta blockers, Simbrinza would likely
who have an allergy to sulfonamide be an ideal add-on to a prostaglandin
antimicrobials. drug, once individual trials of both
This class of drug is represented brinzolamide and brimonidine are
by the orange-capped bottles of ge- found to be efficacious. Commonly,
neric dorzolamide and Alcons Azopt if the prostaglandin brought us close
(brinzolamide) suspension. Only Azopt to target intraocular pressure but fell
and Simbrinza are glaucoma suspen- short, it is likely that adding generic
sions, which have to be shaken before brinzolamide or generic brimonidine
each instillation. Brimonidine and dor- alone will get the IOP to target, and
zolamide are found in combination using a more expensive combination
with 0.5% timolol. drug may not be necessary.
Cosopt is unique in that it is ge-
more likely to cause allergic disease, it COMBINATION nerically available as a traditional
is also less expensive than the generic GLAUCOMA DROPS bottled product and as a brand name-
0.15% and the brand-name-protected Three combination drugs are avail- protected, preservative-free unit dose
Alphagan-P. So, it is occurring more able: Cosopt (0.5% timolol with product. The carbonic anhydrase
commonly that we must balance cost 0.2% dorzolamide, Akorn), Com- inhibitors reduce intraocular pres-
to the patient with tolerabilitya bigan (0.5% timolol with 0.2% bri- sure by suppressing aqueous produc-
highly subjective call. monidine, Allergan) and Simbrinza tion, and do so by only about 15%.
Carbonic anhydrase inhibitors (0.2% brimonidine with 1% brinzo- Like brimonidine, they are approved
(CAIs) only reduce intraocular pres- lamide suspension, Alcon). as TID products, yet we tend to use
sure about 15% in our experience, Simbrinza is the only suspension them twice daily in general clinical
and also have to be used twice daily; combination drug. Simbrinzas main care. Dorzolamide is an ophthalmic
for improved Many patients with dry eye disease matory drugs (NSAIDs), the tetracyclines,
will benefit from fish oil supplementa- azithromycin, cyclosporine all have mod-
patient care tionusually about 2,000mg per day. Let est anti-inflammatory effects (and as-yet-
them know it takes four to six months to unapproved lifitegrast is expected to) but
and outcomes. gain the therapeutic effect as evidenced do not come close to the efficacy of a ste-
by decreasing need to use artificial tears. roid. Dont hesitate with inflammation;
Further, not all people can swallow these properly suppress it.
rather larger capsules; for this subset of
patients, liquid supplementation will be OCT technology is one of the most
helpful. We recommend either Coromega helpful ancillary instruments available to
Omega-3 Orange Squeeze or Nordic Nat- analyze and document retinal and nerve
urals Omega 3 Liquid. changes. It is fast becoming standard
of care, if it isnt already. It can be espe-
When inflammation is a significant cially helpful for assessing retinal nerve
component of any anterior segment dis- fiber layer thickness in glaucoma evalua-
ease, always consider prescribing a topical tions, and retinal evaluations in cases of
corticosteroid. Nonsteroidal anti-inflam- unexplained vision loss. Subtle epiretinal
FROM THE
LITERATURE considered reasonable care.
No testing occurred in 25% of Plaquenil patients.
2016 PLAQUENIL UPDATE Amsler grid testing is of no value in HCQ testing, yet was
A major article in the American Journal of Ophthalmology done on 40% of subjects.
(September 2015) on hydroxychloroquine (HCQ) merits Retinal and comprehensive ophthalmologists see the
highlighting. Key findings from this review of patient care majority of subjects for HCQ screening, but are appropri-
at a large, tertiary medical center were eye opening; from ately screening subjects less than half the time.
these, we provide some clinical point-
ers (in italics). The import of all the recent literature
Based on ideal body weight indicates that we are failing to pro-
calculations, 50% of patients were vide subjects proper HCQ screening,
overdosed at the typical dosage of which is of particular concern given
400mg/day. the rising detection rate of toxicity.
At initial screening visits, about It is our opinion that evaluating the
50% of patients received a 10-2 plus an patients ideal body weight, per-
objective testusually a HD-OCT. forming the appropriate testing, and
This should be a standard baseline communicating with the Plaquenil
work-up for 100% of subjects taking prescriber perfectly meets the stan-
Plaquenil. dard of excellence in clinical care. If
Diagnostic testing was underper- you do not have the requisite diag-
formed. Only a 10-2 or only an objec- nostic instrumentation, then send
tive test (OCT, FAF or mf ERG) was your patients to an optometrist in
This is a classic presentation of bulls
accomplished in about 30% of subjects. eye maculopathya very sad, and very your area who does.
At least one subjective test (usu- preventable, expression of permanent Au A, Parikh V, Modi YS, et al. Hydroxychloroquine
ally at 10-2 with white target) and one screening practice patterns within a large multispe-
vision loss from HCQ toxicity. cialty ophthalmic practice. Am J Ophthalmol. 2015
objective test (usually a HD-OCT) is Sep;160(3):561-568.
and Ophthalmology. Better yet, form month to share and discuss pertinent cies where such journal club mem-
groups of four to six optometrists articles. This is vastly superior to at- bers can receive continuing education
where journal subscription costs are tending any lecture (including ours!). credit for such scholarly endeavors.
shared, and meet for two hours once a We urge state boards to create poli- An easy portal to engage such sub-
All instruments pictured are made by Storz Ophthalmic Instruments/Bausch + Lomb Instruments
HANDHELD INSTRUMENTS IN Kimura spatula. Our instrument of loose or irregular epithelial tissue,
PRIMARY EYE CARE choice in obtaining corneal tissue remove erosive conjunctival concre-
associated with bacterial keratitis for tions and perform eyelash epilation.
Having a variety of essential hand gram/giemsa staining, and material This tool is especially helpful in epi-
instruments in your examination/ for bacterial cultures. lating tiny, short, blond lashes.
treatment rooms can greatly expand
your ability to care for a wider
array of patient care needs. Some
examples are: removing corneal
foreign bodies, scraping along the Iris scissors. These are perfectly Curved-tip serrated forceps. This
eyelid margin to enhance meibum suited for destruction of symptom- can be used in a wide variety of
flow into the tear film, removing atic bulbar conjunctival lymphan- applications, but works especially
erosive concretions from the tar- giectatic cysts. Three or four good well at removing ticks and crab lice
sal conjunctiva, epilating trichiatic slices across and through these from the lid tissues.
lashes, debriding irregular epithelium cysts will not only instantaneously
associated with corneal abrasions, deflate them, but this utter destruc-
performing anterior stromal micro- tion prevents them from reforming.
puncture, destroying symptomatic The same can be accomplished by
lymphangectatic bulbar conjuncti- using a sterile needle to deflate the
val cysts, removing crab lice from cyst, but without destruction of the Epilation forceps. This instrument
infested eyelashes, dilating punctal cyst, reformation commonly occurs. is obviously intended for removing
orifices for punctal plug insertion, Beyond topical anesthesia with pro- trichiatic lashes, and do indeed work
irrigating the nasolacrimal system, paracaine, we also instill 2.5% phen- well for this purpose. However, for
using an eyelid retractor to enable ylephrine to minimize any bleeding some of the stubby, maldeveloped
double eversion, incorporating a since these conjunctival cysts often lashes, jewelers forceps often work
metal spatula to accomplish bac- have blood vessels, because they better.
terial culturing, corneal rust ring are simply outpocketings of con- Wide-tipped:
removal, scleral depression, and so junctival tissue.
on. The following is a more detailed
description of some instruments we
find useful in everyday practie.
Narrow-tipped:
Golf club spud. This instrument
is one of the most versatile and
widely used tools in all of eye care. Shahinian cannula. This blunt-
Its fort is enabling the removal of tipped cannula is perfect for irrigat-
corneal foreign bodies; however, ing the nasolacrimal ducts when
more recently, Korb and associates evaluating epiphora associated with Stromal puncture needle. This is
have shown it can be used to gently nasolacrimal stenosis or obstruction. a short, 25-gauge needle that has
scrape along the lower eyelid mar- been precisely bent to perform
gin to enhance meibum flow poste- safe application of corneal micro-
riorly into the pre-corneal tear film puncture to treat focal (not diffuse)
enhancing tear film function.1 Lastly, corneal erosions. If there is a large
it is the instrument of choice in area of loosely adherent epithelium,
removing transconjunctival erosion debridement and diamond burr
of calcium concretion bodies from Jewelers forceps. This highly ver- buffing or polishing of the debrided
the tarsal conjunctiva. satile instrument provides multifac- surface tissue may best serve the
eted utility. It can be used to remove patient. Placement of a bandage/
corneal foreign bodies, debride therapeutic soft contact lens after