OPTOMETRY
`Ocular therapeutics
`
`Compiled by Dr Genevieve Napper, Ian
`Douglas and Dr Julie Albietz
`
`New dry eye products
`Some exciting new therapeutic agents for
`dry eye and related disorders have been
`released in the USA. They are Systane
`(Alcon), Restasis (Allergan) and Refresh
`Endura (Allergan). Systane is now avail-
`able in Australia.
`Systane is a sterile multidose aqueous
`tear solution. It contains HP Guar
`(hydroxypropyl guar) derived from guar,
`a form of gum, and is preserved with
`Polyquad, a relatively non-cytotoxic pre-
`servative. When HP-par combines with
`physiological tears, it crosslinks with
`borate, forming a network with a gel-like
`consistency. The crosslinked HP-guar and
`borate in Systane binds to the hydropho-
`bic ocular surface, especially to damaged
`epithelial cells, so the dwell time (the
`length of time it remains on the ocular
`surface) of this gel network is claimed to
`be longer than those of other artificial
`tears, maintaining a protective shield
`across the ocular surface. It is claimed that
`the protective shield allows natural heal-
`ing of the cornea and conjunctiva to occur.
`According to data provided by Alcon,
`Systane significantly reduces some symp
`toms of dryness and conjunctival staining
`(www.systane.com). Systane will be avail-
`able on the PBS from 1 November 2003 as
`a Restricted Benefit (1 t 5 repeats),
`Restasis (Allergan), cyclosporine oph-
`thalmic emulsion 0.05%, was launched in
`the USA in May 2003. It has a role in con-
`trolling inflammation, especially in severe
`steroid-resistant atopic keratoconjunctivi-
`tis. It has been successfully used in tear
`deficient patients, both autoimmune and
`non-autoimmune, in whom tear produc-
`tion is presumed to be suppressed due to
`ocular inflammation associated with kera-
`toconjunctivitis sicca. Topical cyclosporine
`improves tear secretion, reduces ocular
`
`surface staining and inflammation, re-
`duces the rate of ocular surface cellular
`turnover and restores goblet cells in eyes
`with moderate to severe keratoconjuncti-
`vitis sicca. No significant ocular or systemic
`side effects have been reported with long-
`term use. Transient ocular burning and
`irritation on instillation are common side
`effects. It is contraindicated in patients
`with active ocular infection. In Federal
`Drug Administration
`trials,
`the
`lacrimogenic effect of cyclosporine did not
`occur in patients already taking anti-
`inflammatory drugs or in patients with
`punctal plugs. Interestingly, only 15 per
`cent of patients had improved Schirmer
`wetting compared to five per cent in the
`vehicle treated group and it took six
`months to improve Schirmer strip wetting.
`Further studies are required to identify
`patients who are most likely to benefit and
`test parameters that are best to identify
`and monitor patients’ responses to the
`medication.
`Refresh Endura (Allergan) is derived
`from the ophthalmic emulsion vehicle for
`Restasis. In FDA Phase 2 and 3 trials, this
`emulsion vehicle was found to reduce
`symptoms of ocular irritation by stabilis-
`ing the tear film and reducing tear evapo-
`ration. On application to the eye, the elec-
`trolytes in the tear film dissolve the
`polymer matrix, releasing the emulsion
`components. When the components sepa-
`rate, the oil floats to the lipid layer, the water
`enhances the aqueous volume, and the
`ocular lubricant combines with the mucin
`layer. Refresh Endura is packaged in the
`USA in a non-preserved unit dose form.
`Sources and further references
`Restasis package insert. 2002 Allergan, Inc.
`(www.restasis.com)
`Kunert KS, Tisdale AS, Stern ME, Smith JA,
`Gipson IK. Analysis of topical cyclosporine
`treatment of patients with dry eye syn-
`drome: effect on conjunctival lymphocytes.
`Arch Ophthalmol2000; 118: 1489-1496.
`Sall K, Stevenson OD, Mundorf TK, Reis BL.
`Two multicenter, randomized studies of the
`
`Clin Exp Optom 2003; 86: 6: 414-415
`
`efficacy and safety of cyclosporine ophthal-
`mic emulsion in moderate to severe dry eye
`disease. CsA Study Group. Ophthalmology
`2000; 107: 631-639.
`Turner K, Pflugfelder SC, Ji Z, Feuer WJ, Stern
`M, Reis BL. Interleukin-6 levels in the con-
`junctival epithelium of patients with dry eye
`disease treated with cyclosporine ophthal-
`mic emulsion. Cornea 2000; 19: 492-496.
`Brignole F, Pisella PJ, De Saint Jean M,
`Goldschild M, Goguel A, Baudouin C. Flow
`cytometric analysis of inflammatory mark-
`ers in KCS: 6-month treatment with topical
`cyclosporin A. Invest Ophthalmol Vis Sn’2001;
`42: 90-95.
`GottschJD, Akpek EK, DartJK, Watson S, Chris-
`ten W, Dursun D, Yo0 S, O’Brien TP, Schein
`OD. A Randomized, multi-center trial of
`topical cyclosporin 0.05% in steroid-resist-
`ant atopic keratoconjunctivitis. ARVO
`Abstract 2003: Poster: 672/B647.
`ChengY, Brown KM, Prudhomme RK. Charac-
`terization and intermolecular interactions
`of hydroxypropyl guar solutions. Biomam
`molecules 2002: 3: 456-461.
`
`Preservative and antibiotic
`toxicity to the ocular surface
`Commercially available multidose topical
`medications contain preservatives, stabilis-
`ers and other additives. These compounds
`supply stability and retard microbial con-
`tamination and growth, thus ensuring a
`longer shelf life. The most common pre-
`servatives are benzalkonium chloride
`(BAK: 0.005-0.02%), chlorbutanol(O.5%)
`and thimerosal (0.001-0.005%). BAK is
`the preservative in most cases. At these
`concentrations, these agents may be toxic
`to the corneal epithelium, stroma and en-
`dothelium when used more than four times
`per day. Preservative toxicity is always a con-
`sideration in long-term, highdose use of
`ocular medications and can mask the signs
`of the condition being treated.
`Antibiotics may also be toxic to the ocu-
`lar surface and delay wound healing.
`Aminoglycoside toxicity is well recognised,
`with neomycin and gentamicin being the
`most cytotoxic. Clinical signs include
`punctate keratitis, injection in the inferior
`cul-de-sac and a weepy erythema and
`
`Clinical and Experimental Optometry 86.6 November 2003
`41 4
`
`APOTEX 1038, pg. 1
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`

`
`oedema of the eyelid tissues. These re-
`sponses are usually not serious and occur
`mostly after the drug is used for longer
`than one or two weeks. Tobramycin (an-
`other aminoglycoside) and chlorampheni-
`col do not appear to retard wound heal-
`ing’-’ but excessive dosing (for example,
`more than four times per day) or pro-
`longed dosing can be cytotoxic to the cor-
`
`neal e p i t h e l i ~ m . ~ . ~ Excessive dosing of
`ciprofloxacin (Ciloxin, Alcon) and, to a
`lesser extent, ofloxacin (Ocuflox,
`Allergan) is also cytotoxic to the corneal
`epithelium4 and can retard epithelial
`wound healing.6 Co-administration of a
`non-preserved lubricant and an antibiotic
`has a beneficial effect on the recovery of
`the ocular surface.’ This study compared
`the effects of three different treatments,
`each applied six times per day, on corneal
`epithelial wound healing and haze in 18
`myopic patients who had PRK surgery. The
`treatments were ciprofloxacin, ofloxacin,
`and a combination of ofloxacin with car-
`boxymethyl cellulose lubricant (Refresh
`Plus, Allergan).
`Eyes treated with ciprofloxacin were sig-
`nificantly more prone to impaired or de-
`layed epithelial wound healing and to the
`development of stromal haze than those
`treated with either ofloxacin and Refresh
`Plus or ofloxacin alone. The ofloxacin and
`Refresh Plus combination delayed healing
`less than ofloxacin alone.7
`
`References
`1. Nelson JD, Silverman V, Lima PH, Beckman
`G. Corneal epithelial wound healing: a tis-
`sue culture assay on the effect of antibiot-
`ics. CurrEyeRes 1990; 9: 277-285.
`2. Petroutsos G, Guimaraes R, Giraud J ,
`Pouliquen Y. Antibiotics and corneal epi-
`thelial wound healing. Arch Ophthalmol
`1983; 101: 1775-1778.
`3. Gilbert ML, Wilhelmus KR, Osato MS.
`Comparative bioavailability and efficacy of
`topical tobramycin. Invest
`fortified
`Ophthalmol Vir Sci 1987; 28: 881-885.
`4. Matsumoto S, Stern ME. Effect of anti-
`infective ophthalmic solutions on corneal
`cells in uitro. Adu Ther2000; 17: 148-151.
`5. Berry M, Gurung A, Easty DL. Toxicity of
`antibiotics and antifungals on cultured hu-
`man corneal cells: effect Of mixingiexposure
`and concentration. Eye 1995; 9: 110-1 15.
`6. Moreira LB, Lee RF, de Oliveira C, LaBree
`PJ, ~
`L, ~
`~
`~
`~
`fluoro-
`of topical
`f
`f
`~
`~
`quinolones on corneal re-epithelialization
`
`Ocular therapeutics
`
`Drug group
`
`Generic brand
`
`Premium brand
`
`Price reductlon over
`premium brand
`
`Antibiotic
`Fluoroquinolone
`Anti-glaucoma
`Topical Beta antagonist
`Parasympathomimetic
`Artificial tears
`Paraffin
`Hypromellose
`
`CiloQuin
`
`Ciloxan
`
`TenoptlOptimol
`Piloptllsopto Carpine
`
`Timoptol
`PV Carpine
`
`Duratears
`PolyvisclLacrilube
`In-a-wink Moisturising Genteal
`
`$2.40
`
`$0.99
`$1.71
`
`$1.24
`$2.00
`
`Source: schedule of Pharmaceutical Benefits May 2002 Commonwealth of Australia P: 229-235
`
`Table 1. Generic drugs: categories of brand equivalents
`
`Surg 1997; 23: 845-848.
`7. Pate1 GM, Chuang AZ, Kiang E, Ramesh N,
`Mitra S, Yee RW. Epithelial healing rates
`with topical ciprofloxacin, ofloxacin, and
`ofloxacin with artificial tears after
`photorefractive keratectomy. J Cat Refract
`Surg 2000; 26: 690-694.
`
`Generic drugs
`Generic medications or brand equivalents
`are medications that can be supplied in
`place of that written on the prescription,
`usually at a lower cost. In the case of brand
`equivalents for topical ocular medications,
`all have been shown to be therapeutically
`equivalent so it would be expected that
`they would have the same clinical effect
`as the premium brand. If a prescription
`specifies ‘no substitution’, the exact brand
`of medication as specified in the prescrip-
`tion must be supplied.
`There are relatively few brand equiva-
`lents of topical ophthalmic drugs in Aus-
`tralia, which can be supplied at a lower
`cost. The Table 1 sh6ws the three catego-
`ries of brand equivalents.
`
`Optometrists’ therapeutic
`prescribing habits
`Since January 2003, Optometrists Associa-
`tion Victorian Division has been surveying
`therapeutically qualified optometrists
`within Victoria. The e-mail survey looks at
`the medications prescribed and whether
`~
`~
`~
`l
`l
`
`it was necessary to involve a general medi-
`
`~
`
`medication to be prescribed via the Phar-
`maceutical Benefits Scheme (PBS).
`About 30 per cent of therapeutically
`qualified optometrists have responded to
`the survey. In the the nine months to
`September 2003, the survey respondents
`had written 507 prescriptions for 25
`medictions. The five most common medi-
`cations prescribed by therapeutically
`qualified optometrists were:
`chloramphenicol (various brands)
`fluorometholone (Flucon, FML)
`fluorometholone acetate (Flarex)
`prednisolone acetate (Prednefrin
`Forte)
`lodoxamide trometamol (Lomide)
`On 41 occasions in the nine months to
`September 2003, the optometrists had
`involved the patient’s GP to allow the
`prescription to be prescribed via the PBS.
`
`Contributions
`The authors welcome comments or con-
`tributions from readers, including optom-
`etrists and pharmaceutical manufacturers.
`Contact:
`Genevieve Napper
`c/o Clinical and Expen’mtal Optometry,
`PO Box 185, Carlton South VIC 3053
`g.napper@bigpond.com
`Ian Douglas
`i.douglas@optometry.unimelb.edu.au
`Julie Albietz:
`
`julie@darkoptics.com.au
`
`Clinical and Experimental Optometry 86.6 November 2003
`41 S
`
`APOTEX 1038, pg. 2