New ophthalmic agents offer convenience and other advantages over older drugs. by Theresa Waldron
April 01, 1999 HOSPITAL PRACTICE - FOR YOUR EYES
New drugs approved by the Food & Drug Administration since January 1998 for treating ophthalmic conditions include agents to treat allergic conjunctivitis, post-operative inflammation following cataract extraction, and ocular hypertension. What follows is a report on some of the agents, several of which have advantages over previously available formulations.
Dorzolamide HCl/timolol maleate: Combining two commonly used glaucoma drugs into one eye drop formulation, dorzolamide hydrochloride-timolol maleate ophthalmic solution (Cosopt), from Merck & Co., West Point, Pa., is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to beta-blockers alone. It is the first ophthalmic solution combining a topical carbonic anhydrase inhibitor (CAI), dorzolamide, and a topical beta-blocking agent, timolol.
In premarketing studies of dorzolamide-timolol administered b.i.d., the drug produced reduction in intraocular pressure greater than that seen when either dorzolamide HCl ophthalmic solution (Trusopt, Merck) or timolol maleate ophthalmic solution (Timoptic, Merck) was used as sole therapy.
Dorzolamide-timolol's advantage is that it simplifies glaucoma therapy into one regimen. "Patients may be confused by multiple daily applications of more than one drug, or they may give up altogether due to complex instructions," said Michael Kass, M.D., professor of ophthalmology at Washington University School of Medicine in St. Louis.
Jimmy Bartlett, O.D., professor of optometry and pharmacology at the University of Alabama at Birmingham, agrees. "It's certainly a big convenience factor," he said. "I would recommend that if pharmacists have a patient who is using the individual medications [dorzolamide and timolol], they might want to suggest to the patient--or to the practitioner--a switch over to Cosopt."
Bartlett indicated that the combination drug retails for about $45 for a 5-cc bottle. However, he added, the cost is approximately the same as the cost of the two drugs used separately.
Because it is absorbed systemically, dorzolamide-timolol is contraindicated in patients with current bronchial asthma or a history of bronchial asthma, or in patients with chronic obstructive pulmonary disease. The most commonly reported adverse events reported with the drug in premarketing trials were burning or stinging of the eyes and changes in taste.
Loteprednol etabonate: Bausch & Lomb Pharmaceuticals, Rochester, N.Y., has introduced two new ophthalmic products--loteprednol etabonate ophthalmic suspension 0.5% (Lotemax) and loteprednol etabonate ophthalmic suspension 0.2% (Alrex).
Loteprednol etabonate 0.5% is a topical, site-specific steroid used to treat postoperative eye inflammation after surgery for cataracts or other conditions. It also can be used for other inflammatory eye conditions. During premarketing trials, loteprednol etabonate 0.5% was found to have a low incidence of increased intraocular pressure, which is a side effect of ophthalmic steroid use.
"Lotemax is one of several antiallergic drops that's a good drop," said Richard Bensinger, M.D., chief of ophthalmology at Swedish Hospital in Seattle.
According to Bartlett, loteprednol etabonate 0.5% is a "unique and novel steroid" for the eye. "It's novel in that it was designed with a retrometabolic drug design in mind," he said. Retrometabolic means that scientists in the laboratory took an inactive metabolite of prednisolone and modified it into an active compound (loteprednol), which, when given to the patient, is very rapidly metabolized by esterase enzymes in local eye tissues. Esterase enzymes in the cornea break down the drug very quickly, he said.
As the drug penetrates the cornea, "the active [entity] achieves high drug levels and is therefore a very effective steroid. It's also very rapidly metabolized and, at least in theory, doesn't hang around long enough to cause side effects," Bartlett explained. "It's a very site-specific drug, so it doesn't raise intraocular pressure as much."
Bartlett added that loteprednol etabonate 0.5% appears to be effective for at least four clinical indications: anterior uveitis, seasonal allergic conjunctivitis, giant papillary conjunctivitis, and postoperative cataract inflammation.
According to product literature, loteprednol etabonate 0.5%--as with other ophthalmic corticosteroids--is contraindicated in most viral diseases of the cornea and conjunctiva, including epithelial herpes simplex keratitis. Adverse reactions include abnormal vision/blurring and burning on instillation. Product information warns against prolonged use of loteprednol etabonate 0.5%, because it may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision, and posterior subcapsular cataract formation. Prolonged use also may lead to secondary ocular infections. That is an important warning for pharmacists, Bartlett emphasized.
"Pharmacists will sometimes refill steroid prescriptions for the eye," he continued. "But that is an absolute no-no unless they are authorized by the practitioner. Sometimes a patient will come in asking for a refill on a topical steroid, and even though refills may not be indicated on the prescription, pharmacists will just hand [the patient] a new bottle. That's a very bad practice."
Alrex, the new loteprednol etabonate 0.2%, is indicated for the treatment of ophthalmic allergies, particularly seasonal allergic conjunctivitis.
"One of the complications of steroid use is elevated pressure in the eye, and Alrex seems to have less of a tendency to do that," said Bensinger. "So it's useful for people who are going to be on an anti-inflammatory steroid drop for an extended period of time."
Loteprednol etabonate 0.2% is different in viscosity from loteprednol etabonate 0.5%, Bartlett pointed out. "The 0.2% is actually more viscous--it's a little bit thicker--so it will stay in the eye longer and better," he said.
Product information for loteprednol etabonate 0.2% carries the same contraindications as for loteprednol etabonate 0.5%--including not using it in viral diseases of the eye and avoiding prolonged use of the drug. Adverse reactions associated with loteprednol etabonate 0.2% include abnormal vision/blurring and burning on instillation.
Brinzolamide: Azopt (brinzolamide ophthalmic suspension 1%), from Alcon Laboratories, Fort Worth, is a new topical CAI for treating elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. In double-masked, controlled clinical trials, brinzolamide significantly lowered intraocular pressure (4 mm/Hg-5 mm/Hg).
According to Alcon, the pH of brinzolamide is equivalent to that of human tears, making it more comfortable for patients. In two clinical trials to evaluate ocular comfort, 5% of glaucoma patients experienced burning and stinging with brinzolamide compared with 58% of those using a currently available CAI. The most common adverse events reported with brinzolamide were blurred vision and sour or unusual taste. Because the drug is a sulfonamide and is absorbed systemically, the same types of adverse reactions that occur with sulfonamides may occur with brinzolamide.
Diclofenac: Alcon has also released diclofenac, cited as a topical generic equivalent to Voltaren, a nonsteroidal anti-inflammatory drug for treating postoperative inflammation following cataract extraction.
The steroidal drug PredForte (prednisolone acetate suspension) is often used for the same indication. "The advantage of diclofenac is that the competitive product for this use is not another nonsteroidal [drug] but is, in fact, a steroid," Bensinger said. "And steroids have the risk of elevating intraocular pressure. So [Alcon's] aim is to put out a product that will not do that at all, and this product won't."
Bartlett said diclofenac is ideal for patients who have had pressure-elevation problems in the past with topical steroids. He said another major use is pain control after surgery or in patients who have superficial eye injuries.
According to product information, NSAIDs such as diclofenac have the potential for increased bleeding time due to interference with thrombocyte aggregation, which may cause increased bleeding of ocular tissues. Thus, the manufacturer recommends that diclofenac be used with caution in surgical patients with known bleeding tendencies or in patients receiving other medications that may prolong bleeding time. The most common adverse events reported with diclofenac are transient burning and stinging, keratitis, and elevated intraocular pressure.
Ciprofloxacin HCl ointment: A third new product from Alcon, ciprofloxacin hydrochloride ophthalmic ointment 0.2% (Ciloxin), has advantages over eye drops because it has to be used only b.i.d. or t.i.d., compared with at least q.i.d. for Ciloxin drops. "It's a new formulation of an older drug," said Bensinger. "Ciloxin is a fluoroquinolone. Alcon has a Ciloxin drop, which you had to put in three, four, or five times a day. But the new formulation is one that extends the life of the product in the eye. It's a question simply of convenience rather than difference in efficacy."
According to product information, ciprofloxacin ointment is indicated for the treatment of bacterial conjunctivitis caused by susceptible strains of gram-positive and gram-negative microorganisms. As with other antibacterial preparations, prolonged use of ciprofloxacin ointment may cause an overgrowth of nonsusceptible organisms. It also may retard corneal healing and cause visual blurring. (Also, patients with contact lenses should not use them if they have bacterial conjunctivitis.) The most commonly reported adverse events with ciprofloxacin ointment are white precipitate and discomfort.
Pediatric trifluridine: A pediatric form of trifluridine (Viroptic ophthalmic solution 1%) was approved for inflammation of the cornea caused by herpes simplex in children aged six and above. Available from King Pharmaceuticals, Bristol, Tenn., pediatric trifluridine is effective against both type 1 and type 2 of the herpes simplex virus. "Viroptic has been around for a long time, and it is the standard treatment for herpes infection of the eye," said Bensinger.
The only truly novel ophthalmic chemical entity approved in 1998 and so far in 1999 has been loteprednol, Bartlett said. However, new medications are on the horizon, particularly for treating glaucoma.
Theresa Waldron
Based in the Atlanta area, the author writes frequently on health-related subjects.
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