New drugs join current therapies in fight against allergic conjunctivitis

Issue: April 2000

As research on the allergic cascade has evolved over the years, scientists have learned more about the mechanism, such as the function of the mediators and the mast cells. In turn, they have developed allergy medications based on these findings, resulting in a rush of new products in time for this year’s spring allergy season.

“Considerable progress has been made in understanding the mechanism responsible for ocular allergy,” said George Minno, PhD, director of medical marketing for CIBA Vision Ophthalmics in Duluth, GA. “Recent studies have revealed that complex interactions of genetic and environmental factors are responsible for the development of allergic diseases. Additionally, significant strides have been made in the understanding of the roles of the multiple mediators and cell types involved in the allergic response. These advances are changing the fundamental way we treat allergies and have resulted in the identification of many potential targets for new drugs. Five years ago, the primary focus centered on the mast cell and histamine; however, today, therapies are directed at inhibiting other components in the allergic cascade. As our understanding of allergy increases, we can expect continued advances in the future.”

Innovations in mast-cell stabilizers

Alamast (pemirolast potassium ophthalmic solution 0.1%, Santen Pharmaceuticals) is a topical mast-cell stabilizer indicated for preventing ocular itching due to allergic conjunctivitis. The ophthalmic solution, which will be launched at the Association for Vision in Research Ophthalmology meeting in May, is intended to inhibit the in vivo Type I immediate hypersensitivity reaction. Studies have shown that pemirolast potassium inhibits the antigen-induced release of inflammatory mediators from human mast cells as well as the chemotaxis of eosinophils into ocular tissue and blocks the release of mediators from human eosinophils.

While the solution is indicated for one to two drops in each eye four times daily, Gregg J. Berdy, MD, FACS, a cornea and external disease specialist in St. Louis, said that its potential for twice-daily dosing may increase patient compliance. “If you look at the data from Japan, it was used twice a day with good results,” said Dr. Berdy.

He noted that while many ocular allergic agents may sting upon instillation, he has found Alamast to be a comfortable drop, with only a minority of patients in the clinical trials complaining of a stinging or burning sensation. Dr. Berdy recommended instilling a drop in the eye 5 to 10 minutes prior to contact lens insertion in the morning and again following lens removal.

“Mast-cell stabilizers are great drugs, so I don’t know if it’s any better than what’s out there, but it will be advantageous if you can use it twice a day,” Dr. Berdy said. “Start with four times and experiment. Patients may find that they get efficacy with twice-a-day dosing. However, this still needs to be proven in the patient population.”

Introduced March 1, Alocril (nedocromil sodium ophthalmic solution 2%, Allergan) is a topical treatment for itch associated with allergic conjunctivitis.

“The new trend today for allergy is dual-action or multiple-action drugs,” Stefan D. Trocme, MD, cornea/external disease specialist, told Primary Care Optometry News. “Alocril stabilizes and prevents actions from eosinophils and neutrophils and it prevents neuronal actions.” Alocril additionally prevents other surface cells from secreting inflammatory mediators and decreases chemotaxis. According to Dr. Trocme, Alocril is the first ocular allergy drug to have more than three multiple actions.

Alocril is to be used twice per day — once in the morning and once at night. It has a rapid onset of action. “You don't have to wait for days [for Alocril to work] like you do with traditional mast-cell stabilizers,” Dr. Trocme said. “Alocril will act within minutes of application.” While some ocular allergy medications are infamous for their stinging upon instillation in the eye, this is not true with Alocril, he said. There is little stinging associated with Alocril use, making it a comfortable therapy for ocular allergy sufferers.

Alocril was approved by the FDA for the treatment of itch associated with allergic conjunctivitis. The drug's safety profile allows it to be used in children 3 years and older. Recommended dosing is one or two drops in each eye twice per day until the pollen season is over or exposure to the offending allergen is terminated. The most frequently reported adverse event was headache, which occurred equally in Alcoril- and placebo-treated patients.

An article on the comparison of nedocromil sodium drops to oral terfenadine and to placebo, published in Clinical Therapeutics, concluded that nedocromil was most useful in treating seasonal allergic conjunctivitis. In nedocromil-treated patients, 36.7% experienced relief of symptoms in 2 minutes or less, compared with 24.7% of patients that received terfenadine and 29.1% in patients that received placebo. In the nedocromil treatment group, 77.2% reported relief of symptoms in 15 minutes or less, compared with 58.8% of the terfenadine group and 55.8% of the placebo group. While all three groups demonstrated symptom improvements, nedocromil sodium was associated with a statistically significant faster onset of action than the other two treatment groups.

Mast-cell stabilizers as sole therapy

Prescribing only mast-cell stabilizers for patients is sufficient when patients do not have heavy symptomatology, said Joseph P. Shovlin, OD, in private practice at the Northeastern Eye Institute in Scranton, PA. “If you’re just trying to get control, perhaps after the patient’s acute symptoms are over and you’re just using it on a prophylactic or maintenance basis, patients would do well with a regimen where they could just get by with a mast-cell stabilizer,” he told Primary Care Optometry News. “For instance, we have keratoconus patients use a maintenance drug such as Crolom (cromolyn sodium 4%, Bausch & Lomb) or Alomide (lodoxamide tromethamine TN, Alcon) a few times a day in addition to their contact lens usage from April until the first frost in October. Until we pass through that seasonal aspect of their disease, we’ll often just rely on a mast-cell stabilizer rather than the combination drug.”

Crolom lends itself well to patients suffering from low-grade giant papillary conjunctivitis caused by contact lens wear, said Bobby Christensen, OD, FAAO, in private practice in Midwest City, OK. He suggested Alomide as a long-term therapy for juvenile vernal conjunctivitis with a secondary use for the adult form of vernal-like conjunctivitis.

“This is a group of patients who acquire allergies as they get older,” said Dr. Christensen. “They don’t wear contact lenses, and when you evert the upper eyelid, you observe that they have small papillae with matter. These patients also complain of chronic itch. In this particular group of patients, Alomide works very well, and sometimes even as a maintenance dose is prescribed through the spring or fall allergy season.”

Safety and ease of use make mast-cell stabilizers a top choice for practitioners, said Dr. Shovlin. “I think Alomide is a little more potent than cromolyn sodium because it’s a broader spectrum efficacy, but they all have relative spectrums of efficacy and relative safety profiles that are high, so they’re very simple and safe to use,” he noted.

Antihistamines, multiaction drugs

When a patient presents with moderate to severe itching but little matter on the tarsal conjunctiva, Dr. Christensen said that he will prescribe an antihistamine drop alone. “If the patient comes in with an eye that is not red, but is complaining of itch, I would use an antihistamine and cold compresses, which works very well,” he advised.

When allergic symptoms extend beyond itching and the eye begins to exhibit signs of redness, inflammation and greater amounts of matter, Dr. Shovlin suggested an antihistamine/mast-cell stabilizer combination to more effectively control the symptoms. “The polypharmacy approach is really a very attractive one, because you’re getting a dual effect using two separate medications that are combined in one drop, so it’s convenient for the patient, especially with the dosing regimen,” he said.

Dr. Christensen says that when a mast-cell stabilizer is not enough to manage the allergy, he proceeds to the dual-action drop Patanol (olopatadine HCl 0.1%, Alcon). “When I make the jump to Patanol is when the eye is more inflamed and the patient has more tarsal conjunctiva reaction as well as the antihistamine-related symptoms of itching,” he said. “Patanol works well at covering the bases, especially for the contact lens wearer. Patients can put it in before they put in their contact lenses and after they take them out.”

The newest addition to the antihistamine/mast-cell stabilizer market is Zaditor (ketotifen fumarate 0.025%, CIBA Vision Ophthalmics), which was launched in November 1999. Dr. Minno said that the solution, approved for temporary prevention of itching due to allergic conjunctivitis, differs from its competitors because of its multiple actions on the allergic cascade. “Not only is it an antihistamine and a mast-cell stabilizer, but preclinical studies have demonstrated that ketotifen (Zaditor) has effects on other cells and mediators in the allergic cascade,” he said. “These multiple actions make Zaditor different from what is currently available.”

Zaditor bypasses its combination competitors also because of its extended duration of action, said Dr. Minno. “Having the longer indication is definitely good for people with contact lenses,” he stated. “This way, they can instill the drop in the morning and insert the lens, and they shouldn’t need another drop until they’re ready to take the lens out at the end of the day.”

Dr. Christensen prescribes the drug for more severe inflammatory responses, although he said that because the medication is recently launched, his experience is limited. “I consider it to be a slightly stronger drug for when I’ve got more of an inflammatory response and want to inhibit the eosinophils,” he said. “Zaditor seems to be clinically effective.”

Combination drugs: are they covered?

While mast-cell stabilizers are cost-effective forms of therapy for allergic conjunctivitis, some managed care plans are unwilling to pay for the more expensive multiple-action medications. Dr. Christensen said that if a particular health care company will not cover a mast-cell stabilizer/antihistamine drug, the practitioner can prescribe two separate, less expensive medications in place of one when a patient really needs it.

“If patients are on managed care plans that have a formulary, then instead of going to Patanol, for instance, I will give them Livostin (levocabastine HCl, CIBA Vision Ophthalmics) and Crolom. This provides a mast-cell stabilizer and an antihistamine,” he said, noting that the downside is less convenience, which may result in reduced patient compliance. “From a cost standpoint to the company, when you add those both together, they’re more expensive than the Patanol would have been, but that’s the way some of the formularies are set up. My philosophy is, I have to go with what’s best for the patient. If money becomes an issue, I have to start changing how I approach it.”

Dr. Minno said that CIBA Vision is confident that this will be a non-issue with Zaditor. “Zaditor is the only product that lasts up to 12 hours,” he said.

Using steroids for allergy treatment

For patients suffering from more severe allergies and a broad cross-section of symptoms, the practitioner may want to turn to steroids for treatment. However, Charles Slonim, MD, clinical associate professor of ophthalmology at University of South Florida College of Medicine in Tampa, FL., said that they should be used with caution because of potential side effects. “To have a fear of steroids is good,” said Dr. Slonim. “All steroids eliminate virtually all of the combat signs and symptoms of allergic conjunctivitis, allergic blepharitis, etc.” He said that while antihistamines, mast-cell stabilizers and even multiple-action medications relieve only part of the problem, steroids are all-inclusive. “By being an anti-inflammatory and by working in all aspects of the allergy cascade, steroids block almost every inflammatory pathway along the cascade,” he said, “whereas all of the other drugs work on only one arm, or limb, of the cascade. That’s why steroids are so potent and so good for inflammation.”

Acute episodes where a patient is suffering from severe conjunctival edema and an inflamed, not infectious, eye that is causing the patient great distress may warrant the use of steroids, said Dr. Slonim. “These patients don’t want to go back to work; it’s hard for them to work because of the tearing and the discomfort,” he said. “For those patients, a steroid as a first-line drug is very helpful. You treat the acute episodes — which can last a week to 2 weeks — then, when the episode subsides, or if you think it’s going to become chronic, you can switch them to something else.”

Dr. Slonim said that he will prescribe steroids such as Alrex (loteprednol 0.2%, Bausch & Lomb) and Lotemax (loteprednol 0.5%, Bausch & Lomb). With these drugs’ safety profiles, he said that eye care practitioners may not be as gun-shy about using them. “They can prescribe them for things that they know a steroid will work well for, such as inflammation, especially inflammation associated with an allergy, and take comfort in the fact that the safety profile is not going to get their patient in trouble,” he said.

“Seeing that a product like Alrex works very well, I’m less likely to be hesitant to use it as the first-line drug and then switch to something different,” Dr. Slonim continued. “Eye care practitioners can do the same thing: you have to get over the fear of using them, but you have to have a healthy fear of them. There are good indications for them, and when used judiciously, steroids can be a major part of the anti-allergy ophthalmic armamentarium.”

Immunosuppressants for severe allergy

Some practitioners contend that using cyclosporine helps control signs and symptoms of severe allergic conjunctivitis. Michael Raizman, MD, a cornea specialist at Ophthalmic Consultants of Boston, said that for about the past 10 years, he has been using 0.05% cyclosporine in eye drop form on patients with severe allergies, dosing two to four times a day. He said that he often finds the medication preferable to a steroid for long-term use.

“It’s preferable because it’s so safe,” said Dr. Raizman. “It has different mechanisms of action that may actually make it more potent than steroids in some cases. It’s very good at inhibiting eosinophils, as well as mast cells and other inflammatory cells in the allergic response in the eye.”

Dr. Raizman said that he typically suggests cyclosporine for patients with chronic allergies as well as for those with vernal or atopic conjunctivitis. A patient need not have severe allergies, however, for him to prescribe the drop. “If patients are steroid dependent or if they have corneal toxicity from allergy, I’ll use cyclosporine,” he said.

Restasis (cyclosporine ophthalmic emulsion 0.05%, Allergan), recommended for keratoconjunctivitis sicca, was not recommended for approval by the Food and Drug Administration (FDA) Ophthalmic Drugs Subcommittee in July of last year. However, on Aug. 24, 1999, Restasis was issued an approvable letter for keratoconjunctivitis sicca treatment. Dr. Raizman said that if approved, this dry eye medication could aid in managing allergies.

“I have not used that specific product, but my previous experience suggests that Restasis will be quite safe and effective for treating allergy,” he said.

On Dec. 9, 1999, Allergan sent a resubmission of the approvable letter based on questions posed by the FDA regarding the efficacy of the drug. June 9, 2000, will be the 6-month mark of the company’s resubmission, by which time the FDA must inform Allergan of its decision.

For Your Information:

George Minno, PhD, is the director of medical marketing for CIBA Vision Ophthalmics. He may be reached at 11460 Johns Creek Parkway, Duluth, GA 30097-1556; (800) 227-1524; fax: (678) 415-3592.

Gregg J. Berdy, MD, FACS, is a cornea and external disease specialist and a clinical instructor of ophthalmology at Washington University. He may be reached at 456 North New Ballas Rd., Ste. 386, St. Louis, MO 63141; (314) 993-5000; fax: (314) 993-5558. Dr. Berdy has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

Stefan D. Trocme, MD, can be reached at Department of Ophthalmology UTMB, Clinical Sciences Bldg., Room 340, Galveston, TX 77550-0787; (409) 772-8104; fax: (409) 772-8106; e-mail: strocme@utmb.edu. Dr. Trocme has received research grants from Allergan.

Joseph P. Shovlin, OD, in private practice at the Northeastern Eye Institute, may be reached at 200 Mifflin Ave., Scranton, PA 18503; (717) 342-3145; fax: (717) 344-1409; e-mail: jshovlin@aol.com. Dr. Shovlin has no direct financial interest in the products mentioned in this article. He is a paid consultant for Alcon.

Bobby Christensen, OD, FAAO, is in private practice at Heritage Park Vision Source, 6912 E. Reno, Ste. 101, Midwest City, OK 73110; (405) 732-2277; fax: (405) 737-4766. Dr. Christensen has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

Charles Slonim, MD, is in private group practice and is a clinical associate professor of ophthalmology at the University of South Florida. He may be reached at 4444 East Fletcher Ave., Ste. D, Tampa, FL 33613; (813) 971-3846; fax: (813) 977-2611; e-mail: cslonim@tampabay.rr.com. Dr. Slonim has no direct financial interest in the products mentioned in this article. He is a paid consultant for Bausch & Lomb Pharmaceuticals.

Michael Raizman, MD, is an associate professor of ophthalmology at Tufts University School of Medicine and a cornea specialist at Ophthalmic Consultants of Boston. He may be reached at 50 Staniford Street, 6^th floor, Boston, MA 02114; (617) 742-6366, ext. 2605; fax: (617) 723-7028. Primary Care Optometry News could not confirm whether or not Dr. Raizman has a direct financial interest in the products mentioned in this article, or if he’s a paid consultant for any companies mentioned.