OTC or Rx Allergy Drops?

BY MARK B. ABELSON, M.D., PAUL GOMES, M.S., KAI ZHANG, M.D.

When allergy sufferers first see a general practitioner, allergist or ophthalmologist, it's virtually guaranteed that they've already tried one or several OTC products. Many of these patients are non-responders or otherwise have not achieved adequate relief in terms of efficacy profile or duration of action. This OTC failure manifests as late-phase inflammation and swelling in addition to ocular itching and insufficient redness relief. Allergic conjunctivitis signs and symptoms remain uncontrolled despite q.i.d. ophthalmic antihistamine/vasoconstrictor use, and patients need more effective agents, possibly of a different class of medications.

Last year, ketotifen became available for OTC use, making it the first antihistamine/mast cell stabilizer OTC product. This previously prescription-only product has revolutionized the OTC market and raised questions as to whether prescription medications are worth their price. When considering which anti-allergic medications to recommend to your patients, it's important to differentiate between the antihistamine/vasoconstrictor OTC products and OTC ketotifen, and to recognize the additional benefits prescription products provide.

Self-Diagnosing and Self-Medicating

OTC products are well known, inexpensive and widely available, and are therefore the obvious choice for the individual who experiences intermittent signs and symptoms of allergic conjunctivitis. But are patients correctly self-diagnosing prior to purchasing OTC products? Burning eyes and itchy eyes represent different underlying mechanisms; therefore, ocular lubricants cannot help the allergic conjunctivitis patient beyond flushing allergen from the eye.

When patients accurately self-diagnose and investigate the proper medications, they're faced with an abundance of products, from homeopathic solutions with no regulatory-defined clinical benefit (caveat emptor) to FDA-approved antihistamine/vasoconstrictor combinations and anthihistamine/mast cell stabilizers. Opcon-A (naphazoline/pheniramine, Bausch & Lomb), Naphcon-A (naphazoline/pheniramine, Alcon), Vasocon-A (antazoline/naphazoline, Novartis) and Visine-A (naphazoline/pheniramine, Johnson & Johnson) form the historic mainstay of currently marketed topical OTC products.

Antihistamines work for up to 2 hours, and currently marketed vasoconstrictors for 1 hour, so these combination product are dosed every 2 hours, up to four times a day. All-day relief is therefore difficult to obtain with current antihistamine/vasoconstrictors. Furthermore, overuse can cause tachyphylaxis, which may be misinterpreted as "rebound redness."

OTC Ketotifen

Recently, a seismic shift has occurred in the OTC market with the introduction of ketotifen, as OTC anti-allergic medications can now be dosed b.i.d. Ketotifen fumarate 0.025% (Alaway, Bausch & Lomb, and Zaditor, Novartis) provides longer-lasting moderate itch relief (8 to 12 hours) than the older OTC products, but it does not have any demonstrated clinically significant effect on ocular redness. Alaway, a new formulation of ketotifen, is better priced than Zaditor, has demonstrated bioequivalence,¹ and is the product leader. It's a cost-effective and safe way to self-manage seasonal ocular allergies, but it's still not quite up to the standard set by the prescription ophthalmic anthistamine/mast cell stabilizers. A future ketotifen product looks to include a vasoconstrictor and will provide redness relief. (See www.clinicaltrials.gov.)

To become OTC, a medication must satisfy two main criteria: (1) it must be safe, and (2) the condition it's indicated for must be self-diagnosable. We can expect that more agents will move outside of the physician-controlled system as healthcare policy recognizes the safety and high-specificity of the current agents and those in development. OTC products also cut healthcare costs: why should a patient pay a doctor to diagnose itchy eyes, when the patient described that very symptom to the doctor?

Prescription Products

OTC failure is quite common. Historically, prescription anti-allergic agents have provided a broad spectrum of action, increased durations of action, enhanced comfort profiles and heightened efficacies. Current prescription drugs include antihistamines and mast cell stabilizers. On their own, mast cell stabilizers do not provide immediate relief of allergic conjunctivitis signs and symptoms, need to be used long-term for benefits to manifest and are dosed up to q.i.d.

Antihistamine/mast cell stabilizers provide the immediate relief of an antihistamine combined with the extended duration of action of a mast cell stabilizer. The introduction of Patanol (olopatadine 0.1%, Alcon Laboratories) over a decade ago revolutionized the treatment of allergic conjuncti vitis, as it was the first topical prescription dual-acting antihistamine/mast cell stabilizer indicated for twice-daily treatment of all the signs and symptoms of seasonal allergic conjunctivitis. It has an impressive safety and efficacy profile,^2,3 and holds nearly 80% of the market. Optivar (azelastine 0.05%, Meda Pharmaceuticals) and Elestat (epinastine 0.05%, Inspire Pharmaceuticals)⁴ are also available as prescription dual-acting medications. Topical dualacting antihistamine/mast cell stabilizers do not have the drying effects commonly encountered with systemic antihistamines.^5,6

For patients who present with persistent ocular allergy signs and symptoms, particularly the inflammation and corneal involvement and papillae that are indicative of late-phase reactions or chronic allergy, topical steroids, specifically Alrex (loteprednol etabonate 0.2%, Bausch & Lomb) are indicated. As a soft steroid, the likelihood of steroid side effects is reduced when Alrex is used as a pulse therapy for 2 weeks. For mild seasonal allergic conjunctivitis, steroids are not first-line therapies, given their side effect profile when used for long term.

More Comprehensive Relief in the Future

A large subset of allergy patients experience chronic, episodic signs and symptoms, particularly inflammatory symptoms in addition to recurrent itching and redness. This patient population, currently treated with steroids, needs the help of ophthalmologists and the new prescription therapies in development. New prescription medications will need to mitigate ocular inflammation and provide sustained relief of all the signs and symptoms of allergic conjunctivitis in once-daily formulations. With rapid scientific advances in allergy and inflammation, novel drug targets against allergy such as the stem cell factor (i.e., KIT ligand) and the kinases in phosphoinositide-3-kinase (PI3K) pathway are being identified, and more effective mast cell stabilizers are in development.⁷ Successful development of these novel agents will significantly enhance the armamentarium of anti-allergic prescription medicines available to physicians.

The mast cell contains a host of pre- and newly formed mediators. Histamine has been the therapeutic target of choice for the last two decades. Other mast cell mediators include various leukotrienes, cytokines, chemokines and vasoactive amines, all of which increase vasodilation and recruit inflammatory cells to the conjunctiva over the 6 to 24 hours after allergen exposure. They also promote eosinophil migration, adhesion to conjunctival epithelial cells and subsequent degranulation.⁸ Major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO) and eosinophil-derived neurotoxin (EDN) are among the eosinophil-derived mediators. Combined, these mediators instigate further mast cell and basophil degranulation, activate neutrophils, damage epithelial cells, activate angiogenesis and enhance the Th2-type allergic response.^9,10

As the allergic reaction becomes more severe, these mediators appear in tears, and eosinophils are present in the conjunctival subepithelium and epithelium.^11-13 Clinically, the late-phase mediators and eosinophils that are associated with chronic allergic conjunctivitis present as conjunctival and lid swelling, along with inflammation. As we further elucidate the role of the eosinophil in the clinical presentation of allergic rhinoconjunctivitis, anti-allergic therapies with eosinophil inhibitory action will likely become available.

We frequently state that approximately 20% of the U.S. population has seasonal or perennial allergic conjunctivitis. Clinical experience has demonstrated that within the population of general allergy patients, the incidence of ocular allergy approaches 80%. Itchy eyes is the most common symptom of allergic conjunctivitis patients,¹⁴ and in those with concomitant rhinitis, it competes with nasal congestion as the most bothersome symptom.¹⁵ Patients with mild rhinitis may notice that use of an ophthalmic anti-allergic medication not only controls their itchy eyes, but also reduces or eliminates the need for a systemic or intranasal medication.¹⁶ To this end, a 2005 study unequivocally demonstrated the positive quality of life benefits of the addition of an ophthalmic antihistamine/mast cell stabilizer to patients' current anti-allergy treatment regimens, either intranasal sprays or systemic antihistamines.¹⁷ Future ophthalmic medications, especially those that have potent late-phase activity, may provide comprehensive relief of allergic rhinoconjunctivitis. More comprehensive control of allergic conjunctivitis may also minimize allergic rhinitis and asthma symptoms, as fewer mediators will drift from the eye to the nose.

Finding the Allergy Patients

In the burgeoning OTC market, attracting more allergy patients to your practice will require a multi-pronged approach. An awareness of when the allergy season begins is key: January through April is the ideal time to begin asking patients if they're concerned about the upcoming allergy season and initiating discussions about treatment options. Utilizing questionnaires can also provide insight into patients' likelihood of experiencing perennial allergies.

Ocular allergy is not always a benign affliction. It's also important to recognize concomitant conditions — rubbing itchy eyes, for example, may introduce bacteria to the eye, resulting in bacterial conjunctivitis or lead to chalazions. Patients must then be treated for the infection and inflammation, but also for the underlying allergic condition — of which they may not even be aware. Contact lens patients may be another minimally tapped patient base, as allergic conjunctivitis is the number one reason for contact lens discontinuation. In fact, at least one contact lens manufacturer is developing a new contact lens/anti-allergic medication combination product. (See www.clinicaltrials.gov.)

Another approach may be to establish alliances with pharmacists and leave practice information in the surrounding area to reach patients who habitually shop OTC products. Directly relating an ophthalmologist with allergy treatment can remind allergy patients of the prescription option, and may direct those consumers whose allergy symptoms are not fully controlled by OTC products to your practice.

Perhaps the most effective means of finding allergy patients is by establishing solid relationships with area primary care physicians, ear-nose-throat specialists and allergists, who are often the first to see patients with allergic conjunctivitis. Referrals from such specialties represent an expanding patient population that may otherwise not be reached.

The Final Word

Prescription medications provide longer-lasting, more rapid relief while maintaining high comfort profiles with a greater efficacy profile. Patients who have experienced OTC failure and contact their physician are looking for something that the physician feels demonstrates a better efficacy profile. We can feel comfortable and confident that recommending the current prescription products — antihistamine/mast cell stabilizers such as olopatadine, or steroids like loteprednol — will provide a greater likelihood of improved therapy and help address OTC failure. Whether your prescribing habits include olopatadine, epinastine, azelelastine or loteprednol, you can be assured that the prescription products will continue to provide enhanced therapy to patients seeking more control over their ocular allergy signs and symptoms. OM

References

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