Article Date: 6/1/2001

TOPICAL ANTIHISTAMINE

Topical Antihistamine Proven Safe in Single-use Lens Wear

By Mark D. Kirstein, OD, Michael B. Raizman, MD, Jason S. Rothman, MD, and Kimberly M. Farea, OD
June 2001

This study found that a topical antihistamine is safe and tolerated when used by patients during daily disposable lens wear.

Seasonal allergic conjunctivitis (SAC) is the most frequently diagnosed type of allergic conjunctivitis. Epidemiologic studies have shown that it affects seven to 10 percent of the general population. Although traditional topical treatments, including antihistamines, vasoconstrictors, mast cell stabilizers and nonsteroidal anti-inflammatory agents, are effective, the recommended removal of contact lenses prior to the use of these agents is inconvenient.

Soft contact lenses can absorb topical ophthalmic solutions after their instillation into the cul-de-sac, which may increase adverse effects of the drug. Furthermore, benzalkonium chloride, a widely-used preservative known to cause morphologic and physiologic disturbances to the corneal epithelium, has limited washout in low water content daily wear contact lenses. Daily disposable lenses may lower this risk.

Levocabastine is a potent and selective H1-receptor antagonist. Published data show that it is effective monotherapy for the treatment of SAC in both the antigen challenge model and environmental studies. Momose et al investigated soft contact lens adsorption of levocabastine 0.025% eyedrops and its effect in rabbit eyes. Rabbits wore the lenses for six days (eight hours daily) while receiving levocabastine 0.025% eyedrops eight times daily. Evaluations revealed no signs of ocular irritation and only slight accumulation of LEV and its preservative, benzalkonium chloride 0.15mg/ml (BAK), by the soft contact lenses.

We thought the growing popularity of daily disposable contact lenses and high incidence of SAC warranted a human safety trial evaluating the potent topical antihistamine levocabastine hydrochloride 0.05% ophthalmic suspension (Livostin, Novartis Ophthalmics), preserved with 0.15 mg/mL of benzalkonium chloride. Our study is the first, to our knowledge, to evaluate the safety of levocabastine 0.05% ophthalmic suspension in humans wearing daily disposable contact lenses.

Materials and Methods

Study medication. Levocabastine hydrochloride 0.05% ophthalmic suspension (Livostin) is a potent, selective histamine H1 antagonist approved for topical ophthalmic use. Each milliliter contains 0.54mg levocabastine hydrochloride (equivalent to 0.5mg levocabastine), 0.15mg benzalkonium chloride, propylene glycol, polysorbate 80, hydroxymethylcellulose and purified water. It has a pH of 6.0 to 8.0. The chemical name for levocabastine hydrochloride is (-)-trans-1-[cis-4-Cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylisonipecotic acid monohydro-chloride. It is indicated for the temporary relief of the signs and symptoms of SAC.

Contact lenses. CIBA Vision Focus Dailies daily disposable contact lenses (69 percent water, 31 percent nelfilcon A, base curve 8.6mm, diameter 13.8mm) were worn during the study. Preservative- free saline solution helped facilitate placement of the lenses.

Study Design

This single-centered, randomized, prospective fellow eye comparison study took place at Ophthalmic Consultants of Boston. During the first visit (study day 0), study subjects provided a complete medical and ophthalmic history as well as informed consent. Investigators performed refractions and slit lamp examinations. After subjects were fitted for contact lenses, they were given at least a four-week supply of daily disposable contact lenses, two contact lens cases, preservative-free sterile saline solution (for lubrication purposes or to facilitate lens replacement) and a 5ml bottle of Livostin.

Study subjects placed new daily disposable contact lenses in both eyes each morning by 10:00 a.m. and removed them each evening for two days without using the study drug. If the lenses were tolerated, subjects continued wearing them as before and placed one drop of Livostin in one eye (randomly assigned by the investigator) at 10:00 a.m., 2:00 p.m. and 6:00 p.m. After removing the contact lenses each evening, subjects placed one drop of Livostin in the same assigned eye. Each subject used the medication in the same eye for 28 ±2 days (until study day 30 ±2).

On study days 9 ±1 and 30 ±2 (visits two and three), investigators assessed visual acuity and performed a slit lamp examination. Differences between eyes treated with Livostin and fellow untreated eyes were evaluated. The presence of conjunctival hyperemia, chemosis, papillae and follicles, iris pathology, anterior chamber inflammation, as well as corneal opacity, neovascularization, edema and epithelial defects were noted.

Contact lenses worn the day prior to each examination were collected dry at visits two and three. Study drug was collected on study day 30 ±2. Subjects returned one week later on study day 37 ±2 (visit four) for a visual acuity assessment and slit lamp examination. All visits included a query of adverse events and ocular symptoms since the previous visit.

Bio-Concept Laboratories, Inc. analyzed the contact lenses collected on study days 9 ±1 and 30 ±2, using several methods of High Performance Liquid Chromatography (HPLC) to analyze the adsorption of both levocabastine and benzalkonium chloride into the contact lenses.

Results

We enrolled 20 subjects in the study. One subject developed a peripheral inflammatory infiltrate in the untreated eye and was terminated from the study on day 13. Some 19 patients completed the study.

During the first four weeks of the study, eight eyes treated with Livostin (42 percent of subjects) developed symptoms of dryness compared with fellow untreated eyes (two of these subjects developed dryness in both eyes during the first week of treatment). One eye remained dry seven days after discontinuing the drops. Seven of the treated eyes developed transient blurring of vision, two treated eyes developed transient mild ocular itching, four treated eyes developed transient ocular burning (one subject reported transient burning in both eyes at the four-week visit), and increased blinking was recorded in a treated eye when compared with the non-treated fellow eye during the four weeks of using Livostin. One eye developed transient mild eye pain during the first week. Four subjects developed a mild papillary reaction in both eyes, and one subject developed a mild papillary reaction in the untreated eye alone. In two subjects, bilateral papillae remained one week after discontinuing the drops. One subject developed trace bilateral hyperemia which remained one week after discontinuing the drops. We noted one subject to have small follicles bilaterally at visit three, while another subject was noted to have small bilateral follicles at visit four. Nine subjects developed trace bilateral punctate epitheliopathy, both eyes in four subjects, untreated eyes alone in four subjects and the treated eye in one subject. Two subjects had punctate epitheliopathy one week after discontinuing the study drug (both eyes in one subject and the treated eye in one subject). Two subjects developed mild headaches during the four week treatment, but these subsided after discontinuation of Livostin (Table 1).

With a detection limit of 0.75 micrograms of levocabastine per lens, and 0.3 micrograms of benzalkonium chloride per lens, one subject's lens used in the treated eye collected at visit three possibly adsorbed a trace amount of levocabastine (estimated at 0.45 micrograms/lens) and a trace amount of benzalkonium chloride (estimated at 0.12 micrograms/lens), each below the limit of detection. One subject's lens used in the treated eye, collected at visit two, possibly contained trace amounts (estimated at 0.22 micrograms/lens) of levocabastine at visit three. No other collected lenses adsorbed a detectable amount of either levocabastine or benzalkonium chloride.

Conclusion

Patients treated with Livostin while wearing daily disposable contact lenses may develop transient eye irritation after drug instillation. This may manifest itself as transient blurring of vision, ocular burning or pain, itching and increased blinking. Transient dryness after using Livostin was the most common symptom reported. These findings are not surprising, as ocular irritation is the most common symptom reported in previous studies evaluating levocabastine. Contact lens use, not the study drug, likely caused the follicles, mild papillary reaction and hyperemia seen in our group of patients, as these were bilateral. We think contact lens use probably also caused the mild punctate staining noted during the study, as this was not observed more frequently in eyes treated with Livostin. No subjects developed corneal opacities or edema, iris pathology, anterior chamber inflammation nor changes in visual acuity.

Daily disposable contact lenses worn while patients are treated with Livostin may adsorb trace amounts of levocabastine or its preservative, benzalkonium chloride. Subjects whose contact lenses absorbed trace amounts of levocabastine and benzalkonium did not have a different profile of ocular signs and symptoms compared with the other subjects.

The data from this pilot study suggest that the use of Livostin four times daily for four weeks while wearing daily disposable contact lenses is safe and well tolerated by patients. Although contact lenses may alter the pharmacokinetics of levocabastine and benzalkonium chloride, our study illustrates that the use of Livostin while wearing daily disposable contact lenses is safe and associated with minimal symptoms. 

This study was supported by a research grant from Novartis Ophthalmics.

References are available upon request. To receive references via fax, call (800) 239-4684 and request document #72. (Have a fax number ready.)

Dr. Kirstein practices with Ophthalmic Consultants of Boston. He is an American Academy of Optometry Diplomate in Low Vision.
Dr. Raizman is a cornea specialist at Ophthalmic Consultants of Boston, Associate Professor of Ophthalmology at Tufts University School of Medicine in Boston and Director, Cornea and Anterior Segment Service, New England Eye Center, Boston.
Dr. Rothman is an ophthalmology resident at Tufts University School of Medicine. He has served as an investigator in several ophthalmic drug studies.
Dr. Farea is a resident at Puget Sound VA Health System in Tacoma, WA.

 

TABLE    Recorded Signs and Symptoms for Each Visit   

 

Day 9 ± 1 Treated
 Eye  


Untreated
Eye   


Both  
Eyes 

Day 30 ±2   Treated
 Eye


Untreated
Eye   


Both
Eyes   

Day 37 ±2   Treated Eye


Untreated 
Eye


Both
Eyes

Dryness   

5   

0   

2   

8   

0   

0   

1   

0   

0

Blurring of vision   

3   

0   

0   

7   

0   

0   

0   

0   

0

Itching   

2   

0   

0   

0   

0   

0   

0   

0   

0

Burning   

3   

0   

0   

3   

0   

1   

0   

0   

0

Increased blinking   

1   

0   

0   

0   

0   

0   

0   

0   

0

Eye pain   

1   

0   

0   

0   

0   

0   

0   

0   

0

Hyperemia   

0   

0   

1   

0   

0   

1   

0   

0   

1

Papillae   

0   

0   

3   

0   

1   

4   

0   

0   

2

Follicles   

0   

0   

0   

0   

0   

1   

0   

0   

1

Punctate epitheliopathy   

2   

3   

2   

1   

1   

3   

1   

0   

1  



Contact Lens Spectrum, Issue: June 2001