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Allergen Challenge Studies Versus Placebo

Conjunctival allergen challenge (CAC) studies are a useful model for reproducing the ocular responses to allergens and for evaluating the inhibitory effects of anti-allergy drugs. The following studies demonstrate the rapid and long lasting effect of Zaditen^® (ketotifen) 0.025% eye drops in preventing symptoms and signs of allergic conjunctivitis, such as ocular itching and redness.

Efficacy of ketotifen fumarate 0.025% ophthalmic solution compared with placebo in the conjunctival allergen challenge model. Abelson MB; Chapin MJ; Kapik BM; Shams NBK: Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Ophthalmic Research Associates Inc, North Andover, MA, USA; Novartis Ophthalmics Inc, Duluth, GA, USA. Arch Ophthalmol 2003; 121: 626-630

BACKGROUND: Ketotifen fumarate blocks histamine (H) receptors, stabilizes mast cells, and acts as an eosinophil inhibitor (decreases chemotaxis and activation of eosinophils).

OBJECTIVE: To assess the efficacy of ketotifen 0.025% ophthalmic solution in the prevention of symptoms of allergic conjunctivitis, using the conjunctival allergen challenge model.

METHODS: This was a single-center, double-masked, randomized, placebo-controlled, contralateral-eye comparison, allergen challenge trial conducted in the United States. Subjects were randomized to receive ketotifen 0.025% in one eye and placebo in the other. At visits 1 and 2, allergen challenges were performed to determine the allergen concentration eliciting a qualifying reaction for each subject. At the 3 subsequent visits, subjects received 1 drop of ketotifen 0.025% ophthalmic solution in one eye and vehicle solution as placebo in the other eye 15 minutes (visit 3), 6 hours (visit 4) and 8 hours (visit 5) before allergen challenge. The primary efficacy measure was the subject's rating of itching at 3, 7 and 10 minutes after challenge.

RESULTS: Of the 89 subjects randomly assigned to masked trial medication at visit 3, 72 completed the study. At visits 3, 4, and 5, mean itching scores were significantly better for ketotifen-treated eyes at all postchallenge time points, compared with placebo (p < 0.001). Also at visits 3, 4, and 5, ketotifen was statistically superior to placebo in reducing ocular hyperemia at all postchallenge time points (p < 0.05).

CONCLUSIONS: Ketotifen was safe and statistically effective in reducing ocular itching and hyperemia associated with allergic conjunctivitis. Ketotifen’s rapid onset of action (within 15 minutes) and extended duration of action (at least 8 hours) make it a valuable treatment for allergic conjunctivitis.

Efficacy and safety of ketotifen fumarate 0.025% in the conjunctival antigen challenge model of ocular allergic conjunctivitis.  Greiner JV; Mundorf T; Dubiner H; Lonsdale J; Casey R; Parver L; Kapik BM; Shams NBK; Abelson MB: Schepens Eye Research Institute, Harvard Medical School, Boston, MA, USA; Presbyterian Medical Tower, Charlotte, NC, USA; Clayton Eye Center, Morrow, GA, USA; Lewiston, ME, USA; Jules Stein Eye Institute, Los Angeles, CA, USA; Washington DC, USA; Novartis Ophthalmics Inc, Duluth, GA, USA. Am J Ophthalmol 2003; 136: 1097-1105

PURPOSE: To determine the duration of action of ketotifen 0.025% eye drops vs placebo taken as single or multiple doses in an allergen challenge model.

DESIGN: Two randomized, multicenter, double-masked, contralateral placebo-controlled studies, one a single-dose and one a multiple-dose study.

METHODS: Two conjunctival provocation tests (CPTs) were initially conducted to confirm reproducibility of subject responses in both studies. Subjects in study 1 (n = 87) received single doses of ketotifen in one eye and placebo in the other 15 minutes, 6 hours, and 8 hours before CPT. Subjects in study 2 (n = 85) received ketotifen or placebo once 8 hours before CPT. Single-dose efficacy results were used to further qualify a subject as a responder. Responders were re-randomized to a 4-week twice daily dosing regimen with a CPT 8 hours after the final dose. In both studies, ocular symptoms were assessed at three time points 3 to 15 minutes after challenge. There were no significant differences in adverse events between groups.

RESULTS: For both studies, ocular itching and vascular injection were significantly reduced (p < 0.003) at all time points after instillation of ketotifen, with a maximum reduction at 7 minutes postchallenge. In study 2, chemosis, tearing, and lid swelling were also assessed and were significantly reduced (p < 0.008) after instillation of ketotifen.

CONCLUSIONS: Ketotifen 0.025% eye drops were safe and statistically effective in preventing ocular itching, injection, and other signs and symptoms of allergic conjunctivitis at 15 minutes, 6 hours, and 8 hours after a single dose and at 8 hours after the final dose of a 4-week twice daily regimen.

Efficacy and safety of single- and multiple-dose ketotifen fumarate 0.025% ophthalmic solution in a pediatric population. Abelson MB; Ferzola NJ; McWhirter CL; Crampton HJ: Schepens Eye Research Institute, Harvard Medical School,Boston, MA, USA; Ophthalmic Research Associates Inc, North Andover, MA, USA;Novartis Ophthalmics Inc, Duluth, GA, USA. Pediatr Allergy Immunol (In press). 

BACKGROUND: Allergic conjunctivitis can seriously disrupt children's daily activities. This study assessed the efficacy (onset and duration of action) and safety of ketotifen fumarate 0.025% ophthalmic solution compared with vehicle placebo in pediatric subjects after single and multiple dosing.

METHODS: This was a double-masked, multicenter, fellow-eye, placebo-controlled,conjunctival allergen challenge trial. Eligible subjects (8-16-yr-olds) who produced a qualifying reaction to allergen were randomized to a single dose (one drop) of ketotifen fumarate in one eye and vehicle placebo in the fellow eye, followed by an allergen challenge at 15 minutes and 8 hours post-dose. Subjects who had a qualifying reaction to allergen in the placebo-treated eye and a qualifying response to ketotifen in the active-treated eye following the single dose were re-randomized to a multiple-dose treatment period. They were instructed to instill one drop of ketotifen fumarate in one eye and placebo in the other eye twice daily for 4 weeks. An allergen challenge was conducted 8 h after the last dose. The primary efficacy assessment was ocular itching, judged by the subject at 3, 7, and 10 min post-allergen challenge after single- and multiple-dose treatments. Other ocular signs and symptoms were assessed at 7, 10, and 15 min post-dose.

RESULTS: A total of 133 subjects were randomized to single-dose treatment; 105 were evaluable for efficacy. Of these, 60 were re-randomized to multiple-dose treatment, and 55 were evaluable for efficacy. After single and multiple doses, ketotifen fumarate significantly inhibited ocular itching compared with placebo at all post-challenge timepoints (p < 0.001) and also significantly reduced hyperemia, chemosis, and lid swelling (p = 0.031). No drugrelated systemic adverse events were reported, and ocular adverse events were comparable to placebo. No subject discontinued prematurely due to an adverse event.

CONCLUSIONS: These results indicate that ketotifen fumarate 0.025% ophthalmic solution is an effective and safe treatment option for children with allergic conjunctivitis.