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Efficacy and Tolerability of Ketotifen in the Treatment Of Seasonal Allergic

Conjunctivitis: Comparison between Ketotifen 0.025% and 0.05% Eye Drops

Article  in  Ocular Immunology and Inflammation · October 2018

DOI: 10.1080/09273948.2018.1530363

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ISSN: 0927-3948 (Print) 1744-5078 (Online) Journal homepage: http://www.tandfonline.com/loi/ioii20

Efficacy and Tolerability of Ketotifen in the

Treatment Of Seasonal Allergic Conjunctivitis:
Comparison between Ketotifen 0.025% and 0.05%
Eye Drops

Andrea Leonardi, Decio Capobianco, Nicola Benedetti, Antonio Capobianco,

Fabiano Cavarzeran, Tania Scalora, Rocco Modugno & Oren Mark Feuerman

To cite this article: Andrea Leonardi, Decio Capobianco, Nicola Benedetti, Antonio Capobianco,
Fabiano Cavarzeran, Tania Scalora, Rocco Modugno & Oren Mark Feuerman (2018): Efficacy
and Tolerability of Ketotifen in the Treatment Of Seasonal Allergic Conjunctivitis: Comparison
between Ketotifen 0.025% and 0.05% Eye Drops, Ocular Immunology and Inflammation, DOI:
10.1080/09273948.2018.1530363

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Ocular Immunology & Inflammation, 2018; 00(00): 1–5
© Taylor & Francis Group, LLC
ISSN: 0927-3948 print / 1744-5078 online
DOI: 10.1080/09273948.2018.1530363

ORIGINAL ARTICLE

Efficacy and Tolerability of Ketotifen in the

Treatment Of Seasonal Allergic Conjunctivitis:
Comparison between Ketotifen 0.025% and 0.05%
Eye Drops
Andrea Leonardi1, Decio Capobianco2, Nicola Benedetti3, Antonio Capobianco4, Fabiano
Cavarzeran1, Tania Scalora1, Rocco Modugno1, and Oren Mark Feuerman1

1
Department of Neuroscience, Ophthalmology Unit, University of Padova, Padova, Italy, 2Ophthalmology
Service, ASL Napoli-1, Napoli, Italy, 3Ophthalmology Service, Casa di Cura Don Lorenzo Avezzano,
L’Aquila, Italy, and 4Ophthalmology Service, Fondazione Gemelli, Roma, Italy

ABSTRACT
Purpose: To study the tolerability and efficacy of two formulations of topical ketotifen ophthalmic solutions for
the treatment of seasonal allergic conjunctivitis (SAC).
Methods: 81 active SAC patients were treated with either ketotifen 0.025% or 0.05% eye drops for 3 weeks.
Allergic signs and symptoms were evaluated at baseline (V0), after 7 (V1) and 21 days (V2). Drugs tolerability
and ratings of global efficacy were recorded.
Results: Both concentrations of ketotifen were highly effective. The total signs and symptoms scores (TSSS) were
significantly better reduced by ketotifen 0.025% compared to 0.05% at both V1 and V2 (p < 0.001). Ketotifen
0.025% was better tolerated than 0.05% at the first instillation and at days 2, 4, and 6 (p < 0.0001), and had a
better responder rate (p < 0.001) according to the patient’s and investigator’s assessments.
Conclusions: Ketotifen 0.025% was more effective and better tolerated than 0.05% in SAC.
Keywords: Environmental study, ketotifen, ocular allergy, seasonal allergic conjunctivitis, tolerability

Ocular allergies (OA), either seasonal/intermittent or accompanied by immediate ocular itching,2 with tear
perennial/persistent, are characterized by a clinical histamine values peaking 5 minutes after conjunctival
reaction involving the conjunctiva and the eyelids allergen challenge.3 Redness and chemosis have a
always associated with ocular itching, the quintessential slower onset after challenge but persist for a longer
symptom of allergy consequence of mast cell degranu- period of time. Therefore mast cells and histamine
lation. In fact, IgE-mediated mast cell activation and receptors are the main targets for anti-allergic treatment
release of the main mediator, histamine, has been in all forms of OA. Mast cell stabilizers inhibit mast cell
described in all allergic ocular diseases: seasonal allergic degranulation by blocking calcium-mediated release of
conjunctivitis (SAC), perennial conjunctivitis (PAC), inflammatory mediators, including histamine, from
vernal keratoconjunctivitis (VKC), atopic keratocon- mast cells.4 The first approved drug in its class was
junctivitis (AKC).1 In addition to histamine, conjuncti- cromolyn sodium 4%, approved in 1984 for use in
val mast cells have been shown to release several VKC. Others that followed include lodoxamide tro-
mediators and cytokines, and to be heterogeneous in methamine 0.1%, nedocromil sodium 2%, and permir-
phenotype, biochemical properties, and functional olast potassium 0.1% and N-spaglumic acid 4%, are
responses.2 Histamine release is a rapid process beneficial because they can target both early and late

Received 1 May 2018; revised 23 September 2018; accepted 26 September 2018

Correspondence: Andrea Leonardi, MD, Department of Neuroscience, Ophthalmology Unit, University of Padua, via Giustiniani 2 35128,
Padua, Italy. E-mail: [email protected]
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/ioii.

1
2 A. Leonardi et al.

phase allergic reactions. However, they are only effec- suffered from active mild-to-moderate SAC, defined
tive if mast cells are deactivated prior to an allergic by an ocular itching score of at least 2+and total
response. Thus, therapy must be initiated at least symptom score of at least 5, were treated with two
2 weeks prior to antigen exposure. different concentrations of ketotifen eye drops. The
First generation antihistamines are still used in com- study was conducted in accordance with the
bination with vasoconstrictors for the treatment of OA Declaration of Helsinki and was approved by the
because of their rapid onset of action and easy over the local institutional review board. Patients enrolled in
counter accessibility. However, due to the short dura- the study were adults with a clinical history of SAC
tion of effects, usually 2 hours, dosing may be necessary and a previous positive skin test or radioallergosor-
up to four times per day. In addition, the vasoconstric- bent test (RAST) within the past 36 months to at least
tor causes stinging upon instillation, can lead to one common allergen prevalent during the study per-
rebound congestion and local toxicity, and are contra- iod: blue grass or ragweed pollen, alternaria, or other
indicated in the presence of narrow angles. The second- local weed pollens. Women of childbearing potential
generation of topical antihistamines levocabastine and were required to use an adequate birth control
emedastine eye drops share several benefits including method during the study period. Patients suspended
longer duration of action, lasting 4 hours, and less sting- all systemic and local drugs for at least five days prior
ing upon instillation. to study commencement. Exclusion criteria were the
The last generation of anti-allergic ophthalmic following: the presence of any ocular pathology other
compounds share the mast cell stabilization and the than acute SAC (i.e. dry eye, chronic allergic conjunc-
antihistaminic activity in the same molecule: azelas- tivitis, VKC, viral or bacterial conjunctivitis); history
tine hydrochloride 0.05%, epinastine hydrochloride of herpes keratitis; use of contact lenses during the
0.05%, ketotifen fumarate 0.025% and 0.05%, and olo- course of the study; any other medical condition that
patadine hydrochloride 0.1%. Olopatadine 0.2%, the could have interfered with the results of the study;
first daily dosing ocular anti-allergic compound, use of non-steroidal anti-inflammatory agents, mast
bepotastine besilate 1.5%, and once daily dosing alcaf- cell stabilizers, antihistamines, decongestants, or α-
tadine 0.25%, approved by FDA, are not available in adrenoreceptor antagonists; use of topical (ocular) or
the European countries. These agents combine the systemic corticosteroids within two weeks before the
season-long prevention of allergy attacks by mast start of the study; intraocular pressure (IOP) greater
cell stability with the instant gratification afforded than 21 mmHg in either eye or any type of glaucoma;
by the antihistamine, alleviating the immediate signs history of ocular surgery or laser within the previous
and symptoms of the patient. Because of their long 6 months; best-corrected visual acuity (Snellen) in
duration of action, they are prescribed for twice daily either eye worse than 20/100.
dosing; these are considerable advantages over mast On the day of enrollment, the signs (conjunctival
cell stabilizers. All topical antihistamines and mast redness, conjunctival chemosis, watery discharge
cell stabilizers reduce symptoms and signs of seasonal increase, eyelid swelling) and symptoms (itching,
allergic conjunctivitis when compared with placebo in tearing, burning) were reported according to a scoring
the short term.5 system of 0 to 3 (0 = none, 1 = mild, 2 = moderate,
Among these drugs, ketotifen fumarate ophthalmic 3 = severe) and considered as baseline (V0). The total
solution is a cyproheptadine derived anti-allergic signs score, the total symptoms score and the total
drug that possesses both a mast cell stabilizing effect signs and symptoms scores (TSSS) for each subject
and H1-receptor antagonistic activity.6 Ketotifen were obtained adding the values of each symptoms
fumarate attenuated the local allergic reaction in and signs. Patients who met inclusion and exclusion
patients with SAC7 and in human conjunctival aller- criteria scores were randomized into two groups of
gen challenge model both in adults and pediatric subjects to receive either 0.025% ketotifen (Zaditen
populations.8–13 Oftabak, Thea, France) or 0.05% ketotifen (Ketoftil,
The aim of this study was to evaluate the efficacy Farmigea, Italy). They were instructed to administer
and tolerability of two different concentrations of bilaterally two drops/eye twice a day (at approxi-
ketotifene eye drops in patients affected by active mately 08.00 and 20.00 hours) from day 0 (V0, base-
SAC as they present in the common clinical outpatient line) to day 21. Signs and symptoms of SAC were then
practice. evaluated on days 7 (V1) and 21 (V2) approximately
at the same time of day (±2 hours) as on V0.
Following the patients’ random assignment to treat-
ment groups, a trained nurse coordinator instilled the
MATERIAL AND METHODS first dose of medication, one drop in each eye, at the
study center. One minute later patients were queried
A single-masked, randomized, multicenter study was about the ocular comfort of the medication rating ocular
performed in four centers. A total of 81 patients who comfort/tolerability on a 4-point scale assessing the

Ocular Immunology & Inflammation

 Ketotifen in Allergic Conjunctivitis 3

degree of burning/stinging sensation (0 = absence of

burning sensation or discomfort at instillation; 1 = mild
(slightly perceptible); 2 = moderate (uncomfortable);
3 = severe (intense/extremely intense).
Using a daily diary at home, patients were asked to
evaluate the local tolerability to the eye drops using
the same 0–3 discomfort scale on days 2, 4, and 6 of
treatment. The global assessment of the treatment was
also evaluated by both the investigator and the
patients at V1 and V2 using a −1 to 3 scale: −1 = dete-
rioration/worsening; 0 = no relief; 1 = poor, but some
relief; 2 = good/distinct relief; 3 = excellent/complete
or almost complete relief of ocular allergy symptoms.
According to this assessment scale a responder was
defined by a score of 2 or 3 (complete or distinct
relief).
The primary efficacy outcome was the reduction of FIGURE 1. Total score of signs (conjunctival redness, conjunc-
TSSS at V2 between the two treatments. Other second- tival chemosis, watery discharge increase, eyelid swelling) and
symptoms (itching, tearing, burning) according to the scoring
ary efficacy outcomes were individual scores for signs system of 0 to 3 (0 = none, 1 = mild, 2 = moderate, 3 = severe),
and symptoms, the patients and investigators’ assess- assessed on day 0, Day 7 and Day 21 . * = p < 0.0001.
ment of global efficacy, and the responder rate (patient
assessment at V2 and investigator assessment at V1 and
(p < 0.001) (Figure 1). The total symptom score was
V2). Local safety evaluation was assessed by the differ-
also in favor of the 0.025% formulation at both V1
ence in tolerability of both treatments after the first
(p < 0.0003) and V2 (p < 0.0001). Similarly, the total
instillation and during the study period.
sign score was better reduced by the 0.025% formula-
Other ocular safety evaluations included external
tion at both V1 and V2 (p < 0.0001). Ketotifen 0.025%
and slit-lamp evaluation, applanation tonometry,
was statistically significant more effective than ketoti-
visual acuity, and fundus examination. Subjects were
fen 0.05% in reducing all signs and symptoms at V2
asked to report any adverse events or side effects that
compared to baseline (Table 1).
may have occurred between visits.
Ketotifen 0.025% was better tollerated than ketoti-
Signs, symptoms, ratings of global efficacy and
fen 0.05% at the first instillation (1.57 ± 0.9 vs
tolerability were compared between groups with a
2.12 ± 0.7, p < 0.0001) and at days 2, 4, and 6
two-factor (treatment and time) ANOVA with
(p < 0.0001) (Figure 2).
repeated measures on time factor and Bonferroni
At each follow-up visit, patients and investigators
post-hoc test for multiple comparisons using a
found ketotifen 0.025% superior to ketotifen 0.05% in
mixed-model procedure. The intention to treat popu-
relieving the signs and symptoms of allergic
lation (all subjects that receive any study drug and
conjunctivitis.
who participated in at least one assessment) coincided
In fact, the mean global efficacy based on patient
with the full analyses set since all the patients con-
and investigator assessments for each treatment
cluded the study. All tests were two sided; a p value
group, showed a significant better response for keto-
less than or equal to 0.05 was considered statistically
tifen 0.025% at V1 and at V2 for both patients and
significant. All statistics were performed using the
investigator assessments (p < 0.001) (Figure 3). No
SAS version 9.4 software (SAS Institute, Cary, NC).
ocular or systemic side effects were reported by the
patients in both groups.

RESULTS
DISCUSSION
All 81 enrolled patients concluded the study (40 in the
ketotifen 0.025% group and 41 in the ketotifen 0.05% Deciding on which therapy to prescribe for the treat-
group). No statistical differences in demographics or ment of SAC, the efficacy is heavily dependent on
baseline characteristics were found between the two compliance. Patient perception data can be helpful in
groups. Both ketotifen 0.025% and 0.05% were effec- selecting the therapy that will be most accepted and
tive in reducing the TSSS, the total sign score, the total thus most adhered to. The objective of this study was
symptom score and single sings and symptoms at V2 to examine two concentrations available in the market
compared to V0 (p < 0.001). of the anti-allergy ophthalmic agent, ketotifen, to
The TSSS was significantly better reduced by keto- determine which was more effective in reducing
tifen 0.025% compared to 0.05% at both V1 and V2 signs and symptoms, and which the patients

© 2018 Taylor & Francis Group, LLC

4 A. Leonardi et al.

TABLE 1. Signs and symptoms of SAC assessed according to a scoring system of 0 to 3 (0 = none, 1 = mild, 2 = moderate, 3 = severe).

Baseline (Visit 0) Day 21 (Visit 2)

Ketotifen 0.05% Ketotifen 0.025% Ketotifen 0.05% Ketotifen 0.025%

Mean (SD) Mean (SD) Mean (SD) Mean (SD) P value

Itching 2.24 (0.7) 2.25 (0.9) 1.17 (0.9) 0.75 (0.6) 0.0004
Tearing 1.85 (1.0) 1.75 (1.1) 1.04 (0.9) 0.37 (0.5) < 0.0001
Burning 1.82 (0.7) 2.00 (0.7) 0.87 (0.7) 0.35 (0.5) < 0.0001
Conjunctival hyperemia 2.03 (0.9) 2.10 (0.8) 1.17 (0.8) 0.17 (0.3) < 0.0001
Conjunctival chemosis 1.68 (0.6) 1.67 (0.8) 0.70 (0.7) 0.17 (0.3) < 0.0001
Eyelid swelling 1.73 (0.8) 1.65 (0.9) 0.780 (0.8) 0.137 (0.7) 0.0043
Watery discharge 1.58 (1.0) 1.647 (0.9) 0.70 (0.8) 0.22 (0.4) 0.0009

Fourth-generation antihistamines include dual

mechanism topical antihistamine-mast cell stabilizer
medications. They offer the rapid onset of symptom
relief through H1 receptor blockade and provide
long-term inhibition of mediator release via mast cell
stabilization.5 Typically, compliance is better when
compared to mast cell stabilizers alone because pre-
treatment is not required and the long duration of
action, usually 8 hours, requires only twice daily
dosing.
In this study, both concentrations of ketotifen were
effective in reducing ocular allergic TSSS, ocular itch-
ing and hyperemia associated with allergic conjuncti-
vitis. However, it is clear that patients had a better
response using ketotifen 0.025% over 0.05%. In fact
not only TSSS and single signs and symptoms were
FIGURE 2. Responder rate on day 21 according to patient better reduced by the 0.025% formulation but also
assessment and investigator assessment. * = p < 0.001. tolerability and subjective global assessment were sig-
nificantly in favor of ketotifen 0.025%. In the present
study, ketotifen 0.025% was in its preservative-free
formulation while ketotifen 0.05% was in the pre-
served ophthalmic solutions. This may have been
one reason of the better tolerance of the 0.025%
formulation.14
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.10
Ketotifen significantly decreased the signs and symp-
toms of ocular and nasal allergic rhinoconjunctivitis in
the allergen challenge model with an adjunctive
improvement of its effect when oral desloratadine was
added.15 Besides the well-known effect in reducing signs
and symptoms of OA, significantly diminished produc-
tion of eotaxin and expression of CD29 by epithelial cells
in patients with SAC.16
In conclusions, ketotifen eye drop, a dual acting
antihistamine-mast cell stabilizers with rapid-onset
FIGURE 3. Burning/stinging sensation after first instillation, at
days 2, 4 and 6 scored according to a 4-point scale.
of symptom relief, was shown to be an effective in
* = p < 0.0001. reducing signs and symptoms of allergic conjunctivi-
tis in this positive controlled seasonal study. Of the
two concentrations available, the 0.025% was shown
preferred in terms of tolerability and subjective global
to be not only more effective but also preferred by the
efficacy under a real-life condition.
patients. This study gives some new perspectives on

Ocular Immunology & Inflammation

 Ketotifen in Allergic Conjunctivitis 5

the decision of the ophthalmic anti-allergy options performance of olopatadine hydrochloride 0.1% ophthal-
available. The results of this study can be kept in mic solution and ketotifen fumarate 0.025% ophthalmic
mind as useful pieces of information to consider solution in the conjunctival antigen challenge model. Clin
Ther. 2000;22(7):826–833. doi:10.1016/S0149-2918(00)80055-
when making therapy choices. 7.
9. D’Arienzo PA, Leonardi A, Bensch G. Randomized,
double-masked, placebo-controlled comparison of the
efficacy of emedastine difumarate 0.05% ophthalmic
DECLARATION OF INTEREST solution and ketotifen fumarate 0.025% ophthalmic
solution in the human conjunctival allergen challenge
The authors report no conflicts of interest. The model. Clin Ther. 2002;24:409–416.
authors alone are responsible for the content and 10. Abelson MB, Chapin MJ, Kapik BM, Shams NBK. Efficacy
writing of the paper. of ketotifen fumarate 0.025% ophthalmic solution com-
pared with placebo in the conjunctival allergen challenge
model. Arch Ophthalmol. 2003;121(5):626–630. doi:10.1001/
archopht.121.5.626.
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