Therapeutic Class Overview Ophthalmic Antihistamines

Page 1 of 4

08/25/2014

Therapeutic Class Overview

Ophthalmic Antihistamines

Therapeutic Class

• Overview/Summary:

All of the ophthalmic antihistamines listed in Table 1 are Food and Drug Administration (FDA)-

approved for the prevention or treatment of the signs and symptoms of allergic conjunctivitis.

1-11

Ketotifen (Alaway

, Zaditor

) is also indicated for the temporary relief of itchy eyes due to pollen,

ragweed, grass, animal hair and dander.

6,7

Allergic conjunctivitis is the most common form of ocular

allergy. Itching manifests as the primary symptom; however, other common symptoms include ocular

burning, chemosis, conjunctival and eyelid edema, hyperemia, photophobia and tearing.

Symptoms

usually occur in both eyes, yet one eye may be affected more than the other.

Vernal conjunctivitis is

a severe form of allergic conjunctivitis that may involve the cornea.

None of the ophthalmic

antihistamines are FDA-approved for the treatment of vernal conjunctivitis. Following topical

administration to the conjunctiva, ophthalmic antihistamines competitively bind histamine receptor

sites to reduce itching and vasodilation.

1-11

The ocular antihistamines are relatively selective for the

histamine type 1 (H

-antihistamine) receptor but may also inhibit the degranulation of mast cells,

thereby limiting the release of inflammatory mediators such as histamine, eosinophil and neutrophil

chemotactic factors.

1-3,5-10

Emedastine (Emadine

) has only H

-antihistamine activity.

Ophthalmic

antihistamines have demonstrated a faster onset of action compared to oral antihistamines and

ophthalmic mast-cell stabilizers and they are all approved for use in children.

1-11

The most common

adverse events associated with these agents are ocular burning, stinging and headache.

1-11

general, drug interactions are limited due to low systemic bioavailability via the ocular route. The

administration schedule for these products ranges from once daily to four times daily, with only

alcaftadine (Lastacaft

) and olopatadine 0.2% (Pataday

) available for once daily use.

1,9

Azelastine

(Optivar

), epinastine (Elestat

) and ketotifen are available generically. Ketotifen is also available

over-the-counter.

Table 1. Current Medications Available in the Therapeutic Class

1-11

Generic (Trade Name)

Food and Drug Administration-

Approved Indications

Dosage

Form/Strength

Generic

Availability

Alcaftadine (Lastacaft

)

Allergic conjunctivitis

†

Ophthalmic solution:

0.25% (3 mL)

Azelastine (Optivar

®*

)

Allergic conjunctivitis

†

Ophthalmic solution:

0.05% (6 mL)



Bepotastine (Bepreve

)

Allergic conjunctivitis

†

Ophthalmic solution:

1.5% (5, 10 mL)

Emedastine (Emadine

)

Allergic conjunctivitis

‡

Ophthalmic solution:

0.05% (5 mL)

Epinastine (Elestat

®*

)

Allergic conjunctivitis

Ophthalmic solution:

0.05% (5 mL)



Ketotifen (Alaway

Zaditor

)

Allergic conjunctivitis

, ocular

itching

║

Ophthalmic solution:

0.025% (OTC, RX)

(5, 10 mL)

#

Olopatadine (Pataday

Patanol

)

Allergic conjunctivitis

†‡

Ophthalmic solution:

0.1% (5 mL)

0.2% (2.5 mL)

OTC=over-the-count, RX=prescription

* Available generically in one dosage form or strength.

† For the treatment of ocular itching associated with allergic conjunctivitis.

‡ For the treatment of signs and symptoms of allergic conjunctivitis.

§ For the prevention of ocular itching associated with allergic conjunctivitis.

║For the temporary relief of itchy eyes due to pollen, ragweed, grass, animal hair and dander.

# Product is also available over-the-counter in at least one dosage form or strength.

Therapeutic Class Overview: ophthalmic antihistamines

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Evidence-based Medicine

• The ophthalmic antihistamines are significantly more effective compared to placebo for reducing the

symptoms of allergic conjunctivitis including ocular itching and conjunctival redness.

16-20

• Limited head-to-head trials comparing olopatadine, azelastine and ketotifen have failed to

consistently show the “superiority” of one ophthalmic antihistamine over another for the management

of allergic conjunctivitis.

21-26

• A meta-analysis of four trials found that patients were 1.3 times more likely to perceive their treatment

response as “good” with ophthalmic antihistamines compared to patients receiving pure ophthalmic

mast-cell stabilizers; however, the difference was not statistically significant.

• The ophthalmic antihistamines have consistently demonstrated a greater improvement in allergy

symptoms and/or patient comfort scores compared to ophthalmic mast-cell stabilizers and ocular

vasoconstrictors; however, many of these trials were conducted using single doses of study

medication (conjunctival allergen challenge model) in a small number of patients.

28-38

Key Points within the Medication Class

• According to Current Clinical Guidelines:

o Ophthalmic formulations of agents from the following classes are useful in treating allergic

conjunctivitis: corticosteroids, vasoconstrictor/antihistamine combinations, antihistamines,

nonsteroidal anti-inflammatories (NSAIDs), mast-cell stabilizers, antihistamine/mast-cell

stabilizers and immunosuppressants.

o An over-the-counter (OTC) antihistamine/vasoconstrictor or second-generation topical

histamine H

-receptor antagonist is recommended for mild allergic conjunctivitis. No

preference is given to any one OTC antihistamine/vasoconstrictor or antihistamine.

o If the condition is frequently recurrent or persistent, use mast-cell stabilizers. No single mast-

cell stabilizer is preferred over another.

o Medications with antihistamine and mast-cell stabilizing properties may be utilized for either

acute or chronic disease. No one antihistamine/mast-cell stabilizer is preferred over

another.

o If the symptoms are not adequately controlled, a brief course (one to two weeks) of low-

potency topical corticosteroid may be added to the regimen. The lowest potency and

frequency of corticosteroid administration that relieves the patient’s symptoms should be

used because of the potential for adverse events with their protracted use (e.g., cataract

formation and elevated intraocular pressure).

14,39

o Ketorolac, a NSAID, is also Food and Drug Administration-approved for the treatment of

allergic conjunctivitis.

14,39

• Other Key Facts:

o Alcaftadine and emedastine are classified as pregnancy category B while the other agents in

this class have a pregnancy category C rating.

o Alcaftadine and olopatadine 0.2% are the only agents within the class that are approved for

once daily use.

o Ophthalmic formulations of azelastine, epinastine and ketotifen are available generically.

o Ketotifen is also available over-the-counter.

References

1. Lastacaft [package insert]. Irvine (CA); Allergan Inc.; 2011 Sep.

2. Optivar

[package insert]. Somerset (NJ): Meda Pharmaceuticals, Inc.; 2014 Apr.

3. Bepreve

[package insert]. Tampa (FL): Bausch & Lomb, Inc.; 2014 Jan.

4. Emadine

[package insert]. Fort Worth (TX): Alcon Laboratories, Inc.; 2007 Jul.

5. Elestat

[package insert]. Irvine (CA): Allergan, Inc.; 2011 Dec.

6. Alaway

[package insert]. Tampa (FL): Bausch & Lomb, Inc.; 2014 Apr.

7. Zaditor

[package insert]. Duluth (GA): Novartis Ophthalmics; 2012 Dec.

8. Ketotifen Fumarate. Micromedex® Healthcare Series [database on the Internet]. Greenwood Village (CO): Thomson

Healthcare; Updated periodically [cited 2014 Aug 19]. Available from: http://www.thomsonhc.com/.

9. Pataday

[package insert]. Fort Worth (TX): Alcon Laboratories, Inc.; 2011 Jul.

10. Patanol

[package insert]. Fort Worth (TX): Alcon Laboratories, Inc.; 2011 Sep.

Therapeutic Class Overview: ophthalmic antihistamines

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11. Drug Facts and Comparisons [database on the Internet]. St. Louis: Wolters Kluwer Health, Inc.; 2013 [cited 2014 Aug 25].

Available from: http://online.factsandcomparisons.com.

12. Hamra P, Dana R. Allergic Conjunctivitis: Clinical Manifestation and Diagnosis. In: Trobe J (Ed). UpToDate [database on the

internet]. Waltham (MA): UpToDate; 2014 Feb. [cited 2014 Aug 19]. Available from: http://www.utdol.com/utd/index.do

13. Hamra P, Dana R. Allergic conjunctivitis: Management. In: Trobe J (Ed). UpToDate [database on the internet]. Waltham (MA):

UpToDate; 2014 Feb [cited 2014 Aug 19]. Available from: http://www.utdol.com/utd/index.do

14. American Optometric Association. Optometric Clinical Practice Guideline. Care of the patient with conjunctivitis. [guideline on

the Internet]. 2007 [cited 2014 Aug 25]. Available from: http://www.aoa.org/x4813.xml

15. Drugs@FDA [database on the Internet]. Rockville (MD): Food and Drug Administration (US), Center for Drug Evaluation and

Research; 2014 [cited 2014 Aug 25]. Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

16. Torkildsen G, Shedden A. The safety and efficacy of alcaftadine 0.25% ophthalmic solution for the prevention of itching

associated with allergic conjunctivitis. Curr Med Res Opin. 2011 Mar;27(3):623-31.

17. Greiner JV, Edwards-Swanson K, Ingerman A. Evaluation of alcaftadine 0.25% ophthalmic solution in acute allergic

conjunctivitis at 15 minutes and 16 hours after instillation vs placebo and olopatadine 0.1%. Clin Ophthalmology.2011; 5:87-93.

18. Abelson MB, Torkildsen GL, Williams JI, et al; Bepotastine Besilate Ophthalmic Solutions Clinical Study Group. Time to onset

and duration of action of the antihistamine bepotastine besilate ophthalmic solutions 1.0% and 1.5% in allergic conjunctivitis: a

phase III, single-center, prospective, randomized, double-masked, placebo-controlled, conjunctival allergen challenge

assessment in adults and children. Clin Ther. 2009;31(9):1908-21.

19. Macejko TT, Bermann MT, Williams JI, Gow JA, Gomes PJ, McNamara TR, et al. Multicenter Clinical Evaluation of Bepotastine

Besilate Ophthalmic Solutions 1.0% and 1.5% to Treat Allergic Conjunctivitis. Am J Ophthlmol. 2010;150:122-7.

20. Abelson MB, Spangler DL, Epstein AB, Mah FS, Crampton HJ. Efficacy of once-daily olopatadine 0.2% ophthalmic solution

compared to twice-daily olopatadine 0.1% ophthalmic solution for the treatment of ocular itching induced by conjunctival

allergen challenge. Curr Eye Res. 2007 Dec;32(12):1017-22.

21. Abelson MB, Spangler DL, Epstein AB, Mah FS, Crampton HJ. Efficacy of once-daily olopatadine 0.2% ophthalmic solution

compared to twice-daily olopatadine 0.1% ophthalmic solution for the treatment of ocular itching induced by conjunctival

allergen challenge. Curr Eye Res. 2007 Dec;32(12):1017-22.

22. Spangler DL, Bensch G, Berdy GJ. Evaluation of the efficacy of olopatadine hydrochloride 0.1% ophthalmic solution and

azelastine hydrochloride 0.05% ophthalmic solution in the conjunctival allergen challenge model. Clin Ther. 2001

Aug;23(8):1272-80.

23. Berdy GJ, Spangler DL, Bensch G, Berdy SS, Brusatti RC. A comparison of the relative efficacy and clinical performance of

olopatadine hydrochloride 0.1% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution in the conjunctival

antigen challenge model. Clin Ther. 2000 Jul;22(7):826-33. [abstract]

24. Leonardi A, Zafirakis P. Efficacy and comfort of olopatadine vs ketotifen ophthalmic solutions: a double-masked, environmental

study of patient preference. Curr Med Res Opin. 2004 Aug;20(8):1167-73.

25. Ganz M, Koll E, Gausche J, Detjen P, Orfan N. Ketotifen fumarate and olopatadine hydrochloride in the treatment of allergic

conjunctivitis: a real-world comparison of efficacy and ocular comfort. Adv Ther. 2003 Mar-Apr;20(2):79-91. [abstract]

26. Avunduk AM, Tekelioglu Y, Turk A, Akyol N. Comparison of the effects of ketotifen fumarate 0.025% and olopatadine HCl 0.1%

ophthalmic solutions in seasonal allergic conjunctivitis: a 30-day, randomized, double-masked, artificial tear substitute-

controlled trial. Clin Ther. 2005;27(9):1392-402.

27. Owen CG, Shah A, Henshaw K, Smeeth L, Sheikh. Topical treatments for seasonal allergic conjunctivitis: systematic review

and meta-analysis of efficacy and effectiveness. Br J Gen Pract. 2004 Jun;54:451-6.

28. Greiner JV, Udell IJ. A comparison of the clinical efficacy of pheniramine maleate/naphazoline hydrochloride ophthalmic

solution and olopatadine hydrochloride ophthalmic solution in the conjunctival allergen challenge model. Clin Ther.

2005;27(5):568-77.

29. Owen CG, Shah A, Henshaw K, Smeeth L, Sheikh. Topical treatments for seasonal allergic conjunctivitis: systematic review

and meta-analysis of efficacy and effectiveness. Br J Gen Pract. 2004 Jun;54:451-6.

30. James IG, Campbell LM, Harrison JM, Fell PJ, Ellers-Lenz B, Petzold U. Comparison of the efficacy and tolerability of topically

administered azelastine, sodium cromoglycate and placebo in the treatment of seasonal allergic conjunctivitis and

rhinoconjunctivitis. Curr Med Res Opin. 2003;19(4):313-20.

31. Greiner JV, Michaelson C, McWhirter CL, Shams NB. Single dose of ketotifen fumarate 0.025% vs 2 weeks of cromolyn

sodium 4% for allergic conjunctivitis. Adv Ther. 2002 Jul-Aug;19(4):185-93. [abstract]

32. Discepola M, Deschenes J, Abelson M. Comparison of the topical ocular antiallergic efficacy of emedastine 0.05% ophthalmic

solution to ketorolac 0.5% ophthalmic solution in a clinical model of allergic conjunctivitis. Acta Ophthalmol Scand Suppl.

1999;(228):43-6. [abstract]

33. Orfeo V, Vardaro A, Lena P, Mensitieri I, Tracey M, DeMarco R. Comparison of emedastine 0.05% or nedocromil sodium 2%

eye drops and placebo in controlling local reactions in subjects with allergic conjunctivitis. Eur J Ophthalmol. 2002 Jul-

Aug;12(4):262-6. [abstract]

34. Greiner JV, Minno G. A placebo-controlled comparison of ketotifen fumarate and nedocromil sodium ophthalmic solutions for

the prevention of ocular itching with the conjunctival allergen challenge model. Clin Ther. 2003 Jul;25(7):1988-2005.

35. Butrus S, Greiner JV, Discepola M, Finegold I. Comparison of the clinical efficacy and comfort of olopatadine hydrochloride

0.1% ophthalmic solution and nedocromil sodium 2% ophthalmic solution in the human conjunctival allergen challenge model.

Clin Ther. 2000 Dec;22(12):1462-72.

36. Alexander M, Allegro S, Hicks A. Efficacy and acceptability of nedocromil sodium 2% and olopatadine hydrochloride 0.1% in

perennial allergic conjunctivitis. Adv Ther. 2000 May-Jun;17(3):140-7. [abstract]

37. Yaylali V, Demirlenk I, Tatlipinar S, et al. Comparative study of 0.1% olopatadine hydrochloride and 0.5% ketorolac

tromethamine in the treatment of seasonal allergic conjunctivitis. Acta Ophthalmol Scand. 2003;81:378-82.

Therapeutic Class Overview: ophthalmic antihistamines

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38. Berdy GJ, Stoppel JO, Epstein AB. Comparison of clinical efficacy and tolerability of olopatadine hydrochloride 0.1%

ophthalmic solution and loteprednol etabonate 0.2% ophthalmic suspension in the conjunctival allergen challenge model. Clin

Therap. 2002;24(6):918-29.

39. American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice Pattern Guidelines. Conjunctivitis.

[guideline on the Internet]. 2011 [cited 2014 Aug 25]. Available from:

http://one.aao.org/CE/PracticeGuidelines/PPP_Content.aspx?cid=79f4327d-6b7d-42e7-bbf3-585e7c3852c7.

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Therapeutic Class Review

Ophthalmic Antihistamines

Overview/Summary

The ophthalmic antihistamines are Food and Drug Administration (FDA)-approved for the management of

the signs and symptoms associated with allergic conjunctivitis and include alcaftadine (Lastacaft

azelastine (Optivar

), bepotastine (Bepreve

), emedastine (Emadine

), epinastine (Elestat

), ketotifen

(Alaway

, Zaditor

) and olopatadine (Pataday

, Patanol

1-10

Ketotifen is also approved for the temporary

relief of itchy eyes due to pollen, ragweed, grass, animal hair and dander.

6-8

Based on clinical features,

allergic conjunctivitis may be subdivided into acute, seasonal or perennial allergic conjunctivitis, with

acute allergic conjunctivitis being the most common.

Ocular itching and redness (hyperemia) are the

main symptoms of allergic conjunctivitis while ocular burning, chemosis, conjunctival and eyelid edema,

photophobia and tearing may also be reported.

Symptoms are usually present bilaterally; however, one

eye may be more affected than the other.

Vernal conjunctivitis is a severe form of allergic conjunctivitis

that may involve the cornea.

None of the ophthalmic antihistamines are FDA-approved for the treatment

of vernal conjunctivitis. Allergic conjunctivitis results from a type I immunoglobulin E (IgE)-mediated

hypersensitivity, where the immediate response to allergens is mediated predominantly by mast cells.

Mast cells are present in high concentrations in the conjunctiva and release chemical mediators when

activated by allergen-IgE cross-linkage. Histamine, the primary mediator during the early response,

causes itching, vasodilation and vasopermeability. During the late phase of the allergic reaction, mast

cells release chemokines and cytokines, which results in the influx of other inflammatory cells and

continued inflammation.

All of the ophthalmic antihistamines with the exception of emedastine have demonstrated both histamine

type 1 (H

-antihistamine) and mast cell stabilizing properties.

1-10

Following topical administration to the

conjunctiva, ophthalmic antihistamines competitively bind to histamine receptor sites to reduce itching

and vasodilation. They also inhibit the degranulation of mast cells, thereby limiting the release of

inflammatory mediators such as histamine, eosinophil and neutrophil chemotactic factors and platelet-

activating factor.

Ophthalmic antihistamines have demonstrated a faster onset of action compared to

oral antihistamines and ophthalmic mast cell stabilizers.

All of the ophthalmic antihistamines are

approved for use in children.

1-10

Alcaftadine and emedastine are classified as pregnancy category B,

while the other agents in this class are pregnancy category C. The most common adverse events

associated with the use of the ophthalmic antihistamines are ocular burning, stinging and headache.

1-10

The ophthalmic antihistamines are generally administered one to four times daily; however, alcaftadine

and olopatadine 0.2% (Pataday

) approved for once daily use.

1,9

Ophthalmic formulations of azelastine

and epinastine are available generically, and ketotifen is available over-the-counter (OTC).

According to the American Academy of Ophthalmology, mild allergic conjunctivitis may be treated with an

OTC antihistamine/vasoconstrictor or ophthalmic antihistamine.

Ophthalmic vasoconstrictors have a

may cause rebound hyperemia and conjunctivitis medicamentosa; therefore, they should only be used

short-term.

Ophthalmic mast cell stabilizers have a slower onset of action compared to ophthalmic

antihistamines, usually requiring five to 14 days for full efficacy, and are dosed four times a day, which

makes their use impractical.

However, they may be used if the condition is recurrent or persistent.

Ophthalmic allergy preparations with dual H

-antihistamine and mast cell stabilizing properties may be

used for either acute or chronic disease, and no preference is given to one specific ophthalmic

antihistamine vs another.

Glucocorticoid preparations are indicated for refractory symptoms, but due to

the potential for serious, vision-threatening side effects, their use should be limited a maximum of two

weeks and monitored by an ophthalmologist.

The results of some head-to-head studies have

demonstrated small differences between agents; however, the clinical significance of these differences

has not been established. Many of these studies were conducted using single doses of study medication

(conjunctival allergen challenge model) and enrolled a small number of patients.

Therapeutic Class Review: ophthalmic antihistamines

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Medications

Table 1. Medications Included Within Class Review

1-10

Generic Name (Trade Name)

Medication Class

Generic Availability

Alcaftadine ophthalmic (Lastacaft

)

Antihistamine/Mast cell stabilizer

Azelastine ophthalmic (Optivar

®*

)

Antihistamine/Mast cell stabilizer



Bepotastine ophthalmic (Bepreve

)

Antihistamine/Mast cell stabilizer

Emedastine ophthalmic (Emadine

)

Antihistamine

Epinastine ophthalmic (Elestat

®*

)

Antihistamine/Mast cell stabilizer



Ketotifen ophthalmic (Alaway

Zaditor

)

Antihistamine/Mast cell stabilizer



†

Olopatadine ophthalmic (Pataday

Patanol

)

Antihistamine/Mast cell stabilizer

*Generic available in at least one dosage form and/or strength.

†Product is also available over-the-counter in at least one dosage form or strength.

Indications

Table 2. Food and Drug Administration-Approved Indications

1-10

Generic Name

Allergic Conjunctivitis

Ocular Itching

Alcaftadine



Azelastine



†

Bepotastine



†

Emedastine



‡

Epinastine



Ketotifen

* (prescription)



(over-the-counter)

Olopatadine



(0.2%

†

, 0.1%

║

)

* Prevention of ocular itching associated with allergic conjunctivitis.

†Treatment of ocular itching associated with allergic conjunctivitis.

‡Temporary relief of the signs and symptoms of allergic conjunctivitis.

§Temporary relief of itchy eyes due to pollen, ragweed, grass, animal hair and dander.

║Treatment of the signs and symptoms of allergic conjunctivitis.

Pharmacokinetics

Table 3. Pharmacokinetics

1-10

Generic

Name

Onset

(minutes)

Duration

(hours)

Excretion (%)

Active

Metabolites

Serum

Half-Life

(hours)

Alcaftadine

Not reported Not reported Not reported

Carboxylic acid

metabolite

Azelastine

3 8 Feces (75)

N-desmethyl-

azelastine)

Bepotastine <15 (1 to 2

hours peak)

8 Urine (75 to 90)

Minimal (not

reported)

Not

reported

Emedastine

Not reported

Urine (44)

None

3 to 4

Epinastine

3 to 5 8

Feces (30); urine

(55)

Not reported 12

Ketotifen

Minutes 8 to 12

Feces (30 to 40);

urine (60 to 70)

Ketotifen N-

glucuronide, nor-

ketotifen

9 to 21

Olopatadine

<30

Urine (60 to 70)

None

*Half-life reported for the active metabolite.

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Clinical Trials

Clinical trials evaluating the safety and efficacy of the ophthalmic antihistamines for their respective Food

and Drug Administration (FDA)-approved indications are summarized in Table 4.

15-43

Due to the rapid onset of action of the ophthalmic antihistamines, most trials used the conjunctival

allergen challenge model to establish the relative efficacy of these formulations compared to placebo. The

results of most trials demonstrated improvements in symptoms, especially for itching, in those treated with

ophthalmic antihistamines and antihistamines/mast cell stabilizers compared to placebo.

In one trial, ophthalmic alcaftadine significantly reduced conjunctival redness and most other allergic

signs and symptoms at both 15 minutes and 16 hours following drug administration compared to placebo

(P<0.05 for both comparisons).

In a second trial of patients with a history of ocular allergens (N=170), all

treatment groups (ophthalmic alcaftadine 0.05%, 0.10%, 0.25% and ophthalmic olopatadine 0.1%) were

associated with lower ocular itching scores compared to placebo (P<0.05 for all comparisons). Compared

to placebo, all treatments significantly improved conjunctival redness scores at both 15 minutes and 16

hours following administration (P<0.05 for all comparisons). A clinically significant difference (≥1 unit

difference from placebo) was only reported for the ophthalmic alcaftadine 0.25% treatment group. At 16

hours following administration, patients receiving ophthalmic alcaftadine 0.25% reported lower ocular

itching scores following allergen challenge compared to patients receiving ophthalmic olopatadine

(P=0.017).

Using the conjunctival allergen challenge model for allergic conjunctivitis, ophthalmic bepotastine was

shown to be more effective than placebo in relieving ocular itching after 15 minutes and eight hours in

adults and children.

17,19

In a two-week trial comparing ophthalmic bepotastine to ophthalmic olopatadine

0.2%, there was a similar improvement in the relief of morning ocular itch between treatments (P value

not reported). Patients treated with ophthalmic bepotastine reported a significantly greater relief in

evening ocular itch compared to patients receiving ophthalmic olopatadine (P=0.011). With regard to

patient preference, significantly more patients favored treatment with ophthalmic bepotastine compared to

ophthalmic olopatadine for the all-day relief of ocular itching (63.3 vs 36.7%; P=0.04).

Using the conjunctival allergen challenge model, one dose of ophthalmic olopatadine 0.2% was

comparable to two doses of ophthalmic olopatadine 0.1%, and both regimens were more effective than

placebo in terms of mean itching scores.

Both strengths of ophthalmic olopatadine were found to be

safe and well tolerated. Using the conjunctival allergen challenge model, ophthalmic olopatadine 0.1%

was significantly more effective compared to ophthalmic azelastine in the management of itching

associated with allergic conjunctivitis. Both agents were also more effective than placebo.

Clinical trials

comparing ophthalmic olopatadine to ophthalmic ketotifen have produced mixed results. Using the

conjunctival allergen challenge model, ophthalmic olopatadine 0.1% was more effective in reducing the

itching associated with allergic conjunctivitis compared to ophthalmic ketotifen (N=32).

In this trial,

olopatadine 0.1% caused less ocular discomfort than ophthalmic ketotifen and was preferred by 73% of

patients compared to 27% with ophthalmic ketotifen. In an environmental study of patient preference, a

significantly higher percentage of patients with active symptoms of seasonal or perennial allergic

conjunctivitis selected ophthalmic olopatadine 0.1% over ophthalmic ketotifen primarily on the basis of

efficacy and comfort (N=100).

In a three-week parallel-group trial in patients with seasonal allergic

conjunctivitis (N=66), ophthalmic ketotifen was associated with higher global efficacy ratings compared to

ophthalmic olopatadine 0.1% at day 21 (91 vs 55% and 94 vs 42% for patient and investigator

assessment, respectively). Comfort ratings were comparable between the two agents.

In a similar 30-

day trial in patients with seasonal allergic conjunctivitis, ophthalmic ketotifen and ophthalmic olopatadine

0.1% were comparable with regard to scores for tearing, itchiness, redness, chemosis and reduction in

eyelid (P values not reported).

Using the conjunctival allergen challenge model, ophthalmic emedastine and ophthalmic ketotifen

significantly reduced the mean itching scores at all time points compared to placebo (P<0.05); however,

there was no statistically significant difference between ophthalmic emedastine and ophthalmic ketotifen

(P values not reported).

In a randomized controlled trial of patients with seasonal allergic conjunctivitis

Therapeutic Class Review: ophthalmic antihistamines

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08/25/2014

(N=100), no differences in efficacy were reported between ophthalmic formulations of emedastine,

epinastine, ketotifen and olopatadine (P values not reported). All agents were more efficacious in

preventing itching and redness compared to ophthalmic fluorometholone (P<0.001 for all).

In a small trial (N=40) measuring ocular comfort, ophthalmic epinastine was rated as more comfortable

compared to ophthalmic azelastine or ophthalmic ketotifen after administration of a single drop.

Ophthalmic ketotifen was reported to be more comfortable than ophthalmic azelastine.

Using the

conjunctival allergen challenge model, ophthalmic olopatadine 0.1% was significantly more effective in

controlling itching, redness and chemosis compared to ophthalmic epinastine.

Ophthalmic olopatadine

0.2% was also shown to be more effective in preventing ocular itching and redness compared to

ophthalmic epinastine.

The ocular allergy preparations gave similar results in terms of reducing

chemosis, eyelid swelling and tearing.

Using the conjunctival allergen challenge model, ophthalmic naphazoline/pheniramine and ophthalmic

olopatadine were associated with significantly lower ocular allergy index scores (erythema, eyelid

swelling, chemosis and itching) compared to placebo.

Ophthalmic naphazoline/pheniramine was more

effective than ophthalmic olopatadine in relieving redness and chemosis, while ophthalmic olopatadine

was more effective than ophthalmic naphazoline/pheniramine for relieving itching.

The efficacy of ophthalmic formulations of cromolyn, azelastine and placebo was evaluated in patients

with seasonal allergic conjunctivitis or rhinoconjunctivitis (N=144).

Both active treatments demonstrated

a marked effect on itching, tearing and conjunctival redness on day three with a sustained improvement

on days seven and 14. Global assessment of efficacy was at least “satisfactory” for 90, 81 and 66% of

patients receiving ophthalmic azelastine, cromolyn and placebo, respectively.

Using the conjunctival allergen challenge model, a single dose of ophthalmic ketotifen was shown to be

more effective than a two-week regimen of ophthalmic cromolyn 4% in alleviating symptoms of allergic

conjunctivitis (N=56).

In another conjunctival allergen challenge trial, ophthalmic ketotifen was

significantly more effective than ophthalmic nedocromil for reducing ocular itching after both the five-

minute and 12-hour allergen challenges (N=59).

Ophthalmic ketotifen-treated eyes were significantly

more comfortable compared to ophthalmic nedocromil-treated eyes at one to 10 minutes after medication

administration. While ophthalmic emedastine and ophthalmic nedocromil were both more effective than

placebo in controlling ocular itching and redness after an allergen challenge, ophthalmic emedastine was

more effective compared to ophthalmic nedocromil in alleviating redness and itching at three and 10

minutes after an allergen challenge (N=30).

In a small trial, a single dose of ophthalmic olopatadine 0.1% was reported by patients to be more

comfortable and efficacious in reducing the itching caused by an allergen challenge than a two-week

course of ophthalmic nedocromil (N=52).

In a two-week crossover trial, physicians and patients judged

ophthalmic nedocromil and ophthalmic olopatadine 0.1% to be similarly effective in preventing signs and

symptoms of perennial allergic conjunctivitis.

Comparative studies have shown ophthalmic olopatadine

and ophthalmic emedastine were more effective in reducing ocular itching than ophthalmic ketorolac, a

nonsteroidal anti-inflammatory drug.

37,42

Therapeutic Class Review: ophthalmic antihistamines

Page 5 of 36

Table 4. Clinical Trials

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

Allergic Conjunctivitis

Torkildsen et al

Alcaftadine 0.25% one drop in each

eye once daily

placebo one drop in each eye once

daily

DB, MC, PC, RCT

Patients >10 years

of age with a

history of allergic

conjunctivitis and a

reproducible,

positive reaction to

a CAC

N=58

4 visits (study

duration not

reported)

Primary:

Ocular itching

(assessed by

subject at three,

five and seven

minutes following

CAC) and

conjunctival

redness

(assessed by

investigator at

seven, 15 and 20

minutes following

CAC)

Secondary:

Other signs and

symptoms of

allergic

conjunctivitis

(assessed by

investigator at

seven, 15 and 20

minutes following

CAC)

Primary:

Alcaftadine was associated with a statistically significant reduction in

conjunctival redness following the 16-hour (duration of action) and

15-minute (onset of action) CAC tests compared to placebo.

The differences in mean ocular itching scores at the 16-hour CAC

test were -1.731, -1.687 and -1.576 at three, five and seven minutes

following CAC, respectively, compared to placebo (P<0.001 for all

time points).

The differences in mean ocular itching scores at the 15 minute CAC

test were -1.500, -1.491 and -1.474 at three, five and seven minutes

following CAC, respectively, compared to placebo (P<0.001 for all

time points).

Mean conjunctival redness scores were significantly improved for

patients receiving alcaftadine compared to the placebo group at

seven, 15 and 20 minutes following the 15 minute and 16 hour CAC

tests (P<0.05 for all time points). The differences between groups

were not clinically significant (>1 point difference in absolute mean

scores groups).

Secondary:

Alcaftadine was associated with a statistically significant reduction in

most secondary endpoints following the 16-hour and 15-minute CAC

tests compared to placebo.

Adverse events occurred more frequently in the placebo group

compared to alcaftadine group (13.3 vs 6.7%; P value not reported).

Greiner et al

Alcaftadine 0.05% (dose and

frequency not reported)

AC, DB, PC, PRO,

RCT

Patients >18 years

of age with a

N=170

5 weeks

Primary:

Ocular itching (at

visit four, five

minutes after an

allergen

Primary:

All active treatment groups exhibited greater clinically (>1 unit

difference) and statistically significant (P<0.001) reductions in itching

scores at all time points following the 15 minute CAC test compared

to placebo. At seven minutes following a CAC test, alcaftadine

Therapeutic Class Review: ophthalmic antihistamines

Page 6 of 36

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

alcaftadine 0.01% (dose and

frequency not reported)

alcaftadine 0.25% (dose and

frequency not reported)

olopatadine 0.1% (dose and

frequency not reported)

placebo (dose and frequency not

reported)

history of ocular

allergies and/or a

positive skin test

reaction to

specified allergens

within the last 24

months and best-

corrected visual

acuity of 0.6 log

MAR or better in

each eye

challenge),

conjunctival

redness (at visit

four, 15 minutes

after an allergen

challenge)

Secondary:

Ciliary and

episcleral

redness,

chemosis, lid

swelling, tearing,

ocular mucus

discharge, nasal

symptoms and

adverse events

0.25% was significantly more effective at preventing ocular itching

compared to olopatadine (P=0.017).

At the 15-minute CAC test, mean conjunctival redness scores for all

active treatments were significantly lower at every time point

compared to placebo (P<0.05 for all).

Mean reductions in scores for olopatadine (-1.27 units) and

alcaftadine 0.25% (-1.35 units) achieved clinical significance

compared to placebo at seven minutes following CAC test (P value

not reported).

At the 16-hour CAC test (duration of action), alcaftadine was

associated with lower mean ocular itching scores compared to both

placebo and olopatadine (P values not reported). At seven minutes

following CAC test, ocular itching scores were significantly lower

with alcaftadine 0.25% compared to olopatadine (P=0.017).

At the 16-hour CAC test, alcaftadine 0.25% and olopatadine

exhibited statistically significant reductions in mean conjunctival

redness scores compared to placebo (P<0.05).

Secondary:

At both the 15-minute and 16-hour CAC tests, all treatment groups

exhibited significantly greater improvements in all secondary

endpoints compared to placebo (P<0.05).

All ocular adverse events were self-limited and mild in severity. The

most common non-ocular adverse event was nasopharyngitis. No

ocular adverse events were reported in the olopatadine treatment

group.

Abelson et al

Bepotastine 1% one drop in each

eye once daily

DB, PC, PRO,

RCT

Patients ≥10 years

of age with a

N=107

7 weeks (5

visits)

Primary:

Ocular itching at

three, five and

seven minutes

following CAC,

Primary:

Bepotastine 1 and 1.5% were associated with clinically and

statistically significant reductions in mean ocular itching scores

compared to placebo in the 15-minute onset of action and eight-hour

duration of action CAC tests (P<0.001 for all).

Therapeutic Class Review: ophthalmic antihistamines

Page 7 of 36

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

bepotastine 1.5% one drop in each

eye once daily

placebo one drop in each eye once

daily

history of allergic

conjunctivitis,

study used CAC

model

redness at seven,

15 and 20 minutes

following CAC and

safety

Secondary:

Not reported

Statistically significant reductions in conjunctival hyperemia were

achieved with both bepotastine concentrations; however, these

reductions were not considered clinically significant.

Overall, 13 patients experienced a treatment-emergent adverse

event considered related to the study drug, six whom received

bepotastine 1%, four who received bepotastine 1.5% and three who

received placebo).

Secondary:

Not reported

Williams et al

Bepotastine 1% one drop in each

eye once

bepotastine 1.5% one drop in each

eye once

placebo one drop in each eye once

DB, PC, RCT, SC

Patients ≥10 years

of age with a

history of ocular

allergies, positive

skin test to cat

hair, cat dander,

grasses, ragweed,

and/or trees within

the past 24

months and

positive bilateral

CAC reaction

within 10 minutes

of allergen

instillation

N=107

3 weeks

(4 visits)

Primary:

Patient-assessed

ocular itching,

physician-

assessed

conjunctival

redness and

safety

Secondary:

Patient-assessed

tearing, ciliary and

episcleral

redness, eyelid

swelling,

chemosis and

mucous

discharge

Primary:

The mean ocular itching scores in the PP population were

significantly lower with bepotastine 1 and 1.5% compared to placebo

(P<0.001 for both). There was a statistically significant reduction in

CAC-induced ocular itching 16 hours following administration of

bepotastine 1 and 1.5% compared to placebo in the ITT populations

(P≤0.001 for both).

In the PP population, 40.0% of patients receiving bepotastine 1.5%

experienced a two-unit reduction in ocular itching at one or more

CAC time points compared to 34.3% of those in the bepotastine 1%

group and 5.9% in the placebo group (P<0.05 for both compared to

placebo).

Of patients with severe itching, a two-unit reduction in ocular itching

score at one or more time points occurred in 8.7% of the placebo

group compared to 37.5 and 43.5% of patients receiving bepotastine

1% (P=0.001) and 1.5% (P=0.008), respectively.

Bepotastine 1% was significantly more effective compared to

placebo for reducing mean conjunctival redness seven minutes

following the 16-hour CAC test (P≤0.012). There were no clinically

significant differences (one unit or more change) in conjunctival

redness between bepotastine (1 or 1.5%) and placebo at any time

Therapeutic Class Review: ophthalmic antihistamines

Page 8 of 36

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

point 16 hours after dosing.

Secondary:

Compared to placebo, bepotastine 1 and 1.5% were associated with

statistically significant reductions in eyes with tearing (51.2 and 85.6

vs 27.5%, respectively; P<0.05 for both compared to placebo).

Improvements in tearing were significantly greater in patients

receiving bepotastine 1.5% compared to those treated with

bepotastine 1% (P=0.0046).

Macejko et al

Bepotastine 1% one drop in each

eye prior to CAC test

bepotastine 1.5% one drop in each

eye prior to CAC test

placebo one drop in each eye prior

to CAC test

DB, MC, PC, PRO,

RCT

Patients ≥10 years

of age with a

history of allergic

conjunctivitis, a

positive allergen

skin test within the

previous 24

months and CAC

response on two

separate

occasions

N=130

7 weeks

Primary:

Scores for ocular

itching and

conjunctival

hyperemia

Secondary:

Not reported

Primary:

Within three minutes following CAC test and at each other time point

thereafter (performed 15 minutes or eight hours following drug

administration), treatment with bepotastine 1 and 1.5% was

associated with a significant reduction in ocular itching scores

compared to placebo (P<0.0001 for both). Ocular itching

improvements for bepotastine 1 and 1.5% were substantially less at

the 16-hour CAC test compared to the 15- minute and eight-hour

CAC tests.

Conjunctival redness scores were significantly improved at most

time points following the 15-minute CAC test for the 1 and 1.5%

concentrations of bepotastine compared to placebo (P≤0.0125 for

both).

The most commonly reported adverse events included

nasopharyngitis (8.5%), eye irritation (3.8%) and mild taste on

instillation (3.1%). There were no reports of drowsiness or dry

mouth. Dry eye was reported for a single subject in each of the

placebo and bepotastine 1% treatment groups. Most events were

reported as mild and transient. No patients discontinued therapy due

to an adverse event.

Secondary:

Not reported

Therapeutic Class Review: ophthalmic antihistamines

Page 9 of 36

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

McCabe et al

Bepotastine 1.5% one drop in

affected eye(s) twice daily

olopatadine 0.2% one drop in

affected eye(s) once daily

AC, RCT, SB, XO

Patients ≥18 years

of age with allergic

conjunctivitis and

no concurrent

unrelated ocular

diseases and no

plans to undergo

ocular surgery

during the study

period

N=30

2 weeks

Primary:

Relief of ocular

itch, itchy/runny

nose, ocular

allergy symptoms,

eye drop comfort

and patient

preference

Secondary:

Not reported

Primary:

There was a similar improvement in the relief of morning ocular itch

between patients receiving bepotastine and olopatadine (P value not

reported). Patients treated with bepotastine reported a significantly

greater relief in evening ocular itch compared to patients receiving

olopatadine (P=0.011).

Olopatadine was significantly more effective at relieving ocular

itching in the morning compared to the evening (P<0.0001),

whereas bepotastine was equally effective at both time points.

For the all-day relief of ocular itching, significantly more patients

favored treatment with bepotastine compared to treatment with

olopatadine (63.3 vs 36.7%; P=0.04).

Bepotastine was significantly more effective at relieving morning and

evening itchy/runny nose compared to olopatadine (P=0.0001).

Bepotastine provided significantly more itchy/runny nose relief in the

evening compared to the morning (P<0.035), whereas olopatadine

provided a similar relief between morning and evening.

A significantly greater proportion of patients preferred bepotastine

compared to olopatadine for all-day relief of itchy/runny nose (66.7

vs 33.3%; P=0.01).

A greater proportion of patients preferred bepotastine with regard to

eye drop comfort compared to olopatadine (56.7 vs 43.3%; P value

not reported).

Treatment with bepotastine was significantly more effective for relief

of morning and evening ocular allergy symptoms (P=0.032 and

P<0.0001, respectively) compared to treatment with olopatadine.

Bepotastine was equally efficacious for improving ocular allergy

symptoms in the morning and evening, whereas olopatadine was

Therapeutic Class Review: ophthalmic antihistamines

Page 10 of 36

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

significantly more effective in the morning (P<0.001).

Significantly more patients preferred bepotastine for the overall

treatment of allergic conjunctivitis compared to olopatadine (66.7 vs

33.3%; P=0.01).

Secondary:

Not reported

Abelson et al

Olopatadine 0.1% one drop in one

eye every eight hours for two doses

olopatadine 0.2% one drop in one

eye once

placebo one drop in one eye every

eight hours for two doses

Study medications were

administered contralaterally.

DB, PC, RCT

Patients who

responded to the

ocular allergen

challenge, study

used CAC model

N=23

3 weeks

(3 visits)

Primary:

Ocular itching at

three, five and

seven minutes

following CAC

(allergen

administered 24

hours after study

drug instilled) and

safety

Secondary:

Not reported

Primary:

At the 24-hour CAC test, olopatadine 0.1 and 0.2% significantly

reduced itching scores compared to placebo (P=0.002 and

P=0.0007, respectively). There were no statistically significant

differences between patients receiving olopatadine 0.1 and 0.2%

(P=0.081).

Olopatadine 0.1 and 0.2% were both found to be safe and well

tolerated as used in this study. No adverse events were reported.

Secondary:

Not reported

Spangler et al

Azelastine 0.05% one drop in one

eye once

olopatadine 0.1% one drop in one

eye once

AC, DB, MC, PRO,

RCT

Patients with a

history of allergic

conjunctivitis,

study used CAC

model

N=111

21 days (3

visits)

Primary:

Ocular itching

assessments

every 30 seconds

for a total period

of 20 minutes

following CAC and

mean itching

scores

Secondary:

Primary:

At visit three (evaluation visit), azelastine and olopatadine

significantly improved ocular itching scores compared to placebo

following a CAC test (P<0.05 for both).

Olopatadine was significantly more effective compared to azelastine

for preventing ocular itching at 3.5 minutes through 20 minutes

following CAC test (P<0.05).

No adverse events were reported.

Therapeutic Class Review: ophthalmic antihistamines

Page 11 of 36

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

placebo (artificial tears) one drop in

one eye once

Study medications were

administered contralaterally.

Not reported

Secondary:

Not reported

D’Arienzo et al

Emedastine 0.05% in one eye

ketotifen 0.025% in one eye

placebo in one eye

Study medications were

administered contralaterally.

AC, DB, PC, RCT,

Patients with a

history of allergic

conjunctivitis,

study used CAC

model

N=45

3 weeks (3

visits)

Primary:

Ocular itching at

three, five and 10

minutes following

CAC and safety

Secondary:

Not reported

Primary:

Both emedastine and ketotifen significantly reduced mean itching

scores at all time points following CAC test compared to placebo

(P<0.05 for all).

There were no statistically significant differences between

emedastine and ketotifen in mean itching scores at any time points

following CAC test (P values not reported).

No adverse events were reported.

Secondary:

Not reported

Torkildsen et al

Epinastine 0.05% one drop in one

eye at each visit

ketotifen 0.025% or azelastine

0.05% one drop in other eye at

each visit

AC, DB, RCT, SC,

Patients with

allergic

conjunctivitis

N=40

4 weeks (4

visits)

Primary:

Ocular comfort at

zero, one, two and

five minutes

following

administration

(visit one), patient

description of

ocular sensation

three minutes

following

administration,

ocular drying

(visits two to four)

and safety

Primary:

The mean ocular comfort score was significantly lower (indicating

more comfort) with epinastine compared to azelastine at one, two

and five minutes and compared to ketotifen at zero minutes

(immediately) following instillation (P<0.05 for all). The mean ocular

comfort score was significantly lower with ketotifen compared to

azelastine at one and two minutes (P<0.05 for both).

The proportion of patients who reported positive descriptors (e.g.,

refreshing, soothing) with epinastine, ketotifen and azelastine was

85, 55 and 41%, respectively (P values not reported).

There were no significant differences between the treatments with

regard to ocular drying (P values not reported).

None of the 26 reported adverse events were considered to be

Therapeutic Class Review: ophthalmic antihistamines

Page 12 of 36

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

Secondary:

Not reported

serious (six for epinastine, seven for ketotifen and 12 for azelastine;

P values not reported).

Secondary:

Not reported

Lanier et al

Epinastine 0.05% one drop in one

eye once

olopatadine 0.1% one drop in one

eye once

placebo one drop in one eye once

Study medications were

administered contralaterally.

AC, DB, PC, PRO,

RCT, SC

Patients with a

history of allergic

conjunctivitis,

study used CAC

model

N=66

Duration not

reported (3

visits)

Primary:

Ocular itching at

three, five and

seven minutes

following CAC,

redness and

chemosis at 10,

15 and 20 minutes

following CAC

Secondary:

Not reported

Primary:

Patients receiving olopatadine experienced significantly lower mean

itching and conjunctival redness scores compared to patients

receiving epinastine (P=0.003 and P<0.001, respectively).

Olopatadine treatment was associated with significantly less

chemosis, ciliary redness and episcleral redness compared to

epinastine treatment (P≤0.001 for all). Comparisons to placebo were

not reported.

Secondary:

Not reported

Mah et al

Epinastine 0.05% one drop in one

eye once

olopatadine 0.2% one drop in one

eye once

placebo one drop in one eye once

Study medications were

AC, DB, PC, RCT

Patients who

responded to the

ocular allergen

challenge, study

used CAC model

N=92

7 weeks

(4 visits)

Primary:

Ocular itching at

three, five and

seven minutes

following CAC,

redness at seven,

15 and 20 minutes

following CAC,

drop comfort at 30

seconds, one, two

and five minutes

following CAC and

safety

Secondary:

Primary:

Patients treated with olopatadine experienced significantly lower

mean ocular itching scores compared to those treated with

epinastine at five (P=0.024) and seven minutes (P=0.003) following

CAC test.

Olopatadine treatment was associated with significantly lower mean

ocular redness scores compared to epinastine treatment at all time

points following CAC test (P<0.05).

Olopatadine was rated as significantly more comfortable compared

to epinastine at one minute following administration (P=0.003).

Adverse events were not considered serious and were unrelated to

study medication.

Therapeutic Class Review: ophthalmic antihistamines

Page 13 of 36

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

administered contralaterally.

Not reported

Secondary:

Not reported

Berdy et al

Ketotifen 0.025% one drop in one

eye once

olopatadine 0.1% one drop in one

eye once

Study medications were

administered contralaterally.

AC, DB, PRO,

RCT, SC

Patients

responding to a

CAC

N=32

Duration not

reported (3

visits)

Primary:

Ocular itching at

three, five and 10

minutes following

CAC (12 hours

after

administration),

ocular comfort and

patient satisfaction

Secondary:

Not reported

Primary:

Twelve hours following administration, efficacy scores for

olopatadine were significantly higher at three and five minutes

following CAC test compared to ketotifen (1.84 and 1.75 vs 1.25 and

1.34, respectively; P<0.05 for both).

Olopatadine-treated eyes were rated as significantly more

comfortable immediately following administration compared to eyes

treated with ketotifen (P<0.05) and 12 hours later, as measured by

patient ratings of ocular comfort.

Of the 22 patients who had a preference, 16 (73%) were more

satisfied with olopatadine than with ketotifen.

Secondary:

Not reported

Leonardi et al

Ketotifen 0.025% one to two drops

in each eye daily as needed

olopatadine 0.1% one to two drops

in each eye daily as needed

Patients were instructed to use

both medications as needed over

four weeks, but not to exceed two

drops of medication per-eye per-

day.

AC, DB, MC

Patients with

current symptoms

of SAC or PAC

N=100

4 weeks (2

visits)

Primary:

Patient rating of

comfort, efficacy

and preference

Secondary:

Not reported

Primary:

A significantly greater percentage of patients (81%) preferred

olopatadine compared to ketotifen with regard to comfort, efficacy,

improvement in symptoms of allergy and which medication they

would select if visiting the their physician (P<0.0001).

Seventy-six percent of patients considered both efficacy and comfort

when making their preference decisions (P<0.0001). No adverse

events were reported.

Secondary:

Not reported

Therapeutic Class Review: ophthalmic antihistamines

Page 14 of 36

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

Ganz et al

Ketotifen 0.025% one drop in both

eyes twice daily

olopatadine 0.1% one drop in both

eyes twice daily

AC, DB, PG, PRO,

RCT

Patients with SAC

N=66

3 weeks

Primary:

Responder rate

(patients with

“excellent” or

“good” global

efficacy) on day

five and 21,

patient and

investigator

ratings of global

efficacy, comfort

and safety

Secondary:

Not reported

Primary:

The responder rate was higher with ketotifen compared to

olopatadine on day five (72 vs 54% for patient assessment and 88

vs 55% for investigator assessment, respectively) and day 21 (91 vs

55% and 94 vs 42%, respectively; P values not reported).

Global efficacy ratings were higher with ketotifen, and severity

scores for hyperemia and itching were significantly lower compared

to olopatadine (P values not reported).

Both drugs elicited comparable comfort ratings (P values not

reported). The most common adverse events were burning/stinging

and headache.

Secondary:

Not reported

Avunduk et al

Ketotifen 0.025% two drops in both

eyes twice daily

olopatadine 0.1% two drops in both

eyes twice daily

placebo (artificial tears) two drops

in both eyes twice daily

AC, DB, PRO,

RCT

Patients with SAC

N=39

30 days

Primary:

Scores for itching,

tearing, redness,

chemosis, eyelid

swelling and

safety

Secondary:

Not reported

Primary:

Mean itching scores were significantly lower on days 15 and 30 in

patients treated with ketotifen and olopatadine compared to placebo

(P<0.05 for all). There were no statistically significant differences in

mean itching scores between patients receiving ketotifen or

olopatadine at any time point.

Mean tearing scores were significantly lower on days 15 and 30 for

patients receiving ketotifen compared to patients receiving placebo

(P<0.05 for both). Mean tearing scores were significantly lower on

day 15 (P<0.05) but not day 30 (P value not reported) for patients

receiving olopatadine compared to patients receiving placebo. There

were no statistically significant differences in mean tearing scores

between ketotifen and olopatadine treatment groups.

No statistically significant differences in mean scores for redness,

chemosis or eyelid swelling were reported between patients

receiving ketotifen, olopatadine or placebo. No adverse events were

observed during the study.

Therapeutic Class Review: ophthalmic antihistamines

Page 15 of 36

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

Secondary:

Not reported

Borazan et al

Ketotifen 0.025% one drop in one

eye twice daily

olopatadine 0.1% one drop in one

eye twice daily

emedastine 0.05% one drop in one

eye twice daily

epinastine 0.05% one drop in one

eye twice daily

fluorometholone 0.1% one drop in

one eye twice daily

placebo one drop in one eye twice

daily

One eye of each patient was

treated with the study drug and the

other eye was treated with placebo.

AC, DB, PC, PRO,

RCT

Patients with SAC

N=100

2 weeks

Primary:

Scores for itching,

redness, tearing,

chemosis and

eyelid swelling

assessed after

one and two

weeks of

treatment and

conjunctival

impression

cytology at

baseline and after

treatment

Secondary:

Not reported

Primary:

After one and two weeks of treatment, all agents were significantly

more effective in alleviating itching, redness, tearing, chemosis and

eyelid swelling compared to placebo (P<0.001 for all).

Fluorometholone was significantly less effective in reducing itching

and redness at all visits compared to the other agents (P values not

reported). Although scores for tearing, chemosis and eyelid swelling

showed a clinical improvement in all groups, there were no

statistically significant differences between treatment groups (P

values not reported).

At the end of treatment, conjunctival impression cytology scores

were significantly lower for all active treatments compared to

placebo (P<0.01). There were no statistically significant differences

between treatment groups (P values not reported).

Secondary:

Not reported

Therapeutic Class Review: ophthalmic antihistamines

Page 16 of 36

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

Greiner et al

Olopatadine 0.1% 40 µL in one eye

once

naphazoline/pheniramine 0.025%/

0.3% 40 µL one eye once

placebo 40 µL in one eye once

AC, DB, PC, PRO,

RCT

Patients with

allergic

conjunctivitis,

study used CAC

model

N=83

Duration not

reported (3

visits)

Primary:

Ocular allergy

index including

erythema in three

vessel beds,

chemosis, eyelid

swelling and

itching at seven,

12 and 20 minutes

following CAC

Secondary:

Not reported

Primary:

At visit three (evaluation visit), both olopatadine and

naphazoline/pheniramine treatments were associated with

significantly lower ocular allergy index scores compared to placebo

at all time points (P<0.001).

Ocular allergy index scores were significantly lower with

naphazoline/pheniramine treatment compared to olopatadine at 12

minutes and 20 minutes (P=0.005 and P=0.001, respectively).

Olopatadine was associated with significantly lower itching scores

compared to naphazoline/pheniramine at seven minutes following

the CAC test (P=0.029).

Secondary:

Not reported

Owen et al

Ophthalmic antihistamines

(antazoline* one trial, azelastine

one trial, emedastine one trial,

levocabastine* six trials )

ophthalmic mast cell stabilizers

(cromolyn 17 trials, lodoxamide one

trial and nedocromil five trials)

ophthalmic mast cell stabilizers

(cromolyn five trials, lodoxamide

one trial and nedocromil two trials)

MA of 40 DB, RCT

Patients with SAC

N=not

reported

Duration

varied

Primary:

Subjective

symptoms (e.g.,

ocular itching,

burning, soreness

and lacrimation)

and patient’s

perception of

improvement in

subjective

symptoms

Secondary:

Not reported

Primary:

Most studies showed improvement in symptoms, especially for

itching, in those treated with antihistamines compared to placebo.

No antihistamine was more effective than another.

Limited evidence suggests that antihistamines have a faster

therapeutic effect compared to mast cell stabilizers; however, there

was little difference in treatment efficacy after two weeks.

Two short-term allergen provocation studies reported significantly

less ocular itching and redness in patients treated with

antihistamines compared to patients treated with mast cell

stabilizers (P<0.05); however, no significant differences in subjective

symptoms were noted in six long-term studies. Patients using

antihistamines were 1.3 times (95% CI, 0.8 to 2.2) more likely to

perceive a “good” treatment effect compared to patients using mast

cell stabilizers; however, this was not statistically significant.

Eight studies recorded subjective symptoms comparing cromolyn to

placebo. An improvement in subjective symptoms was reported in

Therapeutic Class Review: ophthalmic antihistamines

Page 17 of 36

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

placebo

five studies with no difference between treatments reported in three

trials. A MA of six trials demonstrated that patients using cromolyn

were 17 times (95% CI, 4 to 78) more likely to perceive benefit than

those using placebo (of note, trials reporting marked and statistically

significant benefits of cromolyn over placebo had small sample

sizes.) No clinically relevant adverse events were reported with

cromolyn treatment.

In a small trial lasting four weeks, patients using lodoxamide

reported significantly fewer symptoms of burning and itching, eyelid

swelling, lacrimation and photophobia compared to those using

placebo (P values not reported).

Subjective symptoms were less pronounced in patients using

nedocromil compared to patients using placebo with the differences

reported as statistically significant in three studies. Patients using

nedocromil were 1.8 times (95% CI, 1.3 to 2.6) more likely to report

that their symptoms were “moderately” or “totally” controlled than

those receiving placebo. Unpleasant taste following administration

was the most reported adverse event.

Patients using mast cell stabilizers were 4.9 times (95% CI, 2.5 to

9.6) more likely to perceive benefit from treatment compared to

patients receiving placebo. No trials directly compared mast cell

stabilizers with one another.

Secondary:

Not reported

James et al

Azelastine (strength not reported)

in both eyes twice daily

cromolyn (strength not reported) in

DB (azelastine vs

placebo), MC, PG,

OL (azelastine vs

cromolyn)

Patients with SAC

rhinoconjunctivitis

N=144

2 weeks

Primary:

Ocular signs and

symptoms, global

assessment of

efficacy and safety

Secondary:

Not reported

Primary:

Both azelastine and cromolyn demonstrated an effect on itching,

tearing and conjunctival redness on day three with a sustained

improvement on days seven and 14 compared to placebo. A clear

response to treatment occurred in 85.4% of azelastine patients and

83.0% of cromolyn patients compared to 56.3% of patients receiving

placebo (P=0.005 and P=0.007, respectively).

Therapeutic Class Review: ophthalmic antihistamines

Page 18 of 36

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

both eyes four times daily

placebo in both eyes twice daily

and symptomatic

at time of inclusion

Global assessment of efficacy was at least satisfactory for 90.0% of

azelastine patients, 81.3% of cromolyn patients and 66.3% of

placebo-treated patients (P values not reported).

The most frequent adverse events were transient application site

reactions, which tended to disappear with increasing duration of

treatment, and, less frequently, taste perversion.

Secondary:

Not reported

Greiner et al

Cromolyn 4% in one eye four times

daily for two weeks then one drop

once at the final visit

placebo other eye four times daily

for two weeks then ketotifen

0.025% one drop once

AC, SB

Patients who

responded to the

conjunctival

provocation test,

study used CAC

model

N=56

2 weeks

Primary:

Ocular itching,

tearing and

redness following

CAC, comfort and

safety

Secondary:

Not reported

Primary:

At the 15-minute and four-hour CAC tests, ketotifen was significantly

more effective than cromolyn in preventing itching (P<0.001) and

redness (P≤0.001) at most assessments. Tearing scores were

higher in patients receiving cromolyn compared to patients receiving

ketotifen.

Patients reported greater comfort in the eyes treated with ketotifen

compared to cromolyn; however, the difference was not statistically

significant (P=0.066). The most common adverse event associated

with cromolyn was burning/stinging.

A single dose of ketotifen was more effective than a two-week

regimen of cromolyn in alleviating symptoms of allergic conjunctivitis

in the CAC model.

Secondary:

Not reported

Katelaris et al

Cromolyn 2%* one drop in both

eyes four times daily

olopatadine 0.1% one drop in both

AC, DB, MC, PG,

RCT

Patients ≥4 years

of age with SAC

N=185

6 weeks

Primary:

Scores for ocular

itching and

conjunctival

redness

Secondary:

Physicians’

Primary:

After the first administration of cromolyn and olopatadine, self-rated

ocular itching and redness scores decreased significantly from

baseline (P<0.05 both). At 30 minutes after the first administration,

self-rated ocular itching and redness decreased by 30 and 20% in

each group, respectively. By four hours, itching had decreased by

38% in both groups, and redness had decreased by 26% with

cromolyn and 38% with olopatadine. Differences between

Therapeutic Class Review: ophthalmic antihistamines

Page 19 of 36

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

eyes twice daily and placebo one

drop both eyes twice daily

impression of

overall

improvement and

safety

treatments were not statistically significant.

The reductions in ocular itching were significantly greater with

olopatadine compared to cromolyn from days three to 42 (P<0.05).

Improvements in ocular redness scores were significantly greater

with olopatadine compared to cromolyn at day 42 (P<0.05).

Secondary:

The difference in physicians’ impression of overall improvement on

days 30 and 42 significantly favored olopatadine over cromolyn

(P<0.05 on both days).

Both treatments were well tolerated by patients in all age groups;

however, olopatadine appeared to have better local tolerability in

children <11 years of age compared to cromolyn.

Discepola et al

Emedastine 0.05% in one eye and

placebo in other eye once

ketorolac 0.5% in one eye and

placebo in the other eye once

Patients received the alternate

treatment in one eye and placebo

in the contralateral eye at day 14.

AC, DB, PC, RCT,

SC, XO

Patients with a

history of allergic

conjunctivitis,

study used CAC

model

N=36

4 weeks

Primary:

Ocular itching and

redness at three,

10 and 20 minutes

following CAC and

ocular discomfort

Secondary:

Not reported

Primary:

Emedastine significantly inhibited ocular itching and redness in

vascular beds compared to placebo (P<0.05). Ketorolac failed to

significantly inhibit ocular itching or redness compared to placebo (P

value not reported).

Patient assessment of comfort indicated emedastine was

significantly more comfortable compared to ketorolac upon topical

ocular administration (P<0.05).

Secondary:

Not reported

Orfeo et al

Emedastine 0.05% in one eye once

and placebo other eye once

nedocromil 2% in one eye once

AC, DB, PC, RCT,

Patients with a

history of allergic

conjunctivitis,

study used CAC

model

N=30

Duration not

reported (3

visits)

Primary:

Ocular itching and

redness at three,

10 and 20 minutes

following CAC

Secondary:

Not reported

Primary:

Emedastine and nedocromil were significantly more effective

compared to placebo in controlling ocular itching and redness

following CAC test (P<0.01).

Emedastine was significantly more effective in alleviating redness

and itching at three and 10 minutes after the allergen CAC test

compared to nedocromil (P<0.01).

Therapeutic Class Review: ophthalmic antihistamines

Page 20 of 36

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

and placebo other eye once

Each patient received both study

drugs on two different visits.

Secondary:

Not reported

Greiner et al

Ketotifen 0.025% one drop in one

eye once

nedocromil 2% one drop in one eye

once

placebo (artificial tears) one drop in

one eye once

Study medications were

administered contralaterally.

AC, DB, PC, RCT,

Patients >10 years

with a history of

allergic

hypersensitivity to

animal dander or

grass, tree or

ragweed pollens,

study used CAC

model

N=59

35 days (4

visits)

Primary:

Ocular itching

every 30 seconds

for 20 minutes

following CAC

(five minutes and

12 hours after

medication

administration);

medication

comfort at zero,

one, two, five and

10 minutes after

administration,

terms used to

describe comfort,

patient preference

based on comfort

and perceived

efficacy and safety

Secondary:

Not reported

Primary:

Eyes treated with ketotifen experienced significantly less ocular

itching compared to eyes treated with nedocromil and placebo after

both the five-minute and 12-hour CAC tests (P<0.05 for both). Eyes

treated with nedocromil did not experience improvements in ocular

itching compared to eyes treated with placebo at any time point.

Ketotifen-treated eyes were not significantly more comfortable

compared to placebo-treated eyes; however, ketotifen was

significantly more comfortable than nedocromil at one, two, five and

10 minutes following administration (P<0.05 for all).

Five minutes after administration, “comfortable” was the most

common descriptive term for ketotifen and placebo (72 and 49%,

respectively, compared to 27% for nedocromil). “Stinging” was the

most common descriptive term for nedocromil (31%). The proportion

of unfavorable descriptive terms (burning, stinging or irritation) was

6% for ketotifen, 12% for placebo and 55% for nedocromil (P values

were not reported).

Based on comfort and subjective efficacy, 60% of patients preferred

ketotifen, 21% preferred nedocromil and 19% preferred placebo.

No serious adverse events were reported. Mild burning was reported

by two patients for nedocromil-treated eyes.

Secondary:

Not reported

Butrus et al

Nedocromil 2% one drop in one

eye twice daily for two weeks then

AC, DB, PC, RCT,

Patients with

N=52

21 days (3

visits)

Primary:

Ocular itching at

three, five and 10

minutes following

Primary:

Olopatadine was significantly more effective in reducing itching

following at all time points compared to nedocromil (P<0.001).

Therapeutic Class Review: ophthalmic antihistamines

Page 21 of 36

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

one drop once

placebo one drop in one eye twice

daily for two weeks then

olopatadine 0.1% one drop in one

eye once

placebo one drop in one eye twice

daily

Study medications were

administered contralaterally.

allergic

conjunctivitis,

study used CAC

model

CAC and patient

preference based

on comfort and

efficacy

Secondary:

Not reported

Eyes treated with olopatadine were rated as being significantly more

comfortable compared to eyes treated with nedocromil (P=0.034).

Of the 14 patients treated with olopatadine and nedocromil, 10

patients (71%) were more satisfied with olopatadine than

nedocromil, and four patients (29%) had no preference.

Secondary:

Not reported

Alexander et al

Olopatadine 0.1% twice daily

nedocromil 2% twice daily

After one week, patients XO to the

other treatment for one week.

AC, RCT, XO

Patients with PAC

and previous

olopatadine

experience

N=28

2 weeks

Primary:

Patient

satisfaction,

severity of ocular

symptoms (daily

diary scores),

physician’s

assessment of

clinical signs and

global

assessments of

effectiveness

Secondary:

Not reported

Primary:

Of the 28 patients, 16 (57.1%) would request a nedocromil

prescription and 10 (35.7%) would request an olopatadine

prescription (P=0.157). Twenty-two patients (78.6%) would

recommend nedocromil to other allergy sufferers, while 18 patients

(64.3%) would recommend olopatadine (P=0.480).

Both drugs significantly (P<0.01) decreased erythema, conjunctival

injection and overall conjunctival signs from baseline. Light

sensitivity scores were significantly lower with nedocromil

(P=0.0125). Other symptom scores were comparable between

medications.

Both physicians and patients judged nedocromil and olopatadine to

be similarly effective in preventing signs and symptoms of allergic

conjunctivitis.

Secondary:

Not reported

Therapeutic Class Review: ophthalmic antihistamines

Page 22 of 36

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

Yaylali et al

Olopatadine 0.1% in one eye twice

daily and placebo in the other eye

twice daily

ketorolac 0.5% in one eye four

times daily and placebo in the other

eye four times daily

AC, PC, PG, RCT,

Patients with SAC

N=40

15 days

Primary:

Hyperemia and

itching at 30

minutes then at

two, seven and 15

days

Secondary:

Not reported

Primary:

Hyperemia and itching were significantly improved in eyes treated

with olopatadine and ketorolac compared to eyes treated with

placebo at all time points (P<0.05 for all).

The mean hyperemia score was lower in the olopatadine group

compared to the ketorolac group; however, the difference was not

statistically significant. The mean itching score was significantly

lower in the olopatadine group compared to the ketorolac group

from day two through to the end of the study (P<0.05).

Secondary:

Not reported

Berdy et al

Olopatadine 0.1% one drop in both

eyes four times daily for 14 days,

then one drop in both eyes at

evaluation visit

loteprednol 0.2% one drop in both

eyes four times daily for 14 days,

then one drop in both eyes at

evaluation visit

placebo one drop in both eyes four

times daily for 14 days, then one

drop in both eyes at evaluation visit

AC, DB, PG, RCT,

Patients >18 years

of age with a

history of SAC or

PAC with no

severe atopic,

vernal or giant

papillary

conjunctivitis

N=50

21 days

Primary:

Scores for itching

and redness and

IOP

Secondary:

Not reported

Primary:

Greater itching relief was achieved following treatment with

olopatadine compared to loteprednol at three, five and 10 minutes

following CAC test (P=0.001, P<0.001 and P<0.001, respectively).

Treatment with loteprednol significantly decreased itching scores

compared to treatment with placebo at three and five minutes

following CAC test (P<0.05 for both). No statistically significant

difference between these two groups was reported at 10 minutes (P

value not reported).

Olopatadine provided a significant improvement in itching relief

compared to placebo (P<0.001 at three, five and 10 minutes).

Olopatadine was significantly more effective for the prevention of

ocular redness compared to loteprednol at minutes 10, 15 and 20

(P=0.003, P=0.011 and P=0.034, respectively).

No statistically significant difference in the prevention of ocular

redness was reported at minutes 10, 15 and 20 for loteprednol

compared to placebo (P value not reported).

Olopatadine was significantly more effective for preventing ocular

Therapeutic Class Review: ophthalmic antihistamines

Page 23 of 36

Study and Drug Regimen

Study Design and

Demographics

Sample Size

and Study

Duration

End Points Results

redness at 10, 15 and 20 minutes compared to placebo (P<0.001,

P=0.012 and P=0.027, respectively).

There was a statistically significant increase in IOP during the third

visit with loteprednol compared to both olopatadine and placebo

(P<0.001 for both).

There were no adverse events reported during the course of study.

Secondary:

Not reported

*Agent not available in the United States.

The conjunctival allergen challenge model usually consisted of three visits. At visit one, the allergen concentration that elicited the desired ocular allergic response was determined, and this

concentration was confirmed at visit two. At visit three, the study drugs were administered prior to the allergen challenge.

Study abbreviations: AC=active-controlled, CI=confidence interval, DB=double-blind, MA=meta-analysis, MC=multicenter, OL=open-labeled, PC=placebo-controlled, PG=parallel-group,

PRO=prospective, RCT=randomized controlled trial, SB=single-blind, SC=single center, XO=cross over

Miscellaneous abbreviations: CAC=conjunctival allergen challenge, IOP=intraocular pressure, ITT=intent to treat population, MAR=Minimum angle of resolution, SAC=seasonal allergic conjunctivitis,

PAC=perennial allergic conjunctivitis, PP=per-protocol population

Therapeutic Class Review: ophthalmic antihistamines

Page 24 of 36

Special Populations

Table 5. Special Populations

1-10

Generic

Name

Population and Precaution

Elderly/

Children

Renal

Dysfunction

Hepatic

Dysfunction

Pregnancy

Category

Excreted

in Breast

Milk

in children <2 years of

age have not been

established.

Ketotifen

No evidence of overall

differences in safety or

efficacy observed

between elderly and

younger adult patients.

Safety and effectiveness

in children <3 years of

age have not been

established.

No dosage

adjustment is

required.

No dosage

adjustment is

required.

Unknown

Olopatadine

No evidence of overall

differences in safety or

efficacy observed

between elderly and

younger adult patients.

Safety and effectiveness

in children <3 years

(0.1%) and <2 years

(0.2%) of age have not

been established.

No dosage

adjustment is

required.

No dosage

adjustment is

required.

Unknown

Adverse Drug Events

Table 6. Adverse Drug Events

1-10

Adverse Event(s)

Alcaftadine

Azelastine

Bepotastine

Emedastine

Epinastine

Ketotifen

Olopatadine

Central Nervous System

Abnormal dreams

Asthenia

Fatigue

1 to 10

Headache

2 to 5

1 to 3

10 to 25

Dermatological

Dermatitis

Pruritus

1 to 10

Rash

Gastrointestinal

Nausea

Taste perversion

Ocular

Blurred vision

1 to 10

Therapeutic Class Review: ophthalmic antihistamines

Page 26 of 36

Adverse Event(s)

Alcaftadine

Azelastine

Bepotastine

Emedastine

Epinastine

Ketotifen

Olopatadine

Burning

1 to 10

Conjunctival injection

10 to 25

Conjunctivitis

1 to 10

Corneal infiltrates

Corneal staining

Discharge

Discomfort

Dry eye

Eyelid disorder/edema

Folliculosis

1 to 10

Foreign body sensation

Hyperemia

1 to 10

Irritation

2 to 5

Itching

1 to 10

Keratitis

Lacrimation disorder



Mydriasis

Pain

1 to 10

Photophobia

Redness

Stinging

Tearing

Respiratory

Asthma

1 to 10

Cold/flu symptoms

1 to 10

<10

Cough

1 to 3

Dyspnea

1 to 10

Nasopharyngitis

2 to 5

Pharyngitis

1 to 10

1 to 3

<10

Rhinitis

1 to 10

1 to 3

10 to 25

Sinusitis

1 to 3

Other

Allergic reaction

Back pain

Bitter taste

Hypersensitivity

Infection

Influenza

Percent not specified.

- Event not reported or incidence <1%.

Therapeutic Class Review: ophthalmic antihistamines

Page 27 of 36

Contraindications

Table 7. Contraindications

1-10

Contraindication(s)

Alcaftadine

Azelastine

Bepotastine

Emedastine

Epinastine

Ketotifen

Olopatadine

Known or suspected

hypersensitivity to any

components of the product

  

 

Warnings/Precautions

Table 8. Warnings and Precautions

1-10

Warning/Precaution

Alcaftadine

Azelastine

Bepotastine

Emedastine

Epinastine

Ketotifen

Olopatadine

Contact lens use: patients

should not wear a contact

lens if eye is red

      

Contact lens use; remove

contact lenses prior to

instilling this product, as the

preservative, benzalkonium

chloride may be absorbed by

soft contact lenses

      

Contamination of tip and

solution; do not to touch

eyelids or surrounding areas

with the dropper tip of the

bottle

      

For topical use only



Drug Interactions

No drug interactions have been reported for ophthalmic antihistamines.

1-10

Therapeutic Class Review: ophthalmic antihistamines

Page 28 of 36

Dosage and Administration

Table 9. Dosing and Administration

1-10

Generic

Name

Adult Dose Pediatric Dose Availability

Alcaftadine

Allergic conjunctivitis:

Ophthalmic solution:

instill one drop into

affected eye(s) once

daily

Allergic conjunctivitis:

Children ≥2 years of age, refer to adult

dose.

Safety and effectiveness in children <2

years of age have not been established.

Ophthalmic

solution:

0.25% (3 mL)

Azelastine Allergic conjunctivitis:

Ophthalmic solution:

instill one drop in

affected eye(s) twice

daily

Allergic conjunctivitis:

Children ≥3 years of age, refer to adult

dose.

Safety and effectiveness in children <3

years of age have not been established.

Ophthalmic

solution:

0.05% (6 mL)

Bepotastine

Allergic conjunctivitis:

Ophthalmic solution:

instill one drop in

affected eye(s) twice

daily

Allergic conjunctivitis:

Children ≥2 years of age, refer to adult

dose.

Safety and effectiveness in children <2

years of age have not been established.

Ophthalmic

solution:

1.5% (5, 10 mL)

Emedastine

Allergic conjunctivitis:

Ophthalmic solution:

instill one drop in

affected eye(s) up to

four times daily

Allergic conjunctivitis:

Children ≥3 years of age, refer to adult

dose.

Safety and effectiveness in children <3

years of age have not been established.

Ophthalmic

solution:

0.05% (5 mL)

Epinastine

Allergic conjunctivitis:

Ophthalmic solution:

instill one drop in

affected eye(s) twice

daily

Allergic conjunctivitis:

Children ≥2 years of age, refer to adult

dose.

Safety and effectiveness in children <2

years of age have not been established.

Ophthalmic

solution:

0.05% (5 mL)

Ketotifen Allergic conjunctivitis,

ocular itching:

Ophthalmic solution:

instill 1 drop in

affected eye(s) twice

daily

Allergic conjunctivitis, ocular itching:

Children ≥3 years of age, refer to adult

dose.

Safety and effectiveness in children <3

years of age have not been established.

Ophthalmic

solution:

0.025% (5, 10

mL)

Olopatadine

Allergic conjunctivitis:

Ophthalmic solution:

initial, instill one drop

(0.1%) in affected

eye(s) twice daily or

one drop (0.2%) in

affected eye(s) once

daily

Allergic conjunctivitis:

Children ≥2 (0.2%) and ≥3 (0.1%) years

of age, refer to adult dose.

Safety and effectiveness in children <3

years (0.1%) and <2 years (0.2%) of

age have not been established.

Ophthalmic

solution:

0.1% (5 mL)

0.2% (2.5 mL)

Therapeutic Class Review: ophthalmic antihistamines

Page 29 of 36

Clinical Guidelines

Table 10. Clinical Guidelines

Clinical Guideline

Recommendations

American Optometric

Association:

Optometric Clinical

Practice Guideline:

Care of the Patient

With Conjunctivitis

(2007)

Allergic conjunctivitis (includes atopic keratoconjunctivitis, simple allergic

conjunctivitis, seasonal or perennial conjunctivitis and vernal conjunctivitis)

• The treatment of allergic conjunctivitis is based upon identification of

specific antigens and elimination of specific pathogens, when

practical, and upon the use of medications that decrease or mediate

the immune response. The use of supportive treatment, including

unpreserved lubricants and cold compresses, may provide

symptomatic relief.

• The following agents are useful in treating allergic conjunctivitis:

topical corticosteroids (numerous products listed),

vasoconstrictors/antihistamines (specific products not listed),

antihistamines (azelastine, emedastine and levocabastine*), NSAIDs

(ketorolac), mast cell stabilizers (cromolyn, lodoxamide, nedocromil

and pemirolast), antihistamines/mast cell stabilizers (ketotifen and

olopatadine) and immunosuppressants; and systemic

immunosuppressants and antihistamines.

• Topical corticosteroids are effective in relieving the acute symptoms of

allergy; however, their use should be limited to the acute suppression

of symptoms because of the potential for adverse side effects with

prolonged use (e.g., cataract formation and elevated intraocular

pressure).

• Topical vasoconstrictors/antihistamines cause vascular constriction,

decrease vascular permeability and reduce ocular itching by blocking

histamine H

receptors. The guideline does not address the role of

prescription vasoconstrictors in the management of allergic

conjunctivitis.

• Topical antihistamines competitively bind with histamine receptor sites

and reduce itching and vasodilation. Azelastine, emedastine and

levocabastine* are effective in reducing the symptoms of allergic

conjunctivitis, and emedastine may be more efficacious than

levocabastine*.

• Topical diclofenac and ketorolac, which are both NSAIDS, are

effective in reducing the signs and symptoms associated with allergic

conjunctivitis, although only ketorolac is FDA approved for this

indication.

• Nedocromil, an effective treatment for seasonal allergic conjunctivitis,

is more effective than cromolyn (2%

†

) in treating vernal conjunctivitis.

Nedocromil was less effective than fluorometholone in treating severe

vernal keratoconjunctivitis but has fewer side effects. Lodoxamide has

demonstrated a greater improvement in the signs and symptoms of

allergic eye disease, including vernal keratoconjunctivitis, than

cromolyn (2

†

or 4%). Pemirolast has FDA approval as a treatment to

relieve (to prevent) itching associated with allergic conjunctivitis.

• Ketotifen and olopatadine are selective histamine H

-receptor

antagonists that also have mast cell stabilizing properties. Olopatadine

may be more effective than other mast cell stabilizing agents in

targeting the subtype of mast cell found in the conjunctiva. Compared

to ketorolac or ketotifen, olopatadine is more effective in relieving the

itching and redness associated with acute allergic conjunctivitis.

• Systemically administered cyclosporine may be an effective treatment

Therapeutic Class Review: ophthalmic antihistamines

Page 30 of 36

Clinical Guideline

Recommendations

for patients with severe atopic keratoconjunctivitis. Topical

cyclosporine is an alternative to topical corticosteroids for treatment of

patients with severe atopic keratoconjunctivitis. Topical cyclosporine

may also be beneficial in patients with vernal keratoconjunctivitis who

have failed conventional therapy.

• Systemic antihistamines are useful when the allergic response is

associated with lid edema, dermatitis, rhinitis or sinusitis. They should

be used with caution because of the sedating and anticholinergic

effects of some first-generation antihistamines. Newer antihistamines

are much less likely to cause sedation, but their use may result in

increased ocular surface dryness.

Viral conjunctivitis

• Most viral conjunctivitis is related to adenoviral infection; however, no

antiviral agent has been demonstrated to be effective in treating these

infections.

• Topical NSAID therapies have shown no benefit in reducing viral

replication, decreasing the incidence of sub-epithelial infiltrates or

alleviating symptoms.

• Topical antibiotics are not routinely used to treat viral conjunctivitis,

unless there is evidence of secondary bacterial infection.

• The treatment of herpes simplex conjunctivitis may include the use of

antiviral agents such as trifluridine, although there is no evidence that

this therapy results in a lower incidence of recurrent disease or

keratitis.

• Supportive therapy, including lubricants and cold compresses, which

may be as effective as antiviral drugs, eliminates the potential for toxic

side effects.

Topical steroids are specifically contraindicated for treating herpes simplex

conjunctivitis.

American Academy of

Ophthalmology:

Preferred Practice

Pattern: Conjunctivitis

(2011)

Seasonal allergic conjunctivitis

• Treatment of conjunctivitis is ideally directed at the root cause.

Indiscriminate use of topical antibiotics or corticosteroids should be

avoided because antibiotics can induce toxicity, and corticosteroids

can potentially prolong adenoviral infections and worsen herpes

simplex virus infections.

• Treat mild allergic conjunctivitis with an over-the-counter (OTC)

antihistamine/vasoconstrictor or second-generation topical histamine

-receptor antagonist. The guideline does not give preference to one

OTC antihistamine/vasoconstrictor or antihistamine vs another. The

guideline does not address the role of prescription vasoconstrictors in

the management of allergic conjunctivitis.

• If the condition is frequently recurrent or persistent, use mast-cell

stabilizers. The guideline does not give preference to one mast-cell

stabilizer vs another.

• Medications with antihistamine and mast-cell stabilizing properties

may be utilized for either acute or chronic disease. The guideline does

not give preference to one antihistamine/mast-cell stabilizer vs

another.

• If the symptoms are not adequately controlled, a brief course (one to

two weeks) of low-potency topical corticosteroid may be added to the

regimen. The lowest potency and frequency of corticosteroid

administration that relieves the patient’s symptoms should be used.

Therapeutic Class Review: ophthalmic antihistamines

Page 31 of 36

Clinical Guideline

Recommendations

• Ketorolac, a nonsteroidal anti-inflammatory drug (NSAID), is also

Food and Drug Administration (FDA)-approved for the treatment of

allergic conjunctivitis.

• Additional measures include allergen avoidance and using cool

compresses, oral antihistamines and artificial tears, which dilute

allergens and treat coexisting tear deficiency. Frequent clothes

washing and bathing before bedtime may also be helpful.

• Consultation with an allergist or dermatologist may be helpful for

patients with disease that cannot be adequately controlled with topical

medications and oral antihistamines.

Vernal/atopic conjunctivitis

• General treatment measures include modifying the environment to

minimize exposure to allergens or irritants and using cool compresses

and ocular lubricants. Topical and oral antihistamines and topical

mast-cell stabilizers may be beneficial in maintaining comfort.

• For acute exacerbations, topical corticosteroids are usually necessary

to control severe symptoms. The minimal amount of corticosteroid

should be used based on patient response and tolerance. Topical

cyclosporine is effective as adjunctive therapy to reduce the amount of

topical corticosteroid used to treat severe atopic keratoconjunctivitis.

For entities such as vernal keratoconjunctivitis, which may require

repeat short-term therapy with topical corticosteroid, patients should

be informed about potential complications of corticosteroid therapy,

and general strategies to minimize corticosteroid use should be

discussed.

• For severe sight-threatening atopic keratoconjunctivitis that is not

responsive to topical therapy, systemic immunosuppression may be

warranted. Eyelid involvement may be treated with pimecrolimus or

tacrolimus. Patients should be told to keep these medications away

from the conjunctival and corneal surface and from the tear film. Both

agents are rarely associated with the development of skin cancer and

lymphoma.

• Frequency of follow-up visits is based on the severity of disease

presentation, etiology and treatment. Consultation with a

dermatologist is often helpful. If corticosteroids are prescribed,

baseline and periodic measurement of intraocular pressure and

papillary dilation should be performed to evaluate for glaucoma and

cataract(s).

Mild bacterial conjunctivitis

• Mild bacterial conjunctivitis may be self-limited and resolve

spontaneously without treatment in immunocompetent adults.

• Ophthalmic antibacterial therapy is associated with earlier clinical and

microbiological remission compared to placebo at days two to five of

treatment. The advantages persist over six to 10 days, but the benefit

over placebo lessens over time.

• The choice of ophthalmic antibiotic is usually empirical.

• A five to seven day course of ophthalmic broad-spectrum antibiotic is

usually effective.

• The most convenient or least expensive option can be selected.

Severe bacterial conjunctivitis

Therapeutic Class Review: ophthalmic antihistamines

Page 32 of 36

Clinical Guideline

Recommendations

• Severe bacterial conjunctivitis is characterized by copious purulent

discharge, pain and marked inflammation of the eye.

• The choice of ophthalmic antibiotic is guided by the results of

laboratory tests.

• Methicillin-resistant Staphylococcus aureus (MRSA) has been isolated

with increasing frequency from patients with bacterial conjunctivitis.

Many MRSA organisms are resistant to commercially available

ophthalmic antibiotics.

• Systemic antibiotic therapy is necessary to treat conjunctivitis due to

Neisseria gonorrhoeae and Chlamydia trachomatis.

• If corneal involvement is present, the patient should also be treated

topically for bacterial keratitis.

Herpes simplex virus conjunctivitis

• Topical and/or oral antiviral treatment is recommended for h

erpes simple

virus conjunctivitis to prevent corneal infection.

•

Possible options include topical ganciclovir 0.15% gel applied three to fiv

times per day, trifluridine 1% solution applied five to eight times per day,

or oral acyclovir 200 to 400 mg administered five times per day.

• Oral valacyclovir and famciclovir also can be used.

• Topical antiviral agents may cause toxicity if used for more than two

weeks.

• Topical corticosteroids potentiate herpes simplex virus infection and

should be avoided.

• Follow-

up care management within one week of treatment is advised an

should include an interval history, visual acuity measurement and slit-

lamp biomicroscopy.

• Neonates require prompt consultation with the pediatrician or primary

care physician, because systemic herpes simplex virus

infection is a life

threatening condition.

*Product is not available in the United States.

†Cromolyn 4% but not 2% is available in the United States. The concentrations of cromolyn that were used in the original clinical

studies are noted in this table.

Conclusions

The ophthalmic antihistamines are Food and Drug Administration-approved for the management of the

signs and symptoms associated with allergic conjunctivitis, the most common form of ocular allergy. The

class of ophthalmic antihistamines includes alcaftadine (Lastacaft

), azelastine (Optivar

), bepotastine

(Bepreve

), emedastine (Emadine

), epinastine (Elestat

), ketotifen (Alaway

, Zaditor

) and olopatadine

(Pataday

, Patanol

). Most of these agents have been shown to have both histamine type 1 (H

antihistamine) and mast cell stabilizing properties. The ophthalmic antihistamines reduce itching and

redness through competitive binding with histamine receptor sites and inhibiting the degranulation of mast

cells, thus limiting the release of inflammatory mediator associated with the development of allergy

symptoms.

1-10

Few distinguishing characteristics exist between the available ophthalmic antihistamines, but alcaftadine

and olopatadine 0.2% may be administered once daily, while remaining agents in this class are

administered two to four times daily. In addition, ophthalmic alcaftadine and ophthalmic emedastine are

classified as pregnancy category B; other agents in this class are pregnancy category C.

2-11

Currently

ophthalmic formulations of azelastine, epinastine and ketotifen are available generically. Ophthalmic

formulations of ketotifen are also available in over-the-counter (OTC) formulations. Due to the ophthalmic

Therapeutic Class Review: ophthalmic antihistamines

Page 33 of 36

administration of these agents, relatively few adverse reactions have been reported, the most common

being ocular burning and stinging and headache.

According to the American Academy of Ophthalmology, mild allergic conjunctivitis may be treated with an

OTC ophthalmic antihistamine/vasoconstrictor or ophthalmic antihistamine.

Ophthalmic allergy

preparations with dual antihistamine and mast cell stabilizing properties may be used for either acute or

chronic disease, with no preference given to one agent over another.

The use of ophthalmic

vasoconstrictors including phenylephrine, should be limited due to their short duration of action and

potential to cause rebound hyperemia and conjunctivitis medicamentosa.

Ophthalmic mast cell

stabilizers may be used if the condition is recurrent or persistent, but they have a slower onset of action

than other agents.

12,14

Glucocorticoid preparations are indicated for refractory symptom, but due to the

potential for serious, vision-threatening side effects, their use should be limited a maximum of two weeks

and monitored by an ophthalmologist.

Several studies have been conducted to directly compare ophthalmic ketotifen and ophthalmic

olopatadine. These studies have produced mixed results, generally demonstrating no difference between

the agents. Results of some studies suggest that ophthalmic olopatadine may be preferred and better

tolerated by patients.

27-30

There are limited head-to-head studies that compare the clinical efficacy of the

other agents in this class to one another, and all are considered equally efficacious at improving ocular

allergy symptoms.

16,23-26,31

While some studies reported statistically significant differences in symptom

scores, the overall clinical significance of these differences is not known, as many of these trials were

conducted using single doses of study medication (in the conjunctival allergen challenge model) and

generally enrolled a small number of patients.

Therapeutic Class Review: ophthalmic antihistamines

Page 34 of 36

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