Antihistamine_20-_20Ophthalmic_20_Mast_20Cell_20Stabilizing_20Agents___20Drug_20Class_20Review

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					Drug Class Review: Ophthalmic Antihistamine/mast cell stabilizer

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Drug Class Review: Ophthalmic Antihistamine/Mast cell stabilizing agents VHA Pharmacy Benefits Management Strategic Healthcare Group and the Medical Advisory Panel

Introduction
Ocular allergic diseases have common characteristics of all allergies, including inflammation, chronicity, and recurrence. The traditional signs of inflammation, including redness, pain, swelling, and warmth of the area, are hallmarks of ocular allergy. Common ophthalmologic conditions include seasonal allergic conjunctivitis (SAC), vernal keratoconjunctivitis (VKC), vernal keratitis, and vernal conjunctivitis. Many of these diseases are present for at least 6 weeks; most are present for a much longer duration. This review will focus on the safety and efficacy of the agents as well as a comparison of the evidence available for each to determine if the agents are equally efficacious and safe. The agents included in this review can be found in Table 1.
Table 1: Ocular Antihistamine/Mast Cell Stabilizer Agents available in the U.S Generic
Azelastine Emedastine difumurate Epinastine HCL Ketotifen fumarate Olopatadine HCL

Brand (Manufacturer)
Optivar ( MedPointe Healthcare) Emadine (Alcon) Elestat (Allergan) Zaditor (Novartis) Patanol(Alcon) Olopatadine (Alcon)

Strengths & formulations
0.5mg/ml 6ml 0.05% 5ml 0.05% 5ml 0.025% 5ml 0.1% 5ml

FDA approval date
May 22, 2000 December 29, 1997 October 16, 2003 July 2, 1999 December 18, 1996

FDA-Approved Indications and Off-Label Uses 1-5
Ketotifen (Zaditor®), Olopatadine (Patanol®) and epinastine ( Elestat®) are indicated for the prevention of itching associated with allergic conjunctivitis.). Emedastine (Emadine®) and azelastine (Optivar®) are indicated for the treatment/relief of the itching associated with allergic conjunctivitis.

Methods
The agents included in this review include azelastine, emedastine difumurate, epinastine, ketotifen fumarate and olopatadine HCL. Computerized databases, including MEDLINE and Pub Med were searched for literature on the pharmacokinetics, pharmacodynamics, safety and efficacy of the ophthalmic antihistamine/mast cell stabilizing agents. Additionally, evidence based resources such as Cochrane and DARE were searched for these same criteria. Clinical trials, metaanalysis and pending publications were included in the review. Only articles published in English were considered. Literature searches included a time frame from January 1995 to January 2006.

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Pharmacology 1-6
Ophthalmic antihistamine/mast cell stabilizers combine H1-receptor actions to block ocular itching and redness with H2-receptor affinity. The H2-receptor activity limits vasodilatation, stabilization of mast cell and basophil surfaces, vascular permeability, and mucous discharge which all contribute to the inflammatory response of further redness. The agents in this class of drugs can be distinguished by the type of histamine receptor which is blocked as well as the ability to stabilize activated mast cells and prevent the release of cytokines. A comparison of the agents can be found in Table 2.

Table 2: Mechanism of Action Drug
Azelastine Emedastine difumurate Epinastine HCL Ketotifen fumarate Olopatadine HCL antihistaminic x x x x x x x x Mast cell stabilizing x

Pharmacokinetics 1-5
The topical administration of these agents has become a preferred route as it lessens systemic effects and shortens the onset of action. The pharmacokinetics of the agents can be viewed as a compilation of data regarding both topical and systemic administration of the agents. Table 3 compares the agents in terms of typical pharmacokinetic measures. The onset and duration are derived from package insert as well as clinical trial of the topical products. The remaining measures have been derived mainly from systemic administration of the agents.
Table 3: Pharmacokinetic properties
Azelastine 0.05%9 Onset Duration Metabolism Elimination 3 min 8-10hrs cP450 Clearance 0.5L/hr/kg; 75% in feces, 10% unchanged Emedastine 0.05%12 30 min 5-8 hours n/a 44% of an oral dose is excreted in the urine Epinastine 0.05% Rapid, 3-5 minutes 8 hours < 10% Total clearance 56 L/hr; IV dose excreted unchanged renal (55%) via active tubular secretion; 30% fecal elimination Plasma 12 hours 64%
7

Ketotifen 0.025%8 15 minutes 8 hours n/a n/a

Olopatadine 0.1% 10,11 n/a >8 hours Minimal 60-70% unchanged renal

Half-life Protein Binding/

22 hours 88%, metabolite 97% bound

3-4 hours n/a

n/a n/a

Plasma 3 hours 54-55%

h=hour; IV=intravenous; kg=kilogram; L=liter min.=minutes; n/a= not available

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Dosing and Administration 1-5
Table 4: Dosing and administration Drug
Azelastine Emedastine difumurate Epinastine HCL Ketotifen fumarate Olopatadine HCL dosing One drop both eyes BID One drop both eyes QID One drop both eyes BID One drop both eyes BID One- two drop both eyes BID

BID-twice daily, QID four times daily

Efficacy
All of the agents in this review have been compared to placebo in vitro, in vivo and in conjunctival antigen challenge (CAC) models.13-28 The results of these investigations have shown azelastine, emedastine, epinastine, ketotifen and olopatadine to be superior to placebo. Outcome measures have included itching and symptoms scores, hyperemia development, expression of cellular inflammation markers, histamine release and other cytokine expression. There have been trials which have compared the agents to others within this therapeutic class. Levocabastine is no longer marketed; making the results of those studies difficult to apply in practice.29-33 The majority of the studies comparing the agents involved in this review used the CAC model. In these studies, olopatadine has demonstrated statistical superiority to azelastine41and ketotifen.36 Emedastine demonstrated equivalence to ketotifen40. Epinastine was shown to be superior to olopatadine in reducing ocular itching in a small conjunctival antigen challenge study.43 Table 5 summarizes the results of these active comparator trials. There is conflicting evidence from several of these trials. In a 3-week parallel group study of ketotifen and olopatadine in 66 patients with seasonal allergic conjunctivitis, ketotifen was found to have higher global efficacy ratings and to reduce the severity of hyperemia and itching more than olopatadine38. Both agents had comparable comfort ratings. In contrast, in a 2-week study of 80 patients with symptomatic allergic conjunctivitis, ketotifen was less efficacious than olopatadine and was found to trigger mild symptoms, such as stinging, in 23% of patients.36 Several of the agents have been compared to other traditional therapies for allergic conjunctivitis such as sodium cromoglycate, nedocromil and naphazaline.43- In these trials the newer combination products demonstrated equal or superior efficacy and better patient acceptance. Meta-analyses & Systematic Reviews The evidence supporting the use of topical treatments for providing symptomatic relief from the symptoms of ocular allergy was reviewed by Owen et al46 in a systematic review/meta-analysis. The studies reviewed included randomized, controlled trials of topical mast cell stabilizers, topical antihistamines with placebo and trials of the active agents compared to each other. The overall results of the review demonstrated the benefit of topical agents in managing the symptoms associated with ocular allergy. There was not supporting evidence to determine if one agent was more efficacious than another. The authors conclude that choice of an agent should take into consideration the ease of use, patient preference and cost.

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Table 5 Clinical efficacy trials
Reference Artal et al34 Design N=80, DB,R,MC Agent 0.05%KET one drop one eye KET one drop one eye KET one drop in affected eye every 12 hr Comparator 0.1% OLO one drop, other eye OLO one drop one eye OLO one drop in affected eye Efficacy parameter Choice of agent based on ocular comfort CAC with subject satisfaction Clinical improvement Results 100% selected OLO

Berdy et al35 Aguilar et al36

N=32 N=80

16 of 22 patients (73%) preferred OLO over KET OLO 80-87.5% improved in 7 days KET 60-75% improved at 7 days. Stinging in 23% of KET patients, none in OLO

Avunduk et al37

N=39, R DB, PC

KET 2 drops per eye twice daily

OLO 2 drops per eye twice daily

Clinical scores and expression of cell adhesion molecules

Both KET and OLO reduced expression of cell adhesion molecules and decreased clinical symptoms better than artificial tears. No significant differences between active comparators Responder rate, KET 72%, OLO 54% at day 5 and 91% vs 55% at day 21 respectively 81% of patients preferred OLO for comfort and reduction of symptoms (p<0.001) Both active treatments inhibited itching compared to placebo (p< 0.05). No preference of one agent versus the other OLO significantly more effective than AZE in reducing itching at 3.5 and 20 minutes in CAC (p<0.05) OLO significantly better on itching (p=0.003) and redness scores (p<0.001)

Ganz et al38

N=66, R, DB

KET 0.025%

OLO 0.1%

Responder rate, global efficacy Patient preference for comfort and efficacy over a 4 week period Relief of itching and CAC

Leonardi et al39

N=100 MC, DB patients received both treatments N=45 R,DB,PC Patients may receive both active treatments N=111 R, DB, PC

KET 0.025%

OLO 0.1%

D’Arienzo et al40

KET 0.025%

EME 0.05%

Spangler et al41

OLO 0.1%

AZE 0.05%

Itching and CAC

Lanier, et al42

N=66 DB, R, PC

OLO 0.1%

EPI 0.05%

Itching, conjunctival redness scores from CAC

DB-double blind, R-randomized, MC-multicenter, PC placebo controlled KET- ketotifen fumarate, OLO-olopatadine, AZE-azelastine, EPI-epinastine, EME-emedastine, CAC-conjunctival antigen challenge model

Cost Effectiveness Analysis
The cost effectiveness of emedastine versus levocabastine was conducted with a model based on a clinical trial.47 This analysis was based in a European setting and involved seven countries and 221 patients. Emedastine was found to economically dominant over levocabastine based on less itching, less redness and a longer time period without symptoms. These outcomes were extrapolated from the clinical trials which used practitioner interviews for a primary outcome variable. This information is of limited usefulness as levocabastine is no longer manufactured and emedastine has twice daily dosing compared to once daily dosing for the other agents in this class. It should not be assumed that the results of this analysis can be extrapolated to the other products.

Safety /Tolerability1-5, 48-50
Generally the topical ophthalmic agents for the treatment of allergic conjunctivitis are well tolerated and have similar adverse effects. Adverse events reported may be ocular or non-ocular. It is difficult to clearly delineate the
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causality of the reported adverse events due to the similarity of the signs and symptoms of the underlying disease process. Common ocular adverse events reported with ophthalmic therapy include conjunctival hyperemia, transient burning or stinging upon instillation, eyelid edema and ocular irritation. Some common non-ocular adverse effects include headache, sinusitis, and rhinitis. No clinically relevant changes were observed regarding visual acuity, intraocular pressure, ocular signs, or fundus parameters in the studies reviewed. It has been observed during therapy with this class of agents that destabilization of ocular membranes can occur with over use of an agent. This results in a worsening of ocular itching and redness. An in vitro membrane model investigated the development of this phenomenon, comparing azelastine, ketotifen, emedastine, epinastine and olopatadine. The trial demonstrated that olopatadine was the least surface active of the agents and theoretically less chance of causing a destabilization effect.53 The clinical significance of this is unknown.

Table 9: Treatment-emergent adverse events
Agent Azelastine Clinical Studies Controlled multipledose studies where patients were treated for up to 56 days Adverse Reaction Comments Most frequently reported: -transient eye burning/stinging (approximately 30%) -headaches (approximately 15%) -bitter taste (approximately 10%) Reported in 1-10% of patients: -Asthma, conjunctivitis, dyspnea, eye pain, fatigue, influenza-like symptoms, pharyngitis, pruritus, rhinitis and temporary blurring. Most frequent was headache 11%. Reported in less than 5% of patients: -Abnormal dreams, asthenia, bad taste, blurred vision, burning or stinging, corneal infiltrates, corneal staining, dermatitis, discomfort, dry eye, foreign body sensation, hyperemia, keratitis, pruritus, rhinitis, sinusitis and tearing. Most frequently reported ocular events occurring in approximately 1-10% of patients: -Burning sensation in the eye, folliculosis, hyperemia, and pruritus. Most frequently reported non-ocular adverse events: -Infection (cold symptoms and upper respiratory infections) seen in approximately 10% of patients, and headache, rhinitis, sinusitis, increased cough, and pharyngitis seen in approximately 1-3% of patients. Some of these events were similar to the underlying disease being studied. Conjunctival injection, headaches, and rhinitis were reported at an incidence of 1025%. The following ocular and non-ocular adverse reactions were reported at an incidence of less than 5%: Ocular: Allergic reactions, burning or stinging, conjunctivitis, discharge, dry eyes, eye pain, eyelid disorder, itching, keratitis, lacrimation disorder, mydriasis, photophobia, and rash. Non-Ocular: Flu syndrome, pharyngitis. Headaches were reported at an incidence of 7%. Adverse experiences reported in less than 5% of patients: -Asthenia, blurred vision, burning or stinging, cold syndrome, dry eye, foreign body sensation, hyperemia, keratitis, lid edema, pharyngitis, pruritus, rhinitis, sinusitis, and taste perversion.

Emedastine

Controlled clinical studies lasting for 42 days

Epinastine

Reported adverse events

Ketotifen

Controlled clinical studies

Olopatadine

Reported adverse events

Contraindications

These agents are contraindicated in persons with a known hypersensitivity to the active agent or any of the solution's components.
Precautions

To prevent contaminating the dropper tip and solution, care should be taken not to touch the eyelids or surrounding areas with the dropper tip of the bottle. Keep bottle tightly closed when not in use. Patients should be advised not to wear a contact lens if their eye is red. These agents should not be used to treat contact lens related irritation. The preservative, benzalkonium chloride, may be absorbed by soft contact lenses.
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Drug Class Review: Ophthalmic Antihistamine/mast cell stabilizer

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Patients who wear soft contact lenses and whose eyes are not red, should be instructed to wait at least ten minutes after instilling the ophthalmic solution before they insert their contact lenses. Special Populations
Pregnancy category

Category B: Emedastine Category C: Olopatadine, azelastine, epinastine and ketotifen.
Nursing Mothers

It is not known whether azelastine HCl is excreted in human milk. Emedastine, epinastine, ketotifen, and olopatadine have been identified in breast milk in rats following oral administration. It is not known whether topical ocular administration could result in sufficient systemic absorption to produce detectable quantities in breast milk. Nevertheless, caution should be exercised when the ophthalmic solution is administered to a nursing mother. Pediatric Azelastine, emedastine, epinastine, ketotifen, olopatadine safety and effectiveness in pediatric patients below the age of 3 have not been established. Elderly No overall differences in safety or effectiveness have been observed between elderly and younger patients. Hepatic/Renal Impairment No studies in this population noted. Drug Interactions No significant interactions found or known. Caution is always advised with multiple medications.

Conclusion
The topical agents reviewed have demonstrated efficacy over placebo in clinical trials and in CAC models. In clinical efficacy trials comparing the agents to others within the class, all the agents were all successful in decreasing symptom scores and improving eye itching/redness. Several methods were used to rate these effects such as patient preference, global efficacy as measured by patient and provider and laboratory testing of markers of cellular inflammation. The adverse event profile of the agents is extremely similar. It is difficult to compare across trials and determine a single preferred agent as the methods and efficacy parameters are different in each of the trials. Emedastine would not be an agent of choice as it is dosed four times daily and is not a dual mechanism agent. Among the other agents, there is evidence to support effectiveness for each of them with no clearly superior agent.

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27. Orfeo V, Vardaro A, Lena P, Mensitieri I, Tracey M, De Marco 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. 28. Abelson MB, Kaplan AP. A randomized, double-blind, placebo-controlled comparison of emedastine 0.05% ophthalmic solution with loratadine 10 mg and their combination in the human conjunctival allergen challenge model. Clin Ther. 2002 Mar;24(3):445-56. 29. Abelson MB, Greiner JV. Comparative efficacy of olopatadine 0.1% ophthalmic solution versus levocabastine 0.05% ophthalmic suspension using the conjunctival allergen challenge model. Curr Med Res Opin. 2004 Dec;20(12):1953-8. 30. Giede C, Metzenauer P, Petzold U, Ellers-Lenz B. Comparison of azelastine eye drops with levocabastine eye drops in the treatment of seasonal allergic conjunctivitis. Curr Med Res Opin. 2000;16(3):153-63. PMID: 11191004 31. Verin P, Easty DL, Secchi A, Ciprandi G, Partouche P, Nemeth-Wasmer G, et al. Clinical evaluation of twice-daily emedastine 0.05% eye drops (Emadine eye drops) versus levocabastine 0.05% eye drops in patients with allergic conjunctivitis. Am J Ophthalmol. 2001 Jun;131(6):691-8. 32. Netland PA, Leahy C, Krenzer KL. Emedastine ophthalmic solution 0.05% versus levocabastine ophthalmic suspension 0.05% in the treatment of allergic conjunctivitis using the conjunctival allergen challenge model. Am J Ophthalmol. 2000 Dec;130(6):717-23. 33. Secchi A, Leonardi A, Discepola M, Deschenes J, Abelson MB. An efficacy and tolerance comparison of emedastine difumarate 0.05% and levocabastine hydrochloride 0.05%: reducing chemosis and eyelid swelling in subjects with seasonal allergic conjunctivitis. Emadine Study Group. Acta Ophthalmol Scand Suppl. 2000;(230):48-51. 34. Artal MN, Luna JD, Discepola M. A forced choice comfort study of olopatadine hydrochloride 0.1% versus ketotifen fumarate 0.05%. Acta Ophthalmol Scand Suppl. 2000;(230):64-5. 35. Berdy GJ, Spangler Dl, Bensch G, et al. 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. 36. Aguilar AJ. Comparative study of clinical efficacy and tolerance in seasonal allergic conjunctivitis management with 0.1% olopatadine hydrochloride versus 0.05% ketotifen fumarate. Acta Ophthalmol Scand Suppl. 2000;(230):52-5. 37. 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 conjunctivities: a 30-day, randomized, double-masked, artificial tear substitute-controlled trial. Clin Ther. 2005 Sep;27(9):1392-402. 38. 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. 39. Leonardi A, Zafirakis P. Efficacy and comfort of olopatadine versus ketotifen ophthalmic solutions: a double-masked, environmental study of patient preference. Curr Med Res Opin. 2004 Aug;20(8):1167-73. 40. D'Arienzo PA, Leonardi A, Bensch G. Randomized, double-masked, placebo-controlled comparison of the efficacy of emedastine difumarate 0.05% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution in the human conjunctival allergen challenge model. Clin Ther. 2002 Mar;24(3):409-16. 41. 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. 42. Lanier BQ, Finegold I, D'Arienzo P, Granet D, Epstein AB, Ledgerwood GL. Clinical efficacy of olopatadine vs epinastine ophthalmic solution in the conjunctival allergen challenge model. Curr Med Res Opin. 2004 Aug;20(8):1227-33. PMID: 15324525 43. 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 May;27(5):568-77. PMID: 15978305 44. 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 rhino-conjunctivitis. Curr Med Res Opin. 2003;19(4):313-20. 45. Katelaris CH, Ciprandi G, Missotten L, Turner FD, Bertin D, Berdeaux G; International Olopatadine Study Group. A comparison of the efficacy and tolerability of olopatadine hydrochloride 0.1% ophthalmic
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Prepared by: Kathryn Tortorice, Pharm D, BCPS, Don Nichols MD and Julie Liss Pharm D Points of contact: Julie Liss, PharmD, DOD Pharmacoeconomic Center, 2421 Dickman Road, Fort Sam Houston, TX 78234-5081 (210) 295-2792. Kathy Tortorice, PharmD, BCPS VA Pharmacy Benefits Management Office, Hines, IL. 60141 708-786-7873 Version 1, last major revision May 2006 Check for updated versions at: www.pbm.va.gov or www.pec.ha.osd.mil

October 2006 Check for updated versions at: www.pbm.med.va or vaww.pbm.va.gov