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Therapeutic Class ReviewSM Allergic conjunctivitis Updated with bepotastine ophthalmic solution (Bepreve®) February 2010

Executive Summary

New Product for Review: Dossier Provided by Manufacturer: Yes Bepotastine ophthalmic solution (Bepreve®) 1.5% Dossier Evaluation: (1) Missing significant details [Ista] of trials; no pharmacoeconomic model. 1 - Dossier missing significant clinical trial(s). 2 - Mfg. provided all relevant trials; Missing pharmacoeconomic model. 3 - Mfg. provided all relevant trials and information. Conclusion · Bepotastine ophthalmic solution (Bepreve) does not bring clinical value to the treatment of allergic conjunctivitis. · There is no reliable evidence to suggest superiority of bepotastine ophthalmic solution (Bepreve) over less expensive available ophthalmic antihistamines, mast cell stabilizers or NSAIDs for the treatment of allergic conjunctivitis. Background · Seasonal allergic conjunctivitis (SAC), due to environmental allergens, is a common condition and generally self-limited. Treatments target underlying inflammation, as well as symptom relief and prevention, including: o OTC ophthalmics: antihistamines, vasoconstrictor agents, artificial tears o Prescription ophthalmic antihistamines, mast-cell stabilizers and NSAIDs o Oral antihistamines o Use of cool compresses, allergen avoidance. · Ophthalmic antihistamines block the inflammatory effects of histamine and provide relief from ocular symptoms, without systemic absorption or related adverse events. Ophthalmic mast-cell stabilizers are also effective for prevention of ocular symptoms, but must be used consistently. Ophthalmic NSAIDs are another option, with ketorolac 0.5% indicated for treatment of SAC. [14]

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·

The previous review of this class of medications did not conclude that one antihistamine or mast cell stabilizer was clearly more efficacious than another. NSAIDs were not previously evaluated for treatment of allergic conjunctivitis.

Evidence · Two trials comparing bepotastine ophthalmic solution (Bepreve) to its vehicle for allergic conjunctivitis were not reliable because of issues with validity. These studies used a conjunctival allergen challenge (CAC) model to simulate SAC symptoms and test drug efficacy based on response to a one-time dose. Though CAC response is a surrogate for efficacy, drug efficacy in the CAC model does not validate efficacy nor is it indicative of clinical outcomes in treatment of SAC. Results may not be generalizable to patients presenting with SAC. · Two head-to-head trials comparing ophthalmic antihistamine-mast cell stabilizers (ketotifen versus olopatadine 0.1% (Patanol)) and mast cell stabilizers (nedocromil (Alocril) versus pemirolast (Alamast)) for treatment of allergic conjunctivitis were not reliable because of issues with validity. · There were no comparative trials of olopatadine (Pataday) 0.2% and other ophthalmic antihistamines for treatment of allergic conjunctivitis that met inclusion criteria for this review. · There were no comparative trials of ophthalmic NSAIDs for treatment of allergic conjunctivitis that met inclusion criteria for this review. · Overall, there is no reliable evidence to differentiate the products in this class. Efficacy is based on the CAC model. Though the CAC model is the gold-standard for establishing short-term efficacy of antihistamine-mast cell stabilizers, response does not necessarily translate in to longterm clinical benefit in patients with active allergic conjunctivitis from chronic environmental exposure. [13, 17] · Considerations in Subpopulations: - Pediatrics: The safety and efficacy of bepotastine ophthalmic solution (Bepreve) in pediatric patients below 2 years of age have not been established. - Geriatrics: No overall differences in safety or effectiveness have been observed between elderly and younger patients. - Gender, race, ethnicity: There is no apparent treatment difference due to gender, race, or ethnicity.

Non-Evidence Considerations Weighed in the Formulary Decision for ophthalmic antihistamines, mast cell stabilizers and NSAIDs Cost Bepotastine ophthalmic solution (Bepreve) is significantly more costly than other formulary alternatives. There are five generic options (one OTC) available for the treatment of allergic conjunctivitis. Several generics (Optivar, Patanol, Pataday, Xibrom) are expected within the next year. Over-the-counter ophthalmic products have not historically been covered under the prescription benefit at Regence. Disease Severity / Potential Allergic conjunctivitis is a common condition, but the medications in this review for Clinical Benefit. have questionable effectiveness in relieving only some of the symptoms, as there are no reliable comparative studies in patients with active seasonal allergic conjunctivitis. In discussions with the manufacturer, it appears bepotastine ophthalmic solution (Bepreve) will be marketed for non-ocular symptomatic relief, though this has not been validated in reliable clinical trials. Clinical experience Bepotastine has been available in Japan since 2000, as an oral agent for systemic treatment of allergic rhinitis, urticaria and pruritus.

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Member Impact Issues of convenience, administration, dosage forms

Olopatadine (Pataday) 0.2% is the second most commonly used agent in the class. Bepotastine ophthalmic solution (Bepreve) is not more convenient, as many of the formulary alternatives are twice daily dosing. Olopatadine (Pataday) 0.2% is the only option that is dosed once-daily. Most drugs in this review are not used chronically by Regence members, as evidenced by a low refill rate (see Cost Data, page 6).

Expert Opinion Expert opinion was sought from providers including primary care and ophthalmology. Comments from two providers included: · Providers generally us the least expensive OTC agents (ketotifen, Zaditor) as first line therapy, particularly for PRN use; stinging can be a problem. · One provider noted artificial tears may be equivalent to the ophthalmic allergy agents, which seem to have limited efficacy. · Mast-cell stabilizers are second-line for more severe symptoms; consistent use is needed for optimal effect, however compliance is poor. Therapy is guided by samples. · When mast cell stabilizers are ineffective, low potency steroids are effective, but used sparingly. · Patanol and Elestat are most popular. Neither provider had experience with Bepreve, as it's not allergy season and it just came out. · Because there are OTCs available with the same mechanism of action, brand name medications for allergic conjunctivitis may not be needed on formulary. · Use of prescription ophthalmics is low, perhaps because nasal steroids treat eye symptoms. Product Value Bepotastine ophthalmic solution (Bepreve) appears to add no additional value over current medication options for the treatment of allergic conjunctivitis and is more expensive than the formulary alternatives or OTC products. Decision Maintain current non-preferred/non-formulary status of bepotastine ophthalmic solution (Bepreve) because it offers no additional clinical value over less costly alternatives. Add olopatadine (Pataday) 0.2% as formulary/preferred, as it is dosed once daily, is the second most commonly prescribed drug in the class, is very similar in cost, contains the same ingredient, and is expected to go generic at the same time as formulary/preferred olopatadine (Patanol) 0.1%.

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I.

Pr oducts

A. Current ophthalmic antihistamines, mast cell stabilizers, and NSAIDs for allergic

conjunctivitis

Drug Products* FDA approval

a

Patent Expiration(s)c 9/2014

FDA approved indications

Usual Dose/Route

Potential Off-label Usesd --

Antihistamine-mast cell stabilizers bepotastine (Bepreve) 9/2009 1.5% [1] azelastine (Optivar) 0.05% [2] epinastine (Elestat) 0.05% [5] OTC ketotifen 0.025% (generic -Alaway, Claritin Eye, Zyrtec Itchy Eyes, Zaditor)

[3,6,7]

5/2000

11/2010 - 5/2011

e,f

10/2003

10/200811/2020 n/a

5/2006

olopatadine (Patanol) 0.1% [10]

12/1996

6/2011e

Treatment of itching associated with allergic conjunctivitis. Treatment of itching of the eye associated with allergic conjunctivitis. Prevention of itching associated with allergic conjunctivitis. Temporary prevention of itching of the eye due to allergic conjunctivitis. OTC: Temporary relief of itchy eyes due to ragweed, pollen, grass, animal hair and dander. Treatment of signs and symptoms of allergic conjunctivitis. Treatment of ocular itching associated with allergic conjunctivitis Temporary relief of the signs and symptoms of allergic conjunctivitis. Treatment of vernal keratoconjunctivitis, vernal conjunctivitis, and vernal keratitis. Treatment of vernal keratoconjunctivitis, vernal conjunctivitis, and vernal keratitis. Treatment of itching associated with allergic conjunctivitis. Prevention of itching of the eye due to allergic conjunctivitis. Post-op inflammation following cataract extraction Post-op pain and photophobia following corneal refractive surgery

1 drop twice daily to affected eye 1 drop twice daily to affected eye 1 drop twice daily to affected eye 1 drop twice daily (at an interval of every 8-12 hrs) to affected eye

--

Treatment of itching associated with allergic conjunctivitis. --

olopatadine (Pataday) 0.2% [11] Antihistamines emedastine (Emadine) 0.05% [4] Mast cell stabilizers cromolyn 4% (generic)

[3]

12/2004

6/2011e

1 drop twice daily (at an interval of every 6-8 hrs) to affected eye 1 drop once daily to affected eye

--

--

12/1997

12/2013

1 drop up to 4 times daily to affected eye 1-2 drops 4-6 times daily to affected eye 1-2 drops 4 times daily to affected eye, for up to 3 months 1-2 drops twice daily to affected eye 1-2 drops 4 times daily to affected eye 1 drop 4 times daily beginning 1 day postop x 14 days. 1-2 drops 1hr pre-op, then 4 times daily x 3 days post-op

--

10/1984

n/a

Prevention of itching associated with allergic conjunctivitis. Prevention of itching associated with allergic conjunctivitis. --

lodoxamide (Alomide) 0.1% [8]

9/1993

10/2012

nedocromil (Alocril) 2%

[9]

12/1999

8/2012

pemirolast (Alamast) 0.1% [12] NSAIDs diclofenac sodium 0.1% (generic)

9/1999

7/2011

Treatment of itching associated with allergic conjunctivitis. - Corneal abrasion - keratitis - laser photocoagulation - light intolerance - pain associated with foreign body - cystoid macular edema - Seasonal allergic conjunctivitis [19] - cystoid macular

03/91

n/a

flurbiprofen 0.03%

12/86

n/a

Inhibition of intraoperative

1 drop q30min 2hrs

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(generic)

miosis.

prior to surgery x 4 gtts.

ketorolac tromethamine 0.5% (generic)

11/92

n/a

Seasonal allergic conjunctivitis Post-op inflammation following cataract extraction Post-op pain and inflammation following cataract extraction Post-op pain and inflammation following cataract extraction

1 drop 4 times daily 1 drop 4 times daily beginning 1 day postop x 14 days. 1 drop twice daily beginning 1 day postop x 14 days. 1 drop 3 times daily beginning 1 day PREop, continuted on day of surgery then 14 days post-op.

edema - inflammation post cataract surgery - uveitis syndrome - cystoid macular edema - pain due to corneal abrasion - - - - conjunctivitis blepharitis episcleritis scleritis

bromfenac 0.09% (Xibrom)

03/05

1/2009 f

nepafenac ophthalmic suspension 0.1% (Nevanac)

a

08/05

6/6/2014

Date applies to approval date for the original brand name medication where there are now generics available. Cost estimate based on AWP (average wholesale price) listed in Medispan or RegenceRx Rx Price Guide as of October 6, 2009 for 1 month of therapy (or one bottle, approximately 30 days of therapy). c Based on patents listed in Orange Book as of 12/8/09. d As listed in © 1974 - 2009 Thomson MICROMEDEX database or as referenced. e Patent being disputed, therefore date of generic availability is difficult to estimate. ANDA on file with the FDA. f Generic expected soon. * All products are ophthalmic solutions, except as noted. OTC = over-the-counter, non-prescription product.

b

B. Pipeline products

Pipeline Medication

None

Manufacturer

Anticipated Launch

Potential Indication

Comments

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VIII.

1. 2. 3.

References

Bepotastine (Bepreve) 1.5% [AMCP dossier]. Irvine, CA: ISTA Pharmaceuticals, Inc.; October 2009. Azelastine (Optivar) 0.05% [package insert]. Somerset, NJ: Meda Pharmaceuticals, Inc.; 2008. Drug Facts and Comparisons. Drug Facts and Comparisons 4.0 [online]. 2009. Available from Wolters Kluwer Health, Inc. at: http://online.factsandcomparisons.com/index.aspx. Accessed December 9, 2009. Emedastine (Emadine) 0.05% [package insert]. Fort Worth, TX: Alcon Laboratories, Inc; 2002. Epinastine 0.5% (Elestat) [package insert]. Irvine, CA: Allergan Inc.; 2008. Ketotifen (Alaway) 0.025% [package label]. Rochester, NY: Bausch & Lomb; 2007. Ketotifen (Zaditor) 0.025% [package insert]. Duluth, GA: Novartis Ophthalmics; 2002. Lodoxamide (Alomide) 0.1% [package insert]. Fort Worth, TX: Alcon Laboratories, Inc.; 2002. Nedocromil (Alocril) 2% [package insert]. Irvine, CA: Allergan Inc.; 2008. Olopatadine (Patanol) 0.1% [package insert]. Fort Worth, TX: Alcon Laboratories, Inc.; 2007. Olopatadine (Pataday) 0.2% [package insert]. Fort Worth, TX: Alcon Laboratories, Inc.; 2009. Pemirolast (Alamist) 0.1% [package insert]. Jacksonville, FL: Vistakon Pharmaceuticals, LLC., Inc; 2005. Owen CG, Shah A, Henshaw K, Smeeth L, Sheikh A. Topical treatments for seasonal allergic conjunctivitis: systematic review and meta-analysis of efficacy and effectiveness. Br J Gen Pract. 2004 Jun;54(503):451-6. American Academy of Ophthalmology Cornea/External Disease Panel, Preferred Practice Patterns Committee. Conjunctivitis. San Francisco (CA): American Academy of Ophthalmology (AAO); 2008. Available at: www.aao.org/ppp. Accessed December 8, 2009. [email protected] [page on internet]. Label, approval history and review for Bepreve: Medical Review 22228. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022288s000TOC.cfm Accessed December 9, 2009. Abelson MB, Torkildsen GL, Williams JI, Gow JA, Gomes PJ, McNamara TR; 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, singlecenter, prospective, randomized, double-masked, placebo-controlled, conjunctival allergen challenge assessment in adults and children. Clin Ther. 2009 Sep;31(9):1908-21. 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. Shulman DG. Two mast cell stabilizers, pemirolast potassium 0.1% and nedocromil sodium 2%, in the treatment of seasonal allergic conjunctivitis: a comparative study. Adv Ther. 2003 JanFeb;20(1):31-40.

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