VA Class:OP300

AHFS Class:

• Corticosteroids 52:08.08

Generic Name(s):

• Loteprednol Etabonate

Chemical Name:

• 17-(ethyl carbonate) chloromethyl 11β,17-dihydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate

Molecular Formula:

• C₂₄H₃₁ClO₇

Loteprednol etabonate is a synthetic nonfluorinated corticosteroid.1,2,3,4,5,6,7,8,9,10,11,13,16,17,31

Allergic and Inflammatory Ocular Disorders

Loteprednol etabonate 0.2% ophthalmic suspension is used for the symptomatic relief of seasonal allergic (hay fever, pollinosis) conjunctivitis.2,12,17,19 Loteprednol etabonate 0.5% ophthalmic suspension also is used for the symptomatic relief of allergic conjunctivitis.1,10,17

Avoidance of allergen and other triggering factors (e.g., irritants) and application of cold compresses and lubricating eye drops are the initial means of managing allergic conjunctivitis.20,21,22 Drug therapy generally is reserved for use when such avoidance is not possible or is ineffective, and can include both prophylactic (e.g., topical mast-cell stabilizers such as cromolyn sodium, lodoxamide tromethamine, olopatadine hydrochloride) and symptomatic (e.g., topical and/or systemic antihistamines, topical vasoconstrictors, topical steroidal and nonsteroidal anti-inflammatory agents [NSAIAs]) therapy.20,21,22 The specific therapy(ies) employed will depend on the characteristics and severity of the allergic conjunctivitis.20,21,22 For patients with seasonal allergic conjunctivitis, prophylaxis with a mast-cell stabilizer often is initiated before and maintained throughout the pollen season, and symptomatic therapy with other agents (e.g., topical antihistamines, topical NSAIAs) generally is initiated as necessary to provide acute relief.20,21 Topical corticosteroids usually are reserved for short-term use in patients with moderate to severe symptoms of allergic conjunctivitis.20 Regardless of the therapy employed (antihistamine, NSAIA, corticosteroid, vasoconstrictors), relief of all of the clinically important manifestations of allergic conjunctivitis may not be possible despite combined topical and/or systemic administration.20,23 In general, the least toxic therapy providing adequate relief should be employed.20,21,22,23

Results from 2 double-blind, placebo-controlled clinical studies indicate that ophthalmic therapy with loteprednol etabonate 0.2% is more effective than vehicle in providing symptomatic relief of seasonal allergic conjunctivitis.2,12,17,19,26,30 In these studies, improvement in ocular manifestations (e.g., ocular itching, bulbar conjunctival injection) occurred within 2 hours following initiation of therapy and persisted through day 14 of therapy.2,12,17,19 At day 14, complete resolution of symptoms of bulbar conjunctival injection occurred in 31-36 or 9-15% of patients receiving loteprednol etabonate or vehicle, respectively, while resolution of itching was reported in 54-58 or 38% of these patients, respectively.12,17,19

Loteprednol etabonate 0.5% ophthalmic suspension is used for the symptomatic relief of corticosteroid-responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe such as allergic conjunctivitis, acne rosacea keratitis, superficial punctate keratitis, herpes zoster keratitis, iritis, and cyclitis.1,8,9,10,11,17

Results from one randomized, double-blind, placebo-controlled study indicate that short-term ophthalmic therapy (6 weeks) with loteprednol etabonate 0.5% initiated before the period of peak pollen exposure, is more effective than vehicle in providing symptomatic relief of seasonal allergic conjunctivitis (e.g., ocular itching, bulbar conjunctival injection).1,10,17,30 In this study, 94 or 78% of patients receiving loteprednol etabonate 0.5% or vehicle, respectively, were asymptomatic (i.e., with scores of mild or none for itching and bulbar injection) during the 3-week peak pollen season.10,17 In addition, 77 or 68% of patients receiving the 0.5% suspension or vehicle, respectively, were asymptomatic (i.e., with scores of mild or none for discomfort, tearing, and chemosis), while 86 or 64% of patients receiving the drug or vehicle, respectively, were considered asymptomatic according to the investigator global assessment (e.g., conjunctival injection, tearing, erythema, chemosis, foreign body sensation).10,17

In controlled studies in patients with contact lens-associated giant papillary conjunctivitis, ophthalmic therapy with loteprednol etabonate 0.5% for 4-6 weeks was associated with greater improvement in papillae, conjunctival injection and itching, and lens intolerance than administration of vehicle.1,8,9,11,17 In these studies efficacy of loteprednol etabonate was evident within 1 week of initiation of therapy and persisted for up to 6 weeks while therapy was continued; patients generally resumed contact lens wear within 2-3 days after starting therapy.1,8,9,11

Loteprednol etabonate 0.5% ophthalmic suspension also is used in the treatment of anterior uveitis.1,29 Results from controlled clinical studies in patients with acute anterior uveitis indicate that loteprednol etabonate 0.5% is less effective than prednisolone acetate 1% in the management of anterior uveitis as determined by reductions from baseline in anterior chamber cells and flare.1,29 At day 28, 87 or 72% of patients receiving prednisolone or loteprednol etabonate, respectively, experienced resolution of anterior chamber cells.1,29

Postoperative Ocular Inflammation

In ophthalmology, topical loteprednol etabonate 0.5% suspension is used after ocular surgery for the treatment of postoperative ocular inflammation.1,27,28 In controlled studies, topical application to the eye of loteprednol etabonate 0.5% suspension was more effective than vehicle in the management of postoperative anterior chamber inflammation as determined by slit-lamp biomicroscopic evaluation of the number of anterior chamber cells and severity of anterior chamber flare.1,27,28,30

Bacterial Ophthalmic Infections

Loteprednol etabonate is used topically in conjunction with topical tobramycin in some cases of bacterial ocular infections.31 Concomitant therapy with loteprednol etabonate and tobramycin may be used for steroid-responsive ocular inflammatory conditions for which a corticosteroid is indicated and where a superficial ocular bacterial infection or risk of ocular bacterial infection exists.31

Administration

Loteprednol etabonate alone or in fixed combination with tobramycin is applied topically to the eye as an ophthalmic suspension.1,2,8,9,10,11,12,13 The suspension should be shaken vigorously prior to use.1,2,30,31 Care should be taken to avoid contamination of the container.1,2,31

Dosage

Safety and efficacy of ophthalmic suspensions containing loteprednol etabonate alone or in fixed combination with tobramycin have not been established in children younger than 18 years of age.1,2,26,31

Allergic Conjunctivitis

For the symptomatic relief of seasonal allergic conjunctivitis in adults, the usual dosage of loteprednol etabonate is 1 drop of a 0.2% suspension in the affected eye(s) 4 times daily.2 Some clinicians recommend that the drug be used only for short-term therapy (e.g., less than 2 weeks).26

Inflammatory Ocular Disorders

For the symptomatic relief of corticosteroid-responsive inflammatory conditions in adults, the usual dosage of loteprednol etabonate is 1 or 2 drops of a 0.5% suspension in the affected eye(s) 4 times daily.1,8,9,10,11 When appropriate, therapy can be initiated with a dosage of 1 drop of loteprednol etabonate 0.5% in the affected eye(s) every hour.1 When improvement occurs, frequency of application can be decreased.1,26,30 Therapy should not be discontinued prematurely.1 Patients whose ocular condition (e.g., uveitis) fails to improve after 2 days of loteprednol therapy should be reevaluated.1,26

Postoperative Ocular Inflammation

For the treatment of postoperative ocular inflammation in adults, the usual dosage of loteprednol etabonate is 1 or 2 drops of a 0.5% suspension applied topically to the eye(s) undergoing surgery 4 times daily beginning 24 hours after surgery and continuing for 2 weeks after surgery.1,27,28

IOP should be monitored in patients receiving the drug for 10 days or longer.1,2

Bacterial Ophthalmic Infections

When the fixed-combination suspension containing loteprednol etabonate and tobramycin (Zylet^®) is used for the management of corticosteroid-responsive ocular conditions where a superficial ocular bacterial infection or risk of ocular bacterial infection exists, 1 or 2 drops of the suspension should be instilled into the affected eye(s) every 4-6 hours.31 During the initial 24-48 hours, dosing may be increased to every 1-2 hours.31 When improvement occurs, frequency of application can be decreased.31 Therapy should not be discontinued prematurely.1

Chemistry and Stability

Chemistry

Loteprednol etabonate is a synthetic nonfluorinated corticosteroid.1,2,3,4,5,6,7,8,9,10,11,13,16,17 The chemical structure of loteprednol etabonate was designed based on the structure of cortienic acid, an inactive metabolite of prednisolone,1,2,3,4,5,7,8,9,10,11,14,16 and then modified to enhance the drug's therapeutic index.3,4,5,6,7,8,9,10,11,14,16

Loteprednol etabonate differs structurally from other corticosteroids (e.g., hydrocortisone, prednisolone) by the absence of a ketone group at position C-20 and the presence of an ethylcarbonate ester and a chloromethyl carboxylate group at positions 17-α and 17-β in the steroid nucleus, respectively.1,2,3,4,5,7,8,9,10,11,13,15 Esterification of the hydroxyl group at position 17-α and introduction of a chloromethyl carboxylate group at position 17-β result in a compound that is rapidly hydrolyzed in ocular tissues to an inactive metabolite, with a resultant decreased potential for adverse effects (e.g., increase in IOP) commonly associated with topical ophthalmic corticosteroids.1,2,3,4,7,8,9,10,11,13,14,15,16,17,26,30

Loteprednol etabonate occurs as a white to off-white powder.1,2 The drug is insoluble in water and has a solubility of 0.002 mg/mL in 20% propylene glycol at 25°C.30

For topical ophthalmic use, loteprednol etabonate is commercially available as a 0.2 or 0.5% suspension.1,2 Loteprednol etabonate ophthalmic suspensions are sterile, isotonic suspensions of micronized drug in a vehicle of purified water; sodium hydroxide and/or hydrochloric acid may be added to adjust pH to between 5.3-5.6.1,2,30 The commercially available suspensions contain edetate disodium, glycerin, povidone, tyloxapol, and benzalkonium chloride as a preservative.1,2 The ophthalmic suspensions have an osmolality of 250-310 mOsm/kg.1,2

For topical ophthalmic use, loteprednol etabonate in fixed combination with tobramycin is commercially available as a sterile, isotonic suspension.31 Loteprednol etabonate and tobramycin ophthalmic suspension contains edetate disodium, glycerin, povidone, tyloxapol, benzalkonium chloride (as a preservative), and purified water; sulfuric acid and/or sodium hydroxide may be added to adjust pH to between 5.7-5.9.31 The ophthalmic suspension has an osmolality of 260-320 mOsm/kg.31

Stability

Ophthalmic suspensions containing loteprednol etabonate alone or in fixed combination with tobramycin should be stored in a dry place in well-closed containers at a temperature of 15-25°C; freezing should be avoided.1,2,30,31 To prevent sedimentation in the dispensing tip, the ophthalmic suspensions should be stored upright.1,2,31 When stored as directed, loteprednol etabonate 0.2 or 0.5% ophthalmic suspension has an expiration date of 18 or 24 months, respectively, following the date of manufacture.30

Additional Information

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, and dosage and administration of loteprednol etabonate, see the EENT Corticosteroids General Statement 52:08.08.

1. Bausch & Lomb Pharmaceuticals, Inc. Lotemax^® (loteprednol etabonate) ophthalmic suspension 0.5% prescribing information. Tampa, FL; 2005 May.

2. Bausch & Lomb Pharmaceuticals, Inc. Alrex^® (loteprednol etabonate) ophthalmic suspension 0.2% prescribing information. Tampa, FL; 1998 Mar.

3. Hochhaus G, Chen LS, Ratka A et al. Pharmacokinetic characterization and tissue distribution of the new glucocorticoid soft drug loteprednol etabonate in rats and dogs. J Pharm Sci . 1992; 81:1210-15. [PubMed 1491342]

4. Loftsson T, Bodor N. The pharmacokinetics and transdermal delivery of loteprednol etabonate and related soft steroids. Adv Drug Delivery Rev . 1994; 14:293-9.

5. Bodor N, Wu WM, Murakami T et al. Soft drugs 19. Pharmacokinetics, metabolism and excretion of a novel soft corticosteroid, loteprednol etabonate, in rats. Pharm Res . 1995; 12:875-9. [PubMed 7667193]

6. Druzgala P, Wu WM, Bodor N. Ocular absorption and distribution of loteprednol etabonate, a soft steroid, in rabbit eyes. Curr Eye Res . 1991; 10:933-7. [PubMed 1959381]

7. Anon. Corticosteroids. In: Zimmerman TJ, Kooner KS, Sharir M et al, eds. Textbook of ocular pharmacology. Philadelphia: Lippincott-Raven; 1997:620-6.

8. Asbell P, Howes J. A double-masked, placebo-controlled evaluation of the efficacy and safety of loteprednol etabonate in the treatment of giant papillary conjunctivitis. CLAO J . 1997; 23:31-6. [PubMed 9001768]

9. Friedlaender MH, Howes J for the Loteprednol etabonate Giant Papillary Conjunctivitis Study Group I. A double-masked, placebo-controlled evaluation of the efficacy and safety of loteprednol etabonate in the treatment of giant papillary conjunctivitis. Am J Ophthalmol . 1997; 123:455-64. [PubMed 9124242]

10. Dell SJ, Shulman DG, Lowry GM et al, for the Loteprednol Allergic Conjunctivitis Study Group. Am J Ophthalmol . 1997; 123:791-7. (IDIS 387183)

11. Bartlett JD, Howes JF, Ghormley NR et al. Safety and efficacy of loteprednol etabonate for treatment of papillae in contact lens-associated giant papillary conjunctivitis. Curr Eye Res . 1993; 12:313-21. [PubMed 8319490]

12. Dell SJ, Lowry GM, Northcutt JA et al. A randomized, double-masked, placebo-controlled parallel study of a 0.2% loteprednol etabonate in patients with seasonal allergic conjunctivitis. J Allergy Clin Immunol . 1998; 102: 251-5. [PubMed 9723669]

13. Novack GD, Howes J, Crockett RS et al. Changes in intraocular pressure during long-term use of loteprednol etabonate. J Glaucoma . 1998; 7: 266-9. [PubMed 9713785]

14. Bodor N, Bodor N, Wu WM. A comparison of intraocular pressure elevating activity of loteprednol etabonate and dexamethasone in rabbits. Curr Eye Res . 1992; 11:525-30. [PubMed 1505197]

15. Bartlett JD, Horwitz B, Laibovitz R et al. Intraocular pressure response to loteprednol etabonate in known steroid responders. J Ocul Pharmacol . 1993; 9:157-65. [PubMed 8345288]

16. Bodor N. Design of novel soft corticosteroids. Curr Probl Dermatol . 1993; 21:11-9. [PubMed 8299363]

17. Anon. Loteprednol etabonate. Drugs Future . 1997; 22:1086-90.

18. Howes JF, Baru H, Vered M et al. Loteprednol etabonate: comparison with other steroids in two models of intraocular inflammation. J Ocul Pharmacol . 1994; 10:289-93. [PubMed 8207332]

19. Schulman DG, Lothringer LL, Rubin JM et al. A randomized, double-masked, placebo controlled , parallel study of loteprednol etabonate 0.2% in patients with seasonal allergic conjunctivitis. Ophthalmology . 1999; 106:362-9. [PubMed 9951491]

20. Ciprandi G, Buscaglia S, Cerqueti PM et al. Drug treatment of allergic conjunctivitis: a review of the evidence. Drugs . 1992; 43:154-76. [PubMed 1372215]

21. Friedlaender MH. Current concepts in ocular allergy. Ann Allergy . 1991; 67:5-10,13. [PubMed 1859041]

22. Trocme SD. Medical therapy for ocular allergy. Mayo Clin Proc . 1992; 67:557-65. [PubMed 1359206]

23. Reviewers' comments (personal observation) ketorolac tromethamine ophthalmic solution.

24. Tinkelman DG, Rupp G, Kaufman H et al. Double-masked, paired-comparison clinical study of ketorolac tromethamine 0.5% ophthalmic solution compared with placebo eyedrops in the treatment of seasonal allergic conjunctivitis. Surv Ophthalmol . 1993; 38(Suppl): 133-140. [PubMed 8236004]

25. Ballas Z, Blumenthal M, Tinkeman DG et al. Clinical evaluation of ketorolac tromethamine 0.5% ophthalmic solution for the treatment of seasonal allergic conjunctivitis. Surv Ophthalmol . 1993; 38(Suppl): 141-8.

26. Reviewers' comments (personal observations).

27. The Loteprednol Etabonate Postoperative Inflammation Study Group 2. A double-masked, placebo-controlled evaluation of 0.5% loteprednol etabonate in the treatment of postoperative inflammation. Ophthalmology . 1998; 105:1780-6. [PubMed 9754192]

28. Stewart R, Horwitz B, Howes J et al. Double-masked, placebo-controlled evaluation of loteprednol etabonate 0.5% for postoperative inflammation. Loteprednol Etabonate Post-operative Inflammation Study Group 1. J Cataract Refract Surg . 1998; 24:1480-9. [PubMed 9818338]

29. Loteprednol Etabonate US Uveitis Study Group. Controlled evaluation of loteprednol etabonate and prednisolone acetate in the treatment of acute anterior uveitis. Am J Ophthalmol . 1999; 127:537-44. [PubMed 10334346]

30. Bausch & Lomb, Tampa, FL: Personal communication.

31. Bausch & Lomb Pharmaceuticals, Inc. Zylet^® (loteprednol etabonate 0.5% and tobramycin 0.3%) ophthalmic suspension prescribing information. Tampa, FL; 2004 Dec.