ATC Class:S01BA08

VA Class:OP300

AHFS Class:

• Corticosteroids 52:08.08

Associated Monographs

• Beclomethasone

• Budesonide

• Ciclesonide

• Dexamethasone

• Difluprednate

• Flunisolide

• Fluocinolone

• Fluorometholone

• Fluticasone

• Hydrocortisone

• Loteprednol

• Mometasone

• Prednisolone

• Triamcinolone

Corticosteroids are used as topical ophthalmic, otic, and nasal anti-inflammatory agents.

Ophthalmic

Corticosteroids are applied topically to the conjunctiva for the symptomatic relief of corticosteroid-responsive allergic and inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe such as allergic or vernal conjunctivitis, acne rosacea keratitis, superficial punctate keratitis, herpes zoster keratitis, uveitis, iritis, and cyclitis. The drugs also are used topically as anti-inflammatory agents in corneal, conjunctival, and scleral injuries from chemical, radiation, or thermal burns or penetration of foreign bodies and, during the acute phase, may help prevent fibrosis and scarring and resultant visual impairment. Topical ophthalmic corticosteroids also are used prophylactically after ocular surgery (e.g., cataract extraction, glaucoma surgery, corneal transplant) to prevent inflammation, pain, and scarring, but the drugs may possibly delay wound healing.156 The drugs should not be used for minor abrasions or wounds. Ophthalmic corticosteroids are not effective in degenerative disorders (e.g., cataracts). Certain corticosteroids (i.e., fluocinolone acetonide) are implanted intravitreally for long-term management of ocular inflammation (i.e., uveitis).151

Corticosteroids are used topically in conjunction with appropriate anti-infective therapy in some cases of ocular bacterial infections. However, the benefit of concomitant therapy must be weighed against the risk of reduced resistance to bacterial, viral, or fungal infection and suppression by the corticosteroid of signs and symptoms of infection or hypersensitivity. (See Cautions: Precautions and Contraindications.) Although corticosteroids generally are contraindicated in herpetic infections (See Cautions: Precautions and Contraindications), concomitant application of an antiviral agent (e.g., idoxuridine, vidarabine [both no longer commercially available in the US]) and a topical corticosteroid has been reported to be more effective than the antiviral alone in complicated and refractory cases of stromal keratitis and uveitis caused by herpes simplex. In such cases it appears that the antiviral protects the cornea from spontaneous reinfection while the corticosteroid relieves inflammation; therefore, it has been recommended that the antiviral be continued for a few days after the corticosteroid has been discontinued. Corticosteroids are not indicated in ocular fungal infections.

Topical ophthalmic corticosteroid therapy is not curative, and the cause of inflammation should be determined and eliminated if possible. Acute, self-limiting disorders respond more favorably than do chronic conditions. Topically applied ophthalmic corticosteroids appear to be as effective as systemic steroids for the treatment of most anterior ocular inflammations. Subconjunctival injections of repository forms of corticosteroids (e.g., methylprednisolone acetate suspension, triamcinolone acetonide suspension) may be required in severe anterior segment ocular inflammation, and systemic corticosteroid therapy is necessary when deeper ocular structures (e.g., posterior segment of globe, optic nerve, orbit) are involved. Retrobulbar administration of repository forms of corticosteroids is used in some cases of posterior segment disease. (See the Corticosteroids General Statement 68:04.)

Results of various studies indicate that, on a weight basis, the anti-inflammatory activity of ophthalmic corticosteroids in decreasing order is: fluorometholone, dexamethasone, prednisolone, loteprednol etabonate, rimexolone, medrysone, and hydrocortisone. For long-term use, fluorometholone, medrysone, loteprednol etabonate, or rimexolone, which are least likely to increase IOP, may be preferred, especially in patients with increased risk of ocular hypertension during topical corticosteroid therapy. (See Cautions: Adverse Effects.) However, the efficacy of topical medrysone in iritis or anterior and posterior uveitis has not been established.

Otic

Corticosteroids are applied to the ear canal for the symptomatic relief of inflammatory conditions of the external auditory meatus (otitis externa). Corticosteroids are also used topically for the symptomatic relief of otitis externa that is a manifestation of generalized inflammatory dermatoses such as seborrhea, psoriasis, allergic dermatitis, or neurodermatitis.

If possible, the cause of otitis externa should be eliminated or controlled. Corticosteroids are used topically in conjunction with appropriate anti-infective therapy in some cases of bacterial otitis externa. However, the benefit of concomitant therapy must be weighed against the risk of reduced resistance to bacterial, viral, or fungal infection and suppression by the corticosteroid of signs and symptoms of infection or hypersensitivity. (See Cautions: Precautions and Contraindications.) Corticosteroids are not indicated in viral or fungal otic infections. Corticosteroids are also commercially available for otic use in combination with local anesthetics or analgesics. However, local anesthetics present in some otic preparations containing corticosteroids are rarely effective, possibly due to insufficient absorption of the anesthetic in the ear canal. If relief from pain is necessary, a systemic analgesic should be administered.

Nasal

Dexamethasone nasal aerosol is used for the symptomatic relief of inflammatory nasal conditions and nasal polyps (except polyps originating within the sinuses). Fluticasone propionate nasal spray is used for the symptomatic relief of seasonal or perennial allergic rhinitis or perennial nonallergic rhinitis.104 Flunisolide nasal solution and ciclesonide nasal suspension are used for the symptomatic relief of seasonal or perennial rhinitis.157 Budesonide nasal spray is used for the symptomatic management of seasonal or perennial allergic rhinitis.143,144,145,146,147,148,149,150 Mometasone furoate nasal spray is used for the prophylaxis and treatment of nasal symptoms of seasonal allergic rhinitis and for the treatment of nasal symptoms of perennial allergic rhinitis.141 Intranasal mometasone furoate also is used in the management of nasal polyposis.141 Triamcinolone acetonide nasal inhalation aerosol and aqueous suspension are used for the symptomatic treatment of seasonal or perennial allergic rhinitis.153,154 Beclomethasone dipropionate nasal aerosol is used for the symptomatic treatment of seasonal or perennial rhinitis.155 Intranasal beclomethasone dipropionate also is used in the management of nasal polyposis, principally to prevent recurrence of nasal polyps following surgical removal.

For systemic and intralesional uses of the corticosteroids, see 68:04. For other topical uses, see 84:06.08.

Ophthalmic

For topical ophthalmic use, corticosteroids are available as sterile emulsions, ointments, solutions, and suspensions.156 Emulsions, solutions, or suspensions, which cause minimal interference with vision and have minimal effect on corneal reepithelialization, usually are used during the day.156 Ointments provide longer contact with the eye and are usually used at night or in the treatment of inflammatory conditions of the eyelid.

For long-term therapy of noninfectious uveitis, fluocinolone acetonide is available as a sterile implant that is inserted intravitreally into the posterior segment of the affected eye.151

Otic

For topical otic use, corticosteroids are available as creams, ointments, solutions, and suspensions. Because treatment of otitis externa is aimed at restoring the normal physiologic state of the ear canal, it is imperative that the canal be thoroughly cleansed and that the pH of otic preparations be neutral or acidic. Otic preparations should be used sparingly to prevent an accumulation of excess debris in the ear canal.

Nasal

For intranasal use, beclomethasone dipropionate, budesonide, ciclesonide, fluticasone propionate, and mometasone furoate are available as nasal suspensions; flunisolide is available as a nasal solution; and triamcinolone acetonide is available as a nasal aerosol and a suspension.143,153,154,155,157

In general, topical application of corticosteroids to the conjunctiva or external ear or implantation into the posterior segment of the eye does not provoke clinical evidence of systemic absorption, and severe systemic adverse reactions occur infrequently. However, topical application of corticosteroids to the nasal mucosa for prolonged periods may produce systemic effects. For cautions in the systemic use of corticosteroids, see the Corticosteroids General Statement 68:04.

Adverse Effects

Topical or intravitreal ophthalmic corticosteroids may cause increased IOP in some patients. The magnitude of increase in IOP following topical therapy depends on the corticosteroid used and its concentration and on the frequency and duration of administration. Clinically important ocular hypertension may occur following topical ophthalmic corticosteroid therapy for 1-6 weeks and is usually reversible in a few weeks when the drug is discontinued. With prolonged use (usually longer than 1 year), open-angle glaucoma, optic nerve damage, and defects in visual acuity and field of vision may occur. Patients with primary open-angle glaucoma (or their relatives), diabetes mellitus, myopia greater than 5 diopters, or a Krukenberg's spindle have substantially increased risk of ocular hypertension during topical ophthalmic corticosteroid therapy, and the drugs should be used with caution in these patients. Patients with angle-closure or secondary open-angle glaucoma alone do not have an increased risk of ocular hypertension during topical ophthalmic corticosteroid therapy. An increase in IOP has been reported most frequently with 0.1% dexamethasone or dexamethasone phosphate (as the sodium phosphate). In patients with increased IOP prior to corticosteroid therapy and in those susceptible to a rise in IOP during treatment with topical ophthalmic corticosteroids, a clinically important increase in IOP occurs rarely with 1% medrysone; 0.2 or 0.5% loteprednol etabonate, 1% rimexolone, or 0.1% fluorometholone is less likely to cause ocular hypertension than 1 or 1.5% hydrocortisone or 0.1 or 1% prednisolone; and 1 or 1.5% hydrocortisone or 0.1% prednisolone is less likely to cause ocular hypertension than 0.1% dexamethasone. Increased IOP has been reported in 50% or more of patients receiving intravitreal fluocinolone acetonide implants.151 Increased IOP has been reported rarely following intranasal application of aerosolized corticosteroids.

Rarely, transient stinging, burning, or local irritation may occur with ophthalmic or otic application of corticosteroids, and ophthalmic ointments may interfere with vision (e.g., blurred vision, photophobia). Ocular discharge,122,128,129 ocular discomfort or pain,122,128,129 foreign body sensation,122,128,129 hyperemia,122 abnormal vision/blurring,128,129 pruritus,122,128,129 lid margin crusting,122 sticky sensation,122 increased fibrin,122 dry eye,122,128,129 conjunctival edema,122,128,129 corneal staining,122 keratitis,122,128,129 tearing,122,128,129 edema,122 irritation,122 corneal ulcer,122 browache,122 eyelid erythema,128,129 corneal edema,122 infiltrate,122 or corneal erosion122 also have been reported with topical ophthalmic corticosteroids. Mydriasis, ptosis, epithelial punctate keratitis, and possible corneal or scleral malacia have also occurred. Filtering blebs have been reported rarely when ophthalmic corticosteroids were used after cataract surgery.

Prolonged use (usually for longer than 2 years) of topical ophthalmic corticosteroids rarely may cause posterior subcapsular cataracts that do not regress when the drugs are discontinued. In addition, within 2 years of intravitreal insertion of fluocinolone acetonide implants, nearly all phakic eyes are expected to develop cataracts and require cataract surgery.151 With prolonged use or high dosage in diseases where there is thinning of the cornea or sclera, perforation of the globe has occurred, and the drugs should be used with caution and in reduced dosage in patients with these diseases. In high doses, topical ophthalmic corticosteroids may slow corneal wound healing and decrease tensile strength of corneal wounds; however, most ophthalmologists believe that with usual doses the drugs do not slow wound healing after ocular surgery in most patients. Ophthalmic ointments may decrease the rate of corneal reepithelialization. Within a few days after discontinuing topical ophthalmic corticosteroid therapy and occasionally during therapy, acute anterior uveitis has occurred in patients (mainly blacks) without preexisting ocular inflammation or infection.

Because some systemic absorption may occur following topical application or intravitreal implantation of corticosteroids to the eye, the possibility of adverse systemic effects exists. Headache, hypotension, rhinitis, pharyngitis, and taste perversion have been reported in patients following topical instillation of ophthalmic corticosteroids. Other adverse systemic effects associated with systemic corticosteroids are uncommon with topical ophthalmic corticosteroids, even with extended use, but the risk may be increased with frequent topical ophthalmic administration of potent steroids.127

Following application of corticosteroids to the nasal mucosa, nasal irritation and dryness are the most common adverse effects. Headache, lightheadedness, urticaria, nausea, epistaxis, rebound congestion, bronchial asthma, perforation of the nasal septum, and anosmia have been reported. For a more complete discussion of adverse effects, precautions, and contraindications of intranasal steroids, see Beclomethasone Dipropionate 52:08.08, Ciclesonide 52:08.08, Flunisolide 52:08.08, Fluticasone Propionate 52:08.08. Mometasone Furoate 52:08.08, and Triamcinolone Acetonide 52:08.08.

Hypersensitivity has occurred rarely with topical corticosteroid therapy; if signs of hypersensitivity occur or if irritation persists or increases, the drug should be discontinued.

Precautions and Contraindications

Because an apparent association between use of corticosteroids and left ventricular free-wall rupture after a recent myocardial infarction has been suggested, corticosteroids should be used with extreme caution in these patients. Some commercially available formulations of EENT corticosteroids contain sulfites, which may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.

Bacterial keratitis has been reported with the use of multidose containers of topical ophthalmic preparations. These containers had been contaminated inadvertently by patients who, in most cases, had a concurrent corneal disease or disruption of the ocular epithelial surface. Patients should be informed that improper handling of ocular solutions can result in contamination of the solution by common bacteria known to cause ocular infections and should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures. Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic solutions. Patients also should be advised to seek their physician's advice immediately regarding the continued use of the present multidose container if an intercurrent ocular condition (e.g., trauma, ocular surgery or infection) occurs.

Corticosteroids may reduce resistance to and aid in the establishment of bacterial, viral, or fungal infections and mask the clinical signs of infection, preventing recognition of ineffectiveness of the antibiotic, or may suppress hypersensitivity reactions to substances in the product. Fungal infection should be suspected in patients with persistent corneal ulceration who have been or are receiving these drugs, and corticosteroid therapy should be discontinued if fungal infection occurs. The drugs are contraindicated in patients with acute, untreated purulent bacterial, viral, or fungal ocular or otic infections. If bacterial infection is present, appropriate anti-infective therapy should be used and if the infection does not respond promptly, the corticosteroid should be discontinued and other appropriate therapy initiated. Topical or intravitreally implanted corticosteroids are contraindicated in patients with fungal diseases of ocular or auricular structures and in mycobacterial infections of the eye. Ophthalmic corticosteroids should be used with great caution, and only in conjunction with antiviral therapy, in the treatment of stromal keratitis or uveitis caused by herpes simplex. (See Uses: Ophthalmic.) Ophthalmic corticosteroids are contraindicated in acute epithelial herpes simplex keratitis (dendritic keratitis), since more severe scarring of the cornea or corneal perforation may occur, and in patients with vaccinia, varicella, and most other viral diseases (except herpes zoster keratitis) of the cornea and conjunctiva. Topical otic corticosteroids are contraindicated in patients with a perforated tympanic membrane.

Chronic topical ophthalmic corticosteroid therapy should be used only under the close supervision of an ophthalmologist. In patients receiving prolonged (e.g., for 10 days or longer) ophthalmic corticosteroid therapy, IOP should be checked routinely and frequently (about every 2-4 weeks for the first 2 months and then, if no increase in IOP has occurred, about every 1-2 months thereafter), even though it may be difficult in children or uncooperative patients. Following intravitreal implantation of corticosteroids, IOP also should be monitored (e.g., every 3-6 months but more frequently in the immediate period following implantation).151,152 The equatorial and posterior subcapsular portions of the lens should be examined for changes, pupil size and lid position must be noted, and the cornea should be stained with fluorescein and examined for punctate keratitis. Slit-lamp examination must be performed for early signs of herpetic or fungal keratitis, particularly when the drugs are used in patients with stromal herpes simplex keratitis.

Topical corticosteroid therapy is contraindicated in patients hypersensitive to any component of the formulation.

Pediatric Precautions

A reduction in growth velocity has been reported in controlled clinical trials and during postmarketing experience in pediatric patients receiving intranasal corticosteroids.104,141,142,155 This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA)-axis suppression, suggesting that growth velocity may be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA-axis function.104,141,155 The long-term effects of reduction in growth velocity with intranasal corticosteroids, including the impact on final adult height, are unknown.104,141,142 The potential for catch-up growth following discontinuance of treatment with intranasal corticosteroids has not been adequately studied.104,141 Clinicians should monitor closely (e.g., via stadiometry) the growth of children and adolescents receiving corticosteroids by any route of administration.104,141,155 To minimize the systemic effects of intranasal corticosteroids, dosage should be titrated to the lowest possible effective level.104,141

Pregnancy and Lactation

Pregnancy

Some corticosteroids have been shown to be teratogenic when applied in high dosages to the eyes of pregnant animals. Safety of intensive or protracted use of ophthalmic or otic corticosteroids during pregnancy has not been established. EENT corticosteroids should be used in pregnant women, particularly in large doses or for prolonged periods, only when the possible benefits outweigh the potential risks. Women should be instructed to inform their physicians if they become or wish to become pregnant while receiving glucocorticoids. If intranasal corticosteroids must be used during pregnancy or if the patient becomes pregnant while taking the drug, the possible benefits should be weighed against the potential risks. Infants born to mothers who receive nasal corticosteroids during pregnancy should be carefully monitored for symptoms of adrenal insufficiency, and appropriate therapy should be begun immediately if such symptoms appear.

Lactation

It is not known whether topically administered corticosteroids are distributed into milk or whether they can suppress growth or cause other adverse effects in nursing infants. Some manufacturers state that women receiving pharmacologic doses of dexamethasone should be advised not to nurse their infants.

Pharmacology

Following topical application to the conjunctiva, external ear canal, or nasal mucosa, or intravitreal implantation into the posterior segment of the eye,151 corticosteroids inhibit the inflammatory response to mechanical, chemical, or immunologic agents. Although their precise mechanism of action is unknown, corticosteroids inhibit edema, fibrin deposition, capillary dilatation, and migration of leukocytes and phagocytes in the acute inflammatory response. The drugs also reduce capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation.

Application of corticosteroids to the eye may reduce the facility of aqueous outflow, thereby increasing intraocular pressure (IOP) and inducing or aggravating open-angle (simple) glaucoma.

The exact mechanism(s) of action of corticosteroids in allergic rhinitis remains unknown, but may involve reductions in the following: number of mediator cells (basophils,101,106,108,110,111,112,113,114,116,117,118,119 eosinophils,101,102,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121 T-helper cells,107,120 mast cells,101,102,115,120,121 and neutrophils)101,106,110,113 in the nasal mucosa, nasal reactivity to allergens, and release of inflammatory mediators102 and proteolytic enzymes.102 (See Pharmacology in Fluticasone Propionate.) Intranasal corticosteroids (e.g., fluticasone) also may decrease the release of histamine and tryptase in the nasal mucosa.102

Pharmacokinetics

Following topical instillation of corticosteroids into the conjunctival sac, the drugs are absorbed into the aqueous humor, and systemic absorption occurs. However, because topical ophthalmic corticosteroid dosage is less than when the drugs are given systemically, clinical evidence of systemic absorption usually does not occur. Following intravitreal insertion of fluocinolone acetonide implants, plasma concentrations of the drug are below the limit of detection (0.2 ng/mL). Following nasal inhalation of dexamethasone sodium phosphate, enough drug may be absorbed to produce systemic effects, especially with prolonged use. Beclomethasone dipropionate and flunisolide also are absorbed following nasal inhalation, but adrenal suppression has not been observed to date when these drugs were administered intranasally in the usual dosages for prolonged periods.

Chemistry

Hydrocortisone (cortisol) or synthetic derivatives of hydrocortisone are used as topical ophthalmic, otic, or nasal anti-inflammatory agents. These corticosteroids are 21-carbon steroids with the above general structure. Unlike most currently available corticosteroids, fluticasone propionate is synthesized from a 19-carbon androsterone nucleus rather than a 21-carbon pregnane nucleus.100,101 In the corticosteroids, an 11β-hydroxyl group is required for anti-inflammatory activity. Anti-inflammatory corticosteroids may have substitutions at positions 6, 9, and 16. Structural modifications of hydrocortisone affect the topical anti-inflammatory activity, and multiple modifications may produce more pronounced effects than would be predicted on the basis of individual changes. The presence of a C-1 to C-2 double bond enhances anti-inflammatory activity. Substitution of an α-methyl group on C-6 has no consistent effect on activity.123,124 Substitution of a fluorine atom in the 6α- and/or 9α-position, an acetonide group at position 16 and 17, omission of the hydroxyl group at position 17 or 21, or esterification of the hydroxyl group at 17 or 21 profoundly increases anti-inflammatory activity. Omission of the hydroxyl group on C-21 may reduce the propensity for inducing increased intraocular pressure (IOP) with topical ophthalmic corticosteroids. In addition, structural modifications that result in rapid metabolism of the drug to inactive metabolites may decrease the potential for increased IOP. Substitution at C-16 of an α- or β-methyl group has no consistent effect on anti-inflammatory activity. In the androsterone nucleus, esterification of oxygen at position 17 and addition of a fluoromethyl carbothioate group at 17β enhances topical anti-inflammatory activity.

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