FLUOCINONIDE: 1,050 Adverse Event Reports & Safety Profile

DESCRIPTION FLUOCINONIDE CREAM USP, 0.05%, FLUOCINONIDE CREAM USP, 0.05% (Emulsified Base), FLUOCINONIDE GEL USP, 0.05% and FLUOCINONIDE OINTMENT USP, 0.05% are intended for topical administration. The active component in each is the corticosteroid fluocinonide, which is the 21-acetate ester of fluocinolone acetonide and has the chemical name pregna-1,4-diene-3,20-dione,21-(acetyloxy)-6,9-difluoro-11-hydroxy-16,17-[(1-methylethylidene)bis)oxy)]-,(6α,11β,16α)-. It has the following chemical structure: Mol. Formula: C 26 H 32 F 2 O 7 Mol. Wt:

494.53 FLUOCINONIDE CREAM USP, 0.05% contains fluocinonide 0.5 mg/g in a specially formulated cream base consisting of stearyl alcohol, polyethylene glycol-3350, polyethylene glycol-8000, propylene glycol, 1,2,6-hexanetriol, glycerin and citric acid. This white cream vehicle is greaseless, non-staining, anhydrous and completely water miscible. The base provides emollient and hydrophylic properties. FLUOCINONIDE CREAM USP, 0.05% (Emulsified Base) contains fluocinonide 0.5 mg/g in a water-washable aqueous emollient base of stearyl alcohol, cetyl alcohol, mineral oil, propylene glycol, sorbitan monosterarate, polysorbate 60, white petrolatum, citric acid (anhydrous) and purified water. FLUOCINONIDE GEL USP, 0.05% contains fluocinonide 0.5 mg/g in a specially formulated gel base consisting of carbomer 940, edetate disodium, propyl gallate, propylene glycol, sodium hydroxide (to adjust pH) and purified water. This clear, colorless, thixotropic vehicle is greaseless, non-staining and completely water miscible. FLUOCINONIDE OINTMENT USP, 0.05% contains fluocinonide 0.5 mg/g in a specially formulated ointment base consisting of glyceryl monostearate, propylene carbonate, propylene glycol, white petrolatum and white wax. It provides the occlusive and emollient effects desirable in an ointment. In the FLUOCINONIDE CREAM USP, 0.05%, FLUOCINONIDE GEL USP, 0.05%, and FLUOCINONIDE OINTMENT USP, 0.05% formulations, the active ingredient is totally in solution.

Chemical

Structure

AND USAGE Fluocinonide cream USP, 0.1%is a corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid responsive dermatoses in patients 12 years of age or older. ( 1 ) Limitation of Use:

• Treatment beyond 2 consecutive weeks is not recommended and the total dosage should not exceed 60 g per week because of the potential for the drug to suppress the hypothalamic-pituitary-adrenal (HPA) axis. ( 1 )
• Avoid use on the face, groin, or axillae. ( 1.2 )
• Avoid use in perioral dermatitis or rosacea.

1.1 Indication Fluocinonide cream USP, 0.1% is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid responsive dermatoses in patients 12 years of age or older [ see Use in Specific Populations ( 8.4 ) ].

1.2 Limitation of Use Treatment beyond 2 consecutive weeks is not recommended and the total dosage should not exceed 60 g per week because the safety of fluocinonide cream USP, 0.1% for longer than 2 weeks has not been established and because of the potential for the drug to suppress the hypothalamic-pituitary-adrenal (HPA) axis. Therapy should be discontinued when control of the disease is achieved. If no improvement is seen within 2 weeks, reassessment of the diagnosis may be necessary. Do not use more than half of the 120 g tube per week. Fluocinonide cream USP, 0.1% should not be used in the treatment of rosacea or perioral dermatitis, and should not be used on the face, groin, or axillae.

AND ADMINISTRATION For topical use only. Fluocinonide cream USP, 0.1% is not for ophthalmic, oral, or intravaginal use. For psoriasis, apply a thin layer of fluocinonide cream USP, 0.1% once or twice daily to the affected skin areas as directed by a physician. Twice daily application for the treatment of psoriasis has been shown to be more effective in achieving treatment success during 2 weeks of treatment. For atopic dermatitis, apply a thin layer of fluocinonide cream USP, 0.1% once daily to the affected skin areas as directed by a physician. Once daily application for the treatment of atopic dermatitis has been shown to be as effective as twice daily treatment in achieving treatment success during 2 weeks of treatment [ see Clinical Studies (14) ] . For corticosteroid responsive dermatoses, other than psoriasis or atopic dermatitis, apply a thin layer of fluocinonide cream USP, 0.1% once or twice daily to the affected areas as directed by a physician. For topical use only. Fluocinonide cream USP, 0.1% is not for ophthalmic, oral, or intravaginal use. ( 2 ) Psoriasis: apply a thin layer once or twice daily to the affected skin areas. ( 2 )

Atopic

Dermatitis: apply a thin layer once daily to the affected skin areas. ( 2 )

Corticosteroid Responsive

Dermatoses, other than psoriasis or atopic dermatitis: apply a thin layer once or twice daily to the affected areas. ( 2 )

CONTRAINDICATIONS Fluocinonide Cream, USP 0.05% is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation.

REACTIONS The most commonly reported adverse reactions (≥1%) were headache, application site burning, nasopharyngitis, and nasal congestion. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Taro Pharmaceuticals U.S.A., Inc., at 1-866-923-4914 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In clinical trials, a total of 443 adult subjects with atopic dermatitis or plaque-type psoriasis were treated once daily or twice daily with fluocinonide cream USP, 0.1% for 2 weeks. The most commonly observed adverse reactions in these clinical trials were as follows: Table 1: Most Commonly Observed Adverse Reactions (≥1%) in Adult Clinical Trials Adverse Reaction Fluocinonide Cream USP, 0.1%, once daily (n=216)

Fluocinonide

Cream USP, 0.1%, twice daily (n=227)

Vehicle

Cream, once or twice daily (n=211)

Headache

8 (3.7%) 9 (4.0%) 6 (2.8%)

Application Site Burning

5 (2.3%) 4 (1.8%) 14 (6.6%)

Nasopharyngitis

2 (0.9%) 3 (1.3%) 3 (1.4%)

Nasal Congestion

3 (1.4%) 1 (0.4%) 0 Safety in patients 12 to 17 years of age was similar to that observed in adults.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of fluocinonide cream USP, 0.1%: Administration Site Conditions: discoloration, erythema, irritation, pruritus, swelling, pain and condition aggravated.

Immune System

Disorders: hypersensitivity.

Nervous System

Disorders: headache and dizziness. Skin and Subcutaneous Tissue Disorders: acne, dry skin, rash, skin exfoliation and skin tightness. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

AND PRECAUTIONS Fluocinonide cream USP, 0.1% has been shown to suppress the HPA axis. Systemic absorption of fluocinonide cream USP, 0.1% may produce reversible hypothalamic-pituitaryadrenal (HPA) axis suppression, Cushing's syndrome, hyperglycemia and unmask latent diabetes ( 5.1 ) Systemic absorption may require evaluation for HPA axis suppression ( 5.1 ) Modify use should HPA axis suppression develop ( 5.1 ) Potent corticosteroids, use on large areas, prolonged use or occlusive use may increase systemic absorption ( 5.3 ) Local adverse reactions with topical steroids may include atrophy, striae, irritation, acneiform eruptions, hypopigmentation and allergic contact dermatitis and may be more likely to occur with occlusive use or more potent corticosteroids ( 5.3 ) Children may be more susceptible to systemic toxicity when treated with topical corticosteroids. ( 5.1 , 8.4 )

5.1 Effect on Endocrine System Systemic absorption of topical corticosteroids, including fluocinonide cream USP, 0.1%, can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for clinical glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal of the topical corticosteroid. In addition, the use of fluocinonide cream USP, 0.1% for longer than 2 weeks may suppress the immune system [ see Nonclinical Toxicology (13.1) ]. HPA axis suppression has been observed with fluocinonide cream USP, 0.1% applied once or twice daily in 2 out of 18 adult patients with plaque-type psoriasis, 1 out of 31 adult patients with atopic dermatitis and 4 out of 123 pediatric patients with atopic dermatitis [ see Use in Specific Population (8.4) and Clinical Pharmacology (12.2) ]. Because of the potential for systemic absorption, use of topical corticosteroids, including fluocinonide cream USP, 0.1%, may require that patients be periodically evaluated for HPA axis suppression. Factors that predispose a patient using a topical corticosteroid to HPA axis suppression include the use of more potent steroids, use over large surface areas, use over prolonged periods, use under occlusion, use on an altered skin barrier, and use in patients with liver failure. An ACTH stimulation test may be helpful in evaluating patients for HPA axis suppression. If HPA axis suppression is documented, an attempt should be made to gradually withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Manifestations of adrenal insufficiency may require supplemental systemic corticosteroids. Recovery of HPA axis function is generally prompt and complete upon discontinuation of topical corticosteroids. Cushing's syndrome, hyperglycemia, and unmasking of latent diabetes mellitus can also result from systemic absorption of topical corticosteroids. Use of more than one corticosteroid-containing product at the same time may increase the total systemic absorption of topical corticosteroids. Studies conducted in pediatric patients demonstrated reversible HPA axis suppression after use of fluocinonide cream USP, 0.1%. Pediatric patients may be more susceptible than adults to systemic toxicity from equivalent doses of fluocinonide cream USP, 0.1% due to their larger skin surface-to-body-mass ratios [ See Use in Specific Populations (8.4) ].

5.2 Local Adverse Reactions with Topical Corticosteroids Local adverse reactions may be more likely to occur with occlusive use, prolonged use or use of higher potency corticosteroids. Reactions may include atrophy, striae, telangiectasis, burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, and miliaria. Some local adverse reactions may be irreversible.

5.3 Concomitant Skin Infections If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of fluocinonide cream USP, 0.1% should be discontinued until the infection has been adequately controlled.

5.4 Allergic Contact Dermatitis If irritation develops, fluocinonide cream USP, 0.1% should be discontinued and appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation as with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic patch testing.

PRECAUTIONS: General: Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, the addition of occlusive dressings and dosage form. Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids. Pediatric patients may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity (See PRECAUTIONS - Pediatric Use ). This preparation is not for ophthalmic use. Severe irritation is possible if fluocinonide topical solution contacts the eye. If that should occur, immediate flushing of the eye with a large volume of water is recommended. If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. As with any topical corticosteroid product, prolonged use may produce atrophy of the skin and subcutaneous tissues. When used on intertriginous or flexor areas, or on the face, this may occur even with short term use. In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled. Information for Patients: Patients using topical corticosteroids should receive the following information and instructions: 1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. If there is contact with the eye(s) and severe irritation occurs, immediately flush with large volume of water. 2. Patients should be advised not to use this medication for any disorder other than for which it was prescribed. 3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician. 4. Patients should report any signs of local adverse reactions especially under occlusive dressings. 5. Parents of pediatric patients should be advised not to use tight fitting diapers or plastic pants on a child being treated in the diaper area, as these garments may constitute occlusive dressings.

Laboratory

Tests: The following tests may be helpful in evaluating the HPA axis suppression: Urinary free cortisol test; ACTH stimulation test. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of topical corticosteroids. Studies to determine mutagenicity with prednisolone and hydrocortisone have revealed negative results.

Pregnancy

Category C: Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time.

Nursing

Mothers: It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman.

Pediatric

Use: Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and Cushing's syndrome than mature patients because of a larger skin surface area to body weight ratio. Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children.