HALOBETASOL: 418 Adverse Event Reports & Safety Profile

DUOBRII Lotion is a combination product with halobetasol propionate and tazarotene as the active ingredients in a white to off-white lotion formulation intended for topical use. Halobetasol propionate is a synthetic corticosteroid. The chemical name for halobetasol propionate is [(6S,9R,16S,17R)-17-(2-chloroacetyl)-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] propanoate. The structural formula for halobetasol propionate is represented below: Molecular Formula: C 25 H 31 ClF 2 O 5 Molecular Weight:

484.96 Tazarotene is a member of the acetylenic class of retinoids. The chemical name for tazarotene is 6-[(3,4-Dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)ethynyl]-3-pyridinecarboxylic acid ethyl ester. The structural formula for tazarotene is represented below: Molecular Formula: C 21 H 21 NO 2 S Molecular Weight:

351.46 Each gram of DUOBRII Lotion contains 0.1 mg (0.01%) halobetasol propionate and 0.45 mg (0.045%) tazarotene in a white to off-white lotion base consisting of carbomer copolymer type B, carbomer homopolymer type A, diethyl sebacate, edetate disodium dihydrate, light mineral oil, methylparaben, propylparaben, purified water, sodium hydroxide, sorbitan monooleate and sorbitol solution, 70%. chem1.jpg chem2.jpg

INDICATIONS AND USAGE Halobetasol Propionate Ointment 0.05% is a super-high potency corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Treatment beyond two consecutive weeks is not recommended, and the total dosage should not exceed 50 g/week because of the potential for the drug to suppress the hypothalamic-pituitary-adrenal (HPA) axis. Use in children under 12 years of age is not recommended. As with other highly active corticosteroids, therapy should be discontinued when control has been achieved. If no improvement is seen within 2 weeks, reassessment of the diagnosis may be necessary.

AND ADMINISTRATION Shake can prior to use and turn can completely upside down to dispense.

Apply Halobetasol Propionate Topical

Foam as a thin uniform film to the affected skin twice daily for up to two weeks. Rub in gently. Wash hands after applying the product. Discontinue therapy when control is achieved. If no improvement is seen within two weeks, reassessment of the diagnosis may be necessary. Treatment beyond two weeks is not recommended and the total dosage should not exceed 50 grams per week because of the potential for the drug to suppress the hypothalamic-pituitary-adrenal (HPA) axis [see Warnings and Precautions (5.1) ] . Do not use with occlusive dressings unless directed by a physician. Avoid use on the face, groin, or axillae. Avoid contact with eyes. Wash hands after each application, unless it is for treatment of the hands.

Halobetasol Propionate Topical

Foam is for topical use only.

Halobetasol Propionate Topical

Foam is not for ophthalmic, oral, or intravaginal use.

• Shake before use. ( 2 )
• Apply Halobetasol Propionate Topical Foam as a thin uniform film to the affected skin twice daily for up to two weeks. Rub in gently. ( 2 )
• Do not use more than 50 grams per week. ( 2 )
• Discontinue Halobetasol Propionate Topical Foam when control is achieved. ( 2 )
• If no improvement is seen within 2 weeks, reassess diagnosis. ( 2 )
• Treatment beyond 2 consecutive weeks is not recommended. ( 2 )
• Do not use with occlusive dressings unless directed by a physician. ( 2 )
• Avoid use on the face, groin, or axillae. ( 2 )
• Halobetasol Propionate Topical Foam is not for ophthalmic, oral, or intravaginal use. ( 2 )

DUOBRII Lotion is contraindicated in pregnancy ( 4.1 , 8.1 )

4.1 Pregnancy DUOBRII Lotion is contraindicated in pregnancy [ see Warnings and Precautions (5.1) , Use in Specific Populations ( 8.1 , 8.3) ].

REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label:

• Hypothalamic-Pituitary-Adrenal (HPA)

Axis

Suppression and Other Adverse Endocrine Effects [see Warnings and Precautions (5.1) ]

• Allergic Contact Dermatitis [see Warnings and Precautions (5.5) ] The most commonly reported adverse reactions (≥1%) are application site pain and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Padagis ® at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In randomized, multicenter, vehicle-controlled clinical trials, 351 adults with plaque psoriasis were treated with Halobetasol Propionate Topical Foam twice daily for up to two weeks (up to approximately 50 grams per week).

Table

1 presents selected adverse reactions that occurred in at least 1% of subjects.

Table

1: Adverse Reactions Occurring in ≥ 1% of Subjects through Week 2 HBP Foam N=351 Vehicle Foam N=353 Adverse Reaction % % Skin atrophy (n=1) and telangiectasia (n=2) were reported with Halobetasol Propionate Topical Foam, but not with vehicle foam. Application site burning/stinging 12% 15% Application site pain 1% <1% Headache 1% <1%

6.2 Postmarketing Experience Because the 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. The following local adverse reactions have been reported with topical corticosteroids: folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, irritation, striae, and miliaria. They may occur more frequently with the use of occlusive dressings and higher potency corticosteroids, such as halobetasol propionate.

AND PRECAUTIONS

• Embryofetal risk : DUOBRII Lotion contains tazarotene, which is a teratogenic substance. In females of reproductive potential, obtain a negative pregnancy test within 2 weeks prior to initiating treatment and advise patients to use an effective method of contraception during treatment. (5.1)
• Reversible hypothalamic-pituitary-adrenal (HPA) axis suppression may occur, with the potential for glucocorticosteroid insufficiency during or after treatment. (5.2)
• Systemic effects of topical corticosteroids may also include Cushing’s syndrome, hyperglycemia, and glucosuria. (5.2)
• Systemic absorption may require evaluation for HPA axis suppression. (5.2)
• Use of potent corticosteroids on large areas, for prolonged durations, under occlusive dressings, or on an altered skin barrier may increase systemic exposure. (5.2)
• Local Adverse Reactions : Local adverse reactions may include atrophy, striae, telangiectasias, and folliculitis. If these effects occur, discontinue at least until the integrity of the skin has been restored.

Duobrii

Lotion should not be used on eczematous skin, as it may cause severe irritation. (5.3)

• Photosensitivity and Risk for Sunburn : Avoid exposure to sunlight, sunlamps, and weather extremes.

Duobrii

Lotion should be administered with caution if the patient is also taking drugs known to be photosensitizers. (5.4)

• Ophthalmic Adverse Reactions : Use of topical corticosteroids may increase the risk of posterior subcapsular cataracts and glaucoma. If visual symptoms occur, consider referral to an ophthalmologist (5.5) .

5.1 Embryofetal Risk Based on data from animal reproduction studies, retinoid pharmacology, and the potential for systemic absorption, DUOBRII Lotion may cause fetal harm when administered to a pregnant female and is contraindicated during pregnancy. Tazarotene is teratogenic, and it is not known what level of exposure is required for teratogenicity in humans <span class="opacity-50 text-xs">[see Contraindications (4) , Clinical Pharmacology (12.3) ]</span>. Tazarotene elicits teratogenic and developmental effects associated with retinoids after topical or systemic administration in rats and rabbits <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 )]</span>. Advise pregnant females of the potential risk to a fetus. Obtain a pregnancy test within 2 weeks prior to DUOBRII Lotion therapy. Initiate DUOBRII Lotion therapy during a menstrual period. Advise females of reproductive potential to use effective contraception during treatment with DUOBRII Lotion therapy <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 and 8.3 )]</span> .

5.2 Hypothalamic-Pituitary-Adrenal (HPA)

Axis

Suppression and Other Unwanted Systemic Glucocorticoid Effects DUOBRII Lotion contains halobetasol propionate, a corticosteroid, and has been shown to suppress the hypothalamic-pituitary-adrenal (HPA) axis. Systemic effects of topical corticosteroids may include reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal of treatment of the topical corticosteroid. The potential for hypothalamic-pituitary-adrenal (HPA) axis suppression with DUOBRII Lotion was evaluated in a study of 20 adult subjects with moderate to severe plaque psoriasis involving ≥20% of their body surface area. The subjects were treated once daily for 8 weeks and assessed for HPA axis suppression at Weeks 4 and 8. HPA axis suppression occurred in 3 out of 20 (15%) subjects at Week 4 and none (0%) of these 20 subjects had HPA axis suppression at Week 8 [see Clinical Pharmacology (12.2) ] . Because of the potential for systemic absorption, use of topical corticosteroids, including DUOBRII Lotion, may require that patients be evaluated periodically for evidence of HPA axis suppression. Factors that predispose a patient using a topical corticosteroid to HPA axis suppression include the use of more potent corticosteroids, use over large surface areas, occlusive use, use on an altered skin barrier, concomitant use of multiple corticosteroid-containing products, liver failure, and young age. An adrenocorticotropic hormone (ACTH) stimulation test may be helpful in evaluating patients for HPA axis suppression. If HPA axis suppression is documented, attempt to gradually withdraw the drug or reduce the frequency of application. Manifestations of adrenal insufficiency may require supplemental systemic corticosteroids. Recovery of HPA axis function is generally prompt and complete upon discontinuation of topical corticosteroids. Systemic effects of topical corticosteroids may also include Cushing’s syndrome, hyperglycemia, and glucosuria. Use of more than one corticosteroid-containing product at the same time may increase the total systemic exposure to topical corticosteroids. Pediatric patients may be more susceptible than adults to systemic toxicity from the use of topical corticosteroids because of their larger surface-to-body-mass ratio [see Use in Specific Populations (8.4) ] .

5.3 Local Adverse Reactions Local adverse reactions may include atrophy, striae, telangiectasias, folliculitis and contact dermatitis. Some local adverse reactions may be irreversible. If these adverse reactions occur, discontinue the medication at least until the integrity of the skin is restored; do not resume treatment if allergic contact dermatitis is identified. Avoid use of DUOBRII Lotion on eczematous skin, as it may cause severe irritation.

5.4 Photosensitivity and Risk for Sunburn Because of heightened burning susceptibility, exposure to sunlight (including sunlamps) should be avoided unless deemed medically necessary, and in such cases, exposure should be minimized during the use of DUOBRII Lotion. Patients must be instructed to use sunscreens and protective clothing when using DUOBRII Lotion. Patients with sunburn should be advised not to use DUOBRII Lotion until fully recovered. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using DUOBRII Lotion.

Duobrii

Lotion should be administered with caution if the patient is also taking drugs known to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the increased possibility of augmented photosensitivity.

5.5 Ophthalmic Adverse Reactions Use of topical corticosteroids may increase the risk of posterior subcapsular cataracts and glaucoma. Cataracts and glaucoma have been reported postmarketing with the use of topical corticosteroid products. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation.

5.6 Concomitant Skin Infections Use an appropriate antimicrobial agent if a skin infection is present or develops. If a favorable response does not occur promptly, discontinue use of DUOBRII Lotion until the infection has been adequately treated.

PRECAUTIONS General Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing's syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment. Patients applying a topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH stimulation, A.M. plasma cortisol, and urinary free-cortisol tests. Patients receiving super potent corticosteroids should not be treated for more than 2 weeks at a time and only small areas should be treated at any one time due to the increased risk of HPA suppression. Halobetasol propionate ointment, 0.05% produced HPA axis suppression when used in divided doses at 7 grams per day for one week in patients with psoriasis. These effects were reversible upon discontinuation of treatment. 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 corticosteroid. Recovery of HPA axis function is generally prompt upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur requiring supplemental systemic corticosteroids. For information on systemic supplementation, see prescribing information for those products. Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios (see PRECAUTIONS: Pediatric Use ). If irritation develops, halobetasol propionate ointment, 0.05% 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. 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 halobetasol propionate ointment, 0.05% should be discontinued until the infection has been adequately controlled. Halobetasol propionate ointment, 0.05% should not be used in the treatment of rosacea or perioral dermatitis, and it should not be used on the face, groin, or in the axillae. Information for Patients Patients using topical corticosteroids should receive the following information and instructions: 1. The medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes. 2. The medication should not be used for any disorder other than that for which it was prescribed. 3. The treated skin area should not be bandaged, or otherwise covered or wrapped, so as to be occlusive unless directed by the physician. 4. Patients should report to their physician any signs of local adverse reactions. 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 dressing.

Laboratory Tests

The following tests may be helpful in evaluating patients for HPA axis suppression: ACTH-stimulation test; A.M. plasma-cortisol test; Urinary free-cortisol test. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential of halobetasol propionate. Positive mutagenicity effects were observed in two genotoxicity assays. Halobetasol propionate was positive in a Chinese hamster micronucleus test, and in a mouse lymphoma gene mutation assay in vitro . Studies in the rat following oral administration at dose levels up to 50 mcg/kg/day indicated no impairment of fertility or general reproductive performance. In other genotoxicity testing, halobetasol propionate was not found to be genotoxic in the Ames/Salmonella assay, in the sister chromatid exchange test in somatic cells of the Chinese hamster, in chromosome aberration studies of germinal and somatic cells of rodents, and in a mammalian spot test to determine point mutations.

Pregnancy

Teratogenic effects: Pregnancy Category C: Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. Halobetasol propionate has been shown to be teratogenic in SPF rats and chinchilla-type rabbits when given systemically during gestation at doses of 0.04 to 0.1 mg/kg in rats and 0.01 mg/kg in rabbits. These doses are approximately 13, 33 and 3 times, respectively, the human topical dose of halobetasol propionate ointment, 0.05%. Halobetasol propionate was embryotoxic in rabbits but not in rats. Cleft palate was observed in both rats and rabbits. Omphalocele was seen in rats, but not in rabbits. There are no adequate and well-controlled studies of teratogenic potential of halobetasol propionate in pregnant women. Halobetasol propionate ointment, 0.05% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when halobetasol propionate ointment, 0.05% is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of halobetasol propionate ointment, 0.05% in pediatric patients have not been established and use in pediatric patients under 12 is not recommended. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA suppression and Cushing's syndrome when they are treated with topical corticosteroids. They are therefore also at greater risk of adrenal insufficiency during or after withdrawal of treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in infants and children. HPA axis suppression, Cushing's syndrome, linear growth retardation, delayed weight gain and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.

Geriatric

Use Of approximately 400 patients treated with halobetasol propionate ointment, 0.05% in clinical studies, 25% were 61 years and over and 6% were 71 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients; and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.