TRI-LUMA

1 INDICATIONS AND USAGE TRI-LUMA Cream is a combination of fluocinolone acetonide (a corticosteroid), hydroquinone (a melanin synthesis inhibitor), and tretinoin (a retinoid) that is indicated for the short-term treatment of moderate to severe melasma of the face, in the presence of measures for sun avoidance, including the use of sunscreens. ( 1 ) 1.1 Indication TRI-LUMA Cream is a combination of fluocinolone acetonide (a corticosteroid), hydroquinone (a melanin synthesis inhibitor), and tretinoin (a retinoid) that is indicated for the short-term treatment of moderate to severe melasma of the face, in the presence of measures for sun avoidance, including the use of sunscreens. 1.2 Limitations of Use TRI-LUMA Cream is NOT indicated for the maintenance treatment of melasma. After achieving control with TRI-LUMA Cream, some patients may be managed with other treatments instead of triple therapy with TRI-LUMA Cream. Melasma usually recurs upon discontinuation of TRI-LUMA Cream. The safety and efficacy of TRI-LUMA Cream in patients of Fitzpatrick Skin Types V and VI have not been studied. Excessive bleaching resulting in undesirable cosmetic effect in patients with darker skin cannot be excluded. The safety and efficacy of TRI-LUMA Cream in the treatment of hyperpigmentation conditions other than melasma of the face have not been studied. Because pregnant and lactating women were excluded from, and women of childbearing potential had to use birth control measures in the clinical trials, the safety and efficacy of TRI-LUMA Cream in pregnant women and nursing mothers have not been established [ see Use in Specific Populations (8.1, 8.3 )].

2 DOSAGE AND ADMINISTRATION Apply a thin film of TRI-LUMA Cream to the effected area once daily, at least 30 minutes before bedtime. Gently wash the face and neck with a mild cleanser. Rinse and pat the skin dry. Apply TRI-LUMA Cream to the hyperpigmented areas of melasma including about 1/2 inch of normal appearing skin surrounding each lesion. Rub lightly and uniformly into the skin. Therapy should be discontinued when control is achieved. During the day, use a sunscreen of SPF 30, and wear protective clothing. Avoid sunlight exposure. Patients may use moisturizers and/or cosmetics during the day. TRI-LUMA Cream is for topical use only. It is not for oral, ophthalmic, or intravaginal use. Apply a thin film to the affected area once daily, at least 30 minutes before bedtime. ( 2 ) During the day, use a sunscreen of SPF 30, and wear protective clothing. Avoid sunlight exposure. ( 2 )

4 CONTRAINDICATIONS TRI-LUMA Cream is contraindicated in individuals with a history of hypersensitivity to this product or any of its components. TRI-LUMA Cream is contraindicated in individuals with a history of hypersensitivity to this product or any of its components. ( 4 )

5 WARNINGS AND PRECAUTIONS TRI-LUMA Cream contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening asthmatic episodes in susceptible people. If anaphylaxis, asthma or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue TRI-LUMA. ( 5.1 ) TRI-LUMA Cream contains hydroquinone, which may produce exogenous ochronosis, a gradual blue-black darkening of the skin, the occurrence of which should prompt discontinuation of therapy. ( 5.2 ) 5.1 Hypersensitivity TRI-LUMA Cream contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening asthmatic episodes in susceptible individuals. If anaphylaxis, asthma or other clinically significant hypersensitivity reactions occur, institute appropriate therapy and discontinue TRI-LUMA. Allergic contact dermatitis may also occur [ see Warnings and Precautions 5.4 ]. 5.2 Exogenous Ochronosis TRI-LUMA Cream contains hydroquinone, which may produce exogenous ochronosis, a gradual blue-black darkening of the skin, the occurrence of which should prompt discontinuation of therapy. The majority of patients developing this condition are Black, but it may also occur in Caucasians and Hispanics. 5.3 Effects on Endocrine System TRI-LUMA Cream contains the corticosteroid fluocinolone acetonide. 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 by systemic absorption of topical corticosteroid while on treatment. If HPA axis suppression is noted, the use of TRI-LUMA Cream should be discontinued. Recovery of HPA axis function generally occurs upon discontinuation of topical corticosteroids. The ACTH or cosyntropin stimulation test may be helpful in evaluating patients for HPA axis suppression. 5.4 Cutaneous Reactions Cutaneous hypersensitivity to the active ingredients of TRI-LUMA Cream has been reported in the literature. In a patch test study to determine sensitization potential in 221 healthy volunteers, three volunteers developed sensitivity reactions to TRI-LUMA Cream or its components. TRI-LUMA Cream contains hydroquinone and tretinoin that may cause mild to moderate irritation. Local irritation, such as skin reddening, peeling, mild burning sensation, dryness, and pruritus may be expected at the site of application. Transient skin reddening or mild burning sensation does not preclude treatment. If a reaction suggests hypersensitivity or chemical irritation, the use of the medication should be discontinued. Patients should avoid medicated or abrasive soaps and cleansers, soaps and cosmetics with drying effects, products with high concentrations of alcohol and astringents, and other irritants or keratolytic drugs while on TRI-LUMA Cream treatment. Patients are cautioned on concomitant use of medications that are known to be photosensitizing.

6 ADVERSE REACTIONS 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 clinical practice. In the controlled clinical trials, adverse events were monitored in the 161 subjects who used TRI-LUMA Cream once daily during an 8-week treatment period. There were 102 (63%) subjects who experienced at least one treatment-related adverse event during these trials. The most frequently reported events were erythema, desquamation, burning, dryness, and pruritus at the site of application. The majority of these events were mild to moderate in severity. Adverse events reported by at least 1% of patients and judged by the investigators to be reasonably related to treatment with TRI-LUMA Cream from the controlled clinical trials are summarized (in decreasing order of frequency) as follows: Table 1. Incidence and Frequency of Treatment-related Adverse Events with TRI-LUMA Cream in at least 1% or more of Subjects (N=161) Adverse Event n (%) Erythema 66 (41%) Desquamation 61 (38%) Burning 29 (18%) Dryness 23 (14%) Pruritus 18 (11%) Acne 8 (5%) Paresthesia 5 (3%) Telangiectasia 5 (3%) Hyperesthesia 3 (2%) Pigmentary changes 3 (2%) Irritation 3 (2%) Papules 2 (1%) Acne-like rash 1 (1%) Rosacea 1 (1%) Dry Mouth 1 (1%) Rash 1 (1%) Vesicles 1 (1%) In an open-label trial, subjects who had cumulative treatment of melasma with TRI-LUMA Cream for 6 months showed a similar pattern of adverse events as in the 8-week studies. The following local adverse reactions have been reported with topical corticosteroids. They may occur more frequently with the use of occlusive dressings, especially with higher potency corticosteroids. These reactions are listed in an approximate decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, and miliaria. Most common adverse reactions (incidence > 5%) are erythema, desquamation, burning, dryness, pruritus, and acne. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Galderma Laboratories, L.P. at 1-866-735-4137 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8.1 Pregnancy Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. TRI-LUMA Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. TRI-LUMA Cream contains the teratogen, tretinoin, which may cause embryo-fetal death, altered fetal growth, congenital malformations, and potential neurologic deficits. In clinical trials involving TRI-LUMA Cream in the treatment of facial melasma, women of child-bearing potential initiated treatment only after having had a negative pregnancy test and used effective birth control measures during therapy. However, 13 women became pregnant during treatment with TRI-LUMA Cream. Most of the pregnancy outcomes are unknown. Three women gave birth to apparently healthy babies. One pregnancy was terminated prematurely, and another ended in miscarriage. In general, use of drugs should be reduced to a minimum in pregnancy. If a patient has been inadvertently exposed to TRI-LUMA Cream in pregnancy, she should be counseled on the risk of teratogenesis due to this exposure. The risk of teratogenesis due to topical exposure to TRI-LUMA Cream may be considered low. However, exposure during the period of organogenesis in the first trimester is theoretically more likely to produce adverse outcome than in later pregnancy. Tretinoin is considered to be highly teratogenic upon systemic administration. Animal reproductive studies are not available with topical hydroquinone. 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. • In a dermal application study using TRI-LUMA Cream in pregnant rabbits, there was an increase in the number of in utero deaths and a decrease in fetal weights in litters from dams treated topically with the drug product. • In a dermal application study in pregnant rats treated with TRI-LUMA Cream during organogenesis there was evidence of teratogenicity of the type expected with tretinoin. These morphological alterations included cleft palate, protruding tongue, open eyes, umbilical hernia, and retinal folding or dysplasia. • In a dermal application study on the gestational and postnatal effects of a 10-fold dilution of TRI-LUMA Cream in rats, an increase in the number of stillborn pups, lower pup body weights, and delay in preputial separation were observed. An increase in overall activity was seen in some treated litters at postnatal day 22 and in all treated litters at five weeks, a pattern consistent with effects previously noted in animals exposed in utero with retinoic acids. No adequate study of the late gestational and postnatal effects of the full-strength TRI-LUMA Cream has been performed. • It is difficult to interpret these animal studies on teratogenicity with TRI-LUMA Cream, because the availability of the dermal applications in these studies could not be assured, and comparison with clinical dosing is not possible.