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Fluocinolone Acetonide 0.01%, Hydroquinone 4%, Tretinoin 0.05% Cream

For External Use Only

Not for Ophthalmic Use

TABLE OF CONTENTS

1. DESCRIPTION 7. DRUG INTERACTIONS
2. INDICATIONS AND USAGE 8. USE IN SPECIFIC POPULATIONS
3. DOSAGE AND ADMINISTRATION 9. MECHANISM OF ACTION
4. CONTRAINDICATIONS 10. PHARMACOKINETICS
5. WARNINGS AND PRECAUTIONS 11. HOW SUPPLIED/STORAGE AND HANDLING
6. ADVERSE REACTIONS

 

1. DESCRIPTION

Fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05% contains fluocinolone acetonide, USP, hydroquinone, USP, and tretinoin, USP, in a hydrophilic cream base for topical application.

Fluocinolone acetonide is a synthetic fluorinated corticosteroid for topical dermatological use and is classified therapeutically as an anti-inflammatory. It is a white crystalline powder that is odorless and stable in light.

The chemical name for fluocinolone acetonide is: (6α,11β,16α)-6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]-pregna-1,-4-diene-3,20-dione.

Fluocinolone acetonide has the following structural formula:

Empirical formula: C24H30F2O6 - Molecular weight: 452.50

Hydroquinone is classified therapeutically as a depigmenting agent. It is prepared from the reduction of p-benzoquinone with sodium bisulfite. It occurs as fine white needles that darken on exposure to air.

The chemical name for hydroquinone is: 1,4-benzenediol.

Hydroquinone has the following structural formula:

Empirical formula: C6H6O2 - Molecular weight: 110.11

Tretinoin is all-trans-retinoic acid formed from the oxidation of the aldehyde group of retinene to a carboxyl group. It occurs as yellow to light-orange crystals or crystalline powder with a characteristic odor of ensilage. It is highly reactive to light and moisture. Tretinoin is classified therapeutically as a keratolytic.

The chemical name for tretinoin is: (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid.

Tretinoin has the following structural formula:

Empirical formula: C20H28O2 - Molecular weight: 300.44

Each gram of fluocinolone acetonide, hydroquinone, tretinoin cream contains Active: fluocinolone acetonide 0.01% (0.1 mg), hydroquinone 4% (40 mg), and tretinoin 0.05% (0.5 mg).

Inactive: butylated hydroxytoluene, cetyl alcohol, citric acid, glycerin, glyceryl stearate, magnesium aluminum silicate, methyl gluceth-10, methylparaben, PEG-100 stearate, propylparaben, purified water, sodium metabisulfite, stearic acid, and stearyl alcohol.

2. INDICATIONS AND USAGE

Fluocinolone acetonide, hydroquinone, tretinoin cream 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.

The following are important statements relating to the indication and usage of TRILUMA Cream:

• Fluocinolone acetonide, hydroquinone, tretinoin cream, a combination drug product containing corticosteroid, retinoid, and bleaching agent, is NOT indicated for the maintenance treatment of melasma. After achieving control with fluocinolone acetonide, hydroquinone, tretinoin cream, some patients may be managed with other treatments instead of triple therapy with fluocinolone acetonide, hydroquinone, tretinoin cream. Because melasma usually recurs upon discontinuation of fluocinolone acetonide, hydroquinone, tretinoin cream, patients need to avoid sunlight exposure, use sunscreen with appropriate SPF, wear protective clothing, and change to non-hormonal forms of birth control, if hormonal methods are used.

• In clinical trials used to support the use of fluocinolone acetonide, hydroquinone, tretinoin cream in the treatment of melasma, patients were instructed to avoid sunlight exposure to the face, wear protective clothing and use a sunscreen with SPF 30 each day. They were to apply the study medication each night, after washing their face with a mild soapless cleanser.

• The safety and efficacy of fluocinolone acetonide, hydroquinone, tretinoin cream in patients of 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 fluocinolone acetonide, hydroquinone, tretinoin cream in the treatment of hyper-pigmentation conditions other than melasma of the face have not been studied.

• Because pregnant and lactating women were excluded from, and women of child-bearing potential had to use birth control measures in the clinical trials, the safety and efficacy of fluocinolone acetonide, hydroquinone, tretinoin cream in pregnant women and nursing mothers have not been established (See PRECAUTIONS, Pregnancy).

3. DOSAGE AND ADMINISTRATION

Fluocinolone acetonide, hydroquinone, tretinoin cream should be applied once daily at night. It should be applied at least 30 minutes before bedtime.

Gently wash the face and neck with a mild cleanser. Rinse and pat the skin dry. Apply a thin film of the 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. Do not use occlusive dressing.

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.

4. CONTRAINDICATIONS

Fluocinolone acetonide, hydroquinone, tretinoin cream is contraindicated in individuals with a history of hypersensitivity, allergy, or intolerance to this product or any of its components.

5. WARNINGS AND PRECAUTIONS

WARNINGS

Fluocinolone acetonide, hydroquinone, tretinoin cream contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening asthmatic episodes in susceptible people.

Fluocinolone acetonide, hydroquinone, tretinoin cream contains hydroquinone, which may produce exogenous ochronosis, a gradual blue-black darkening of the skin, whose occurrence should prompt discontinuation of therapy. The majority of patients developing this condition are Black, but it may also occur in Caucasians and Hispanics.

Cutaneous hypersensitivity to the active ingredients of fluocinolone acetonide, hydroquinone, tretinoin 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 fluocinolone acetonide, hydroquinone, tretinoin cream or its components.

PRECAUTIONS

General

Fluocinolone acetonide, hydroquinone, tretinoin 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.

Fluocinolone acetonide, hydroquinone, tretinoin cream also 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 fluocinolone acetonide, hydroquinone, tretinoin cream should be discontinued. Recovery of HPA axis function generally occurs upon discontinuation of topical corticosteroids.

Information for Patients

Exposure to sunlight, sunlamp, or ultraviolet light should be avoided. Patients who are consistently exposed to sunlight or skin irritants either through their work environment or habits should exercise particular caution. Sunscreen and protective covering (such as the use of a hat) over the treated areas should be used. Sunscreen use is an essential aspect of melasma therapy, as even minimal sunlight sustains melanocytic activity.

Weather extremes, such as heat or cold, may be irritating to patients treated with fluocinolone acetonide, hydroquinone, tretinoin cream. Because of the drying effect of this medication, a moisturizer may be applied to the face in the morning after washing.

Application of fluocinolone acetonide, hydroquinone, tretinoin cream should be kept away from the eyes, nose, or angles of the mouth, because the mucosa is much more sensitive than the skin to the irritant effect. If local irritation persists or becomes severe, application of the medication should be discontinued, and the health care provider consulted. Allergic contact dermatitis, blistering, crusting, and severe burning or swelling of the skin and irritation of the mucous membranes of the eyes, nose, and mouth require medical attention.

If the medication is applied excessively, marked redness, peeling, or discomfort may occur.

This medication is to be used as directed by the health care provider and should not be used for any disorder other than that for which it is prescribed.

Laboratory Tests

The following tests may be helpful in evaluating patients for HPA axis suppression:

ACTH or cosyntropin stimulation test

A.M. plasma cortisol test

Urinary free cortisol test

6. ADVERSE REACTIONS

In the controlled clinical trials, adverse events were monitored in the 161 patients who used fluocinolone acetonide, hydroquinone, tretinoin cream once daily during an 8-week treatment period. There were 102 (63%) patients who experienced at least one treatment-related adverse event during these studies. 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 fluocinolone acetonide, hydroquinone, tretinoin cream from the controlled clinical studies are summarized (in decreasing order of frequency) as follows:

Table 1: Incidence and Frequency of Treatment-related Adverse Events with Fluocinolone Acetonide, Hydroquinone, Tretinoin Cream in at least 1% or more of Patients (N=161)

In an open-label long-term safety study, patients who have had cumulative treatment of melasma with fluocinolone acetonide, hydroquinone, tretinoin 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 infrequently 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.

Fluocinolone acetonide, hydroquinone, tretinoin cream contains hydroquinone, which may produce exogenous ochronosis, a gradual blue-black darkening of the skin, whose occurrence should prompt discontinuation of therapy.

Cutaneous hypersensitivity to the active ingredients of fluocinolone acetonide, hydroquinone, tretinoin 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 fluocinolone acetonide, hydroquinone, tretinoin cream or its components.

7. DRUG INTERACTIONS

Patients should avoid medicated or abrasive soaps and cleansers, soaps and cosmetics with drying effects, products with high concentration of alcohol and astringent, and other irritants or keratolytic drugs while on fluocinolone acetonide, hydroquinone, tretinoin cream treatment. Patients are cautioned on concomitant use of medications that are known to be photosensitizing.

8. USE IN SPECIFIC POPULATIONS

8.1 Usage in Pregnancy

Teratogenic Effects: Pregnancy Category C

Fluocinolone acetonide, hydroquinone, tretinoin cream contains the teratogen, tretinoin, which may cause embryo-fetal death, altered fetal growth, congenital malformations, and potential neurologic deficits. It is difficult to interpret the animal studies on teratogenicity with fluocinolone acetonide, hydroquinone, tretinoin cream, because the availability of the dermal applications in these studies cannot be assured, and comparison with clinical dosing is not possible. There are no adequate and well-controlled studies in pregnant women. Fluocinolone acetonide, hydroquinone, tretinoin cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Summary Statement on Teratogenic Risk

Fluocinolone acetonide, hydroquinone, tretinoin cream contains the teratogen, tretinoin, which may cause embryo-fetal death, altered fetal growth, congenital malformations, and potential neurologic deficits. However, human data have not confirmed an increased risk of these developmental abnormalities when tretinoin is administered by the topical route.

Clinical considerations relevant to actual or potential inadvertent exposure during pregnancy:

In clinical trials involving fluocinolone acetonide, hydroquinone, tretinoin 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. Thus, safety and efficacy of fluocinolone acetonide, hydroquinone, tretinoin cream in pregnancy has not been established. In general, use of drugs should be reduced to a minimum in pregnancy. If a patient has been inadvertently exposed to fluocinolone acetonide, hydroquinone, tretinoin 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 fluocinolone acetonide, hydroquinone, tretinoin 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.

The prescriber should have the following clinical considerations in making prescribing decisions:

• The potential developmental effects of tretinoin are serious but the risk from topical administration is small.

• Exposure during the period for organogenesis in the first trimester is theoretically more likely to produce adverse outcome than in later pregnancy.

• The risk to the mother for not treating melasma should be determined by the physician with the patient. Mild forms of melasma may not necessarily require drug treatment. Fluocinolone acetonide, hydroquinone, tretinoin cream is indicated for the treatment of moderate to severe melasma. Melasma may also be managed with other forms of therapy such as topical hydroquinone in the presence of sunlight avoidance, or stopping the use of hormonal birth control methods. If possible, delaying treatment with fluocinolone acetonide, hydroquinone, tretinoin cream until after delivery should be considered.

• There are no adequate and well-controlled studies in pregnant women. Fluocinolone acetonide, hydroquinone, tretinoin cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Data Discussion: 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.

1. Human Data.

• In clinical trials involving fluocinolone acetonide, hydroquinone, tretinoin 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 fluocinolone acetonide, hydroquinone, tretinoin cream. Most of the pregnancy outcomes have not been known. Three women gave birth to apparently healthy babies. One pregnancy was terminated prematurely, and another ended in miscarriage.

• Epidemiologic studies have not confirmed an increase in birth defects associated with the use of topical tretinoin. However, there may be limitations to the sensitivity of epidemiologic studies in the detection of certain forms of fetal injury, such as subtle neurologic or intelligence deficits.

2. Animal Data.

• In a dermal application study using fluocinolone acetonide, hydroquinone, tretinoin 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 fluocinolone acetonide, hydroquinone, tretinoin 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 fluocinolone acetonide, hydroquinone, tretinoin 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 fluocinolone acetonide, hydroquinone, tretinoin cream has been performed.

• It is difficult to interpret these animal studies on teratogenicity with fluocinolone acetonide, hydroquinone, tretinoin cream, because the availability of the dermal applications in these studies could not be assured, and comparison with clinical dosing is not possible.

All pregnancies have a risk of birth defect, loss, or other adverse event regardless of drug exposure. Typically, estimates of increased fetal risk from drug exposure rely heavily on animal data. However, animal studies do not always predict effects in humans. Even if human data are available, such data may not be sufficient to determine whether there is an increased risk to the fetus. Drug effects on behavior, cognitive function, and fertility in the offspring are particularly difficult to assess.

8.2 Nursing Mothers

Corticosteroids, when systemically administered, appear in human milk. It is not known whether topical application of fluocinolone acetonide, hydroquinone, tretinoin cream could result in sufficient systemic absorption to produce detectable quantities of fluocinolone acetonide, hydroquinone, or tretinoin in human milk. Because many drugs are secreted in human milk, caution should be exercised when fluocinolone acetonide, hydroquinone, tretinoin cream is administered to a nursing woman. Care should be taken to avoid contact between the infant being nursed and fluocinolone acetonide, hydroquinone, tretinoin cream.

8.3 Pediatric Use

Safety and effectiveness of fluocinolone acetonide, hydroquinone, tretinoin cream in pediatric patients have not been established.

8.4 Geriatric Use

Clinical studies of fluocinolone acetonide, hydroquinone, tretinoin cream did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

9. MECHANISM OF ACTION

One of the components in fluocinolone acetonide, hydroquinone, tretinoin cream, hydroquinone, is a depigmenting agent, and may interrupt one or more steps in the tyrosine-tyrosinase pathway of melanin synthesis. However, the mechanism of action of the active ingredients in fluocinolone acetonide, hydroquinone, tretinoin cream in the treatment of melasma is unknown.

10. PHARMACOKINETICS

Percutaneous absorption of unchanged tretinoin, hydroquinone and fluocinolone acetonide into the systemic circulation of two groups of healthy volunteers (Total n=59) was found to be minimal following 8 weeks of daily application of 1g (Group I, n=45) or 6g (Group II, n=14) of fluocinolone acetonide, hydroquinone, tretinoin cream.

For tretinoin quantifiable plasma concentrations were obtained in 57.78% (26 out of 45) of Group I and 57.14% (8 out of 14) of Group II subjects. The exposure to tretinoin as reflected by the Cmax values ranged from 2.01 to 5.34 ng/mL (Group I) and 2.0 to 4.99 ng/mL (Group II). Thus, daily application of fluocinolone acetonide, hydroquinone, tretinoin cream resulted in a minimal increase of normal endogenous levels of tretinoin. The circulating tretinoin levels represent only a portion of total tretinoin-associated retinoids, which would include metabolites of tretinoin and that sequestered into peripheral tissues.

For hydroquinone quantifiable plasma concentrations were obtained in 18% (8 out of 44) Group I subjects. The exposure to hydroquinone as reflected by the Cmax values ranged from 25.55 to 86.52 ng/mL. All Group II subjects (6g dose) had post-dose plasma hydroquinone concentrations below the quantitation limit. For fluocinolone acetonide, Groups I and II subjects had all post-dose plasma concentrations below quantitation limit.

11. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: TRI-LUMA, by Galderma Labs.

b) Generic drugs: None.

2) How Supplied:

TRI-LUMA Cream is supplied in 30 g aluminum tubes,

NDC 0299-5950-30.

3) Storage and Handling:

Store in a refrigerator, 36° – 46° F (2° – 8° C). Protect from freezing.

Keep tightly closed.

Rx only

Rev 01/13