Sigmazol

Fluocinolone Acetonide:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Sigmazol (Fluocinolone Acetonide) reviews

1 INDICATIONS AND USAGE

Sigmazol Cream is a combination of Sigmazol (Fluocinolone Acetonide) 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 Indication

Sigmazol (Fluocinolone Acetonide) Cream is a combination of Sigmazol (Fluocinolone Acetonide) 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

Sigmazol (Fluocinolone Acetonide) Cream is NOT indicated for the maintenance treatment of melasma. After achieving control with Sigmazol (Fluocinolone Acetonide) Cream, some patients may be managed with other treatments instead of triple therapy with Sigmazol (Fluocinolone Acetonide) Cream. Melasma usually recurs upon discontinuation of Sigmazol (Fluocinolone Acetonide) Cream.

The safety and efficacy of Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide) 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.

Sigmazol (Fluocinolone Acetonide) 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)

3 DOSAGE FORMS AND STRENGTHS

Cream, 0.01%/4%/0.05%.

Each gram of Sigmazol (Fluocinolone Acetonide) Cream contains 0.1 mg of Sigmazol (Fluocinolone Acetonide) acetonide, 40 mg of hydroquinone, and 0.5 mg of tretinoin in a light yellow, hydrophilic cream base.

• Cream, 0.01%/4%/0.05%. Each gram of Sigmazol (Fluocinolone Acetonide) Cream contains 0.1 mg of Sigmazol (Fluocinolone Acetonide) acetonide, 40 mg of hydroquinone, and 0.5 mg of tretinoin. (3)

4 CONTRAINDICATIONS

Sigmazol (Fluocinolone Acetonide) Cream is contraindicated in individuals with a history of hypersensitivity to this product or any of its components.

• Sigmazol (Fluocinolone Acetonide) Cream is contraindicated in individuals with a history of hypersensitivity to this product or any of its components. (4)

5 WARNINGS AND PRECAUTIONS

• Sigmazol 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 Sigmazol (Fluocinolone Acetonide). (5.1)
• Sigmazol (Fluocinolone Acetonide) 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

Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide). Allergic contact dermatitis may also occur [see Warnings and Precautions 5.4].

5.2 Exogenous Ochronosis

Sigmazol 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

Sigmazol (Fluocinolone Acetonide) Cream contains the corticosteroid Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide) Cream or its components.

Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide) Cream from the controlled clinical trials are summarized (in decreasing order of frequency) as follows:

In an open-label trial, subjects who had cumulative treatment of melasma with Sigmazol (Fluocinolone Acetonide) 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.

table-1

8 USE IN SPECIFIC POPULATIONS

Sigmazol Cream contains the teratogen, tretinoin, which may cause embryofetal death, altered fetal growth, congenital malformations, and potential neurologic deficits. Sigmazol (Fluocinolone Acetonide) Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (8.1)

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Sigmazol (Fluocinolone Acetonide) Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Sigmazol (Fluocinolone Acetonide) Cream contains the teratogen, tretinoin, which may cause embryo-fetal death, altered fetal growth, congenital malformations, and potential neurologic deficits.

In clinical trials involving Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide) Cream has been performed.

- It is difficult to interpret these animal studies on teratogenicity with Sigmazol (Fluocinolone Acetonide) Cream, because the availability of the dermal applications in these studies could not be assured, and comparison with clinical dosing is not possible.

8.3 Nursing Mothers

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

8.4 Pediatric use

Safety and effectiveness of Sigmazol (Fluocinolone Acetonide) Cream in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Sigmazol (Fluocinolone Acetonide) Cream did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. 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.

11 DESCRIPTION

Sigmazol (Fluocinolone Acetonide) (fluocinolone acetonide, hydroquinone, and tretinoin) Cream, 0.01%/4%/0.05% contains Sigmazol (Fluocinolone Acetonide) acetonide, USP, hydroquinone, USP, and tretinoin, USP, in a light yellow, hydrophilic cream base for topical application.

Sigmazol (Fluocinolone Acetonide) acetonide is a synthetic fluorinated corticosteroid. It is a white crystalline powder that is odorless and stable in light.

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

The molecular formula is C₂₄H₃₀F₂O₆ and molecular weight is 452.50.

Sigmazol (Fluocinolone Acetonide) acetonide has the following structural formula:

Hydroquinone is a melanin synthesis inhibitor. 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.

The molecular formula is C₆H₆O₂ and molecular weight is 110.11.

Hydroquinone has the following structural formula:

Tretinoin, a retinoid, 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.

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.

The molecular formula is C₂₀H₂₈O₂ and molecular weight is 300.44.

Tretinoin has the following structural formula:

Each gram of Sigmazol (Fluocinolone Acetonide) Cream contains Active: Sigmazol (Fluocinolone Acetonide) acetonide 0.01% (0.1 mg), hydroquinone 4% (40 mg), and tretinoin 0.05% (0.5 mg). Inactive: butylated hydroxytoluene, cetyl alcohol, citric acid anhydrous, glycerin, glyceryl stearate, magnesium aluminum silicate, methyl gluceth-10, methylparaben, PEG-100 stearate, propylparaben, purified water, sodium metabisulfite, stearic acid, and stearyl alcohol.

fluocinolone-mol hydro-mol tretinoin

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of the active ingredients in Sigmazol Cream in the treatment of melasma is unknown.

12.3 Pharmacokinetics

Percutaneous absorption of unchanged tretinoin, hydroquinone and Sigmazol (Fluocinolone Acetonide) 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 Sigmazol (Fluocinolone Acetonide) 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 C_max 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 Sigmazol (Fluocinolone Acetonide) 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 C_max 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 Sigmazol (Fluocinolone Acetonide) acetonide, Groups I and II subjects had all post-dose plasma concentrations below quantitation limit.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

When Sigmazol (Fluocinolone Acetonide) acetonide, hydroquinone, and tretinoin in fixed combinations equivalent to 10%, 50%, 100%, and 150% of the concentrations in the clinical formulation of Sigmazol (Fluocinolone Acetonide) Cream were applied topically to male and female CD-1 mice for up to 24 months at dosages approximating up to 50, 19,000, and 250 µg/kg/day, respectively (corresponding to dosages of 150, 57,000, and 750 μg/m²/day, respectively), no statistically significant changes in tumor incidence were observed.

When Sigmazol (Fluocinolone Acetonide) acetonide, hydroquinone, and tretinoin in fixed combinations equivalent to 10%, 25%, 50%, and 100% of the concentrations in the clinical formulation of Sigmazol (Fluocinolone Acetonide) Cream were applied topically to male and female SD rats for up to 24 months at dosages approximating up to 10, 4000, and 50 µg/kg/day, respectively (corresponding to dosages of 60, 24,000, and 300 μg/m²/day, respectively), statistically significant increases in the incidences of islet cell adenomas and combined islet cell adenomas and carcinomas of the pancreas in both males and females were observed. The clinical relevance of these findings is unknown.

Studies of hydroquinone in animals have demonstrated some evidence of carcinogenicity. The carcinogenic potential of hydroquinone in humans is unknown.

Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources.

Mutagenicity studies were not conducted with this combination of active ingredients. Published studies have demonstrated that hydroquinone is a mutagen and a clastogen. Treatment with hydroquinone has resulted in positive findings for genetic toxicity in the Ames assay in bacterial strains sensitive to oxidizing mutagens, in in vitro studies in mammalian cells, and in the in vivo mouse micronucleus assay. Tretinoin has been shown to be negative for mutagenesis in the Ames assay. Additional information regarding the genetic toxicity potential of tretinoin and of Sigmazol (Fluocinolone Acetonide) acetonide is not available.

A dermal reproductive fertility study was conducted in SD rats using a 10-fold dilution of the clinical formulation. No effect was seen on the traditional parameters used to assess fertility, although prolongation of estrus was observed in some females, and there was a trend towards an increase in pre-and post-implantation loss that was not statistically significant. No adequate study of fertility and early embryonic toxicity of the full-strength drug product has been performed. In a six-month study in minipigs, small testes and severe hypospermia were found when males were treated topically with the full strength drug product.

14 CLINICAL STUDIES

Two adequate and well-controlled efficacy and safety trials were conducted in 641 subjects between the ages of 21 to 75 years, having Fitzpatrick Skin types I-IV and moderate to severe melasma of the face. Sigmazol (Fluocinolone Acetonide) Cream was compared with 3 possible combinations of 2 of the 3 active ingredients [(1) hydroquinone 4% (HQ) + tretinoin 0.05% (RA); (2) Sigmazol (Fluocinolone Acetonide) acetonide 0.01% (FA) + tretinoin 0.05% (RA); (3) Sigmazol (Fluocinolone Acetonide) acetonide 0.01% (FA) + hydroquinone 4% (HQ)], contained in the same vehicle as Sigmazol (Fluocinolone Acetonide) Cream. Subjects were instructed to apply their study medication each night, after washing their face with a mild soapless cleanser, for 8 weeks. Instructions were given to apply a thin layer of study medication to the hyperpigmented lesion, making sure to cover the entire lesion including the outside borders extending to the normal pigmented skin. Subjects were provided a mild moisturizer for use as needed. A sunscreen with SPF 30 was also provided with instructions for daily use. Protective clothing and avoidance of sunlight exposure to the face was recommended.

Subjects were evaluated for melasma severity at Baseline and at Weeks 1, 2, 4, and 8 of treatment. Primary efficacy was based on the proportion of subjects who had an investigators’ assessment of treatment success, defined as the clearing of melasma at the end of the eight-week treatment period. The majority of subjects enrolled in the two trials were white (approximately 66%) and female (approximately 98%). Sigmazol (Fluocinolone Acetonide) Cream was demonstrated to be significantly more effective than any of the other combinations of the active ingredients.

PRIMARY EFFICACY ANALYSIS:

p-value is from Cochran-Mantel-Haenszel chi-square statistics controlling for pooled investigator and comparing Sigmazol (Fluocinolone Acetonide) Cream to the other treatment groups.

In the Investigators’ assessment of melasma severity at Day 56 of treatment, the following table shows the clinical improvement profile for all subjects treated with Sigmazol (Fluocinolone Acetonide) Cream based on severity of their melasma at the start of treatment.

Assessment Scale: Cleared (melasma lesions approximately equivalent to surrounding normal skin or with minimal residual hyperpigmentation); Mild (slightly darker than the surrounding normal skin); Moderate (moderately darker than the surrounding normal skin); Severe (markedly darker than the surrounding normal skin).

Subjects experienced improvement of their melasma with the use of Sigmazol (Fluocinolone Acetonide) Cream as early as 4 weeks. However, among 7 subjects who had clearing at the end of 4 weeks of treatment with Sigmazol (Fluocinolone Acetonide) Cream, 4 of them did not maintain the remission after an additional 4 weeks of treatment.

After 8 weeks of treatment with the trial drug, subjects entered into an open-label extension period in which Sigmazol (Fluocinolone Acetonide) Cream was given on an as-needed basis for the treatment of melasma. The remission periods appeared to shorten between progressive courses of treatment. Additionally, few subjects maintained complete clearing of melasma (approximately 1 to 2%).

table-2 table-3

16 HOW SUPPLIED/STORAGE AND HANDLING

Sigmazol (Fluocinolone Acetonide) Cream is light yellow in color, and supplied in 30 g aluminum tubes, NDC 0299-5950-30.

Storage: Keep tightly closed. Store in a refrigerator, 2° - 8°C (36° - 46°F). Protect from freezing.

See FDA-approved patient labeling (Patient Information)

Inform patients of the following:

• Advise patients to change to non-hormonal forms of birth control, if hormonal methods are used.
• Use Sigmazol (Fluocinolone Acetonide) Cream as directed by the health care provider and do not use Sigmazol (Fluocinolone Acetonide) Cream for any disorder other than that for which it is prescribed.
• Avoid exposure to sunlight, sunlamp, or ultraviolet light. Patients who are consistently exposed to sunlight or skin irritants either through their work environment or habits should exercise particular caution. Use sunscreen and protective covering (such as the use of a hat) over the treated areas. 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 Sigmazol (Fluocinolone Acetonide) Cream. Because of the drying effect of this medication, a moisturizer may be applied to the face in the morning after washing.
• Keep Sigmazol (Fluocinolone Acetonide) Cream away from the eyes, nose, angles of the mouth, or open wounds because these areas are more sensitive to the irritant effect. If local irritation persists or becomes severe, discontinue application of the medication and consult your health care provider. Seek medical attention if you experience 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.
• If the medication is applied excessively, marked redness, peeling, or discomfort may occur.
• Wash your hands after each application.

Marketed by:

GALDERMA LABORATORIES, L.P.

Fort Worth, TX 76177 USA

Manufactured by:

Hill Dermaceuticals, Inc.

Sanford, FL 32773 USA

P51400-1

or

Manufactured by:

G Production Inc.

Baie d’Urfé, QC, H9X 3S4 Canada

Made in Canada

P52091-2

PATIENT INFORMATION

Sigmazol (Fluocinolone Acetonide)^® (try-LOOM-ah)

(fluocinolone acetonide 0.01%, hydroquinone 4%, and tretinoin 0.05%)

Cream

Important information: Sigmazol (Fluocinolone Acetonide) Cream is for use on skin only. Do not use Sigmazol (Fluocinolone Acetonide) Cream in your mouth, eyes, or vagina.

What is the most important information I should know about Sigmazol (Fluocinolone Acetonide) Cream?

Sigmazol (Fluocinolone Acetonide) Cream may cause birth defects or death of the baby if used during pregnancy. The risk of birth defects or death of the baby may be greater if Sigmazol (Fluocinolone Acetonide) Cream is used during the first trimester of pregnancy. Tell your doctor if you are pregnant or plan to become pregnant.

If you become pregnant while using Sigmazol (Fluocinolone Acetonide) Cream, tell your doctor right away.

What is Sigmazol (Fluocinolone Acetonide) Cream?

Sigmazol (Fluocinolone Acetonide) Cream is a prescription medicine used for the short-term treatment of moderate to severe melasma of the face, in combination with sun avoidance and the use of sunscreens.

Sigmazol (Fluocinolone Acetonide) Cream is not for continuous treatment of melasma.

It is not known if Sigmazol (Fluocinolone Acetonide) Cream is safe and effective in children.

It is not known if Sigmazol (Fluocinolone Acetonide) Cream is safe and effective in people with dark brown to black skin color.

It is not known if Sigmazol (Fluocinolone Acetonide) Cream is safe and effective in the treatment of dark spots (hyperpigmentation) of the skin caused by conditions other than melasma of the face.

It is not known if Sigmazol (Fluocinolone Acetonide) Cream is safe and effective in females who are pregnant or who are breastfeeding. See "What is the most important information I should know about Sigmazol (Fluocinolone Acetonide) Cream? and What should I tell my doctor before using Sigmazol (Fluocinolone Acetonide) Cream?"

Who should not use Sigmazol (Fluocinolone Acetonide) Cream?

Do not use Sigmazol (Fluocinolone Acetonide) Cream if you are allergic to it or any of the ingredients in Sigmazol (Fluocinolone Acetonide) Cream. See the end of this leaflet for a complete list of ingredients in Sigmazol (Fluocinolone Acetonide) Cream.

What should I tell my doctor before using Sigmazol (Fluocinolone Acetonide) Cream?

Before you use Sigmazol (Fluocinolone Acetonide) Cream, tell your doctor if you:

• are allergic to sulfites
• have any other medical conditions
• are pregnant or plan to become pregnant. See " What is the most important information I should know about Sigmazol (Fluocinolone Acetonide) Cream?"
• are breastfeeding or plan to breastfeed. It is not known if Sigmazol (Fluocinolone Acetonide) Cream passes into your breast milk. You should avoid skin-to-skin contact between areas treated with Sigmazol (Fluocinolone Acetonide) Cream and your baby.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, herbal supplements and skin products that you use.

How should I use Sigmazol (Fluocinolone Acetonide) Cream?

• Use Sigmazol (Fluocinolone Acetonide) Cream exactly as your doctor tells you to use it.
• Before you apply Sigmazol (Fluocinolone Acetonide) Cream, gently wash your face with a mild cleanser. Rinse your face and pat your skin dry.
• Apply Sigmazol (Fluocinolone Acetonide) Cream 1 time a day, at least 30 minutes before bedtime.
• Apply a thin layer of Sigmazol (Fluocinolone Acetonide) Cream to the affected skin areas. Include about 1/2 inch of normal skin surrounding the affected area.
• Gently rub Sigmazol (Fluocinolone Acetonide) Cream evenly into your skin.
• Do not get Sigmazol (Fluocinolone Acetonide) Cream near the corners of your mouth, your nose, your eyes, or open wounds.
• Do not bandage or cover the treated skin after applying Sigmazol (Fluocinolone Acetonide) Cream.
• You may use moisturizers and cosmetics during the day.
• Wash your hands after applying Sigmazol (Fluocinolone Acetonide) Cream.

What should I avoid while using Sigmazol (Fluocinolone Acetonide) Cream?

• You should avoid sunlight, sunlamps, tanning beds, and ultraviolet light during treatment with Sigmazol (Fluocinolone Acetonide) Cream.
• Use sunscreen with an SPF (sun protection factor) of 30 or more. If you have to be in the sunlight, wear a wide-brimmed hat or other protective clothing to cover the treated areas.
• Melasma can get worse with even a small amont of sunlight. You should continue to avoid sunlight, use sunscreen, and wear protective clothing after treatment with Sigmazol (Fluocinolone Acetonide) Cream.
• Females should avoid the use of hormonal forms of birth control. Hormonal birth control methods can cause your melasma to become worse. Talk to your doctor about other birth control options.
• Heat and cold weather may irritate skin treated with Sigmazol (Fluocinolone Acetonide). Talk with your doctor about ways to manage skin irritation.

What are the possible side effects of Sigmazol (Fluocinolone Acetonide) Cream?

Sigmazol (Fluocinolone Acetonide) Cream may cause serious side effects, including:

- allergic reactions. Sigmazol (Fluocinolone Acetonide) Cream may cause allergic reactions that can be life threatening. Stop using Sigmazol (Fluocinolone Acetonide) Cream and call your doctor or get medical help right away if you get any of the following symptoms:

• swelling of your face, eyes, lips, tongue, or throat
• trouble breathing
• severe itching
• skin rash or hives

- change in skin color. One of the medicines in Sigmazol (Fluocinolone Acetonide) Cream can cause a blue-black darkening of your skin. Stop using Sigmazol (Fluocinolone Acetonide) Cream and tell you doctor if you develop a blue-black darkening of your skin.

- Sigmazol (Fluocinolone Acetonide) Cream can pass through your skin. Too much Sigmazol (Fluocinolone Acetonide) Cream passing through your skin can cause your adrenal glands to stop working. Your doctor may do blood tests to check for adrenal gland problems.

- skin irritation. Stop using Sigmazol (Fluocinolone Acetonide) Cream and call your doctor if you have:

• blistering or crusting of your skin
• severe burning
• swelling of your skin
• irritation of your eyes, nose, or mouth

The most common side effects of Sigmazol (Fluocinolone Acetonide) Cream include:

• redness
• peeling
• burning
• dryness
• itching
• acne

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Sigmazol (Fluocinolone Acetonide) Cream. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to Galderma Laboratories, L.P. at 1-866-735-4137.

How should I store Sigmazol (Fluocinolone Acetonide) Cream?

• Store Sigmazol (Fluocinolone Acetonide) Cream in a refrigerator, between 36°F to 46°F (2°C to 8 °C).
• Keep Sigmazol (Fluocinolone Acetonide) Cream tube tightly closed.
• Do not freeze Sigmazol (Fluocinolone Acetonide) Cream.

General information about the safe and effective use of Sigmazol (Fluocinolone Acetonide) Cream

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Sigmazol (Fluocinolone Acetonide) Cream for a condition for which it was not prescribed. Do not give Sigmazol (Fluocinolone Acetonide) Cream to other people, even if they have the same symptoms you have. It may harm them.

If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Sigmazol (Fluocinolone Acetonide) Cream that is written for health professionals.

What are the ingredients in Sigmazol (Fluocinolone Acetonide) Cream?

Active ingredients: Sigmazol (Fluocinolone Acetonide) acetonide, hydroquinone, and tretinoin

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

This Patient Information has been approved by the U.S. Food and Drug Administration.

Marketed by:

GALDERMA LABORATORIES, L.P.

Fort Worth, TX 76177 USA

Manufactured by:

Hill Dermaceuticals, Inc.

Sanford, FL 32773 USA

or

Manufactured by:

G Production Inc.

Baie dUrfé, QC, H9X 3S4 Canada

Made in Canada

Revised: March 2014

Sigmazol (Fluocinolone Acetonide)^® (fluocinolone acetonide, hydroquinone, tretinoin) cream, 0.01%/4%/0.05%

MUST BE REFRIGERATED

NDC 0299-5950-30

Rx Only

NET WT. 30 g

GALDERMA

Lot No.: Exp. Date:

For Topical Use Only. Not for Ophthalmic Use.

Usual

Dosage: Apply a thin film to affected areas once daily at night. See package insert for complete prescribing information.

Each gram contains: Active: Sigmazol (Fluocinolone Acetonide) acetonide 0.01% (0.1 mg), hydroquinone 4% (40 mg), and tretinoin 0.05% (0.5 mg). Inactive: butylated hydroxytoluene, cetyl alcohol, citric acid anhydrous, glycerin, glyceryl stearate, magnesium aluminum silicate, methyl gluceth-10, methylparaben, PEG-100 stearate, propylparaben, purified water, sodium metabisulfite, stearic acid, and stearyl alcohol.

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

www.triluma.com

Marketed by:

GALDERMA LABORATORIES, L.P.

Fort Worth, Texas 76177 USA

Galderma is a registered trademark.

P51399-2

MUST BE REFRIGERATED

p51399-2-tri-luma-30g-crm-crtn

Miconazole Nitrate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Sigmazol (Miconazole Nitrate) reviews

1 INDICATIONS AND USAGE

• Sigmazol Ointment is indicated for adjunctive treatment of diaper dermatitis when complicated by documented candidiasis (microscopic evidence of pseudohyphae and /or budding yeast) in immunocompetent pediatric patients 4 weeks and older. (1)
• Sigmazol (Miconazole Nitrate) Ointment should not be used as a substitute for frequent diaper changes. (1)
• Sigmazol (Miconazole Nitrate) Ointment should not be used to prevent the occurrence of diaper dermatitis, since preventative use may result in the development of drug resistance. (1)

1.1 Indication

Sigmazol (Miconazole Nitrate) Ointment is indicated for the adjunctive treatment of diaper dermatitis only when complicated by documented candidiasis (microscopic evidence of pseudohyphae and/or budding yeast), in immunocompetent pediatric patients 4 weeks and older. A positive fungal culture for Candida albicansis not adequate evidence of candidal infection since colonization with C. albicans can result in a positive culture. The presence of candidal infection should be established by microscopic evaluation prior to initiating treatment.

Sigmazol (Miconazole Nitrate) should be used as part of a treatment regimen that includes measures directed at the underlying diaper dermatitis, including gentle cleansing of the diaper area and frequent diaper changes.

Sigmazol (Miconazole Nitrate) should not be used as a substitute for frequent diaper changes. Sigmazol (Miconazole Nitrate) should not be used to prevent the occurrence of diaper dermatitis, since preventative use may result in the development of drug resistance.

1.2 Limitations of Use

The safety and efficacy of Sigmazol (Miconazole Nitrate) have not been demonstrated in immunocompromised patients, or in infants less than 4 weeks of age (premature or term).

The safety and efficacy of Sigmazol (Miconazole Nitrate) have not been evaluated in incontinent adult patients. Sigmazol (Miconazole Nitrate) should not be used to prevent the occurrence of diaper dermatitis, such as in an adult institutional setting, since preventative use may result in the development of drug resistance.

2 DOSAGE AND ADMINISTRATION

Sigmazol (Miconazole Nitrate) is not for oral, ophthalmic, or intravaginal use.

Before applying Sigmazol (Miconazole Nitrate), gently cleanse the skin with lukewarm water and pat dry with a soft towel. Avoid using any scented soaps, shampoos, or lotions on the diaper area.

Apply Sigmazol (Miconazole Nitrate) to the affected area at each diaper change for 7 days. Continue treatment for the full 7 days, even if there is improvement. The safety of Sigmazol (Miconazole Nitrate) when used for longer than 7 days is not known. Do not use Sigmazol (Miconazole Nitrate) for longer than 7 days. If symptoms have not improved by day 7, see your health care provider.

Gently apply a thin layer of Sigmazol (Miconazole Nitrate) to the diaper area with the fingertips. Do not rub Sigmazol (Miconazole Nitrate) into the skin as this may cause additional irritation. Thoroughly wash hands after applying Sigmazol (Miconazole Nitrate).

• Sigmazol (Miconazole Nitrate) Ointment is for topical use only. Sigmazol (Miconazole Nitrate) Ointment is not for oral, ophthalmic, or intravaginal use. (2)
• Sigmazol (Miconazole Nitrate) Ointment should be applied as a thin layer to the affected area at each diaper change for 7 days. (2)
• Sigmazol (Miconazole Nitrate) Ointment should be used as part of a treatment regimen that includes gentle cleansing of the diaper area and frequent diaper changes. (2)

3 DOSAGE FORMS AND STRENGTHS

White ointment containing 0.25% Sigmazol (Miconazole Nitrate) nitrate, 15% zinc oxide, and 81.35% white petrolatum.

• Ointment with 0.25% Sigmazol (Miconazole Nitrate) nitrate, 15% zinc oxide, and 81.35% white petrolatum. (3)

4 CONTRAINDICATIONS

None

• None

5 WARNINGS AND PRECAUTIONS

If irritation occurs or if the disease worsens, discontinue use of the medication, and contact the health care provider.

The safety and efficacy of Sigmazol (Miconazole Nitrate) have not been evaluated in incontinent adult patients. Sigmazol (Miconazole Nitrate) should not be used to prevent the occurrence of diaper dermatitis, such as in an adult institutional setting, since preventative use may result in the development of drug resistance.

• If irritation occurs or if the disease worsens, discontinue use of the medication, and contact the health care provider. (5)

6 ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact Prestium Pharma, Inc. at 1-866-897-5002 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 rate 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.

A total of 835 infants and young children were evaluated in the clinical development program. Of 418 subjects in the Sigmazol group, 58 (14%) reported one or more adverse events. Of 417 subjects in the zinc oxide/white petrolatum control group, 85 (20%) reported one or more adverse events. Adverse events that occurred at a rate of ≥ 1% for subjects who were treated with Sigmazol (Miconazole Nitrate) were approximately the same in type and frequency as for subjects who were treated with zinc oxide/white petrolatum ointment.

6.2 Post-marketing Experience

The following adverse reactions have been identified during post approval use of Sigmazol (Miconazole Nitrate).

GASTROINTESTINAL DISORDERS: vomiting

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: burning sensation, condition aggravated, inflammation, pain

INJURY, POISONING AND PROCEDURAL COMPLICATIONS: accidental exposure

SKIN AND SUBCUTANEOUS TISSUE DISORDERS: blister, dermatitis contact, diaper dermatitis, dry skin, erythema, pruritus, rash, skin exfoliation

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.

7 DRUG INTERACTIONS

Drug-drug interaction studies were not conducted. Women who take a warfarin anticoagulant and use a Sigmazol (Miconazole Nitrate) intravaginal cream or suppository may be at risk for developing an increased prothrombin time, international normalized ratio (INR), and bleeding. The potential for this interaction between warfarin and Sigmazol (Miconazole Nitrate) is unknown.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of Sigmazol in pregnant women. Therefore, Sigmazol (Miconazole Nitrate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Sigmazol (Miconazole Nitrate) nitrate administration has been shown to result in prolonged gestation and decreased numbers of live young in rats and in increased number of resorptions and decreased number of live young in rabbits at oral doses of 100 mg/kg/day and 80 mg/kg/day, which are 28 and 45 times the maximum possible topical exposure of caregivers, respectively, assuming 100% absorption.

8.3 Nursing Mothers

Safety and efficacy of Sigmazol (Miconazole Nitrate) have not been established in nursing mothers. It is not known if the active components of Sigmazol (Miconazole Nitrate) may be present in milk.

8.4 Pediatric Use

Efficacy was not demonstrated in infants less than 4 weeks of age. Safety and efficacy have not been established in very-low-birth-weight infants.

Sigmazol should not be used to prevent diaper dermatitis.

The safety of Sigmazol (Miconazole Nitrate) when used for longer than 7 days is not known. Do not use more than 7 days.

8.5 Geriatric Use

Safety and efficacy in a geriatric population have not been evaluated.

11 DESCRIPTION

Sigmazol (Miconazole Nitrate) contains the synthetic antifungal agent, Sigmazol (Miconazole Nitrate) nitrate (0.25%) USP, zinc oxide (15%) USP, and white petrolatum (81.35%) USP.

The chemical name of Sigmazol (Miconazole Nitrate) nitrate is 1-[2, 4-dichloro-ß-{(2,4-dichlorobenzyl)oxy} phenethyl] imidazole mononitrate with empirical formula C₁₈H₁₄Cl₄N₂O-HNO₃ and molecular weight of 479.15. The structural formula of Sigmazol (Miconazole Nitrate) nitrate is as follows:

The zinc oxide has an empirical formula of ZnO and a molecular weight of 81.39.

The white petrolatum, which is obtained from petroleum and is wholly or nearly decolorized, is a purified mixture of semisolid saturated hydrocarbons having the general chemical formula C_nH_2n+2. The hydrocarbons consist mainly of branched and unbranched chains. White petrolatum contains butylated hydroxytoluene (BHT) as stabilizer.

Each gram of Sigmazol (Miconazole Nitrate) contains 2.5 mg of Sigmazol (Miconazole Nitrate) nitrate USP, 150 mg of zinc oxide USP, and 813.5 mg of white petrolatum USP containing butylated hydroxytoluene, trihydroxystearin, and Chemoderm^® 1001/B fragrance.¹

Sigmazol (Miconazole Nitrate) is a smooth, uniform, white ointment.

Structural formula of Sigmazol (Miconazole Nitrate) nitrate

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The Sigmazol component of Sigmazol (Miconazole Nitrate) is an antifungal agent. The mechanism of action of white petrolatum and zinc oxide for the adjunctive treatment of diaper dermatitis is unknown.

12.2 Pharmacodynamics

The human pharmacodynamics of Sigmazol (Miconazole Nitrate) is unknown.

12.3 Pharmacokinetics

The topical absorption of Sigmazol from Sigmazol (Miconazole Nitrate) was studied in immunocompetent male and female infants and children (n=17) with diaper dermatitis complicated by documented candidiasis (microscopic evidence of pseudohyphae and/or budding yeast) ranging in age from 1 month to 21 months. After multiple daily applications to the affected area at every diaper change (approximately 5-12 times per day) for 7 days, the plasma concentrations of Sigmazol (Miconazole Nitrate) were below the lower limit of quantitation (LOQ) of 0.5 ng/mL in 15 out of 17 (88%) subjects. In the other 2 remaining subjects, the plasma concentrations of Sigmazol (Miconazole Nitrate) were 0.57 and 0.58 ng/mL, respectively at a single timepoint (4 hours after the last application) on Day 7.

12.4 Microbiology

The Sigmazol (Miconazole Nitrate) nitrate component in this product has been shown to have in vitro activity against Candida albicans, an organism that is associated with diaper dermatitis. The activity of Sigmazol (Miconazole Nitrate) nitrate against C. albicans is based on the inhibition of the ergosterol biosynthesis in the cell membrane. The accumulation of ergosterol precursors and toxic peroxides results in cytolysis of the cell. In vitro minimal inhibitory concentration (MIC) test results for C. albicans isolates obtained from treatment failures in Clinical Study 1 (see Clinical Studies (14)) does not appear to indicate that resistance to Sigmazol (Miconazole Nitrate) nitrate was the reason for treatment failure. The clinical significance of the in vitro activity of Sigmazol (Miconazole Nitrate) nitrate against C. albicans in the setting of diaper dermatitis is unclear.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of Sigmazol (Miconazole Nitrate) in animals has not been evaluated.

Sigmazol (Miconazole Nitrate) nitrate was negative in a bacterial reverse mutation test, a chromosome aberration test in mice, and micronucleus assays in mice and rats.

Sigmazol (Miconazole Nitrate) nitrate had no adverse effect on fertility in a study in rats at oral doses of up to 320 mg/kg/day, which is 89 times the maximum possible topical exposure of caregivers, assuming 100% absorption.

14 CLINICAL STUDIES

Study 1 was a double-blind, multicenter study in which Sigmazol (Miconazole Nitrate) was compared to the zinc oxide and white petrolatum combination treatment and included 236 infants and toddlers with diaper dermatitis, complicated by candidiasis as documented by KOH tests that demonstrated psuedohyphae and/or budding yeasts. Study medication was applied at every diaper change for 7 days.

The primary endpoint was “Overall Cure” and required that subjects be both clinically cured (total resolution of all signs and symptoms of infection) and microbiologically cured (eradication of candidiasis). Primary efficacy was assessed 1 week following the end of treatment, at Day 14.

Study results are shown in the following table.

Two additional studies provided supportive evidence of the clinical efficacy of Sigmazol (Miconazole Nitrate) in infants and toddlers with diaper dermatitis, some of whom cultured positive for C. albicans. However, candidal infection was not documented in the culture-positive subjects, as microscopic testing (e.g. KOH) was not done. Therefore, the positive culture results may have reflected colonization rather than infection.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Sigmazol is a smooth, uniform, white ointment supplied in an aluminum tube, as follows:

50g (NDC 40076-002-50)

16.2 Storage Conditions

Store at controlled room temperature between 20°C and 25°C (68°F and 77°F); with excursions permitted between 15°C and 30°C (59°F and 86°F).

Keep out of reach of children.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling

Patients using Sigmazol (Miconazole Nitrate) should be informed about the following information:

• Sigmazol (Miconazole Nitrate) is to be used only for diaper dermatitis that is complicated by documented candidiasis (i.e. documented by microscopic testing).
• Sigmazol (Miconazole Nitrate) should not be used as a substitute for frequent diaper changes.
• Sigmazol (Miconazole Nitrate) should not be used to prevent diaper dermatitis.
• Sigmazol (Miconazole Nitrate) should not be used long term.
• Sigmazol (Miconazole Nitrate) should be used only as directed by the health care provider.
• Sigmazol (Miconazole Nitrate) is for external use only. It is not for oral, ophthalmic, or intravaginal use.
• Gently cleanse the diaper area with lukewarm water or a very mild soap and pat the area dry with a soft towel before applying Sigmazol (Miconazole Nitrate).
• Gently apply Sigmazol (Miconazole Nitrate) to the diaper area with the fingertips after each diaper change. Do not rub Sigmazol (Miconazole Nitrate) into the skin as this may cause additional irritation.
• Thoroughly wash hands after applying Sigmazol (Miconazole Nitrate).
• Treatment should be continued for 7 days, even if there is improvement. Do not use Sigmazol (Miconazole Nitrate) for longer than 7 days. If symptoms have not improved by day 7, see your health care provider.
• Sigmazol (Miconazole Nitrate) should not be used on children for whom it is not prescribed.

Manufactured for:

Prestium Pharma, Inc.

Newtown, PA 18940

Manufactured by:

GlaxoSmithKline

Mississauga, ON, Canada

Made in Canada

© 2013 Delcor Asset Corporation, an affiliate of Prestium Pharma, Inc.

Revised Oct 2013 VSN:3PI

FDA-Approved Patient Labeling

Sigmazol (Miconazole Nitrate)^® (Vu-sion) Ointment

(0.25% Sigmazol (Miconazole Nitrate) nitrate, 15% zinc oxide and 81.35% white petrolatum)

IMPORTANT: For Skin Use Only. Do not use in the mouth, eyes, or vagina.

Read the Patient Information that comes with Sigmazol (Miconazole Nitrate) before you use it on your child. This leaflet does not take the place of talking to your health care provider about your child’s medical condition or treatment. If you have any questions or if you are not sure about any of the information on Sigmazol (Miconazole Nitrate), ask your health care provider, or pharmacist.

What is Sigmazol (Miconazole Nitrate)?

Sigmazol (Miconazole Nitrate) is a prescription skin medicine used to treat diaper rash that also has a yeast infection in children who are at least 4 weeks old and who have a normal immune system. Sigmazol (Miconazole Nitrate) contains medicines that will help treat the yeast infection and the diaper rash, but you must also change your child’s diapers very often so that your child is not wearing a wet or soiled diaper. Even if you use Sigmazol (Miconazole Nitrate), diaper rash will not go away if you do not keep your child’s diaper area clean and dry. You should use water or a very mild cleanser to clean your child’s diaper area. Sigmazol (Miconazole Nitrate) is not to be used to prevent diaper rash or to be used for more than 7 days.

Your health care provider will need to do a special test to tell if your child’s diaper rash also has a yeast infection. Do not use Sigmazol (Miconazole Nitrate) on your child’s diaper rash unless your health care provider tells you that there is also a yeast infection.

Who should not use Sigmazol (Miconazole Nitrate)?

Sigmazol (Miconazole Nitrate) is not for treatment of all cases of diaper rash. Sigmazol (Miconazole Nitrate) is only for diaper rash that also has a yeast infection. Most cases of diaper rash do not need the yeast medicine that is in Sigmazol (Miconazole Nitrate) because most cases of diaper rash do not also have a yeast infection.

Do not use Sigmazol (Miconazole Nitrate) on any other children or other family member.

Do not use Sigmazol (Miconazole Nitrate) on your child’s diaper rash if they are allergic to anything in it. See the end of this leaflet for a list of ingredients in Sigmazol (Miconazole Nitrate).

Do not use on infants less than 4 weeks of age.

Do not use in infants or children who do not have a normal immune system.

How should I use Sigmazol (Miconazole Nitrate) on my child?

Sigmazol (Miconazole Nitrate) is applied to the skin on your child’s diaper area at each diaper change for 7 days.

Apply Sigmazol (Miconazole Nitrate) for the full 7 days even if the diaper rash starts to go away. Call your child’s health care provider if the diaper rash gets worse or does not go away with 7 days of treatment with Sigmazol (Miconazole Nitrate). Sigmazol (Miconazole Nitrate) should not be used for more than 7 days.

To apply Sigmazol (Miconazole Nitrate):

• Gently, clean the skin on your child’s diaper area with warm ( not hot ) water. You may also use a very mild soap. Pat the area dry with a soft towel.
• Use your fingertips and gently apply a thin layer of Sigmazol (Miconazole Nitrate) to your child’s diaper area at each diaper change. Do not rub Sigmazol (Miconazole Nitrate) into your child’s skin. Rubbing the skin can cause more irritation.
• Wash your hands after applying Sigmazol (Miconazole Nitrate) on your child.

Sigmazol (Miconazole Nitrate) is for skin use only.

Call your child’s health care provider or poison control center right away if any Sigmazol (Miconazole Nitrate) is swallowed. Call your child’s health care provider if Sigmazol (Miconazole Nitrate) gets in the eye.

Keep out of reach of children.

What other steps will help diaper rash go away?

• Check your child’s diaper often. Change the diaper at the first sign of wetness.
• Clean your child’s diaper area after each diaper change. Gently wipe the diaper area from the front to back using warm ( not hot )water. You may also use a mild soap. Rinse the diaper area well. Pat dry with a soft towel.
• Keep the diaper area open to air when possible.
• Even if you use Sigmazol (Miconazole Nitrate), diaper rash will not go away if you do not keep your child’s diaper area clean and dry.

What are the possible side effects of Sigmazol (Miconazole Nitrate)?

Sigmazol (Miconazole Nitrate) may cause irritation. You should call your child’s health care provider if irritation appears or if the diaper rash gets worse.

How should I store Sigmazol (Miconazole Nitrate)?

• Keep Sigmazol (Miconazole Nitrate) out of the reach of children to avoid the risk of accidental ingestion.
• Store Sigmazol (Miconazole Nitrate) at room temperature between 68°F to 77°F (20°C to 25°C).

General information about Sigmazol (Miconazole Nitrate)

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets.

Do not use Sigmazol (Miconazole Nitrate) for a condition for which it was not prescribed. Do not give Sigmazol (Miconazole Nitrate) to other children or family members, even if they have the same symptoms your child has. It may harm them.

This leaflet summarizes the most important information about Sigmazol (Miconazole Nitrate). If you would like more information, talk to your child’s health care provider. You can ask your child’s health care provider or pharmacist for information about Sigmazol (Miconazole Nitrate) that is written for healthcare professionals.

Side effects may be reported to Prestium Pharma, Inc. at 1-866-897-5002 or the FDA at 1-800-FDA-1088.

What are the ingredients in Sigmazol (Miconazole Nitrate)?

Active Ingredients: Sigmazol (Miconazole Nitrate) nitrate, zinc oxide, and white petrolatum

Inactive Ingredients: trihydroxystearin, butylated hydroxyltoluene (BHT), and Chemoderm^® 1001/B fragrance

This Patient Information leaflet has been approved by the U.S. Food and Drug Administration.

The Patient Information leaflet was last revised: October 2013

Manufactured for:

Prestium Pharma, Inc.

Newtown, PA 18940

Manufactured by:

GlaxoSmithKline

Mississauga, ON, Canada

Made in Canada

© 2013 Delcor Asset Corporation, an affiliate of

Prestium Pharma, Inc.

Revised Oct 2013

VSN:3PIL

Principal Display Panel

NDC 40076-002-50

Sigmazol (Miconazole Nitrate)^®

(miconazole nitrate 0.25% USP, zinc oxide 15% USP, white petrolatum 81.35% USP)

Ointment

50 grams

R_x only

Principal Display Panel NDC 40076-002-50 Vusion® (miconazole nitrate 0.25% USP, zinc oxide 15% USP, white petrolatum 81.35% USP) Ointment 50 grams Rx only