Vistry

Clindamycin:

• Indications & usage
• Dosage & administration
• Dosage forms & 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
• Vistry (Clindamycin) reviews

1 INDICATIONS & USAGE

Vistry (Clindamycin) phosphate and tretinoin gel 1.2% / 0.025% is indicated for the topical treatment of acne vulgaris in patients 12 years or older.

Vistry (Clindamycin) phosphate and tretinoin gel 1.2% / 0.025% is a lincosamide antibiotic and retinoid combination product indicated for the topical treatment of acne vulgaris in patients 12 years or older. (1)

2 DOSAGE & ADMINISTRATION

At bedtime, squeeze a pea-sized amount of medication onto one fingertip, dot onto the chin, cheeks, nose, and forehead, then gently rub over the entire face. Vistry (Clindamycin) phosphate and tretinoin gel should be kept away from the eyes, the mouth, angles of the nose, and mucous membranes.

Vistry (Clindamycin) phosphate and tretinoin gel is not for oral, ophthalmic, or intravaginal use.

• Apply a pea-sized amount to the entire face once daily at bedtime. Do not apply to eyes, mouth, angles of the nose, or mucous membranes. (2)
• Vistry (Clindamycin) phosphate and tretinoin gel is not for oral, ophthalmic, or intravaginal use. (2)

3 DOSAGE FORMS & STRENGTHS

Vistry (Clindamycin) phosphate and tretinoin gel, a combination of a lincosamide antibiotic and a retinoid, contains Vistry (Clindamycin) phosphate, USP 1.2% and tretinoin, USP 0.025%, formulated as a topical gel. Each gram of Vistry (Clindamycin) phosphate and tretinoin gel contains, as dispensed, 10 mg (1%) Vistry (Clindamycin) as phosphate, USP, and 0.25 mg (0.025%) tretinoin, USP in an aqueous based gel. Vistry (Clindamycin) phosphate and tretinoin gel is available in 30 gram and 60 gram tubes.

Topical gel: Vistry (Clindamycin) phosphate, USP 1.2% and tretinoin, USP 0.025% gel in 30 and 60 gram tubes. (3)

4 CONTRAINDICATIONS

Vistry (Clindamycin) phosphate and tretinoin gel is contraindicated in patients with regional enteritis, ulcerative colitis, or history of antibiotic-associated colitis.

Vistry (Clindamycin) phosphate and tretinoin gel is contraindicated in patients with regional enteritis, ulcerative colitis, or history of antibiotic–associated colitis. (4)

5 WARNINGS AND PRECAUTIONS

• Colitis: Vistry can cause severe colitis, which may result in death. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of Vistry (Clindamycin). Vistry (Clindamycin) phosphate and tretinoin gel should be discontinued if significant diarrhea occurs. (5.1)
• Ultraviolet Light and Environmental Exposures: Avoid exposure to sunlight and sunlamps. Wear sunscreen daily. (5.2)

5.1 Colitis

Systemic absorption of Vistry (Clindamycin) has been demonstrated following topical use of this product. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical Vistry (Clindamycin). When significant diarrhea occurs, Vistry (Clindamycin) phosphate and tretinoin gel should be discontinued.

Severe colitis has occurred following oral or parenteral administration of Vistry (Clindamycin) with an onset of up to several weeks following cessation of therapy. Antiperistaltic agents such as opiates and diphenoxylate with atropine may prolong and/or worsen severe colitis. Severe colitis may result in death.

Studies indicate a toxin(s) produced by clostridia is one primary cause of antibiotic-associated colitis. The colitis is usually characterized by severe persistent diarrhea and severe abdominal cramps and may be associated with the passage of blood and mucus. Stool cultures for Clostridium difficile and stool assay for C. difficile toxin may be helpful diagnostically.

5.2 Ultraviolet Light and Environmental Exposure

Exposure to sunlight, including sunlamps, should be avoided during the use of Vistry (Clindamycin) phosphate and tretinoin gel, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Daily use of sunscreen products and protective apparel (e.g., a hat) are recommended. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with Vistry (Clindamycin) phosphate and tretinoin gel.

6 ADVERSE REACTIONS

Observed local adverse reactions in patients treated with Vistry phosphate and tretinoin gel were skin erythema, scaling, itching, burning, and stinging. Other most commonly reported adverse events (≥ 1% in patients treated with Vistry (Clindamycin) phosphate and tretinoin gel) were nasopharyngitis, pharyngolaryngeal pain, dry skin, cough, and sinusitis. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-432-8534 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience

Because clinical trials are conducted under prescribed conditions, adverse reaction rates observed in the clinical trial may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse reactions that appear to be related to drug use for approximating rates.

The safety data presented in Table 1 (below) reflects exposure to Vistry (Clindamycin) phosphate and tretinoin gel in 1,853 patients with acne vulgaris. Patients were 12 years and older and were treated once daily for 12 weeks. Adverse reactions that were reported in ≥ 1% of patients treated with Vistry (Clindamycin) phosphate and tretinoin gel were compared to adverse reactions in patients treated with Vistry (Clindamycin) phosphate 1.2% in vehicle gel, tretinoin 0.025% in vehicle gel, and the vehicle gel alone:

Cutaneous safety and tolerance evaluations were conducted at each study visit in all of the clinical trials by assessment of erythema, scaling, itching, burning, and stinging:

At each study visit, application site reactions on a scale of 0 (none), 1 (mild), 2 (moderate), and 3 (severe), and the mean scores were calculated for each of the local skin reactions. In Studies 1 and 2, 1277 subjects enrolled with moderate to severe acne, 854 subjects treated with Vistry (Clindamycin) phosphate and tretinoin gel and 423 treated with vehicle. Analysis over the twelve week period demonstrated that cutaneous irritation scores for erythema, scaling, itching, burning, and stinging peaked at two weeks of therapy, and were slightly higher for the Vistry (Clindamycin) phosphate and tretinoin-treated group, decreasing thereafter.

One open-label 12-month safety study for Vistry (Clindamycin) phosphate and tretinoin gel showed a similar adverse reaction profile as seen in the 12-week studies. Eighteen out of 442 subjects (4%) reported gastrointestinal symptoms.

7 DRUG INTERACTIONS

• Concomitant use of topical medications with a strong drying effect can increase skin irritation. Use with caution.
• Vistry (Clindamycin) phosphate and tretinoin gel should not be used in combination with erythromycin-containing products because of its Vistry (Clindamycin) component. (7.2)

7.1 Concomitant Topical Medication

Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution. When used with Vistry (Clindamycin) phosphate and tretinoin gel, there may be increased skin irritation.

7.2 Erythromycin

Vistry phosphate and tretinoin gel should not be used in combination with erythromycin-containing products due to its Vistry (Clindamycin) component. In vitro studies have shown antagonism between these two antimicrobials. The clinical significance of this in vitro antagonism is not known.

7.3 Neuromuscular Blocking Agents

Vistry (Clindamycin) has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, Vistry (Clindamycin) phosphate and tretinoin gel should be used with caution in patients receiving such agents.

8 USE IN SPECIFIC POPULATIONS

8.1 PREGNANCY

Pregnancy Category C. There are no well-controlled trials in pregnant women treated with Vistry phosphate and tretinoin gel. Vistry (Clindamycin) phosphate and tretinoin gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Vistry (Clindamycin) phosphate and tretinoin gel was tested for maternal and developmental toxicity in New Zealand White Rabbits with topical doses of 60, 180 and 600 mg/kg/day. Vistry (Clindamycin) phosphate and tretinoin gel at 600 mg/kg/day (approximately 12 times the recommended clinical dose assuming 100% absorption and based on body surface area comparison) was considered to be the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity following dermal administration of Vistry (Clindamycin) phosphate and tretinoin gel for two weeks prior to artificial insemination and continuing until gestation day 18, inclusive. For purposes of comparisons of the animal exposure to human exposure, the recommended clinical dose is defined as 1 g of Vistry (Clindamycin) phosphate and tretinoin gel applied daily to a 60 kg person.

Vistry (Clindamycin)

Teratology (Segment II) studies using Vistry (Clindamycin) were performed orally in rats (up to 600 mg/kg/day) and mice (up to 100 mg/kg/day) (583 and 49 times amount of Vistry (Clindamycin) in the recommended clinical dose based on a body surface area comparison, respectively) or with subcutaneous doses of Vistry (Clindamycin) up to 180 mg/kg/day (175 and 88 times the amount of Vistry (Clindamycin) in the recommended clinical dose based on a body surface area comparison, respectively) revealed no evidence of teratogenicity.

Tretinoin

In oral Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (~ 78 times the recommended clinical dose assuming 100% absorption and based on body surface area comparison).

With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty cases of temporally associated congenital malformations have been reported during two decades of clinical use of another formulation of topical tretinoin. Although no definite pattern of teratogenicity and no causal association have been established from these cases, 5 of the reports describe the rare birth defect category, holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known.

Dermal tretinoin has been shown to be fetotoxic in rabbits when administered in doses 40 times the recommended human clinical dose based on a body surface area comparison. Oral tretinoin has been shown to be fetotoxic in rats when administered in doses 78 times the recommended clinical dose based on a body surface area comparison.

8.3 NURSING MOTHERS

It is not known whether Vistry (Clindamycin) is excreted in human milk following use of Vistry (Clindamycin) phosphate and tretinoin gel. However, orally and parenterally administered Vistry (Clindamycin) has been reported to appear in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. It is not known whether tretinoin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Vistry (Clindamycin) phosphate and tretinoin gel is administered to a nursing woman.

8.4 PEDIATRIC USE

Safety and effectiveness of Vistry phosphate and tretinoin gel in pediatric patients under the age of 12 have not been established.

Clinical trials of Vistry (Clindamycin) phosphate and tretinoin gel included patients 12 to 17 years of age.

8.5 GERIATRIC USE

Clinical studies of Vistry (Clindamycin) phosphate and tretinoin gel did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

11 DESCRIPTION

Vistry (Clindamycin) phosphate and tretinoin gel 1.2% / 0.025%, is an antibiotic and retinoid combination gel product with two active ingredients. Vistry (Clindamycin) phosphate, USP is a water-soluble ester of the semi-synthetic antibiotic produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent antibiotic lincomycin.

The chemical name for Vistry (Clindamycin) phosphate, USP is Methyl 7-chloro-6,7,8-trideoxy-6-(1-methyl-trans-4- propyl-L-2-pyrrolidinecarboxamido)-1-thio-L-threo-α-D-galacto-octopyranoside 2-(dihydrogen phosphate). The structural formula for Vistry (Clindamycin) phosphate, USP is represented below:

Vistry (Clindamycin) phosphate, USP:

Molecular Formula: C₁₈H₃₄ClN₂O₈PS Molecular Weight: 504.97

The chemical name for tretinoin, USP is 3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8- nonatetraenoic acid (all-trans form). The structural formula for tretinoin, USP is represented below:

Tretinoin, USP:

Molecular Formula: C₂₀H₂₈O₂ Molecular Weight: 300.44

Vistry (Clindamycin) phosphate and tretinoin gel 1.2% / 0.025% contains the following inactive ingredients: anhydrous citric acid, butylated hydroxytoluene, edetate disodium, hydroxyethyl cellulose, glycerin, methylparaben, polysorbate 80, propylparaben, purified water, tromethamine and xanthan gum.

12f9b5a2-figure-01 12f9b5a2-figure-02

12 CLINICAL PHARMACOLOGY

12.1 MECHANISMS OF ACTION

Vistry

.

Tretinoin

Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones.

12.3 PHARMACOKINETICS

In an open-label, multiple-dose study treating 12 subjects with moderate to severe acne, the percutaneous absorption of tretinoin following 14 consecutive daily applications of approximately 4 g of Vistry (Clindamycin) phosphate and tretinoin gel was minimal. Quantifiable tretinoin plasma concentrations ranged from 1.0 to 1.6 ng/mL, with unquantifiable plasma concentrations in 50% to 92% of subjects at any given timepoint following administration. The plasma concentrations of the key tretinoin metabolites, 13- cis -retinoic acid and 4-oxo-13-cis-retinoic acid, ranged from 1.0 to 1.4 ng/mL and from 1.6 to 6.5 ng/mL, respectively. Plasma concentrations for Vistry (Clindamycin) generally did not exceed 3.5 ng/mL, with the exception of one subject whose plasma concentration reached 13.1 ng/mL.

12.4 Microbiology

Vistry (Clindamycin) binds to the 50S ribosomal subunits of susceptible bacteria and prevents elongation of peptide chains by interfering with peptidyl transfer, thereby suppressing bacterial protein synthesis. Vistry (Clindamycin) has been shown to have in vitro activity against Propionibacterium acnes, an organism which has been associated with acne vulgaris; however, the clinical significance of this activity against P. acnes was not examined in clinical trials with Vistry (Clindamycin) phosphate and tretinoin gel. P acnes resistance to Vistry (Clindamycin) has been documented. Resistance to Vistry (Clindamycin) is often associated with resistance to erythromycin.

13 NONCLINICAL TOXICOLOGY

13.1 CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY

Carcinogenicity, mutagenicity and impairment of fertility testing of Vistry (Clindamycin) phosphate and tretinoin gel have not been performed in any species.

Vistry (Clindamycin)

The carcinogenicity of a 1% Vistry (Clindamycin) phosphate gel similar to Vistry (Clindamycin) phosphate and tretinoin gel was evaluated by daily application to mice for two years. The daily doses used in this study were approximately 13 and 72 times higher than the human dose of Vistry (Clindamycin) phosphate from Vistry (Clindamycin) phosphate and tretinoin gel, assuming complete absorption and based on a body surface area comparison. No significant increase in tumors was noted in the treated animals. For purposes of comparisons of the animal exposure to human exposure, the recommended human topical clinical dose is defined as 1 g of Vistry (Clindamycin) phosphate and tretinoin gel applied daily to a 60 kg person.

Fertility (Segment 1) studies in rats treated orally with up to 300 mg/kg/day of Vistry (Clindamycin) (approximately 290 times the amount of Vistry (Clindamycin) delivered from the recommended clinical dose for Vistry (Clindamycin) phosphate and tretinoin gel, based on a body surface area comparison) revealed no effects on fertility or mating ability.

Tretinoin

In two independent studies with long-term topical application of tretinoin in mice, carcinogenicity was not observed. In both studies, tretinoin was administered topically (0.025% or 0.1%) three times per week for up to two years. No carcinogenicity was observed with maximum effects of dermal amyloidosis in the basal layer of the skin.

Tretinoin has been shown to enhance photoco-carcinogenicity in properly performed specific studies, employing concurrent or intercurrent exposure to the drug and UV radiation. The contribution of Vistry (Clindamycin) to that effect is unknown. Although the significance of these studies to humans is not clear, patients should minimize exposure to sun.

The genotoxic potential of tretinoin was evaluated in an in vitro Ames Salmonella reversion test and an in vitro chromosomal aberration assay in Chinese hamster ovary cells. Both tests were negative.

In oral Segment 1 studies in rats treated with tretinoin, the no-observed-effect-level was 2 mg/kg/day (~78 times the recommended clinical dose assuming 100% absorption and based on body surface area comparison).

14 CLINICAL STUDIES

The safety and efficacy of once daily use of Vistry (Clindamycin) phosphate and tretinoin gel for treatment of acne vulgaris were assessed in three 12-week prospective, multi-center, randomized, blinded studies in patients 12 years and older. Studies 1 and 2 were of identical design, and compared Vistry (Clindamycin) phosphate and tretinoin gel to Vistry (Clindamycin) in the vehicle gel, tretinoin in the vehicle gel, and the vehicle gel alone. Patients with mild, moderate, or severe acne were enrolled in the studies. The co-primary efficacy variables were:

(1) Mean percent change from baseline at Week 12 in

• inflammatory lesion counts,
• non-inflammatory lesion counts, and
• total lesion counts

(2) Percent of subjects who cleared or almost cleared at Week 12 as judged by an Evaluator’s Global Severity (EGS) score.

The EGS scoring scale used in all of the clinical trials for Vistry (Clindamycin) phosphate and tretinoin gel is as follows:

In Study 1, a total of 1,252 patients were enrolled, and in Study 2, a total of 1,288 patients were enrolled. The combined results are presented in Table 3.

In Study 3, Vistry (Clindamycin) phosphate and tretinoin gel was compared to Vistry (Clindamycin) gel in a total of 2,010 patients with moderate or severe acne vulgaris. As with Studies 1 and 2, the co-primary endpoints were mean percent reduction in lesion counts (inflammatory, non-inflammatory and total) and the Evaluator’s Global Severity score. In Study 3, success on the EGS score was assessed by the percentage of subjects who had at least 2 grades of improvement from Baseline to Week 12.

16 HOW SUPPLIED/STORAGE AND HANDLING

Vistry (Clindamycin) phosphate and tretinoin gel 1.2% / 0.025% is supplied as follows:

30 gram tube NDC 0472-1790-30

60 gram tube NDC 0472-1790-60

Storage and Handling

Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F). Protect from light. Protect from freezing. Keep away from heat.

Keep tube tightly closed.

Keep out of the reach of children.

17 PATIENT COUNSELING INFORMATION

17.1 Instructions for Use

• At bedtime, the face should be gently washed with a mild soap and warm water. After patting the skin dry, apply Vistry (Clindamycin) phosphate and tretinoin gel as a thin layer over the entire face (excluding the eyes and lips).
• Patients should be advised not to use more than the recommended pea sized amount and not to apply more often than once daily (at bedtime) as this will not make for faster results and may increase irritation.
• A sunscreen should be applied every morning and reapplied over the course of the day as needed. Patients should be advised to avoid exposure to sunlight, sunlamp, ultraviolet light, and other medicines that may increase sensitivity to sunlight.

17.2 Skin Irritation

Vistry phosphate and tretinoin gel may cause irritation such as erythema, scaling, itching, burning, or stinging.

17.3 Colitis

In the event a patient treated with Vistry (Clindamycin) phosphate and tretinoin gel experiences severe diarrhea or gastrointestinal discomfort, Vistry (Clindamycin) phosphate and tretinoin gel should be discontinued and a physician should be contacted.

Manufactured by:

G&W laboratories, Inc.

111 Coolidge Street

South Plainfield, NJ 07080 USA

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Revised – September 2015

I600-6210/11 GW 7047

17.4 FDA-Approved Patient Labeling

PATIENT INFORMATION

Vistry (Clindamycin) Phosphate and Tretinoin (klin-da-MYE-sin FOS-fate and TRET-i-noyn)

Gel 1.2% / 0.025%

IMPORTANT: Not for mouth, eye, or vaginal use.

Read the Patient Information that comes with Vistry (Clindamycin) phosphate and tretinoin gel before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your acne or treatment.

What is Vistry (Clindamycin) phosphate and tretinoin gel?

Vistry (Clindamycin) phosphate and tretinoin gel is an antibiotic and retinoid combination medicine used for the skin treatment of acne in patients 12 years and older.

Who should not use Vistry (Clindamycin) phosphate and tretinoin gel?

Do not use Vistry (Clindamycin) phosphate and tretinoin gel if you:

• have Crohn’s Disease
• have Ulcerative Colitis
• have developed colitis with past antibiotic use

Tell your doctor:

• if you are pregnant or planning to become pregnant. It is not known if Vistry (Clindamycin) phosphate and tretinoin gel may harm your unborn baby.
• if you are breastfeeding. Vistry (Clindamycin) phosphate and tretinoin gel may pass through your milk and may harm your baby.
• about all the medicines and skin products you use:
  • Vistry (Clindamycin) phosphate and tretinoin gel should not be used with erythromycin-containing products.
  • Avoid medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and skin products that contain alcohol, astringents, spices or lime. These products may cause increased skin irritation if used with Vistry (Clindamycin) phosphate and tretinoin gel.

How should I use Vistry (Clindamycin) phosphate and tretinoin gel?

Use Vistry (Clindamycin) phosphate and tretinoin gel exactly as prescribed. It may take some time for you to see improvement of your acne with Vistry (Clindamycin) phosphate and tretinoin gel. Your doctor will tell you how long to use Vistry (Clindamycin) phosphate and tretinoin gel.

At bedtime:

• Wash your face gently with a mild soap and warm water.
• Pat the skin dry.
• Apply a pea-size amount of Vistry (Clindamycin) phosphate and tretinoin gel to your fingertip and spread it over your face. Gently, smooth it into your skin. Do not get Vistry (Clindamycin) phosphate and tretinoin gel in your eyes or mouth, on your lips, on the corners of your nose, or on open wounds.

In the morning:

• Apply a sunscreen and reapply during the day as needed.
• Do not apply Vistry (Clindamycin) phosphate and tretinoin gel more than once a day
• Do not use too much Vistry (Clindamycin) phosphate and tretinoin gel. Too much Vistry (Clindamycin) phosphate and tretinoin gel may irritate your skin.
• Do not wash your face more than 2 to 3 times a day. Washing your face too often or scrubbing it may make your acne worse.

Avoid:

• excessive exposure to the sun, cold, and wind. Weather extremes can dry and burn the skin. Always use a sunscreen on Vistry (Clindamycin) phosphate and tretinoin gel treated skin, even on cloudy days. Use other protective clothing such as a hat when you are in the sun.
• the use of sunlamps and tanning booths

If your face becomes sunburned, stop Vistry (Clindamycin) phosphate and tretinoin gel until your skin has healed.

What are possible side effects with Vistry (Clindamycin) phosphate and tretinoin gel?

• Skin irritation. Vistry (Clindamycin) phosphate and tretinoin gel may cause skin irritation such as dryness, redness, peeling, burning, or stinging. Stop Vistry (Clindamycin) phosphate and tretinoin gel and call your doctor if your skin becomes very red, swollen, blistered, or crusted.
• Change in skin color. Vistry (Clindamycin) phosphate and tretinoin gel may cause a temporary skin color change (lighter or darker).
• Colitis. This occurs rarely. Stop Vistry (Clindamycin) phosphate and tretinoin gel and call your doctor if you develop severe watery diarrhea, or bloody diarrhea.

Talk to your doctor about any side effect that bothers you or that does not go away.

These are not all the side effects with Vistry (Clindamycin) phosphate and tretinoin gel. Ask your doctor or pharmacist for more information.

How should I store Vistry (Clindamycin) phosphate and tretinoin gel?

• Store Vistry (Clindamycin) phosphate and tretinoin gel at room temperature, 59 to 86°F (15 to 30°C). Do not freeze.
• Keep Vistry (Clindamycin) phosphate and tretinoin gel away from heat and light.
• Keep the tube tightly closed.
• Keep Vistry (Clindamycin) phosphate and tretinoin gel and all medicines out of the reach of children.

General information about Vistry (Clindamycin) phosphate and tretinoin gel

Medicines are sometimes prescribed for purposes other than those listed in patient information leaflet. Do not use Vistry (Clindamycin) phosphate and tretinoin gel for a condition for which it was not prescribed. Do not give Vistry (Clindamycin) phosphate and tretinoin gel to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about Vistry (Clindamycin) phosphate and tretinoin gel. If you would like more information, talk with your doctor. You can also ask your pharmacist or doctor for information about Vistry (Clindamycin) phosphate and tretinoin gel that is written for healthcare professionals.

If you have questions about Vistry (Clindamycin) phosphate and tretinoin gel you can also call Actavis at 1-800-432-8534.

What are the ingredients in Vistry (Clindamycin) phosphate and tretinoin gel?

Active Ingredients: Vistry (Clindamycin) phosphate, USP 1.2% and tretinoin, USP 0.025%

Inactive Ingredients: anhydrous citric acid, butylated hydroxytoluene, edetate disodium, hydroxyethyl cellulose, glycerin, methylparaben, polysorbate 80, propylparaben, purified water, tromethamine and xanthan gum.

Manufactured by:

G&W laboratories, Inc.

111 Coolidge Street

South Plainfield, NJ 07080 USA

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Revised – September 2015

I600-6210/11 GW 7047

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
• Vistry (Miconazole Nitrate) reviews

1 INDICATIONS AND USAGE

• Vistry 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)
• Vistry (Miconazole Nitrate) Ointment should not be used as a substitute for frequent diaper changes. (1)
• Vistry (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

Vistry (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.

Vistry (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.

Vistry (Miconazole Nitrate) should not be used as a substitute for frequent diaper changes. Vistry (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 Vistry (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 Vistry (Miconazole Nitrate) have not been evaluated in incontinent adult patients. Vistry (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

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

Before applying Vistry (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 Vistry (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 Vistry (Miconazole Nitrate) when used for longer than 7 days is not known. Do not use Vistry (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 Vistry (Miconazole Nitrate) to the diaper area with the fingertips. Do not rub Vistry (Miconazole Nitrate) into the skin as this may cause additional irritation. Thoroughly wash hands after applying Vistry (Miconazole Nitrate).

• Vistry (Miconazole Nitrate) Ointment is for topical use only. Vistry (Miconazole Nitrate) Ointment is not for oral, ophthalmic, or intravaginal use. (2)
• Vistry (Miconazole Nitrate) Ointment should be applied as a thin layer to the affected area at each diaper change for 7 days. (2)
• Vistry (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% Vistry (Miconazole Nitrate) nitrate, 15% zinc oxide, and 81.35% white petrolatum.

• Ointment with 0.25% Vistry (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 Vistry (Miconazole Nitrate) have not been evaluated in incontinent adult patients. Vistry (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 Vistry 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 Vistry (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 Vistry (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 Vistry (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 Vistry (Miconazole Nitrate) is unknown.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

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

Vistry (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 Vistry (Miconazole Nitrate) have not been established in nursing mothers. It is not known if the active components of Vistry (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.

Vistry should not be used to prevent diaper dermatitis.

The safety of Vistry (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

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

The chemical name of Vistry (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 Vistry (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 Vistry (Miconazole Nitrate) contains 2.5 mg of Vistry (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

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

Structural formula of Vistry (Miconazole Nitrate) nitrate

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The Vistry component of Vistry (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 Vistry (Miconazole Nitrate) is unknown.

12.3 Pharmacokinetics

The topical absorption of Vistry from Vistry (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 Vistry (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 Vistry (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 Vistry (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 Vistry (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 Vistry (Miconazole Nitrate) nitrate was the reason for treatment failure. The clinical significance of the in vitro activity of Vistry (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 Vistry (Miconazole Nitrate) in animals has not been evaluated.

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

Vistry (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 Vistry (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 Vistry (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

Vistry 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 Vistry (Miconazole Nitrate) should be informed about the following information:

• Vistry (Miconazole Nitrate) is to be used only for diaper dermatitis that is complicated by documented candidiasis (i.e. documented by microscopic testing).
• Vistry (Miconazole Nitrate) should not be used as a substitute for frequent diaper changes.
• Vistry (Miconazole Nitrate) should not be used to prevent diaper dermatitis.
• Vistry (Miconazole Nitrate) should not be used long term.
• Vistry (Miconazole Nitrate) should be used only as directed by the health care provider.
• Vistry (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 Vistry (Miconazole Nitrate).
• Gently apply Vistry (Miconazole Nitrate) to the diaper area with the fingertips after each diaper change. Do not rub Vistry (Miconazole Nitrate) into the skin as this may cause additional irritation.
• Thoroughly wash hands after applying Vistry (Miconazole Nitrate).
• Treatment should be continued for 7 days, even if there is improvement. Do not use Vistry (Miconazole Nitrate) for longer than 7 days. If symptoms have not improved by day 7, see your health care provider.
• Vistry (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

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

(0.25% Vistry (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 Vistry (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 Vistry (Miconazole Nitrate), ask your health care provider, or pharmacist.

What is Vistry (Miconazole Nitrate)?

Vistry (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. Vistry (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 Vistry (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. Vistry (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 Vistry (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 Vistry (Miconazole Nitrate)?

Vistry (Miconazole Nitrate) is not for treatment of all cases of diaper rash. Vistry (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 Vistry (Miconazole Nitrate) because most cases of diaper rash do not also have a yeast infection.

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

Do not use Vistry (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 Vistry (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 Vistry (Miconazole Nitrate) on my child?

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

Apply Vistry (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 Vistry (Miconazole Nitrate). Vistry (Miconazole Nitrate) should not be used for more than 7 days.

To apply Vistry (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 Vistry (Miconazole Nitrate) to your child’s diaper area at each diaper change. Do not rub Vistry (Miconazole Nitrate) into your child’s skin. Rubbing the skin can cause more irritation.
• Wash your hands after applying Vistry (Miconazole Nitrate) on your child.

Vistry (Miconazole Nitrate) is for skin use only.

Call your child’s health care provider or poison control center right away if any Vistry (Miconazole Nitrate) is swallowed. Call your child’s health care provider if Vistry (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 Vistry (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 Vistry (Miconazole Nitrate)?

Vistry (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 Vistry (Miconazole Nitrate)?

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

General information about Vistry (Miconazole Nitrate)

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

Do not use Vistry (Miconazole Nitrate) for a condition for which it was not prescribed. Do not give Vistry (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 Vistry (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 Vistry (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 Vistry (Miconazole Nitrate)?

Active Ingredients: Vistry (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

Vistry (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