Pimplex

Adapalene:

• Indications and usage:
• Clinical studies:
• Contraindications:
• Precautions:
• Adverse reactions:
• Overdosage:
• Dosage and administration:
• How supplied:
• Pimplex (Adapalene) reviews

INDICATIONS AND USAGE:

Pimplex (Adapalene) cream is indicated for the topical treatment of acne vulgaris.

CLINICAL STUDIES:

Two vehicle-controlled clinical studies were conducted in patients 12 to 30 years of age with mild to moderate acne vulgaris, in which Pimplex (Adapalene) cream was compared with its vehicle. Patients were instructed to apply their treatment medication once daily at bedtime for 12 weeks. In one study patients were provided with a soapless cleanser and were encouraged to refrain from using moisturizers. No other topical medications, other than Pimplex (Adapalene) cream, were to be applied to the face during the studies. Pimplex (Adapalene) cream was significantly more effective than its vehicle in the reduction of acne lesion counts. The mean percent reduction in lesion counts from baseline after treatment for 12 weeks are presented in the following table:

The trend in the Investigator's global assessment of severity supported the efficacy of Pimplex (Adapalene) cream when compared to the cream vehicle.

CONTRAINDICATIONS:

Pimplex (Adapalene) cream should not be administered to individuals who are hypersensitive to Pimplex (Adapalene) or any of the components in the cream vehicle.

PRECAUTIONS:

General:

Certain cutaneous signs and symptoms of treatment such as erythema, dryness, scaling, burning, or pruritus may be experienced with use of Pimplex cream. These are most likely to occur during the first two to four weeks of treatment, are mostly mild to moderate in intensity, and usually lessen with continued use of the medication. Depending upon the severity of these side effects, patients should be instructed to reduce the frequency of application or discontinue use.

If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. Exposure to sunlight, including sunlamps, should be minimized during use of Pimplex (Adapalene). Patients who normally experience high levels of sun exposure, and those with inherent sensitivity to sun, should be warned to exercise caution. Use of sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with Pimplex (Adapalene).

Avoid contact with the eyes, lips, angles of the nose, and mucous membranes. The product should not be applied to cuts, abrasions, eczematous or sunburned skin. As with other retinoids, use of "waxing" as a depilatory method should be avoided on skin treated with Pimplex (Adapalene).

Information for Patients:

Patients using Pimplex (Adapalene) cream should receive the following information and instructions:

• This medication is to be used only as directed by the physician.
• It is for external use only.
• Avoid contact with the eyes, lips, angles of the nose, and mucous membranes.
• Cleanse area with a mild or soapless cleanser before applying this medication.
• Moisturizers may be used if necessary, however, products containing alpha hydroxyl or glycolic acids should be avoided.
• Exposure of the eye to this medication may result in reactions such as swelling, conjunctivitis, and eye irritation.
• This medication should not be applied to cuts, abrasions, eczematous or sunburned skin.
• Wax epilation should not be performed on treated skin due to the potential for skin erosions.
• During the early weeks of therapy, an apparent exacerbation of acne may occur. This is due to the action of this medication on previously unseen lesions and should not be considered a reason to discontinue therapy. Overall clinical benefit may be noticed after two weeks of therapy, but at least eight weeks are required to obtain consistent beneficial effects.

Drug Interactions:

As Pimplex cream has the potential to produce local irritation in some patients, concomitant use of other potentially irritating topical products (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 rind) should be approached with caution. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid in combination with Pimplex (Adapalene) cream. If these preparations have been used, it is advisable not to start therapy with Pimplex (Adapalene) cream until the effects of such preparations in the skin have subsided.

Carcinogenesis, Mutagenesis, and Impairment of Fertility:

Carcinogenicity studies with Pimplex (Adapalene) have been conducted in mice at topical doses of 0.4, 1.3, and 4.0 mg/kg/day, and in rats at oral doses of 0.15, 0.5, and 1.5 mg/kg/day. These doses are up to 8 times (mice) and 6 times (rats) in terms of mg/m²/day the maximum potential exposure at the recommended topical human dose (MRHD), assumed to be 2.5 grams Pimplex (Adapalene) cream, which is approximately 1.5 mg/m² Pimplex (Adapalene). In the oral study, increased incidence of benign and malignant pheochromocytomas in the adrenal medullas of male rats was observed.

No photocarcinogenicity studies were conducted. Animal studies have shown an increased risk of skin neoplasms with the use of pharmacologically similar drugs (e.g., retinoids) when exposed to UV irradiation in the laboratory or to sunlight. Although the significance of these studies to human use is not clear, patients should be advised to avoid or minimize exposure to either sunlight or artificial UV irradiation sources.

Pimplex (Adapalene) did not exhibit mutagenic or genotoxic effects in vivo (mouse micronucleous test) and in vitro (Ames test, Chinese hamster ovary cell assay, mouse lymphoma TK assay) studies.

Reproductive function and fertility studies were conducted in rats administered oral doses of Pimplex (Adapalene) in amounts up to 20 mg/kg/day (up to 80 times the MRHD based on mg/m² comparisons). No effects of Pimplex (Adapalene) were found on the reproductive performance or fertility of the Fo males or females. There were also no detectable effects on the growth, development and subsequent reproductive function of the F₁ generation.

Pregnancy: Teratogenic effects. Pregnancy Category C.

No teratogenic effects were seen in rats at oral doses of 0.15 to 5.0 mg/kg/day Pimplex (up to 20 times the MRHD based on mg/m² comparisons). However, Pimplex (Adapalene) administered orally at doses of≥ 25 mg/kg, (100 times the MRHD for rats or 200 times MRHD for rabbits) has been shown to be teratogenic. Cutaneous teratology studies in rats and rabbits at doses of 0.6, 2.0, and 6.0 mg/kg/day (24 times the MRHD for rats or 48 times the MRHD for rabbits) exhibited no fetotoxicity and only minimal increases in supernumerary ribs in rats. There are no adequate and well-controlled studies in pregnant women. Pimplex (Adapalene) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers:

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Pimplex (Adapalene) cream is administered to a nursing woman.

Pediatric Use:

Safety and effectiveness in pediatric patients below the age of 12 have not been established.

Geriatric Use:

Clinical studies of Pimplex (Adapalene) cream were conducted in patients 12 to 30 years of age with acne vulgaris and therefore did not include subjects 65 years and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

ADVERSE REACTIONS:

In controlled clinical trials, local cutaneous irritation was monitored in 285 acne patients who used Pimplex (Adapalene) cream once daily for 12 weeks. The frequency and severity of erythema, scaling, dryness, pruritus and burning were assessed during these studies. The incidence of local cutaneous irritation with Pimplex (Adapalene) cream from the controlled clinical studies is provided in the following table:

Other reported local cutaneous adverse events in patients who used Pimplex (Adapalene) cream once daily included: sunburn (2%), skin discomfort-burning and stinging (1%) and skin irritation (1%). Events occurring in less than 1% of patients treated with Pimplex (Adapalene) cream included: acne flare, dermatitis and contact dermatitis, eyelid edema, conjunctivitis, erythema, pruritus, skin discoloration, rash, and eczema.

OVERDOSAGE:

Pimplex (Adapalene) cream is intended for cutaneous use only. If the medication is applied excessively, no more rapid or better results will be obtained and marked redness, scaling, or skin discomfort may occur. The acute oral toxicity of Pimplex (Adapalene) cream in mice and rats is greater than 10 mL/kg. Chronic ingestion of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A.

DOSAGE AND ADMINISTRATION:

Pimplex (Adapalene) cream should be applied to affected areas of the skin, once daily at nighttime. A thin film of the cream should be applied to the skin areas where acne lesions appear, using enough to cover the entire affected areas lightly. A mild transitory sensation of warmth or slight stinging may occur shortly after the application of Pimplex (Adapalene) cream.

HOW SUPPLIED:

Pimplex Cream, 0.1% is supplied in a 45 g tube - NDC 0168-0424-46

Storage:

Store at controlled room temperature 68° to 77°F (20° to 25°C). Excursions permitted between 59° and 86° F (15° and 30° C). Protect from freezing.

I2424B

R02/13

#187

E. FOUGERA & CO.

A division of Fougera

PHARMACEUTICALS INC.

Melville, New York 11747

NDC 0168-0424-46

Fougera ^®

Pimplex (Adapalene) CREAM 0.1%

Rx only

For topical use only.

Not for ophthalmic, oral or intravaginal use.

NET WT 45 grams

NDC 0168-0424-46

Rx only

Fougera ^®

Pimplex (Adapalene) CREAM 0.1%

For topical use only.

Not for ophthalmic, oral,

or intravaginal use.

NET WT 45 grams

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
• Pimplex (Clindamycin) reviews

1 INDICATIONS & USAGE

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

Pimplex (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. Pimplex (Clindamycin) phosphate and tretinoin gel should be kept away from the eyes, the mouth, angles of the nose, and mucous membranes.

Pimplex (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)
• Pimplex (Clindamycin) phosphate and tretinoin gel is not for oral, ophthalmic, or intravaginal use. (2)

3 DOSAGE FORMS & STRENGTHS

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

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

4 CONTRAINDICATIONS

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

Pimplex (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: Pimplex can cause severe colitis, which may result in death. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of Pimplex (Clindamycin). Pimplex (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 Pimplex (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 Pimplex (Clindamycin). When significant diarrhea occurs, Pimplex (Clindamycin) phosphate and tretinoin gel should be discontinued.

Severe colitis has occurred following oral or parenteral administration of Pimplex (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 Pimplex (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 Pimplex (Clindamycin) phosphate and tretinoin gel.

6 ADVERSE REACTIONS

Observed local adverse reactions in patients treated with Pimplex phosphate and tretinoin gel were skin erythema, scaling, itching, burning, and stinging. Other most commonly reported adverse events (≥ 1% in patients treated with Pimplex (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 Pimplex (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 Pimplex (Clindamycin) phosphate and tretinoin gel were compared to adverse reactions in patients treated with Pimplex (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 Pimplex (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 Pimplex (Clindamycin) phosphate and tretinoin-treated group, decreasing thereafter.

One open-label 12-month safety study for Pimplex (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.
• Pimplex (Clindamycin) phosphate and tretinoin gel should not be used in combination with erythromycin-containing products because of its Pimplex (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 Pimplex (Clindamycin) phosphate and tretinoin gel, there may be increased skin irritation.

7.2 Erythromycin

Pimplex phosphate and tretinoin gel should not be used in combination with erythromycin-containing products due to its Pimplex (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

Pimplex (Clindamycin) has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, Pimplex (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 Pimplex phosphate and tretinoin gel. Pimplex (Clindamycin) phosphate and tretinoin gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pimplex (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. Pimplex (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 Pimplex (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 Pimplex (Clindamycin) phosphate and tretinoin gel applied daily to a 60 kg person.

Pimplex (Clindamycin)

Teratology (Segment II) studies using Pimplex (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 Pimplex (Clindamycin) in the recommended clinical dose based on a body surface area comparison, respectively) or with subcutaneous doses of Pimplex (Clindamycin) up to 180 mg/kg/day (175 and 88 times the amount of Pimplex (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 Pimplex (Clindamycin) is excreted in human milk following use of Pimplex (Clindamycin) phosphate and tretinoin gel. However, orally and parenterally administered Pimplex (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 Pimplex (Clindamycin) phosphate and tretinoin gel is administered to a nursing woman.

8.4 PEDIATRIC USE

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

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

8.5 GERIATRIC USE

Clinical studies of Pimplex (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

Pimplex (Clindamycin) phosphate and tretinoin gel 1.2% / 0.025%, is an antibiotic and retinoid combination gel product with two active ingredients. Pimplex (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 Pimplex (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 Pimplex (Clindamycin) phosphate, USP is represented below:

Pimplex (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

Pimplex (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

Pimplex

.

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 Pimplex (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 Pimplex (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

Pimplex (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. Pimplex (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 Pimplex (Clindamycin) phosphate and tretinoin gel. P acnes resistance to Pimplex (Clindamycin) has been documented. Resistance to Pimplex (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 Pimplex (Clindamycin) phosphate and tretinoin gel have not been performed in any species.

Pimplex (Clindamycin)

The carcinogenicity of a 1% Pimplex (Clindamycin) phosphate gel similar to Pimplex (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 Pimplex (Clindamycin) phosphate from Pimplex (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 Pimplex (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 Pimplex (Clindamycin) (approximately 290 times the amount of Pimplex (Clindamycin) delivered from the recommended clinical dose for Pimplex (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 Pimplex (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 Pimplex (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 Pimplex (Clindamycin) phosphate and tretinoin gel to Pimplex (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 Pimplex (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, Pimplex (Clindamycin) phosphate and tretinoin gel was compared to Pimplex (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

Pimplex (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 Pimplex (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

Pimplex 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 Pimplex (Clindamycin) phosphate and tretinoin gel experiences severe diarrhea or gastrointestinal discomfort, Pimplex (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

Pimplex (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 Pimplex (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 Pimplex (Clindamycin) phosphate and tretinoin gel?

Pimplex (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 Pimplex (Clindamycin) phosphate and tretinoin gel?

Do not use Pimplex (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 Pimplex (Clindamycin) phosphate and tretinoin gel may harm your unborn baby.
• if you are breastfeeding. Pimplex (Clindamycin) phosphate and tretinoin gel may pass through your milk and may harm your baby.
• about all the medicines and skin products you use:
  • Pimplex (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 Pimplex (Clindamycin) phosphate and tretinoin gel.

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

Use Pimplex (Clindamycin) phosphate and tretinoin gel exactly as prescribed. It may take some time for you to see improvement of your acne with Pimplex (Clindamycin) phosphate and tretinoin gel. Your doctor will tell you how long to use Pimplex (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 Pimplex (Clindamycin) phosphate and tretinoin gel to your fingertip and spread it over your face. Gently, smooth it into your skin. Do not get Pimplex (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 Pimplex (Clindamycin) phosphate and tretinoin gel more than once a day
• Do not use too much Pimplex (Clindamycin) phosphate and tretinoin gel. Too much Pimplex (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 Pimplex (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 Pimplex (Clindamycin) phosphate and tretinoin gel until your skin has healed.

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

• Skin irritation. Pimplex (Clindamycin) phosphate and tretinoin gel may cause skin irritation such as dryness, redness, peeling, burning, or stinging. Stop Pimplex (Clindamycin) phosphate and tretinoin gel and call your doctor if your skin becomes very red, swollen, blistered, or crusted.
• Change in skin color. Pimplex (Clindamycin) phosphate and tretinoin gel may cause a temporary skin color change (lighter or darker).
• Colitis. This occurs rarely. Stop Pimplex (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 Pimplex (Clindamycin) phosphate and tretinoin gel. Ask your doctor or pharmacist for more information.

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

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

General information about Pimplex (Clindamycin) phosphate and tretinoin gel

Medicines are sometimes prescribed for purposes other than those listed in patient information leaflet. Do not use Pimplex (Clindamycin) phosphate and tretinoin gel for a condition for which it was not prescribed. Do not give Pimplex (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 Pimplex (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 Pimplex (Clindamycin) phosphate and tretinoin gel that is written for healthcare professionals.

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

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

Active Ingredients: Pimplex (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