4.1 Hypersensitivity

ACANYA Gel is contraindicated in those individuals who have shown hypersensitivity to clindamycin, benzoyl peroxide, any components of the formulation, or lincomycin. Anaphylaxis, as well as allergic reactions leading to hospitalization, has been reported in postmarketing use with ACANYA Gel [see Postmarketing Experience (6.2)].

4.2 Colitis/Enteritis

ACANYA Gel is contraindicated in patients with a history of regional enteritis, ulcerative colitis, or antibiotic-associated colitis [see Warnings and Precautions (5.1)].

5.1 Colitis

Systemic absorption of clindamycin has been demonstrated following topical use of clindamycin. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical and systemic clindamycin. When significant diarrhea occurs, ACANYA Gel should be discontinued.

Severe colitis has occurred following oral and parenteral administration of 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 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

Minimize sun exposure including use of tanning beds or sun lamps following drug application.

5.3 Concomitant Topical Medications

Concomitant topical acne therapy should be used with caution since a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive agents. If irritancy or dermatitis occurs, reduce frequency of application or temporarily interrupt treatment and resume once the irritation subsides. Treatment should be discontinued if the irritation persists.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions observed in the clinical trials of a drug cannot always be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following selected adverse reactions occurred in less than 0.2% of subjects treated with ACANYA Gel: application site pain (0.1%); application site exfoliation (0.1%); and application site irritation (0.1%).

During clinical trials, subjects were assessed for local cutaneous signs and symptoms of erythema, scaling, itching, burning and stinging. Most local skin reactions increased and peaked around Week 4 and continually decreased over time reaching near baseline levels by Week 12. The percentage of subjects that had symptoms present before treatment, the maximum value recorded during treatment, and the percent with symptoms present at Week 12 are shown in Table 1.

6.2 Postmarketing Experience

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.

Anaphylaxis, as well as allergic reactions leading to hospitalizations, has been reported in postmarketing use of products containing clindamycin/benzoyl peroxide.

7.1 Erythromycin

ACANYA Gel should not be used in combination with topical or oral erythromycin-containing products due to its clindamycin component. In vitro studies have shown antagonism between erythromycin and clindamycin. The clinical significance of this in vitro antagonism is not known.

7.2 Neuromuscular Blocking Agents

Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, ACANYA Gel should be used with caution in patients receiving such agents.

8.1 Pregnancy

Risk Summary

There are no available data on ACANYA Gel use in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. The limited published data on use of clindamycin in pregnant women with exposure during the first trimester are insufficient to inform a drug-associated risk of pregnancy-related adverse outcomes (see Data).In limited published clinical trials with pregnant women, the systemic administration of clindamycin during the second and third trimesters has not been associated with an increased frequency of major birth defects.

In animal reproduction studies, clindamycin did not cause malformations or embryo-fetal development toxicity in pregnant rats and mice when administered during the period of organogenesis at systemic doses up to 240 times the maximum recommended human dose (MRHD) of 2.5 g ACANYA Gel, based on body surface area (BSA) comparisons (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, and other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Human Data

In limited published trials in pregnant women administered clindamycin during the first trimester of pregnancy, there was no difference in the rate of major birth defects reported among in utero exposed infants compared to unexposed infants. These data cannot definitely establish or exclude any clindamycin-associated risk during pregnancy.

Animal Data

Animal reproductive/developmental toxicity studies have not been conducted with ACANYA Gel or benzoyl peroxide. Developmental toxicity studies of clindamycin performed in pregnant rats and mice administered during the period of organogenesis at oral doses of up to 600 mg/kg/day (240 and 120 times the MRHD for, respectively, based on BSA comparisons) or subcutaneous doses of up to 200 mg/kg/day (80 and 40 times the MRHD for clindamycin, respectively, based on BSA comparisons) revealed no malformations or embryo-fetal development toxicity.

8.2 Lactation

Risk Summary

There are no data on the presence of clindamycin or benzoyl peroxide in human milk, the effects on the breastfed child, or the effects on milk production following topical administration. However, clindamycin has been reported to be present in breast milk in small amounts following oral and parenteral administration. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ACANYA Gel and any potential adverse effects on the breastfed child from ACANYA Gel or from the underlying maternal condition.

Clinical Considerations

If used during lactation and ACANYA Gel is applied to the chest, care should be taken to avoid accidental ingestion by the infant.

8.4 Pediatric Use

Safety and effectiveness of ACANYA Gel in pediatric patients under the age of 12 have not been evaluated.

8.5 Geriatric Use

Clinical trials of ACANYA Gel did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.

12.1 Mechanisms of Action

Clindamycin: Clindamycin is a lincosamide antibacterial [see Microbiology (12.4)].

Benzoyl Peroxide: Benzoyl peroxide is an oxidizing agent with bactericidal and keratolytic effects but the precise mechanism of action is unknown.

12.3 Pharmacokinetics

The systemic absorption of clindamycin was investigated in an open-label, multiple-dose trial in 16 adult subjects with moderate to severe acne vulgaris treated with 1 gram of ACANYA Gel applied to the face once daily for 30 days. Twelve subjects (75%) had at least one quantifiable clindamycin plasma concentration above the lower limit of quantification (LOQ = 0.5 ng/mL) on Day 1 or Day 30. On Day 1, the mean (± standard deviation) peak plasma concentration (Cmax) was 0.78 ± 0.22 ng/mL (n=9 with measurable concentrations), and the mean AUC0-t was 5.29 ± 0.81 h.ng/mL (n=4). On Day 30, the mean Cmax was 1.22 ± 0.88 ng/mL (n=10), and the mean AUC0-t was 8.42 ± 6.01 h.ng/mL (n=6). Clindamycin plasma concentrations were below LOQ in all subjects at 24 hours post-dose on the three tested days (Day 1, 15, and 30).

Benzoyl peroxide has been shown to be absorbed by the skin where it is converted to benzoic acid.

12.4 Microbiology

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.

Clindamycin and benzoyl peroxide individually have been shown to havein vitro activity against Propionibacterium acnes, an organism which has been associated with acne vulgaris; however, the clinical significance of this activity against P. acnes is not known.

P. acnes resistance to clindamycin has been documented. Resistance to clindamycin is often associated with resistance to erythromycin.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and impairment of fertility testing of ACANYA Gel have not been performed.

Benzoyl peroxide has been shown to be a tumor promoter and progression agent in a number of animal studies. Benzoyl peroxide in acetone at doses of 5 and 10 mg administered topically twice per week for 20 weeks induced skin tumors in transgenic Tg.AC mice. The clinical significance of this is unknown.

Carcinogenicity studies have been conducted with a gel formulation containing 1% clindamycin and 5% benzoyl peroxide. In a 2-year dermal carcinogenicity study in mice, treatment with the gel formulation at doses of 900, 2700, and 15000 mg/kg/day (1.8, 5.4, and 30 times the MRHD for clindamycin and 3.6, 10.8, and 60 times the MRHD for benzoyl peroxide, respectively, based on BSA comparisons) did not cause any increase in tumors. However, topical treatment with a different gel formulation containing 1% clindamycin and 5% benzoyl peroxide at doses of 100, 500, and 2000 mg/kg/day caused a dose-dependent increase in the incidence of keratoacanthoma at the treated skin site of male rats in a 2-year dermal carcinogenicity study in rats. In an oral (gavage) carcinogenicity study in rats, treatment with the gel formulation at doses of 300, 900, and 3000 mg/kg/day (1.2, 3.6, and 12 times the MRHD for clindamycin and 2.4, 7.2, and 24 times the MRHD for benzoyl peroxide, respectively, based on BSA comparisons) for up to 97 weeks did not cause any increase in tumors.

Clindamycin phosphate was not genotoxic in the human lymphocyte chromosome aberration assay. Benzoyl peroxide has been found to cause DNA strand breaks in a variety of mammalian cell types, to be mutagenic in S. typhimurium tests by some but not all investigators, and to cause sister chromatid exchanges in Chinese hamster ovary cells.

Fertility studies have not been performed with ACANYA Gel or benzoyl peroxide, but fertility and mating ability have been studied with clindamycin. Fertility studies in rats treated orally with up to 300 mg/kg/day of clindamycin (approximately 120 times the MRHD for clindamycin, based on BSA comparisons) revealed no effects on fertility or mating ability.

16.1 How Supplied

ACANYA Gel, 1.2%/2.5%, a white to off-white smooth gel is supplied as:

NDC 13548-132-50                   50 g pump

16.2 Dispensing Instructions for the Pharmacist

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Dispense ACANYA Gel with a 10-week expiration date.

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Specify “Store at room temperature up to 25°C (77°F). Do not freeze.”

16.3 Storage and Handling

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PHARMACIST: Prior to Dispensing: Store in a refrigerator, 2° to 8°C (36° to 46°F).

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PATIENT: Store at room temperature at or below 25°C (77°F).

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Protect from freezing.

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Store pump upright.

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Keep out of the reach of children.

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Keep container tightly closed.