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CLINICAL PHARMACOLOGY Pharmacokinetics Benzoyl peroxide has been shown to be absorbed by the skin where it is converted to benzoic acid. A single dose pharmacokinetic study, involving the application of either one or three units of Aktipak, was performed in 16 adult acne patients to determine systemic absorption of erythromycin. Erythromycin (with a plasma lower limit of quantitation of 2 ng/ml) was not detectable, except in one patient who was in the one unit application group. Pharmacodynamics The exact mechanism by which erythromycin and benzoyl peroxide reduce lesions of acne vulgaris is not fully known. Clinical Studies In two adequate and well controlled clinical studies 228 patients used Aktipak, 113 patients used the currently marketed Benzamycin Topical Gel, and 183 patients used vehicle. Aktipak applied twice daily for 8 weeks was significantly more effective than vehicle and comparable to Benzamycin Topical Gel in the treatment of moderate to moderately severe facial acne vulgaris. Patients entering the study had a minimum of 15 and a maximum of 80 facial inflammatory lesions (papules and pustules) and a minimum of 20 and a maximum of 140 facial non-inflammatory lesions (open and closed comedones). The primary efficacy measures evaluated at week 8 were the lesion counts and the investigator's global assessment. Patients were instructed to wash their face twice daily (morning and evening) with warm water and a mild cleanser provided by sponsor. No abrasive cloths or sponges, alcoholic toners, astringents or medicated solutions were used. The medication was to be applied 15 minutes after washing, in a thin film over the entire facial area. A moisturizer (supplied by the sponsor) or non-medicated make-up could be applied one hour after application, as needed. All medications were to be kept away from the eyes. Sun exposure to the face was to be limited. Outcomes for mean percent reductions in lesion counts and investigators global assessment after 8 weeks of treatment are shown below: Study 1 Aktipak N=119 Benzamycin Topical Gel N=113 Aktipak Vehicle N=38 Benzamycin Topical Gel Vehicle N=37 Mean % Lesion Counts Reduction Inflammatory * 49% 45% 17% 28% Non Inflammatory * 46% 43% 24% 20% Total * 48% 44% 22% 26% Investigator’s Global Global Success * 28% 27% 3% 11% *p-value < 0.05 is for the comparison between Aktipak and Aktipak vehicle Study 2 Aktipak N= 109 Aktipak Vehicle N= 108 Mean % Lesion Count Reduction Inflammatory * 57% 34% Non Inflammatory 36% 30% Total * 45% 31% Investigator’s Global Global Success * 36% 12% *p-value < 0.05 Microbiology Erythromycin acts by inhibition of protein synthesis in susceptible organisms by reversibly binding to 50 S ribosomal subunits, thereby inhibiting translocation of aminoacyl transfer-RNA and inhibiting polypeptide synthesis. Antagonism has been demonstrated in vitro between erythromycin, lincomycin, chloramphenicol and clindamycin. Benzoyl peroxide has been shown to be effective in vitro against Propionibacterium acnes, an anaerobe found in sebaceous follicles and comedones. Benzoyl peroxide is believed to act by releasing active oxygen.

Aktipak (erythromycin 3%-benzoyl peroxide 5%) Topical Gel For Dermatological Use Only - Not for Ophthalmic Use DESCRIPTION Aktipak contains erythromycin [(3R*, 4S*, 5S*, 6R*, 7R*, 9R*, 11R*, 12R*, 13S*, 14R*)-4-[(2,6-dideoxy3C-methyl-3-O-methyl-a-L-ribo-hexopyranosyl)-oxy]-14-ethyl-7,12,13-trihydroxy3,5,7,9,11,13-hexa-methyl-6-[[3,4,6-trideoxy-3-(dimethylamino)-b-D-xylohexopyranosyl]oxy]oxacyclotetradecane-2,10-dione]. Erythromycin is a macrolide antibiotic produced from a strain of Saccharopolyspora erythraea (formerly Streptomyces erythreus). It is a base and readily forms salts with acids. Chemically, erythromycin is (C37H67NO13). It has the following structural formula: Erythromycin has the molecular weight of 733.94. It is a white crystalline powder and has a solubility of approximately 1 mg/mL in water and is soluble in alcohol at 25°C. Aktipak also contains benzoyl peroxide for topical use. Benzoyl peroxide is an oxidizing agent demonstrating antibacterial activity. Chemically, benzoyl peroxide is (C14H10O4). It has the following structural formula: Benzoyl peroxide has the molecular weight of 242.23. It is a white granular powder and is sparingly soluble in water and alcohol and soluble in acetone, chloroform and ether. Each gram of product, as dispensed, contains 30 mg of erythromycin and 50 mg of benzoyl peroxide in a base of SD Alcohol 40B, purified water, hydroxypropyl cellulose, Carbomer Homopolymer Type B, sodium hydroxide, dioctyl sodium sulfosuccinate 75%. Each Aktipak contains 0.8 grams of product.

INDICATIONS Aktipak is indicated for the topical treatment of acne vulgaris. DOSAGE AND ADMINISTRATION Aktipak requires thorough mixing by the patient immediately prior to each use. The medication should be applied twice daily, morning and evening, or as directed by a physician, to affected areas after the skin is thoroughly washed, rinsed with warm water and gently patted dry. HOW SUPPLIED 60 Pouches per carton NDC 70363-007-60 Store at Room Temperature 20 to 25°C (68 to 77°F). Keep away from heat and any open flame. Keep out of reach of children. Manufactured for: Cutanea Life Sciences, Inc. Wayne, PA 19087. Revised: Sep 2016

OVERDOSE No information provided. CONTRAINDICATIONS Aktipak is contraindicated in those individuals who have shown hypersensitivity to any of its components.

SIDE EFFECTS During clinical trials, 550 acne patients were studied. Of these patients, 236 were treated with Aktipak. The most frequently reported adverse event considered at least possibly related was dry skin (7.6%) as compared to Vehicle (3.9%). Application site reactions (stinging, burning sensation, tingling, erythema) were reported in 2.5% of patients versus 1.3% of Vehicle patients. Blepharitis, pruritus and photosensitivity reactions were reported in < 2% of patients who used the dual pouch product. Treatment Groups Summaries Number of Patients (%) COSTART Term Aktipak N = 236 Aktipak Vehicle N = 153 Benzamycin Topical Gel N = 121 Benzamycin Topical Gel Vehicle N = 40 Dry Skin 18 (7.6%) 6 (3.9%) 5 (5.0%) 0 APPLICATION SITE REACTION (stinging,erythema, and burning 6 (2.5%) 2 (1.3%) 1 (0.8%) 0 BLEPHARITIS 4 (1.7%) 1 (0.7%) 0 1 (2.5%) PRURITUS 4 (1.7%) 2 (1.3%) 3 (2.5%) 0 PHOTOSENSITIVITY REACTION (Sunburn, stinging with sun exposure) 3 (1.3%) 0 0 0 PEELING 1 (0.5%) 1 (0.7%) 0 0 DRUG INTERACTIONS No information provided.

WARNINGS No information provided. PRECAUTIONS General For topical use only; not for opthamalic use. Concomitant topical acne therapy should be used with caution because a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating or abrasive agents. If severe irritation develops, discontinue use institute appropriate therapy. The use of antibiotic agents may be associated with the overgrowth of nonsusceptible organisms. If this occurs, discontinue use and take appropriate measures. Avoid contact with eyes and all mucous membranes. Carcinogenesis, Mutagenesis, Impairment Of Fertility The combination of benzoyl peroxide and erythromycin in Aktipak has not been evaluated for its carcinogenic or mutagenic potential or for its effects on fertility. Benzoyl peroxide has been shown to be a tumor promoter and progression agent in a number of animal studies. The clinical significance of this is unknown. Benzoyl peroxide in acetone at doses of 5 and 10 mg administered twice per week induced skin tumors in transgenic Tg.AC mice in a study using 20 weeks of topical treatment. Benzoyl peroxide has been found to cause DNA strand breaks in a variety of mammalian cell types, to be mutagenic in Salmonella typhimurium tests by some but not all investigators, and to cause sister chromatid exchanges in Chinese hamster ovary cells. No animal studies have been performed to evaluate the carcinogenic potential or effects on fertility of topical erythromycin. However, long-term (2-year) oral studies in rats with erythromycin base and erythromycin ethylsuccinate and in rats and mice with erythromycin stearate did not provide evidence of tumorigenicity. The genotoxicity of erythromycin stearate has been evaluated in the Salmonella typhimurium reverse mutation assay, the mouse L5178Y lymphoma cell assay, and for sister chromatid exchanges and chromosomal aberrations in CHO cells. These studies indicated that erythromycin stearate was not genotoxic. There was no apparent effect on male or female fertility in rats fed erythromycin base at levels up to 0.25% of diet. Pregnancy Teratogenic Effects Pregnancy CATEGORY C: Animal reproduction studies have not been conducted with Aktipak or benzoyl peroxide. There was no evidence of teratogenicity or any other adverse effect on reproduction in female rats fed erythromycin base (up to 0.25% diet) prior to and during mating, during gestation and through weaning of two successful litters. There are no well-controlled trials in pregnant women with Aktipak. It is also not known whether Aktipak can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Aktipak should be given to pregnant women only if clearly needed. Nursing Women It is not known whether the ingredients of Aktipak are excreted in human milk after topical application. However, erythromycin is excreted in human milk following oral and parenteral erythromycin administration. Therefore, caution should be exercised when erythromycin is administered to a nursing woman. Pediatric Use Safety and effectiveness of this product in pediatric patients below 12 years of age have not been established.