BENZOYL PEROXIDE: 1,059 Adverse Event Reports & Safety Profile

Clindamycin phosphate and benzoyl peroxide gel, 1.2%/5% is a fixed combination product with two active ingredients in a white to off white gel formulation. 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. Clindamycin phosphate, USP is C 18 H 34 ClN 2 O 8 PS and is a white or almost white, hygroscopic crystalline powder and soluble in water, practically insoluble in dichloromethane, chloroform, benzene and ether. The structural formula for clindamycin phosphate is represented below: Clindamycin phosphate has a molecular weight of 504.96 and its chemical name is methyl 7-chloro-6,7,8-trideoxy-6-(1-methyl- trans -4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L- threo - D-D- galacto -octopyranoside 2-(dihydrogen phosphate). Benzoyl peroxide, USP is C 14 H 10 O 4 . It has the following structural formula: Hydrous benzoyl peroxide, USP has a molecular weight of 242.23. It is white or almost white amorphous or granular powder and practically insoluble in water, slightly soluble in alcohol, soluble in acetone, in chloroform, in dichloromethane and in ether with separation of water Each gram of clindamycin phosphate and benzoyl peroxide gel contains 10 mg (1%) clindamycin, as clindamycin phosphate, and 50 mg (5%) benzoyl peroxide in a base consisting of carbomer homopolymer (type C), dimethicone, disodium lauryl sulfosuccinate, edetate disodium, glycerin, methylparaben, poloxamer 182, purified water, silicon dioxide, and sodium hydroxide.

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Stop use and ask a doctor if: irritation becomes severe Warnings For external use only When using this product - Skin irritation and dryness is more likely to occur if you use antoher topical acne medication at the same time. If irritation occurs only use only one topical acne medication at a time. - Avoid unnecessary sun exposure and use a sunscreen - Avoid contact with with the eyes lips and mouth - Avoid contact with hair and dyed fabrics, which may be bleached by this product - Skin irritation may occur, characterized by redness, burning, itching, peeling or possibly swelling . Irritation may be reduced by using the product less frequently or in a lower concentration. - Do not use if you: Have very sensitive skin Are sensitive to benzoyl peroxide Directions Cleanse the skin thoroughly before applying this product cover the entire with a thin layer one to three times daily Because excessive drying of the skin may occur, start with one application daily then gradually increase to two or three times daily if needed or as directed by a doctor If bothersome dryness or peeling occurs, reduce application to once a day or every other day If going outside apply sunscreen after using this product. If irritation or sensitivity develops stop use of both products and ask a doctor. Inactive ingredients Water (Aqua,Eau), Pentylene Glycol, Hydroxyethyl Acrylates/Sodium Acryloyldimethyl Taurate Copolymer, Squalene, Polysorbate 60, Aloe Bardadensis (Aloe)

Leaf

Juice powder, Phytic Acid, Phyenoxyethanol, Potassium Sorbate, Disodium EDTA.

Directions Sensitivity Test for a New User: Apply product sparingly to one or two small affected areas during the first 3 days. If no discomfort occurs, follow the directions stated below. cover the entire affected area with a thin layer, massaging gently one to two minutes, and rinse thoroughly one to three times daily because excessive drying of the skin may occur, start with one application daily, then gradually increase to two to three times daily if needed or as directed by a doctor if bothersome dryness or peeling occurs, reduce application to once a day or every other day if going outside, apply sunscreen after using this product. If irritation or sensitivity develops, stop use of both products and ask a doctor.

Directions

• Sensitivity Test for a New User: Apply product sparingly to one or two small affected areas during the first 3 days. If no discomfort occurs, follow the directions stated below. cleanthe skin thoroughly before applying this product cover the entire affected area with a thin layer one to three times daily because excessive drying of the skin may occur, start with one application daily, then gradually increase to two to three times daily if needed or as directed by a doctor if bothersome dryness or peeling occurs, reduce application to once a day or every other day if going outside, apply sunscreen after using this product. If irritation or sensitivity develops, stop use of both products and ask a doctor.

Neuac ® (clindamycin phosphate and benzoyl peroxide) Gel, 1.2%/5% is contraindicated in: Patients who have demonstrated hypersensitivity (e.g., anaphylaxis) to clindamycin, benzoyl peroxide, any components of the formulation, or lincomycin. ( 4 ) Patients with a history of regional enteritis, ulcerative colitis, or antibiotic-associated colitis (including pseudomembranous colitis). ( 4 )

4.1 Hypersensitivity Neuac ® (clindamycin phosphate and benzoyl peroxide) Gel, 1.2%/5% 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 clindamycin phosphate and benzoyl peroxide gel, 1.2%/5% [ see Adverse Reactions (6.2) ].

4.2 Colitis/Enteritis Neuac ® (clindamycin phosphate and benzoyl peroxide) Gel, 1.2%/5% is contraindicated in those individuals with a history of regional enteritis, ulcerative colitis, pseudomembranous colitis, or antibiotic-associated colitis [ see Warnings and Precautions (5.1) ].

REACTIONS The most common adverse reactions (incidence ≥ 1%) are pain, dryness, exfoliation erythema, dermatitis, pruritus and irritation (all at the application site). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Galderma Laboratories, L.P. at 1-866-735-4137 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical trials experience The following adverse reactions are discussed in greater detail elsewhere in the labeling: Hypersensitivity <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1 )]</span>

Skin

Irritation [see Warnings and Precautions (5.2) ] Because clinical trials are conducted under widely varying conditions, adverse reaction rates are 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 practice. In two multicenter, randomized, double-blind, vehicle-controlled trials (Trial 1 and 2), 832 subjects 9 years of age and older with facial acne vulgaris applied TWYNEO (N=555) or vehicle (N=277) daily for 12 weeks. The majority of subjects were White (73%) and female (59%).

Approximately

33% were Hispanic/Latino, and 46% were younger than 18 years of age. Adverse reactions reported in ≥ 1.0% of subjects treated with TWYNEO (and for which the rate exceeded the rate for vehicle), as well as the corresponding rates reported in subjects treated with vehicle are presented in Table 1 .

Table

1: Adverse Reactions Reported by ≥ 1% of Subjects with Facial Acne Vulgaris Treated with TWYNEO and More Frequently than Vehicle in Trials 1 and 2 TWYNEO Cream (N = 555) n (%)

Vehicle

Cream (N = 277) n (%)

Application Site

Pain* 59 (10.6) 1 (0.4)

Application Site Dryness

27 (4.9) 1 (0.4)

Application Site Exfoliation

23 (4.1) 0 Application Site Erythema 22 (4.0) 0 Application Site Dermatitis 7 (1.3) 1 (0.4)

Application Site Pruritus

7 (1.3) 0 Application Site Irritation 6 (1.1) 1 (0.4) * Application site pain defined as application site stinging, burning or pain. Local tolerability evaluations were conducted at each study visit in the clinical trial by assessment of erythema, scaling, pigmentation, dryness, itching, burning and stinging.

Table

2 presents the active assessment of the signs and symptoms of local facial tolerability at Week 12 in subjects treated with TWYNEO.

Table

2.

Facial Cutaneous Tolerability

Assessment at Week 12 in Subjects with Acne Vulgaris Treated with TWYNEO TWYNEO (N=494*) (%) Vehicle (N = 264*) (%)

Mild Moderate Severe Mild Moderate

Severe Erythema 33.0 6.9 0.2 26.9 8.0 0 Pigmentation 27.3 6.3 0.4 26.5 4.5 0 Dryness 22.3 5.3 0.4 16.7 2.3 0 Scaling 16.4 2.6 0 12.9 0.8 0 Burning 5.9 2.2 0 3.4 0.8 0 Itching 11.1 1.8 0 8.7 2.7 0 Stinging 5.3 0.2 0 1.9 1.1 0 * The denominators for calculating the percentages were 494 of 555 subjects treated with TWYNEO and 264 of 277 subjects treated with vehicle in these trials who had cutaneous signs and local tolerability results reported at Week 12. Local tolerability scores for erythema, scaling, dryness, itching, burning and stinging rose during the first two weeks of treatment and decreased thereafter.

6.2 Postmarketing Experience The following adverse reactions have been identified during use of benzoyl peroxide. 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.

Immune System

Disorders: Anaphylaxis, angioedema and urticaria

AND PRECAUTIONS

• Colitis: Orally and parenterally administered clindamycin has been associated with severe colitis, which may result in death. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical and systemic clindamycin.

Clindamycin

Phosphate and Benzoyl Peroxide Gel, 1.2%/2.5% should be discontinued if significant diarrhea occurs. (5.1)

• Ultraviolet Light and Environmental Exposure: Minimize sun exposure following drug application. (5.2)

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, Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/2.5% 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.

PRECAUTIONS General: For dermatological use only; not for ophthalmic 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. The use of antibiotic agents may be associated with the overgrowth of non-susceptible organisms including fungi. If this occurs, discontinue use of this medication and take appropriate measures. Avoid contact with eyes and mucous membranes. Clindamycin and erythromycin containing products should not be used in combination. In vitro studies have shown antagonism between these two antimicrobials. The clinical significance of this in vitro antagonism is not known. Information for Patients: Patients using Clindamycin and Benzoyl Peroxide Gel should receive the following information and instructions: 1. Clindamycin and Benzoyl Peroxide Gel is to be used as directed by the physician. It is for external use only. Avoid contact with eyes, and inside the nose, mouth, and all mucous membranes, as this product may be irritating. 2. This medication should not be used for any disorder other than that for which it was prescribed. 3. Patients should not use any other topical acne preparation unless otherwise directed by physician. 4. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using clindamycin and benzoyl peroxide gel. To minimize exposure to sunlight, a wide-brimmed hat or other protective clothing should be worn, and a sunscreen with SPF 15 rating or higher should be used. 5. Patients who develop allergic symptoms such as severe swelling or shortness of breath should discontinue Clindamycin and Benzoyl Peroxide Gel and contact their physician immediately. In addition, patients should report any signs of local adverse reactions to their physician. 6. Clindamycin and Benzoyl Peroxide Gel may bleach hair or colored fabric. 7. Clindamycin and Benzoyl Peroxide Gel can be stored at room temperature up to 25°C (77°F) for 3 months. Do not freeze. Discard any unused product after 3 months. 8. Before applying Clindamycin and Benzoyl Peroxide Gel to affected areas wash the skin gently, then rinse with warm water and pat dry. Carcinogenesis, Mutagenesis, Impairment of 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. In a 52 week dermal photocarcinogenicity study in hairless mice, the median time to onset of skin tumor formation was decreased and the number of tumors per mouse increased following chronic concurrent topical administration of clindamycin and benzoyl peroxide gel with exposure to ultraviolet radiation (40 weeks of treatment followed by 12 weeks of observation). In a 2-year dermal carcinogenicity study in rats, treatment with clindamycin and benzoyl peroxide gel 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. The incidence of keratoacanthoma at the treated site of males treated with 2000 mg/kg/day (8 times the highest recommended adult human dose of 2.5 g clindamycin and benzoyl peroxide gel based on mg/m 2 ) was statistically significantly higher than that in the sham- and vehicle-controls. Genotoxicity studies were not conducted with clindamycin and benzoyl peroxide gel. Clindamycin phosphate was not genotoxic in Salmonella typhimurium or in a rat micronucleus test. Clindamycin phosphate sulfoxide, an oxidative degradation product of clindamycin phosphate and benzoyl peroxide, was not clastogenic in a mouse micronucleus test. 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. Studies have not been performed with Clindamycin and Benzoyl Peroxide Gel or benzoyl peroxide to evaluate the effect on fertility. Fertility studies in rats treated orally with up to 300 mg/kg/day of clindamycin (approximately 120 times the amount of clindamycin in the highest recommended adult human dose of 2.5 g clindamycin and benzoyl peroxide gel, based on mg/m 2 ) revealed no effects on fertility or mating ability. Pregnancy: Teratogenic Effects: Pregnancy Category C: Animal reproductive/developmental toxicity studies have not been conducted with clindamycin and benzoyl peroxide gel or benzoyl peroxide. Developmental toxicity studies performed in rats and mice using oral doses of clindamycin up to 600 mg/kg/day (240 and 120 times amount of clindamycin in the highest recommended adult human dose based on mg/m 2 , respectively) or subcutaneous doses of clindamycin up to 250 mg/kg/day (100 and 50 times the amount of clindamycin in the highest recommended adult human dose based on mg/m 2 , respectively) revealed no evidence of teratogenicity. There are no well-controlled trials in pregnant women treated with Clindamycin and Benzoyl Peroxide Gel . It also is not known whether Clindamycin and Benzoyl Peroxide Gel can cause fetal harm when administered to a pregnant woman.

Nursing

Women: It is not known whether Clindamycin and Benzoyl Peroxide Gel is excreted in human milk after topical application. However, orally and parenterally administered 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.

Pediatric

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

INTERACTIONS Neuac ® (clindamycin phosphate and benzoyl peroxide) Gel, 1.2%/5% should not be used in combination with erythromycin-containing products because of its clindamycin component. ( 7.1 )

7.1 Erythromycin Avoid using Neuac ® (clindamycin phosphate and benzoyl peroxide) Gel, 1.2%/5% in combination with 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 Concomitant Topical Medications Concomitant topical acne therapies 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.

7.3 Neuromuscular Blocking Agents Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Neuac ® (clindamycin phosphate and benzoyl peroxide) Gel, 1.2%/5% should be used with caution in patients receiving such agents.

7.4 Topical Sulfone Products Use of topical benzoyl-peroxide-containing preparations with topical sulfone products may cause skin and facial hair to temporarily change color (yellow/orange).

Active ingredient Purpose Benzoyl Peroxide 5% Acne treatment Uses For the treatment of acne Helps prevent new acne blemishes Keep out of reach of children. If swallowed get medical help or contact Poison Control Center right away Stop use and ask a doctor if: irritation becomes severe Warnings For external use only When using this product - Skin irritation and dryness is more likely to occur if you use antoher topical acne medication at the same time. If irritation occurs only use only one topical acne medication at a time. - Avoid unnecessary sun exposure and use a sunscreen - Avoid contact with with the eyes lips and mouth - Avoid contact with hair and dyed fabrics, which may be bleached by this product - Skin irritation may occur, characterized by redness, burning, itching, peeling or possibly swelling . Irritation may be reduced by using the product less frequently or in a lower concentration. - Do not use if you: Have very sensitive skin Are sensitive to benzoyl peroxide Directions Cleanse the skin thoroughly before applying this product cover the entire with a thin layer one to three times daily Because excessive drying of the skin may occur, start with one application daily then gradually increase to two or three times daily if needed or as directed by a doctor If bothersome dryness or peeling occurs, reduce application to once a day or every other day If going outside apply sunscreen after using this product. If irritation or sensitivity develops stop use of both products and ask a doctor. Inactive ingredients Water (Aqua,Eau), Pentylene Glycol, Hydroxyethyl Acrylates/Sodium Acryloyldimethyl Taurate Copolymer, Squalene, Polysorbate 60, Aloe Bardadensis (Aloe)

Leaf

Juice powder, Phytic Acid, Phyenoxyethanol, Potassium Sorbate, Disodium EDTA.

Inactive ingredients water, polyacrylamide, C13-14 isoalkane, jojoba esters, carbomer, diethylhexyl sodium sulfosuccinate, cocamidopropyl betaine, laureth-7, sodium chloride, sodium citrate, sodium hydroxide, propanediol, ethylhexylglycerin, phenoxyethanol, sodium benzoate

Inactive ingredients water/aqua/eau, glycereth-18 ethylhexanoate, glycereth-18, disiloxane, glycerin, butylene glycol, propanediol, acrylamide/sodium acryloyldimethyltaurate copolymer, allantoin, ascorbyl palmitate, bisabolol, myristyl alcohol, PCA, phytosteryl/octyldodecyl lauroyl glutamate, polygonum cuspidatum root extract, sodium hyaluronate, zingiber officinale (ginger) root extract, fragrance/parfum, carbomer, methyl methacrylate crosspolymer, cetyl hydroxyethylcellulose, hydroxyphenyl propamidobenzoic acid, polyglyceryl-2 isostearate, polysorbate 80, sorbitan oleate, xanthan gum, diethylhexyl sodium sulfosuccinate, isohexadecane, dimethyl isosorbide, tocopherol, citric acid, sodium citrate, sodium hydroxide, caprylyl glycol, decylene glycol, hexylene glycol, pentylene glycol, 1,2-hexanediol, ethylhexylglycerin, hydroxyacetophenone, phenoxyethanol, citral, citronellol, limonene, linalool, carvone, citrus aurantium peel oil, mentha viridis (spearmint) leaf oil, pinene, mica, tin oxide, titanium dioxide (CI 77891), blue 1 (CI 42090), ext. violet 2 (CI 60730), red 33 (CI 17200)