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  • CLASSES

    Antiinfectives for Treatment of Acne
    Peroxide Products for Treatment of Acne

    DEA CLASS

    Rx

    DESCRIPTION

    Topical combination acne product
    Both drug components exhibit antibacterial activity; benzoyl peroxide has drying actions, sebostatic effects, and causes mild skin desquamation
    Use results in improvements in both inflammatory and non-inflammatory acne lesions

    COMMON BRAND NAMES

    Acanya, BenzaClin, Duac, Neuac, ONEXTON

    HOW SUPPLIED

    Acanya/BenzaClin/Benzoyl Peroxide;Clindamycin/Benzoyl Peroxide;Clindamycin Phosphate/Clindamycin Phosphate, Benzoyl Peroxide/Clindamycin, Benzoyl Peroxide/Duac/Neuac/ONEXTON Topical Gel: 1.2-2.5%, 1.2-3.75%, 1.2-5%, 5-1%, 5-300mg, 5-400mg, 5-600mg
    BenzaClin/Benzoyl Peroxide;Clindamycin/Benzoyl Peroxide;Clindamycin Phosphate Topical Pwd F/Recon: 5-300mg, 5-400mg, 5-600mg
    BenzaClin/Benzoyl Peroxide;Clindamycin/Benzoyl Peroxide;Clindamycin Phosphate Topical Sol: 5-1%, 5-300mg, 5-600mg

    DOSAGE & INDICATIONS

    For the treatment of acne vulgaris.
    NOTE: There are reports of an increase of P. acnes resistance to clindamycin in the treatment of acne. In patients with P. acnes resistant to clindamycin, the clindamycin component may provide no additional benefit beyond benzoyl peroxide alone.
    Topical dosage (BenzaClin topical gel)
    Adults, Adolescents, and Children 12 years and older

    Apply twice daily, morning and evening, or as directed by the prescriber to affected areas.

    Topical dosage (Duac topical gel, Acanya topical gel, Neuac topical gel, or Onexton topical gel)
    Adults, Adolescents, and Children 12 years and older

    Apply once daily in the evening or as directed by the prescriber to affected areas.

    For the treatment of moderate to severe acne rosacea†.
    Topical dosage (Duac topical gel)
    Adults

    In 1 study , a recommended dosage was to apply once daily to affected areas. In the 12-week randomized, vehicle-controlled, parallel-group study (n = 53), a 71.3% mean reduction in papules and pustules occurred in the treatment group vs. 19.3% in the vehicle-only group (p = 0.0056), with improvements noticeable by the third week of treatment. Overall rosacea severity and global assessment scores (prescriber and patient) were all improved, with a low incidence of application site reactions to the active treatment.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Maximum dosage information not available.

    Geriatric

    Maximum dosage information not available.

    Adolescents

    Maximum dosage information not available.

    Children

    12 years: Maximum dosage information not available.
    < 12 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Data are not available for this population; no quantitative recommendations are available.

    Renal Impairment

    Data are not available for this population; no quantitative recommendations are available.

    ADMINISTRATION

    Topical Administration

    Before applying to affected areas, wash the skin gently, rinse with warm water, and pat dry.

    Other Topical Formulations

    BenzaClin Topical Gel: Prior to dispensing, tap each vial until powder flows freely. Add 5 mL of purified water to each 25 gram vial or 10 mL of purified water to each 50 gram vial or jar with pump dispenser. Immediately shake to completely dissolve clindamycin. If needed, add additional purified water to bring level up to the mark on the vial. Add the solution in each vial to the gel and stir until homogenous in appearance (roughly 1—1.5 minutes). For the 50 gram pump only, reassemble jar with pump dispenser.
    Acanya and Onexton Topical Gel: Prior to dispensing, store in a refrigerator between 2—8 degrees C (36—46 degrees F). Dispense with a 10 week expiration date and instruct the patient to store at room temperature up to 25 degrees C (77 degrees F).

    STORAGE

    Generic:
    - Do not freeze
    - May be stored at room temperature not exceeding 77 degrees F for up to 3 months
    - Store at or below 77 degrees F
    Acanya :
    - Do not freeze
    - Prior to dispensing, store in refrigerator (36 to 46 degrees F)
    - Protect from freezing
    - Store at room temperature (up to 77 degrees F)
    BenzaClin:
    - Do not freeze
    - Store reconstituted product in accordance with package insert instructions
    - Store unreconstituted product at 68 to 77 degrees F; excursions permitted to 59 to 86 degrees F
    Duac:
    - After dispensing, store at room temperature up to 77 degrees F and use within 60 days
    - Do not freeze
    - Prior to dispensing, store in refrigerator (36 to 46 degrees F)
    Neuac:
    - After dispensing, store at room temperature up to 77 degrees F and use within 60 days
    - Do not freeze
    - Prior to dispensing, store in refrigerator (36 to 46 degrees F)
    ONEXTON:
    - Do not freeze
    - Prior to dispensing, store in refrigerator (36 to 46 degrees F)
    - Store at or below 77 degrees F
    - Store upright

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    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 squamous cell skin tumors in transgenic TgAC mice in a study using 20 weeks of topical treatment. Genotoxicity studies were not conducted with benzoyl peroxide; clindamycin. Clindamycin phosphate was not genotoxic in Salmonella typhimurium or in a rat micronucleus test. 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. Studies have not been performed with benzoyl peroxide; clindamycin 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 benzoyl peroxide; clindamycin, based on mg/m2) revealed no effects on fertility or mating ability.

    Clindamycin hypersensitivity, lincomycin hypersensitivity

    Benzoyl peroxide; clindamycin products are contraindicated in patients with clindamycin hypersensitivity, benzoyl peroxide hypersensitivity, lincomycin hypersensitivity, or hypersensitivity to any other components of the product.

    Eczema, ocular exposure, skin abrasion, skin disease, sunburn, sunlight (UV) exposure

    Avoid accidental exposure of benzoyl peroxide; clindamycin products to the eyes, lips, mucus membranes and inflamed or raw skin due to severe irritation. If unintended mucus membrane or ocular exposure occurs, thoroughly rinse affected areas with water. Use of these products in patients with skin disease such as dermatitis, seborrhea, and eczema or with skin abrasion or inflammation, denuded skin including sunburn or windburn may increase the risk of skin irritation. The drug should be discontinued until skin sensitivity resolves. Patients should limit their sunlight (UV) exposure while using this drug product to decrease the risk for skin irritation. If mild to moderate itching, redness, swelling or dryness occurs, apply a moisturizer daily. If severe itching, redness, swelling or undue dryness occurs, consult health care provider and discontinue use.

    Children, infants, neonates

    Safe and effective use of benzoyl peroxide; clindamycin in neonates, infants, and children younger than 12 years of age has not been established. Avoid use in this patient population.

    C. difficile-associated diarrhea, Crohn's disease, diarrhea, pseudomembranous colitis, ulcerative colitis

    Benzoyl peroxide; clindamycin combination products are contraindicated in patients with a history of regional enteritis (Crohn's disease), antibiotic-associated colitis/pseudomembranous colitis, or ulcerative colitis. Orally and parenterally administered clindamycin has been associated with severe colitis which may result in patient death. Use of topical clindamycin results in some (less than 1% of the topical dose) systemic absorption from the skin surface. Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, including clindamycin, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

    Pregnancy

    There are no available data on benzoyl; peroxide; clindamycin 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 the use of clindamycin exposure during the first trimester of pregnancy are insufficient to inform a drug-associated risk of pregnancy-related adverse outcomes. 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 reproductive studies using oral doses of clindamycin up to 600 mg/kg/day (240 and 120 times the amount of clindamycin in the highest recommended adult human dose, respectively, based on BSA comparisons) or subcutaneous doses of clindamycin up to 200 mg/kg/day (80 and 40 times the amount of clindamycin in the highest recommended adult human dose, respectively, based on BSA comparisons) revealed no evidence of teratogenicity. [51044] [58619]

    Breast-feeding

    There are no data on the presence of clindamycin or benzoyl peroxide in human breast milk, the effects on the breastfed child, or the effects on milk production after topical administration; however, little systemic exposure occurs after topical application of these products. Orally and parenterally administered clindamycin has been reported to appear in breast milk.[28664] [48356] [51044] [58619] Previous American Academy of Pediatrics recommendations considered clindamycin to be generally compatible with breast-feeding.[27500] If benzoyl peroxide; clindamycin is applied to the chest, care should be taken to avoid accidental ingestion by the infant.[51044] [58619] Only water-miscible cream products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins.[48357] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    C. difficile-associated diarrhea / Delayed / Incidence not known

    Moderate

    erythema / Early / 0-26.0
    pseudomembranous colitis / Delayed / 0-1.0
    superinfection / Delayed / Incidence not known

    Mild

    pruritus / Rapid / 0-17.0
    xerosis / Delayed / 0-15.0
    skin irritation / Early / 0.1-0.1
    urticaria / Rapid / Incidence not known
    skin discoloration / Delayed / Incidence not known

    DRUG INTERACTIONS

    Clindamycin; Tretinoin: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided.
    Dapsone: (Minor) Coadministration of topical benzoyl peroxide-containing products with topical sulfone products, such as dapsone, may cause skin and facial hair to temporarily change color to a yellow/orange color.
    Fluocinolone; Hydroquinone; Tretinoin: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. (Minor) Keratolytic agents or products that contain keratolytic agents, such as benzoyl peroxide, can potentiate the skin irritation caused by hydroquinone and hydroquinone-containing products. Also, concurrent use of topical hydroquinone and topical peroxide (e.g., benzoyl peroxide) on the same area of skin can result in transient dark staining of the skin due to oxidation of hydroquinone. Removal of staining can be accomplished by discontinuing concurrent use and by normal soap cleansing. Concurrent application of such agents should generally be avoided.
    Halobetasol; Tazarotene: (Moderate) Concomitant use of tazarotene and dermatologic products containing benzoyl peroxide should be avoided. The manufacturer suggests that a patient's skin rest until the effects of such preparations subside before using tazarotene. When used together as part of acne therapy, these medications should be used separately at different times of the day to minimize skin irritation, unless directed otherwise by the prescriber. If skin irritation occurs, a decrease in dose or frequency of one or both agents may be necessary.
    Hydroquinone: (Minor) Keratolytic agents or products that contain keratolytic agents, such as benzoyl peroxide, can potentiate the skin irritation caused by hydroquinone and hydroquinone-containing products. Also, concurrent use of topical hydroquinone and topical peroxide (e.g., benzoyl peroxide) on the same area of skin can result in transient dark staining of the skin due to oxidation of hydroquinone. Removal of staining can be accomplished by discontinuing concurrent use and by normal soap cleansing. Concurrent application of such agents should generally be avoided.
    Isotretinoin: (Moderate) Benzoyl peroxide will cause additive irritant and drying effects with concomitant oral isotretinoin use. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves.
    Mequinol; Tretinoin: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. (Moderate) Mequinol; tretinoin (Solage) solution contains a high concentration of ethanol which may be very drying to the skin. The concomitant use of other medications or skin-care items with drying effects can be additive or cause irritation, including astringents, benzoyl peroxide, salicylic acid, medicated soaps/shampoos, or hair waxes.
    Porfimer: (Major) Avoid coadministration of porfimer with benzoyl peroxide due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like benzoyl peroxide may increase the risk of a photosensitivity reaction.
    Salicylic Acid: (Moderate) Concurrent use of benzoyl peroxide and topical products containing salicylic acid on the same area of skin will cause additive irritant and drying effects. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves. (Moderate) When concomitantly prescribed for acne therapy, apply salicylic acid and clindamycin topical solutions separately, at different times of the day to minimize skin irritation, unless directed otherwise by the prescriber. If skin irritation occurs, a decrease in dose or frequency of one or both agents may be necessary.
    Sodium Thiosulfate; Salicylic Acid: (Moderate) Concurrent use of benzoyl peroxide and topical products containing salicylic acid on the same area of skin will cause additive irritant and drying effects. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves. (Moderate) When concomitantly prescribed for acne therapy, apply salicylic acid and clindamycin topical solutions separately, at different times of the day to minimize skin irritation, unless directed otherwise by the prescriber. If skin irritation occurs, a decrease in dose or frequency of one or both agents may be necessary.
    Tazarotene: (Moderate) Concomitant use of tazarotene and dermatologic products containing benzoyl peroxide should be avoided. The manufacturer suggests that a patient's skin rest until the effects of such preparations subside before using tazarotene. When used together as part of acne therapy, these medications should be used separately at different times of the day to minimize skin irritation, unless directed otherwise by the prescriber. If skin irritation occurs, a decrease in dose or frequency of one or both agents may be necessary.
    Topical Local Anesthetics: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
    Tretinoin, ATRA: (Moderate) Benzoyl peroxide can potentiate the skin irritation caused by topical tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided.
    Trifarotene: (Moderate) Avoid concurrent use of trifarotene with other topical products that may dry or irritate the skin, such as benzoyl peroxide.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with benzoyl peroxide is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like benzoyl peroxide may increase the risk of a photosensitivity reaction.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no available data on benzoyl; peroxide; clindamycin 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 the use of clindamycin exposure during the first trimester of pregnancy are insufficient to inform a drug-associated risk of pregnancy-related adverse outcomes. 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 reproductive studies using oral doses of clindamycin up to 600 mg/kg/day (240 and 120 times the amount of clindamycin in the highest recommended adult human dose, respectively, based on BSA comparisons) or subcutaneous doses of clindamycin up to 200 mg/kg/day (80 and 40 times the amount of clindamycin in the highest recommended adult human dose, respectively, based on BSA comparisons) revealed no evidence of teratogenicity. [51044] [58619]

    There are no data on the presence of clindamycin or benzoyl peroxide in human breast milk, the effects on the breastfed child, or the effects on milk production after topical administration; however, little systemic exposure occurs after topical application of these products. Orally and parenterally administered clindamycin has been reported to appear in breast milk.[28664] [48356] [51044] [58619] Previous American Academy of Pediatrics recommendations considered clindamycin to be generally compatible with breast-feeding.[27500] If benzoyl peroxide; clindamycin is applied to the chest, care should be taken to avoid accidental ingestion by the infant.[51044] [58619] Only water-miscible cream products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins.[48357] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Benzoyl peroxide and clindamycin exhibit antimicrobial effects against Propionibacterium acnes, the predominant organism in sebaceous follicles and comedones. The antimicrobial effects of benzoyl peroxide against Propionibacterium acnes are due to the release of free-radical oxygen species, which are capable of oxidizing bacterial proteins. Benzoyl peroxide also demonstrates keratolytic activity, which produces drying and desquamative actions that contribute to its efficacy in comedone treatment. Clindamycin antibacterial activity results from inhibition of protein synthesis. The antibiotic binds to the 50 S ribosomal subunits of bacteria, thereby inhibiting protein synthesis. Clindamycin is either bacteriostatic or bactericidal, depending on its concentration at the site of action and on the specific susceptibility of the organism being treated. Propionibacterium acnes is a lipase-producing organism. Inhibition of P. acnes reduces the concentration of free fatty acids in sebum, which may be the cause of inflammatory lesions associated with acne. Propionibacterium acnes has developed resistance to topical clindamycin, therefore it is recommended to change medication therapy if the patient fails to respond in 4—8 weeks. Once an effective regimen is found, patients should continue therapy until new lesions no longer appear.
     
    Although it varies depending on the severity of the acne, combination therapy (i.e., antibiotics and benzoyl peroxide or these combinations with other topical products such as a retinoid or oral anti-acne products) for acne is very common. Most patients will require at least two products (for mild to moderate severity acne) and occasionally up to five products are used concomitantly (for severe acne). It is recommended to simplify the regimen as much as possible as complex regimens decrease compliance and can increase skin irritation. While clinical studies use lesion counts to grade the severity of acne, most clinicians recommend to tailor therapy to treat the most severe lesions present, because adequate treatments for these will be effective against lesser lesions. Acne has been classified into four main types: purely comedonal (or noninflammatory acne) and mild papular, scarring papular, and nodular acne (considered more severe acne). Most patients exhibit some combination of comedonal and inflammatory acne. Patient skin types should also be considered when treating acne, as this will impact vehicle selection. Patients with drier skin may benefit most from creams and patients with oilier skin may do better with gels or solutions. Picking the correct vehicle can reduce the incidence of side effects and thereby increase compliance.

    PHARMACOKINETICS

    Benzoyl peroxide; clindamycin products are applied topically to the skin. In a study of 13 patients with acne vulgaris in which benzoyl peroxide; clindamycin gel was applied to the face and back, the amount of clindamycin excreted in the urine during a 12 hour dosing interval increased from a mean of 5745 ng on day 1 to 12069 ng on day 5.

    Topical Route

    Benzoyl peroxide: Benzoyl peroxide has been shown to be absorbed by the skin where it is converted to benzoic acid; less than 2% of the dose enters the systemic circulation as benzoic acid. It is suggested that the lipophilic nature of benzoyl peroxide acts to concentrate the compound into the lipid-rich sebaceous follicle.[28665]
    Clindamycin: Topical clindamycin has been shown to be systemically absorbed, but the amount is minimal. A comparative study of the pharmacokinetics of benzoyl peroxide; clindamycin (1.2%; 5%) topical gel and 1% clindamycin solution alone in 78 patients indicated that mean plasma clindamycin levels during the four week dosing period were less than 0.5 ng/mL for both treatment groups.[28665] In an in vitro percutaneous penetration study comparing benzoyl peroxide; clindamycin (1%; 5%) topical gel and topical 1% clindamycin gel alone, there was no statistical difference in penetration between the two drugs. The mean systemic bioavailability of topical clindamycin is suggested to be less than 1%. In a study of 13 patients with acne vulgaris in which benzoyl peroxide; clindamycin gel was applied to the face and back, peak plasma concentrations of clindamycin ranged from 1.47 to 2.77 ng/mL on day 1 and 1.43 to 7.18 ng/mL on day 5. The AUC ranged from 2.74 to 12.86 ng x h/mL on day 1 and 11.4 to 69.7 ng x h/mL on day 5. A comparison of the single and multiple day dose plasma and urinary concentrations of clindamycin suggests that there is accumulation of clindamycin after multiple dosing with the gel formulation.[28664] In an open-label, multiple-dose trial in 16 adults, 1 g of benzoyl peroxide; clindamycin (1.2%; 2.5%) topical gel was applied to the face once daily for 30 days. Twelve patients (75%) had at least 1 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 Cmax was 0.78 +/- 0.22 ng/mL (n = 9 with measurable concentrations) and the mean AUC was 5.29 +/- 0.81 h x ng/mL (n = 6). Clindamycin plasma concentrations were below LOQ in all patients at 24 hours after the dose on Days 1, 15, and 30.[51044]