Duac

Clindamycin phosphate, benzoyl peroxide.

Duac gel contains clindamycin (1.2% clindamycin phosphate) at a concentration equivalent to 1% w/w (10 mg/g) and benzoyl peroxide 5% w/w (50 mg/g).

Pharmacology: Pharmacodynamics: Mechanism of Action: Clindamycin: Clindamycin is a lincosamide antibiotic with bacteriostatic action against gram-positive aerobes and a wide range of anaerobic bacteria. Lincosamides such as clindamycin bind to the 50S ribosomal subunit of susceptible bacteria and prevent elongation of peptide chains by interfering with peptidyl transfer, thereby suppressing protein synthesis. The action of clindamycin is predominantly bacteriostatic although high concentrations may be slowly bactericidal against sensitive strains. Clindamycin phosphate is inactive in vitro, and is hydrolysed in vivo to active clindamycin.
Benzoyl Peroxide: Benzoyl peroxide is a higly lipophilic oxidizing agent with bactericidal and mild keratolytic effects. It contributes a nonspecific bactericidal mechanism (the formation of reactive oxygen species) to the combination therapy and thereby suppresses the emergence of drug resistance organisms.
Pharmacodynamic Effects: Clindamycin: Clindamycin has been shown to have in vitro activity against Propionibacterium acnes, an organism that has been associated with acne vulgaris. P. acnes resistance to clindamycin has been documented. Clindamycin in vitro inhibits P. acnes [minimum inhibitory concentration (MIC) 0.4 mcg/mL]. Free fatty acids on the skin surface have been decreased from approximately 14% to 2% following application of clindamycin. It also reduces inflammation by inhibiting leukocyte chemotaxis.
Benzoyl Peroxide: The effectiveness of benzoyl peroxide in the treatment of acne vulgaris is primarily attributable to its bactericidal activity, especially with respect to P. acnes. The bactericidal activity of benzoyl peroxide is due to the release of active or free radical oxygen capable of oxidizing bacterial proteins. Benzoyl peroxide is also believed to be effective in the treatment of acne on account of its anti-inflammatory and mild keratolytic properties.
Resistance and Cross-Resistance: The treatment of acne with topical and oral antibiotics used as monotherapy such as clindamycin and erythromycin has been associated with the development of antimicrobial resistance in P. acnes as well as commensal flora (eg, Staphylococcus aureus, Streptococcus pyogenes). The use of clindamycin may result in developing inducible resistance in these organisms. Benzoyl peroxide has a bactericidal effect and it has not been shown to induce emergence resistance in P. acnes. The inclusion of benzoyl peroxide in Duac has shown to reduce clindamycin resistant P. acne counts (see Precautions). This has not been studied with clindamycin 1%/benzoyl peroxide 3%.The prevalence of acquired resistance may vary geographically and over time for selected organisms. Local information of resistance is desirable, particularly when treating severe infections.
Clinical Studies: The safety and efficacy of Duac were evaluated in 5 randomised double-blind clinical studies of 1319 patients with facial acne vulgaris with both inflammatory and noninflammatory lesions. Treatment was applied once daily for 11 weeks and patients were evaluated and lesions counted 2, 5, 8, and 11 weeks. The mean percentage reduction in the number of all lesions after 11 weeks is shown in Table 1. (See Table 1).

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The mean percentage reduction in total lesions was significantly greater with Duac than clindamycin or vehicle in all 5 studies. The observed improvement was consistently greater with this drug than benzoyl peroxide alone, but the difference did not achieve statistical significance in all individual studies.
Against inflammatory lesions, Duac was significantly superior to clindamycin alone in 4 of 5 studies and to benzoyl peroxide alone in 3 of 5 studies. Against noninflammatory lesions, this drug was significantly superior to clindamycin alone in 4 of 5 studies.
Overall improvement in acne was assessed by the physician and was significantly superior with Duac than with either benzoyl peroxide or clindamycin alone in 3 of 5 studies. An effect on inflammatory lesions was apparent from week 2 of treatment. The effect on noninflammatory lesions was more variable, with efficacy generally apparent after 2-5 weeks of treatment.
Pharmacokinetics: Absorption/Distribution/Metabolism: Clindamycin: Clindamycin phosphate is rapidly hydrolyzed to clindamycin by skin phosphatases. Clindamycin is further metabolized to clindamycin sulfoxide. Significant levels of clindamycin have been detected in comedones of patients who have applied topical clindamycin phosphate for 2 weeks. There is no evidence that the skin acts as a reservoir for clindamycin after repeated applications or that it accumulates systematically. Clindamycin is metabolized in the liver to active and inactive metabolites.
Benzoyl Peroxide: Benzyl peroxide is absorbed in the skin where it is metabolised to benzoic acid. Following topical application, <5% of the dose enters systemic circulation as benzoic acid.
A comparative study of the pharmacokinetics of Duac gel (1 g applied to the face once daily) and 1% clindamycin solution (0.5 g applied to the face twice daily) in 78 patients with moderate to severe acne indicated that mean plasma clindamycin levels during the 4-week dosing period were very low (<0.5 ng/mL) for both treatment groups. The presence of benzoyl peroxide in the formulation did not have an effect on the percutaneous absorption of clindamycin. In an open-label study of patients with moderate to severe acne vulgaris, approximately 4 g of Duac gel was applied once daily for 5 days to the face, upper chest, and upper back and shoulders. Two formulations were studied (24 patients in each group), one containing methylparaben and the other was preservative-free. Clindamycin was slowly absorbed after topical application, reaching maximal observed plasma concentrations within 6-8 hrs. Geometric mean maximal plasma clindamycin exposure (C_max and AUC_0-∞) on day 5 was 1.095 ng/mL and 16.3 ng·h/mL, respectively, in the methylparaben formulation and 0.806 ng/mL and 11.4 ng·h/mL, respectively, in the preservative-free formulation. Systemic exposure to clindamycin sulfoxide was lower relative to clindamycin, as mean C_max and AUC values were approximately 4- to 5-fold higher on average for clindamycin compared with clindamycin sulfoxide. This ratio was comparable across all formulations, indicating that the conversion of clindamycin to its metabolite is not affected by formulation.
Elimination: Clindamycin: Clindamycin has an elimination t_½ of approximately 9 hrs and is excreted mainly in the urine as the parent compound. Following multiple topical applications of clindamycin gel, <0.06% of the total dose was excreted in the urine.
Benzoyl Peroxide: Benzoyl peroxide is excreted as benzoic acid in the urine.
Clindamycin/benzoyl peroxide gel: A comparative study of the pharmacokinetics of Duac gel (1 g applied to the face once daily) and 1% clindamycin solution (0.5 g applied to the face twice daily) in 78 patients for 4 weeks, indicated no statistically significant differences in the amounts of clindamycin and clindamycin sulfoxide excreted in the 24-hr period after the last dose were detected between treatments.
Special Patient Populations: Children: Not relevant for this product.
Elderly: See Dosage & Administration.
Renal Impairment: See Dosage & Administration.
Hepatic Impairment: See Dosage & Administration.
Toxicology: Nonclinical Information: Carcinogenesis/Mutagenesis: No genotoxicity or mutagenicity studies have been conducted with topical clindamycin/benzoyl peroxide gel.
Clindamycin: Clindamycin phosphate was not genotoxic in Salmonella typhimurium, a chromosome aberration assay or in a rat micronucleus test.
Benzoyl Peroxide: Both the carcinogenicity and photocarcinogenicity of benzoyl peroxide have been extensively assessed in both mice and hamsters, by various routes of administration, in studies ranging from 42-100 weeks in duration. The overall conclusion is that benzoyl peroxide is considered to be neither carcinogenic nor photocarcinogenic in topical acne products at a concentration of 2.5-10%.
The genotoxicity of benzoyl peroxide was extensively assessed in vitro and in vivo. While in a few in vitro studies benzoyl peroxide showed weak mutagenicity, the overall genotoxicity profile did not indicate significant biological relevance.
Clindamycin/Benzoyl Peroxide Gel: In a 2-year carcinogenicity study in mice, topical administration of clindamycin 1%/benzoyl peroxide 5% gel at dose levels up to 8000 mg/kg/day (24,000 mg/m²/day) showed no evidence of increased carcinogenic risk, compared with controls.
In a 52-week photococarcinogenicity study in which hairless mice were exposed to both ultraviolet radiation and clindamycin 1%/benzoyl peroxide 5% gel at dose levels up to 2500 mg/kg/day (7500 mg/m²/day), a slight reduction in the median time to onset of tumors was observed, as compared to ultraviolet radiation alone.
Reproductive Toxicology: Fertility and Pregnancy: No fertility studies were conducted with topical clindamycin/benzoyl peroxide gel.
Clindamycin: Fertility studies in rats treated orally with up to 300 mg/kg/day of clindamycin revealed no effects on fertility or mating ability.
Reproduction studies have been performed in rats and mice using SC and oral doses of clindamycin phosphate, clindamycin hydrochloride and clindamycin palmitate. These studies revealed no evidence of fetal harm.
The highest dose used in the rat and mouse teratogenicity studies was equivalent to a clindamycin phosphate dose of 432 mg/kg. For a rat, that dose is 84-fold higher, and for a mouse 42-fold higher, than the anticipated human dose of clindamycin phosphate from 1% clindamycin phosphate foam based on a mg/m² comparison.
Benzoyl Peroxide: In a combined repeat dose and reproduction/development toxicity study, benzoyl peroxide (250, 500, or 1000 mg/kg/day) was administered orally to male rats for 29 days and female rats for 41-51 days. There were no treatment-related changes observed in the mating period, mating rate, conception rate, delivery rate, birth rate, pregnancy period, luteinisation number, implantation number and the rate of losing embryos and fetuses after implantation. In pups, body weight was significantly decreased in the high-dose group. The no-observed-adverse-effect level (NOAEL) for reproductive toxicities was considered to be 500 mg/kg/day.

Treatment of acne vulgaris.

Adults and Adolescents: Duac gel is for topical use only.
Children: The safety and efficacy of Duac gel have not been established in children <12 years, therefore this drug is not recommended for use in this population.
Elderly: There are no specific recommendations for use in the elderly.
Renal Impairment: No dosage adjustment is necessary. As percutaneous absorption of Duac gel is low following topical application, renal impairment is not expected to result in systemic exposure of clinical significance.
Hepatic Impairment: Dosage adjustment is necessary. As percutaneous absorption of Duac gel is low following topical application, hepatic impairment is not expected to result in systemic exposure of clinical significance.
Administration: Duac should be applied in a thin film over entire affected area once daily after washing gently with a mild cleanser and fully drying. If the gel does not rub into the skin easily, too much is being applied. Hands should be washed after application. Patients may also use a moisturizer as needed. If excessive dryness or peeling occurs, frequency of application should be reduced or the application is temporarily interrupted.
Efficacy has not been established for less than once daily dosing frequencies. Patients should be advised that excessive application will not improve efficacy, but may increase the risk of skin irritation.
Two (2)-5 weeks of treatment may be required before a therapeutic effect is observed (see Pharmacology: Pharmacokinetics under Actions). The safety and efficacy of Duac gel has not been studied beyond 12 weeks in acne vulgaris clinical trials. The prescriber should evaluate the benefit of continuing treatment beyond 12 weeks of uninterrupted use.

Signs and Symptoms: Excessive application of Duac may result in severe irritation. In this event, discontinue use and wait until the skin has recovered. Topically applied benzoyl peroxide is not generally absorbed in sufficient amounts to produce systemic effects. Excessive application of topically applied clindamycin may result in absorption of sufficient amounts to produce systemic effects. In the event of accidental ingestion of Duac, gastrointestinal adverse reactions similar to those seen with systemically administered clindamycin may be seen.
Treatment: Appropriate symptomatic measures should be taken to provide relief from irritation due to excessive topical application. Accidental ingestion should be managed clinically or as recommended by the National Poisons Management and Control Center, where available.

Hypersensitivity to lincomycin, clindamycin, benzoyl peroxide or any of the components of Duac.
Duac should not be used in patients with a history of regional enteritis, ulcerative colitis or antibiotic-associated colitis (including pseudomembranous colitis).

Contact with the mouth, eyes, lips, other mucous membranes or areas of irritated or broken skin should be avoided. In case of accidental contact, rinse well with water.
During the 1st week of treatment, an increase in peeling and reddening will occur in most patients. Depending upon the severity of these side effects, patients can use a moisturizer, temporarily reduce the frequency of application of Duac gel or temporarily discontinue use. However, efficacy has not been established for less than once daily dosing frequencies. Concomitant topical acne therapy should be use with caution because possible cumulative irritancy may occur, which sometimes may be severe, especially with the use of peeling desquamating, or abrasive agents.
If severe local irritancy (eg, severe erythema, severe dryness and itching, severe stinging/burning) occurs, Duac should be discontinued. As benzoyl peroxide may cause increased sensitivity to sunlight, sunlamps should not be used and deliberate or prolonged exposure to sunlight should be avoided or minimized. When exposure to strong sunlight cannot be avoided, patients should be advised to use sunscreen product and wear protective clothing. If the patient has sunburn, this should be resolved before using Duac gel. The product may bleach hair and coloured or dyed fabrics. Avoid contact with hair, fabrics, furniture or carpeting.
Pseudomembranous colitis: Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clindamycin, and may range in severity from mild to life -threatening, with an onset of up to several weeks following cessation of therapy. Although this is unlikely to occur with topically applied Duac gel, if prolonged or significant diarrhoea occurs or the patient experiences abdominal cramps, treatment should be discontinued immediately and the patient should be investigated further, as the symptoms may indicate antibiotic-associated colitis.
Resistance to Clindamycin: Benzoyl peroxide reduces the potential for emergence of organisms resistant to clindamycin. However, patients with a recent history of systemic or topical clindamycin or erythromycin use are more likely to have preexisting antimicrobial resistant to Propionibacterium acnes and commensal flora.
Cross Resistance: Cross-resistance has been demonstrated between clindamycin and lincomycin. Resistance to clindamycin is often associated with inducible resistance to erythromycin (see Interactions).
Effects on the Ability to Drive or Operate Machinery: There have been no studies to investigate the effect of Duac on driving performance or the ability to operate machinery. A detrimental effect on such activities would not be anticipated from the adverse reaction profile of clindamycin/benzoyl peroxide.
Use in pregnancy: There are no well-controlled studies in pregnant women treated with topical Duac gel. There are limited data on the use of topical clindamycin or benzoyl peroxide alone in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. No effects during pregnancy are anticipated since systemic exposure to clindamycin and benzoyl peroxide is low (see Pharmacology under Action). However, Duac should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus.
Use in lactation: Duac has not been studied during breastfeeding. Percutaneous absorption of this drug is low. However, it is not know whether clindamycin or benzoyl peroxide is excreted in human milk after topical application. Clindamycin is excreted in human milk following oral and parenteral administration. Duac should be used during lactation only if the expected benefit justifies the potential risk to the infant. To avoid accidental ingestion by the infant if used during lactation, Duac should not be applied to the breast area.

Use in pregnancy: There are no well-controlled studies in pregnant women treated with topical Duac gel. There are limited data on the use of topical clindamycin or benzoyl peroxide alone in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. No effects during pregnancy are anticipated since systemic exposure to clindamycin and benzoyl peroxide is low (see Pharmacology under Action). However, Duac should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus.
Use in lactation: Duac has not been studied during breastfeeding. Percutaneous absorption of this drug is low. However, it is not know whether clindamycin or benzoyl peroxide is excreted in human milk after topical application. Clindamycin is excreted in human milk following oral and parenteral administration. Duac should be used during lactation only if the expected benefit justifies the potential risk to the infant. To avoid accidental ingestion by the infant if used during lactation, Duac should not be applied to the breast area.

Adverse drug reactions (ADRs) are summarized below for topical clindamycin/benzoyl peroxide as a combination including any additional ADRs that have been reported for the single topical active ingredients, benzoyl peroxide or clindamycin. Adverse drug reactions are listed by MedDRA system organ class and by frequency. Frequencies are defined as: Very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000).
Clinical Trial Data: The safety and efficacy of Duac has been evaluated in 5 randomized double-blind clinical trials of 1319 patients (397 used Duac gel) with facial acne vulgaris (see Pharmacology: Pharmacokinetics under Actions). Patients ≥12 years were treated once daily in the evening for 11 weeks. All ADRs reported with Duac gel from these studies are shown in the summary Table 2. (See Table 2.)

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In addition to the ADRs reported in the previous table, in the pivotal trial conducted with topical Duac gel, application site photosensitivity reaction was also reported commonly.
Local Tolerability: During the 5 clinical trials with Duac gel, all patients were graded for facial erythema, peeling, burning and dryness on the following scale: 0=absent, 1=mild, 2=moderate and 3=severe. The percentage of patients that had symptoms present before treatment (at baseline) and during treatment were as follows: (See Tables 3 and 4).

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No formal drug-drug interaction studies have been conducted with Duac gel. It should not be used in combination with erythromycin containing products due to possible antagonism to the clindamycin component.
Clindamycin has shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, Duac gel should be used with caution in patients receiving such agents. Concominant application of Duac gel with tretinoin, isotretinoin and tazarotene should be avoided since benzoyl peroxide may reduce their efficacy and increase irritation. If combination treatment is required, the products should be applied at different times of the day (eg, 1 in the morning and other in the evening).
Using topical benzoyl peroxide-containing preparations at the same time as topical sulfonamide-containing products may cause skin and facial hair to temporarily change colour (yellow/orange).

Store in a refrigerator at 2-8°C. Do not freeze.
Store at temperatures up to 25°C. Discard after 2 months.

Acne Treatment Preparations

D10AF51 - clindamycin, combinations ; Belongs to the class of topical antiinfective preparations used in the treatment of acne.

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