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Newer Approaches in Topical Combination Therapy for Acne

Lisa W. Fu, BHSc and Ronald B. Vender, MD, FRCPC
Department of Medicine, McMaster University, Hamilton, ON, Canada

ABSTRACT

Acne vulgaris is a common chronic inflammatory cutaneous disease involving the pilosebaceous unit. Its pathophysiology is multifactorial and complex, including obstruction of the pilosebaceous unit due to increased sebum production, abnormal keratinization, proliferation of Propionibacterium acnes (P. acnes), and inflammation. Topical agents are the most commonly used therapy for acne. First generation topicals mainly consist of single agent retinoids, benzoyl peroxide (BPO) and antibacterials that target comedones, P. acnes, and inflammation. Novel topical therapies include combination products with advanced vehicle formulations that target multiple acne pathophysiologies and offer simplified treatment regimes. For example, the combination of clindamycin and tretinoin in a unique vehicle formulation allows for progressive follicle penetration and decreased irritation, resulting in increased efficacy. Furthermore, adapalene or clindamycin with BPO combinations target comedones, inflammation, and P. acnes synergistically. These newer combination products have the potential to increase both efficacy and patient adherence when compared with single agent treatment.

Key Words: acne vulgaris, adapalene, benzoyl peroxide, clindamycin, retinoid, topical combination therapies, tretinoin

Introduction

Acne vulgaris is a common chronic inflammatory cutaneous disease involving the pilosebaceous unit. Acne is a common worldwide skin disease that affects about 85% of individuals between the ages of 12-24 years.1 The pathophysiology includes androgen-mediated stimulation of sebaceous gland activity, abnormal keratinization leading to follicular plugging (comedo formation), proliferation of P. acnes within the follicle, and inflammation.2 Genetic factors, stress, and possibly diet may influence the development of acne.2 Acne can cause a considerable amount of emotional distress and physical discomfort, thus medical treatment must be accompanied by patient counseling and education, which can contribute to improved self-esteem and adherence to therapy.

Treatment of Acne Vulgaris

Treatment is targeted to one or multiple pathogenic element(s). Topical therapies remain the most common and effective treatment option for mild to moderate acne and also for maintenance therapy for all levels of acne severity.1 Retinoids (e.g., adapalene, tazarotene, tretinoin) act to reduce dyskeratosis at the pilosebaceous unit, inhibit the formation of microcomedones, and have mild anti-inflammatory effects.3 Advanced vehicle formulations in the form of emollient cream and microsphere gel reduce irritation and enhance efficacy.4 Antimicrobials (e.g., benzoyl peroxide (BPO), clindamycin, erythromycin, sodium sulfacetamide) have bactericidal or bacteriostatic action against P. acnes. Anti-inflammatory agents such as dapsone act through direct inhibition of leukocyte trafficking and the generation of chemical mediators of inflammation by leukocytes and/or potential interference with bacterial synthesis, thereby altering the levels and activity of P. acnes.5

Combination products (e.g., BPO + antibiotic, retinoid + antibiotic) target multiple pathogenic factors, which are complementary and synergistic in mechanisms of action. It also simplifies the treatment regimen and reduces dosing frequency.3 BPO + clindamycin combination products have been widely studied, a recent meta-analysis showed that BPO 2.5% + clindamycin is comparable to BPO 5%+ clindamycin in reducing acne lesion counts.6 Investigators suggest that BPO 2.5% + clindamycin may in fact be more effective in treating non-inflammatory acne lesions possibly because of decreased irritation, thereby encouraging treatment follow-through by patients.6 Furthermore, combination preparations were found to be superior in treating acne lesions compared with using either agent alone.6

The addition of BPO to topical antibiotics and retinoids in managing mild to moderate acne reduces the incidence of bacterial resistance. This bacteriostatic agent is efficacious against both nonresistant and resistant P. acnes strains. BPO acts by producing free-radical oxygen that oxidizes bacterial proteins and exerting a mild keratolytic effect on comedones. In more severe acne, when oral antibiotics are necessary, BPO may contribute to suppressing the emergence of resistant P. acnes strains.7

Newer Fixed-dose Dual-agent Therapies

Clindamycin Phosphate 1.2% + Tretinoin 0.025% Gel (ZianaŽ, Biacna™)

This fixed-dose combination gel was approved by the US FDA in November 2006 and sanctioned by Health Canada in December 2010 for the once-daily treatment of acne vulgaris in patients ≥12 years of age.8 It combines the anti-inflammatory and antibacterial actions of clindamycin with the comedolytic and anticomedogenic actions of tretinoin5 to target several mechanisms in the pathogenesis of acne. Multiple studies have demonstrated significantly greater reductions in comedones and inflammatory lesions by 12 weeks compared with either agent alone or vehicle (Table 1).

Study (12 weeks) Comparative Treatments Study Design Major Results Adverse Effects
Leyden et al.9 n=2219 CTG vs. monotherapy with clindamycin, tretinoin or vehicle Two randomized, doubleblind, multicenter, active drug- and vehiclecontrolled CTG group showed superior efficacy in treating inflammatory and noninflammatory lesions compared with monotherapy or vehicle alone Well tolerated overall; 87.6% of participants reported no adverse events
Yentzer et al.10 n=21 CTG vs. application of two separate generic subcomponents Single-blind, prospective, single center, randomized, controlled CTG group showed a significant reduction in total lesions over length of study; both groups experienced improvement in mild to moderate acne Treatment was well tolerated in both groups
Richter et al.11 n=152 CTG vs. 0.025% tretinoin gel Randomized, doubleblind, multicenter CTG was superior to tretinoin in papular and inflammatory lesions and in overall acne severity Less burning reported with CTG
Zouboulis et al.12 n=206 CTG vs. clindamycin lotion Multicenter, single-blind, randomized, comparative CTG was more effective at reducing acne lesions than clindamycin monotherapy More erythema and desquamation reported with CTG
Table 1. Studies comparing combination clindamycin 1.0%-1.2%-tretinoin 0.025% gel (CTG) to monotherapy with clindamycin, tretinoin, or vehicle.13 n = sample size of study population.

Recommended application is once-daily at bedtime (preferred) or morning (as the vehicle delivery formulation provides for the photostability of tretinoin).8 Patients should be instructed to use only a pea-sized amount. The vehicle is an alcohol free aqueous gel containing a unique formulation of solubilized clindamycin phosphate and stable combinations of both solubilized and crystalline tretinoin.14 The crystalline suspension allows for tretinoin to be released in a rate-controlled manner, thereby resulting in slower and progressive follicular penetration and increased tolerability.14 The long-term efficacy and favorable safety profile was shown in a 52-week study, with the vast majority of participants not experiencing certain local cutaneous reactions, such as no itching (92%), no burning (91%), and no stinging (94%).15 The most frequent adverse events were acne (29/442; 7%, usually a flare), sunburn (12/442; 3%), hypersensitivity (7/442; 2%), contact dermatitis (5/442; 1%), and application-site desquamation (3/442; 1%).15 Common class-wide side-effects from topical retinoids can include peeling, redness, dryness, itching, and photosensitivity. Tretinoin increases the skin's sensitivity to UV light, therefore patients should be reminded to avoid excessive or unnecessary sun exposure and wear sunscreen and protective clothing daily. The contraindications include Crohn's, ulcerative colitis, colitis with previous antibiotic use, and use of concomitant erythromycin containing products; it has a US FDA pregnancy category C classification.8

Adapalene (0.1%) + Benzoyl Peroxide (2.5%) Gel (EpiduoŽ, Tactuo™)

This combination gel was approved by the US FDA in January 2009 and approved by Health Canada in May 2011. It is the first fixed-dose retinoid-BPO treatment that has been developed as a convenient once-daily formulation. Adapalene has comedolytic, anticomedogenic, and anti-inflammatory properties and BPO is a highly lipophilic oxidizing agent with bactericidal and keratolytic effects.16 BPO lowers the incidence of bacterial resistance compared with other topical antibiotics and can be used for the long-term management of acne. The complementary modes of action address three pathophysiologic processes of acne: abnormal keratinization leading to follicular plugging (comedo formation), proliferation of the bacterium P. acnes within the follicle, and inflammation. Multiple studies have demonstrated significantly greater reductions in comedones and inflammatory lesion by 12 weeks compared with either agent alone or vehicle (Table 2).

Studies have shown that this adapalene + BPO combination has a comparable safety profile to adapalene monotherapy.18 The long-term tolerability and safety of adapalene 0.1% + BPO 2.5% gel was evaluated in 452 acne subjects over 12 months, with 327 patients completing the study (72%).21 No subjects discontinued due to lack of efficacy, while 2% discontinued due to adverse events. Overall, treatment was well tolerated with mean scores for local intolerance (comprising erythema, dryness, scaling, and burning/stinging) reported as mild or less in all study visits. The most common adverse event was dry skin (17%). The highest irritation scores were recorded in the first week and subsequently declined thereafter. Adapalene is stable when combined with BPO in the presence or absence of light.15 It has been assigned a pregnancy category C rating.

Study (12 weeks) Comparative Treatments Study Design Major Results Adverse Effects
Gollnick et al.17 n=1670 Adapalene-BPO vs. monotherapy of either drug alone and gel vehicle Randomized, doubleblind, controlled Adapalene-BPO showed significantly greater efficacy than monotherapies Well-tolerated, with comparable tolerability to adapalene monotherapy
Gold et al.18 n=1429 Adapalene-BPO vs. monotherapy of either drug alone and gel vehicle Multicenter, randomized, double-blind, parallelgroup, active- and vehicle-controlled Adapalene-BPO showed higher success rate and reduction of acne lesions than other groups Comparable safety of adapalene-BPO to monotherapies and gel vehicle
Thiboutot et al.19 n=517 Adapalene-BPO vs. monotherapy of either drug alone and gel vehicle Randomized, doubleblind, controlled Adapalene-BPO was considerably more effective than monotherapies; significant reduction in lesion counts at 1 week Similar adverse event frequency and tolerability profile for combination gel vs. adapalene monotherapy
Poulin et al.20 n=243 Adapalene-BPO vs. vehicle Multicenter, randomized, double-blind, controlled Significantly higher lesion maintenance success rate for inflammatory and noninflammatory lesions with adapalene-BPO Adapalene-BPO was safe and well-tolerated
Table 2. Studies comparing adapalene-BPO combination therapy to monotherapy with adapalene, BPO, and vehicle.13

Patient Adherence

Acne is a chronic disease and poor medication adherence is a major contributor to treatment unresponsiveness.10 Convenience and decreased complexity of treatment encourage patient adherence. Effective yet well tolerated treatment regimens offering simplified dosing suited to a patient's lifestyle are more likely to optimize adherence and outcomes. Patients most commonly attribute frustration with the therapeutic regimen and forgetfulness as reasons for failure to use prescribed medication.22

Conclusion

Successful topical treatment of acne depends on appropriate agent selection based on patient-specific acne severity and tolerance, adherence, and adequate follow-up. The advent of combinational therapeutic products provide increased efficacy by targeting multiple pathophysiologic processes. Additional advantages of using combination therapy include reduced complexity of treatment regimen and convenient once-daily dosing. The future of topical acne treatment holds the promise of more novel uses of conventional anti-acne agents formulated with advanced vehicle delivery systems that offer less side-effects, increased tolerance, dosing simplicity, and improved efficacy.

References

  1. Leyden JJ. A review of the use of combination therapies for the treatment of acne vulgaris. J Am Acad Dermatol 49(3 Suppl):S200-10 (2003 Sep).
  2. Haider A, Shaw JC. Treatment of acne vulgaris. JAMA 292(6):726-35 (2004 Aug).
  3. Alexis AF. Clinical considerations on the use of concomitant therapy in the treatment of acne. J Dermatolog Treat 19(4):199-209 (Epub 2008 Jul 09).
  4. Tan JK. Topical acne therapy: current and advanced options for optimizing adherence. Skin Therapy Lett 4(2):1-3 (2009 Jul-Aug).
  5. Katsambas A, Dessinioti C. New and emerging treatments in dermatology: acne. Dermatol Ther 21(2):86-95 (2008 Mar-Apr).
  6. Seidler EM, Kimball AB. Meta-analysis of randomized controlled trials using 5% benzoyl peroxide and clindamycin versus 2.5% benzoyl peroxide and clindamycin topical treatments in acne. J Am Acad Dermatol (Epub 2011 Aug 06).
  7. Dutil M. Benzoyl peroxide: enhancing antibiotic efficacy in acne management. Skin Therapy Lett 15(10):5-7 (2010 Nov-Dec).
  8. Abdel-Naser MB, Zouboulis CC. Clindamycin phosphate/tretinoin gel formulation in the treatment of acne vulgaris. Expert Opin Pharmacother 9(16):2931-7 (2008 Nov).
  9. Leyden JJ, Krochmal L, Yaroshinsky A. Two randomized, double- blind, controlled trials of 2219 subjects to compare the combination clindamycin/ tretinoin hydrogel with each agent alone and vehicle for the treatment of acne vulgaris. J Am Acad Dermatol 54(1):73-81 (2006 Jan).
  10. Yentzer BA, Ade RA, Fountain JM, et al. Simplifying regimens promotes greater adherence and outcomes with topical acne medications: a randomized controlled trial. Cutis 86(2):103-8 (2010 Aug).
  11. Richter JR, Forstrom LR, Kiistala UO, et al. Efficacy of the fixed 1.2% clindamycin phosphate, 0.025% tretinoin gel formulation (Velac) and a proprietary 0.025% tretinoin gel formulation (Aberela) in the topical con- trol of facial acne. J Eur Acad Dermatol Venereol 11(3):227-33 (1998 Nov).
  12. Zouboulis CC, Derumeaux L, Decroix J, et al. A multicentre, single-blind, randomized comparison of a fixed clindamycin phosphate/tretinoin gel formulation (Velac) applied once daily and a clindamycin lotion formulation (Dalacin T) applied twice daily, in the topical treatment of acne vulgaris. Br J Dermatol 143(3):498-505 (2000 Sep).
  13. Feneran AN, Kaufman WS, Dabade TS, et al. Retinoid plus antimicrobial combination treatments for acne. Clin Cosmet Investig Dermatol 4:79-92 (Epub 2011 Jul 16).
  14. Del Rosso JQ, Jitpraphai W, Bhambri S, et al. Clindamycin phosphate 1.2%-tretinoin 0.025% gel: vehicle characteristics, stability, and tolerability. Cutis 81(5):405-8 (2008 May).
  15. Kircik LH, Peredo MI, Bucko AD, et al. Safety of a novel gel formulation of clindamycin phosphate 1.2%-tretinoin 0.025%: results from a 52-week openlabel study. Cutis 82(5):358-66 (2008 Nov).
  16. Tan JK. Adapalene 0.1% and benzoyl peroxide 2.5%: a novel combination for treatment of acne vulgaris. Skin Therapy Lett 14(6):4-5 (2009 Jul-Aug).
  17. Gollnick HP, Draelos Z, Glenn MJ, et al. Adapalene-benzoyl peroxide, a unique fixed-dose combination topical gel for the treatment of acne vulgaris: a transatlantic, randomized, double-blind, controlled study in 1670 patients. Br J Dermatol 161(5):1180-9 (2009 Nov).
  18. Gold LS, Tan J, Cruz-Santana A, et al. Adapalene-BPO Study Group. A North American study of adapalene-benzoyl peroxide combination gel in the treatment of acne. Cutis 84(2):110-6 (2009 Aug).
  19. Thiboutot DM, Weiss J, Bucko A, et al. Adapalene-benzoyl peroxide, a fixeddose combination for the treatment of acne vulgaris: results of a multicenter, randomized double-blind, controlled study. J Am Acad Dermatol 57(5):791-9 (2007 Nov).
  20. Poulin Y, Sanchez NP, Bucko A, et al. A 6-month maintenance therapy with adapalene-benzoyl peroxide gel prevents relapse and continuously improves efficacy among severe acne vulgaris patients: results of a randomized controlled trial. Br J Dermatol 164(6):1376-82 (2011 Jun).
  21. Pariser D, Westmoreland P, Morris A, et al. Long-term safety and efficacy of a unique fixed-dose combination gel of adapalene 0.1%. J Drugs Dermatol 6(9):899-905 (2007 Sep).
  22. Zaghloul SS, Cunliffe WJ, Goodfield MJ. Objective assessment of compliance with treatments in acne. Br J Dermatol 152(5):1015-21 (2005 May).

In this issue:

  1. Psoriasis and the Pregnant Woman: What are the Key Considerations?
  2. Newer Approaches in Topical Combination Therapy for Acne
  3. Update on Drugs and Drug News - October 2011