Interaction of Topical Sulfacetamide
`and Topical Dapsone With Benzoyl Peroxide
`
`Meghan I. Dubina, BS; Alan B. Fleischer Jr, MD
`
`Background: A recent study demonstrated evidence of
`a yellow-orange discoloration of the skin and hair when
`topical dapsone gel was combined with benzoyl perox-
`ide. This phenomenon had previously been observed by
`one of us (A.B.F.) when sulfasalazine was combined with
`benzoyl peroxide. To investigate these interaction phe-
`nomena, topical dapsone gel and sulfacetamide sodium lo-
`tion were combined with various topical acne treat-
`ments, including benzoyl peroxides, clindamycin
`phosphate, and retinoids. Arc h Dermato l. 2009; 145 (9): 102 7-1029
`
`Conclusions: Knowledge of the chemical reaction be-
`tween benzoyl peroxide and sulfacetamide and dapsone
`will help minimize the occurrence of this interaction on
`our patients’ skin.
`
`Observations: Products containing benzoyl peroxide
`produced an orange-brown discoloration when mixed
`with either sulfacetamide or dapsone.
`
`A CNE IS ONE OF THE MOST
`
`common reasons for visits
`to dermatologists in the
`United States.1 It is caused
`by abnormalities of the pi-
`losebaceous unit such as increased sebum
`production, bacterial overgrowth, hyper-
`keratinization, and inflammation.2 Corn-
`bination treatment of acne vulgaris is of-
`ten implemented to address each of these
`abnormalities. Treatment with multiple
`medications is more effective and works
`more quickly than treatment with single
`agents? Therefore, it is vital to under-
`stand possible reactions among topical acne
`medications to minimize adverse events and
`to maximize safety and efficacy,
`One such reaction is the oxidation and
`inactivation of tretinoin by benzoyl perox-
`ide. This reaction is accelerated when the
`medications are exposed to light.3,4 An-
`other reaction was discovered in a recent
`study that evaluated the efficacy of dap-
`sone gel, 5%, in combination with other
`topical acne medications? In that study, 7
`of 100 patients (7%) in the dapsone gel and
`benzoyl peroxide group noted a tempo-
`rary yellow to orange discoloration of the
`skin and/or facial hair after application of
`both medications 10 minutes apart. The dis-
`coloration lasted between 4 and 57 days,
`resolved after discontinuation of treat-
`ment, and caused 2 of the 7 patients to dis-
`continue the clinical trial? According to the
`authors, the patients also complained that
`the products stained their clothing and that
`the stains were difficult to remove. To our
`knowledge, this reaction has not been pre-
`viously reported in the literature. The phe-
`
`nomenon had previously been observed by
`one of us (A.B.F.) when sulfasalazine was
`combined with benzoyl peroxide.
`Dapsone gel (Figure ! A), a synthetic sul-
`fone, was recently approved by the Food and
`Drug Administration in a topical aqueous
`gel form to treat acne vulgaris.<r The anti-
`inflammatory and antimicrobial properties
`of dapsone have previously been imple-
`mented in an oral form to treat dermatitis
`herpetiformis, Hansendisease, and, morehis-
`torically, severe acne.s 10 Systemic dapsone
`is typically reserved for the treatment of se-
`verenodularacneduetoadose-dependent
`hematologic toxic reaction.n The topical
`form was developed with hopes ofminimiz-
`ing this adverse effect and of attaining effi-
`cacy in the treatment of acne vulgaris.
`Sulfacetamide sodium (Figure 1B), a sul-
`fonamide, demonstrates bacteriostatic ac-
`tivity against both gram-negative and gram-
`positive organisms. It competitively
`antagonizes para-aminobenzoic acid, caus-
`ing interference with bacterial DNA syn-
`thesis.12 Benzoyl peroxide (Figure 1C), an
`organic peroxide, is one of the most com-
`monly prescribed acne medications be-
`cause of its antibacterial, antikeratolytic, and
`comedolytic actions.13 It is converted to ben-
`zoic acid in the skin and primarily targets
`the pilosebaceous units.14 The bactericidal
`action of benzoyl peroxide against Propi-
`onibacterium aches is thought to involve the
`release of free-radical oxygen through the
`degradation of bacterial proteins and inter-
`action with microbial cell components.14
`The labile O-O bond is the source of these
`free radicals, which are the active interme-
`diary and the cause of many of benzoyl per-
`
`Author Affiliations:
`Department of Dermatology,
`Wake Forest University School
`of Medicine, Winston-Salem,
`North Carolina.
`
`(REPRINTED) ARCH DERMATOLIVOL 145 (NO. 9), SEP 2009
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`©2009 American Medical Association. All rights reserved.
`
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`

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`Figure 1. Chemical structures of dapsone, sulfacetamide sodium, and benzoyl
`peroxide. A, Dapsone, International Union for Pure and Applied Chemistry
`(IUPAC) name: 4,4’-sulfonylbisbenzenamine; molecular formula: 612H12N202S.
`B, Sulfaeetamide sodium, IUPAC name: N-aeetyl-4-aminobenzenesulfonamide
`sodium; molecular formula: CsHgN2NaO3S. C, Benzoyl peroxide, IUPAC name:
`dibenzoylperoxide; moleeularformula: 014H1004.
`
`oxide’s biologic effects.15,16 The effectiveness of benzoyl per-
`oxide can be enhanced if the molecule gains access to a
`tertiary amine for electron transfer. For example, when ben-
`zoyl peroxide is combined with antibiotics or antifungal
`agents containing tertiary amines, such as erythromycin,
`cfindamycin phosphate, terbinafine, and butenifine, thera-
`peutic results are improved.15,17,1s Detrimental effects can
`also result from the use of these free radicals. When ter-
`tiary amine-containing topical anesthetic agents were ap-
`plied to skin that was pretreated with benzoyl peroxide,
`the anesthetic effect diminished by 75%.19 The aims of this
`study were to further investigate the discoloration reac-
`tion between dapsone gel and benzoyl peroxide and to
`evaluate whether or not a similar reaction would occur with
`sulfacetamide and benzoyl peroxide,
`
`A half a pea-sized amount of sulfacetamide solution, 10%, was
`applied to 8 different sections of a white cotton dinner napkin,
`Then, another half a pea-sized amount of each of the following
`was added to the sulfacetamide and the ingredients were mixed
`together: creamy benzoyl peroxide wash, 8%; clindamycin, 1%,
`plus benzoyl peroxide gel, 5% (BenzaClin, gel 1); clindamycin,
`1%, plus benzoyl peroxide gel, 5% (Duac, gel 2); topical clinda-
`mycin gel, 1%; tretinoin gel, 0.05%; tazarotene cream, 0.1%; and
`adapalene gel, 0.3%. One of the sulfacetamide applications served
`as the control, as no additional product was mixed. The same ap-
`plication process was repeated with dapsone gel, 5%, mixing it
`with each of the additional topical medications and leaving 1 area
`of dapsone gel to serve as the control. Then, photography was
`performed at 30-minute intervals for 6 hours and at 12 hours,
`Finally, the napkin was washed and dried with a nonbleach de-
`
`tergent in a warm/cold cycle to determine whether the product
`residue was easily removable. All photographs are original, with-
`out color correction, but were taken in a room with natural and
`fluorescent lighting, which varied over the course of the day.
`
`In all groups containing sulfacetamide, including the con-
`trol, a faint orange ring was visible at 30 minutes and re-
`mained at 12 hours (Figu~ 2). A yellow tint was present
`in the sulfacetamide plus benzoyl peroxide group at 3 hours,
`followed by a similar yellow tint in both sulfacetamide plus
`benzoyl peroxide and clindamycin plus benzoyl peroxide
`groups at 4 hours. These yellow tints gradually developed
`into an orange-brown color by 12 hours. Aside from the
`faint orange ring, there was no color change in the sulfa-
`cetamide control or in the sulfacetamide plus clindamy-
`cin, sulfacetamide plus tretinoin, sulfacetamide plus taz-
`arotene, or sulfacetamide plus adapalene groups.
`In the groups containing dapsone gel, an orange change
`occurred in the dapsone gel plus benzoyl peroxide group
`at 1 hour, followed by both dapsone plus cfindamycin and
`dapsone plus benzoyl peroxide groups at around 2 hours.
`At 6 hours, these 3 groups were brown. A faint yellow color
`change was noted in the dapsone gel control, dapsone gel
`plus clindamycin, dapsone gel plus tretinoin, dapsone gel
`plus tazarotene, and dapsone gel plus adapalene groups
`at 5 hours; it persisted for 12 hours. After the napkin was
`washed and dried, no product remained in any of the
`groups containing sulfacetamide. In the dapsone gel-
`containing groups--the dapsone plus benzoyl peroxide and
`the 2 combination dapsone gel plus cfindamycin and ben-
`zoyl peroxide products--brown stains remained despite
`washing. Also, a pale-yellow residue was noticeable in all
`other dapsone gel-containing groups.
`
`All benzoyl peroxide products used in this study, includ-
`ing the benzoyl peroxide creamy wash, 8%, and 2 differ-
`ent cfindamycin, 1%, plus benzoyl peroxide gel, 5%, prod-
`ucts produced a discoloration reaction when mixed with
`either sulfacetamide or dapsone gel. Based on these re-
`suits, both sulfacetamide and dapsone gel share a similar
`reaction with benzoyl peroxide, although the exact chemi-
`cal reaction is unclear.
`Because topical medications are frequently used in com-
`bination for the treatment of acne, these results are useful
`in understanding the possible reactions caused by the use
`of various topical acne medications. In these cases, it would
`be beneficial to use the medications at different times of the
`day and to encourage patients to completely wash off the
`benzoyl peroxide before applying other topical agents. Edu-
`cating patients bywarning them about the discoloration and
`inactivation reactions may help stress adherence to the des-
`ignated treatment plan. Emphasizing the possibility of cloth-
`ing stains would also deter patients from drifting from the
`prescribed regimen. Dapsone alone, at least on cloth, can
`impart a slight color. Unlike cloth, skin does not appear to
`be discolored by dapsone gel monotherapy or by dapsone
`in combinationwith non-benzoyl peroxide-containing prod-
`
`(REPRINTED) ARCH DERMATOIJVOL 145 (NO. 9), SEP 2009
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`Correspondence: Alan B. Fleischer Jr, MD, Department
`of Dermatology, Wake Forest University School of Medi-
`cine, Medical Center Boulevard, Winston-Salem, NC
`27157-1071 (afleisch@wfubmc. edu).
`Author Contributions: Dr Fleischer had full access to all
`the data in the study and takes responsibility for the integ-
`rity of the data and the accuracy of the data analysis. Study
`concept and design: Fleischer. Acquisition of data: Dubina
`and Fleischer. Analysis and interpretation of data: Dubina
`and Fleischer. Drafting of the manuscript: Dubina and
`Fleischer. Critical revision of the manuscript for important
`intellectual content: Fleischer. Administrative, technical, or
`material support: Fleischer. Study supervision: Fleischer.
`Financial Disclosure: Dr Fleischer has served on the
`advisory board of Allergan, Amgen, Astellas, Galderma,
`GSK, and Stiefel; has served as a consultant to Astellas,
`Asubio, Combe, Galderma, Gerson Lehrman, Intendis,
`Kikaku America International, Merz, and Novartis Ser-
`entis; has been an investigator for 3M, Abbott, Amgen,
`Astellas, Asubio, Biogen, Dow, Centocor, Coria, Gal-
`derma, GSK, Genentech, Healthpoint, Intendis, Medicis,
`Novartis, Ortho-Neutrogena, Pfizer, and Stiefel; has
`been a member of the speaker bureau of Amgen, Astel-
`las, Galderma, Intendis, Medicis, Novartis, and Stiefel;
`and is now a consultant for Allergan Inc.
`
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`
`After washing
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`Figure 2. Photographs of sulfacetamide sodium and dapsone combined with
`different acne medications on a white cotton napkin at 0 minutes and at 2, 4,
`6, and 12 hours after application and after the napkin is washed,
`
`ucts.5 The colored precipitate that does occur on skin with
`benzoyl products is easily wiped away and does not stain
`skin. Dapsone gel has recently been marketed in the United
`States for the treatment ofacne, andsulfacetamideis already
`being prescribed. It is important for dermatologists and other
`physicians to understand the possible reactions when they
`are developing treatment plans for their patients,
`
`Accepted for Publication: February 1, 2009.
`
`dapsone gel, 5% for the treatment of acne vulgaris. Olin Pharmacokinet. 2007;
`~ 11. ThiboutotDM, WillmerJ, SharataH, HalderR, GarrettS. Pharmacokineticsof
`46(8) :697-712.
`12. Mandell GL, Bennett JE, Uolin R, eds. Mandell, Douglas, and Bennett’s Prin-
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`Inc; 2000.
`13. Burkhart CG, Burkhart ON. Antibacterial properties of benzoyl peroxide in aero-
`bic and anaerobic conditions. IntJDermatol. 2006;45(11):1373-1374.
`14. Akhavan A, Bershad S. Topical acne drugs: review of clinical properties, sys-
`temic exposure, and safety. Am J Olin Dermatol. 2003;4(7):473-492.
`15. Burkhart ON, Specht K, Neckers D. Synergistic activity of benzoyl peroxide and
`erythromycin. Skin PharmacolAppl Skin Physiol. 2000;13(5):292-296.
`16. Burkhart CG, Burkhart ON. Antibacterial properties of soluble benzoyl peroxide.
`lnt J Dermatol. 2008;47(3):301-302.
`17. Burkhart CG, Burkhart CN, Isham N. Synergistic antimicr0bial activity by c0m-
`bining an allylamine with benzoyl peroxide with expanded coverage against yeast
`and bacterial species. BrJDermatol. 2006;154(2):341-344.
`18. Burkhart CG, Burkhart ON. Treatment of acne vulgaris without antibiotics: ter-
`tiary amine-benzoyl peroxide combination vs. benzoyl peroxide alone (Proactiv
`Solution). IntJDermatol. 2007;46(1):89-93.
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`presence of benzoyl peroxide. OermatolSurg. 2005;31(11, pt 1):1479-1480.
`
`(REPRINTED) ARCH DERMATOL/VOL 145 (NO. 9), SEP 2009
`1029
`Downloaded from www.aacchdermatol.com at Allergaaa, on November 19, 2009
`©2009 American Medical Association. All rights reserved.
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`WWW.ARCHDERMATOL.COM
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