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`The Role of Dapsone Gel in the Acne
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`Armamentarium
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`The authors discuss how this agent’s dual anti-inflammatory and anti-microbial
`effects may make it a safe and effective multimodal monotherapy for acne. How-
`ever, they add, further studies are needed. Ache vulgaris, which is characterized by inflam-
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`matory and non-inflammatory lesions beginning during adolescence, is most often manifested on
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`the face and neck. Ache formation is multi-factorial, and includes: disordered keratinocyte desqua-
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`mation, sebum secretion, inflammation, and Propionibacterium aches. Most current treatments for
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`ache focus on limiting one or more of these factors.1 Many topical and oral ache treatments involve
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`anti-bacterial action, but problems arise when bacteria develop resistance, rendering treatment less
`effective. Benzoyl peroxide (BPO) is widely considered first-line topical antibacterial
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`treatment for ache, but it can cause irritation at high concentrations and bleaches clothing and/or
`hair. Topical and oral antibiotics are also common treatments for inflammation in ache,
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`but present a problem due to the aforementioned resistance. A newer therapy for ache is 50/0 dap-
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`sone gel, with initial studies indicating that it is both effective and safe; but further studies remain.
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`Dapsone Properties
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`Dapsone is a sulfone that has been used mainly as an oral medication for leprosy and less com-
`monly as a treatment for ache vulgaris. Although dapsone is classified as an antibiotic due to its
`inhibition of bacterial DNA synthesis, it is also an effective anti-inflammatory agent. Never-
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`theless, due to the concerning side effects that come along with ingestion of the drug (hematologic
`and hepatic issues), a topical formulation has been produced. Blood dapsone levels following topi-
`cal dapsone gel treatment at steady state was demonstrated to be approximately loo-fold
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`lower than exposure to a single loo-mg dose of orally administered dapsone.2 In 2005, the FDA
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`approved dapsone for ache patients under the condition that they test negative for G6PD deficiency;
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`however, following a phase IV trial, the FDA removed this restriction, improving feasibility. Dap-
`sone’s dual anti-inflammatory and anti-microbial effects may offer physicians a novel
`muRimodal monotherapy for targeting acne. Aczone, the trade name for 50/0 dapsone gel, is
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`marketed by Allergan and is available to prescribers and their patients.
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`Dapsone Efficacy
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`Clinical trials have demonstrated reductions in acne lesions with 50/0 dapsone gel use, particularly
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`for inflammatory lesions. One such study enrolled 506 patients older than 12 years of age with a
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`Almirall EXHIBIT 2041
`Amneal v. Almirall
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`The Role of Dapsone Gel in the Acne Armamentarium I The Dermatologist
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`clinical diagnosis of moderate to moderately severe acne vulgaris.1 Patients applied treatment twice
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`daily to affected areas. The clinical trial lasted 12 months. There was a 58.2% decrease in inflam-
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`matory lesions, a 19.50/0 reduction in non-inflammatory lesions, and a total lesion reduction of 490/0
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`(P values all below o.o5). Acne lesion counts decreased over the first 6 months, then leveled out
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`over the next 6 months. Of note, almost 2o0/0 of the participants used prohibited acne medications
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`in addition to twice daily dapsone gel. Another study assessed the efficacy of 5% daspone gel in
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`treating acne vulgaris using global acne assessment score (GAAS) and mean lesion count reductions.
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`Two similar 12-week studies of 3,olo patients were combined to generate the data.3 In the first
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`study, 440/0 of the experimental group (vs. 360/0 of the control group) achieved success using the
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`GAAS scale. In the second study, 370/0 of the experimental group (vs. 3o0/0 of the control group)
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`achieved success using this scale. Combined, 4o0/0 had success with dapsone gel, and 33% had suc-
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`cess in the control group (P <o.ool). In comparing the mean lesion counts, the dapsone group
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`demonstrated greater reductions in inflammatory (48% vs. 420/0), non-inflammatory (320/0 vs.
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`240/0), and total lesion counts (39% vs. 320/0) compared to the control group. Like the previous
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`study, dapsone was more effective in reducing inflammatory lesions than in reducing noninflamma-
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`tory lesions. As early as week 2, a small difference could be seen between control and experimental
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`groups, and this difference grew to statistical significance by week 8. To put this data in perspec-
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`tive, we compared the results from the three large clinical trials to those seen with other commonly
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`used acne treatments. Table 1 - which focuses on inflammatory lesion reduction -- displays results
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`from the clinical trials involving dapsone gel, as well as those from selected trials of other acne
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`preparations. Although we found trials testing the efficacy of other topical gels -- as opposed to
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`creams, lotions, solutions, etc.-- it is impossible to make a clear comparison, as gel formulations can
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`contain a wide variety of ingredients. Thus, the relative efficacy (found by subtracting lesion reduc-
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`tion percentage in the vehicle group from that of the drug treatment group) may not be comparable
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`between treatments.4 As stated above, although the listed trials are each quite different in charac-
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`ter, dapsone gel appears to be similarly effective in reducing inflammatory acne lesions to benzoyl
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`peroxide, topical retinoids, topical antibiotics and oral antibiotics. Its relative efficacy, which
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`appears somewhat lower than other agents, is questionable, as the gel formulations themselves may
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`be promote or inhibit acne formation.4 Furthermore, other confounding variables, including study
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`design and study population, may be responsible for this finding, and further head-to-head compar-
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`ative trials are called for. In the meantime, dapsone may serve an important function in those who
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`develop intolerance to the currently established acne agents or are unable to use them secondary to
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`side effects.
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`Dapsone Tolerability
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`The primary tolerability concern with dapsone is hematological reactions. Patients with glu-
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`cose-6-phosphate dehydrogenase (G6PD) deficiency in particular are at increased risk of hemolysis
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`and hemoglobin denaturation with oral dapsone. These worries led the FDA to initially condition
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`topical dapsone approval on mandatory G6PD deficiency screening. However, the aforementioned
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`The Role of Dapsone Gel in the Acne Armamentarium I The Dermatologist
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`trials of dapsone gel indicated that patients are not at increased risk of hemolytic anemia,
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`methemogoblinemia, or drops in hemoglobin levels, including those with G6PD deficiency.3 Fur-
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`thermore, a 12-week study examining 64 patients with G6PD deficiency (14 were severely deficient)
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`using twice daily 50/0 dapsone gel found a clinically insignificant 0.32 g/dL decrease in Hb level 2
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`weeks after beginning therapy, which was no longer observed at 12 weeks of treatment,s Addition-
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`ally, no relationships were found between changes in Hb level and bilirubin, haptoglobin, LDH lev-
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`els and relative reticulocyte count, arguing against clinically relevant hemolysis. Finally, no clinical
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`signs of hemolytic anemia were observed in subjects applying the dapsone gel. There are local side
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`effects associated with 50/0 dapsone gel. The most common local adverse reactions are oiliness, dry-
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`ness and erythema -- each in nearly 2o0/0 of the patients.3 A much smaller proportion (20/0 or less)
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`of the participants reported burning, pruritus, and irritation at the application site. However, it is
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`important to note that these adverse reactions were reported at comparable rates in the control
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`group, which received vehicle gel treatment. Thus, adverse reactions are probably attributable to
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`the gel vehicle rather than dapsone.
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`Limitations -- Studies Needed (Table 2)
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`Due to the fact that dapsone was only recently approved for use in ache treatment, there remains a
`lack of studies on the bacterial resistance caused by dapsone gel. Oral dapsone used in
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`leprosy does result in resistance and must be given in combination with other drugs.6 What remains
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`to be seen is whether dapsone gel will cause similar resistant strains in ache vulgaris. Such studies
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`have been performed in the past with other ache treatments.7 Another study that could help put
`dapsone’s efficacy into better perspective would be a controlled head-to-head clinical trial
`comparing different acne treatments, including BPO, tetracycline agents, clindamycin, eryth-
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`romycin and topical retinoids, to dapsone gel. Such a study would help clinicians determine which
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`drug is best under a given circumstance, as well as where dapsone fits in the plethora of effective
`ache agents (Figure 1). In comparing other topical treatments with dapsone gel, we must realize
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`that ache treatment vehicles are not placebos, oftentimes exhibiting considerable activity.4 In order
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`to appropriately compare topical ache agents to each other, it would be prudent to use the same
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`vehicle (ie, other topical gels of the same formulation). In this regard, we must also examine the
`interactions of different drugs, both oral and topical, with dapsone, and how they can
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`work with or against each other. Such a study would make it possible to understand dapsone combi-
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`nations are effective and/or safe and which are not. We are most interested to see if dapsone, in
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`combination with other agents, improves efficacy, or if dapsone deactivates or is deactivated by
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`another agent. Furthermore, data are also needed on the effect of combination use on side effects.
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`Michael Ghods is a medical student at the University of California at Davis, School of Medicine, Sacra-
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`mento, CA.
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`Dr. Alikhan is a medical resident at MacNeal Hospital in Berwyn, IL.
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`Dr. Feldman is with the Departments of Dermatology, Pathology, and Public Health Sciences; Wake
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`Forest University School of Medicine; Winston-Salem, NC.
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`Disclosures: Michael Ghods and Drs. Alikhan and Feldman have no conflict of interest with any mate-
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`rial presented in this month’s column.
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