DRUG THERAPY TOPICS
`
`Newer Topical Therapies for the
`Treatment of Acne Vulgaris
`
`James Q. Del Rosso, DO
`
`Newer topical therapies approved by the US Food
`and Drug Administration (FDA) for the treatment of
`acne vulgaris are dapsone gel 5% and clindamy-
`cin phosphate 1.2% and tretinoin 0.025% combi-
`nation gel. Both are formulated in aqueous-based
`gel vehicles. These newer topical acne products
`have been shown to be effective and safe in piv-
`otal 12-week phase 3 trials and long-term studies
`completed over 12 months. This article reviews
`applicable pharmacokinetic, efficacy, and safety
`data reported with both products.
`Cutis. 2007;80:400-410.
`
`T opical therapy is a vital component in the
`
`management of acne vulgaris, regardless of the
`severity of disease.1 In most situations, with
`the exception of mild cases presenting with pre-
`dominantly noninflammatory acne lesions, combina-
`tion topical therapy is considered to be the optimal
`approach. Systemic treatment, such as oral antibiotic
`therapy, is added to a topical treatment program in
`patients presenting with moderately severe to severe
`involvement or when there is a less than favorable
`response to topical treatment alone.1,2 Although
`complete clearance of acne vulgaris is an unrealistic
`expectation in all patients, a properly designed acne
`treatment program that is used consistently can usu-
`ally achieve marked success if tailored to the severity
`of the disease and the specific needs of the patient.
`Two new topical therapies have been approved
`by the US Food and Drug Administration (FDA)
`Accepted for publication September 5, 2007.
`From the dermatology residency program, Valley Hospital
`Medical Center, Las Vegas, Nevada.
`Dr. Del Rosso is a consultant, researcher, and speaker for
`Coria Laboratories, Ltd; Galderma Laboratories, LP; Medicis
`Pharmaceutical Corporation; OrthoNeutrogena; QLT Inc;
`Ranbaxy Pharmaceuticals Inc; SkinMedica; Stiefel
`Laboratories, Inc; and Warner Chilcott.
`Reprints not available from the author.
`
`400 CUTIS®
`
`for the treatment of acne vulgaris. The first is
`dapsone gel 5%, which is formulated in an aqueous
`gel base and approved for twice-daily application.
`The second is a combination aqueous gel formulation
`containing solubilized clindamycin phosphate 1.2%
`and solubilized and crystalline tretinoin 0.025%.
`At present, dapsone gel 5% is not available in
`the marketplace because the manufacturer has
`elected to await FDA evaluation of data on use
`in a cohort of patients with documented glucose
`6-phosphate dehydrogenase (G6PD) deficiency.
`
`DAPSONE GEL 5%
`What information supports the use of topical
`dapsone for the treatment of acne vulgaris?
`Dapsone is a sulfone derivative that has been
`used orally for the treatment of leprosy and sev-
`eral inflammatory dermatoses, including dermatitis
`herpetiformis, pyoderma gangrenosum, bullous lupus
`erythematosus, linear immunoglobulin A dermatosis,
`and bullous pemphigoid.3-5 Dapsone exhibits multiple
`anti-inflammatory activities that support the diversity
`of its applications, primarily including neutrophilic
`dermatoses. Biologic activities observed in some
`reports with dapsone include inhibition of neutrophil
`and eosinophil myeloperoxidase, inhibition of neu-
`trophil adhesion to vascular endothelium, inhibition
`of 5-lipogenase product generation by neutrophils
`and macrophages, suppression of neutrophil recruit-
`ment and migration, and release of lysosomal enzymes
`by neutrophils.3,4
`Prior to the introduction of oral isotretinoin in
`the early 1980s, oral dapsone was used when con-
`ventional topical and systemic antibiotic therapies
`proved to be unsuccessful in patients with severe,
`refractory, inflammatory acne vulgaris. However,
`the use of oral dapsone was limited by the poten-
`tial for serious complications, including hemolytic
`anemia, especially in patients with G6PD defi-
`ciency; methemoglobinemia; agranulocytosis; drug
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`Almirall EXHIBIT 2013
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`Amneal v. Almirall
`IPR2019-00207
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`Drug Therapy Topics
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`Single 100-mg oral dose
`After 15 days of dapsone gel 5%
`
`1200
`
`800
`
`400
`
`40
`30
`20
`10
`0
`
`Concentration, ng/mL
`
`Mean Peak Plasma Dapsone
`
`0
`
`4
`
`8
`
`12
`Hours
`
`16
`
`20
`
`24
`
`Figure 1. Pharmacokinetics of topical application of dapsone gel 5% over 14 days versus a single 100-mg dose of
`oral dapsone. Data from Thiboutot et al.6
`
`hypersensitivity syndrome; and distal motor neu-
`ropathy.3 Additional factors complicating the use of
`oral dapsone for the treatment of acne vulgaris are
`the chronic nature of the disease, which necessitates
`long-term or repeated use of oral dapsone in many
`cases, and the likely concern about side effects from
`parents and/or guardians of patients 18 years and
`younger who commonly present with severe acne
`vulgaris and need treatment.
`Topical dapsone 5%, formulated in an aqueous-
`based gel vehicle, has been developed for treatment
`of acne vulgaris based on the objective of reducing
`acne lesions through anti-inflammatory activities of
`the drug, while circumventing toxicities associated
`with systemic dapsone use. Short-term and long-
`term pharmacokinetic analyses, pivotal phase 3 and
`combination therapy studies, and safety evaluations
`support the use of dapsone gel 5% in patients with
`facial acne vulgaris.6-9 In the 2 pivotal multicenter,
`randomized, double-blind, vehicle-controlled,
`12-week phase 3 trials, inclusive of 3010 subjects,
`1506 subjects were actively treated topically with
`dapsone gel 5% twice daily.7 A randomized, double-
`blind, 12-week topical combination therapy study
`examined the use of dapsone gel 5% concomi-
`tantly with benzoyl peroxide 4% (n(cid:21)98), adapalene
`gel 0.1% (n(cid:21)100), or vehicle gel (n(cid:21)103) for the
`
`treatment of acne vulgaris.8 Evaluation of the tri-
`als completed with dapsone gel 5% to date has
`established efficacy, favorable skin tolerability, and
`safety, with no evidence of clinically relevant hema-
`tologic or systemic abnormalities and no reports of
`hemolytic anemia.
`
`What have the pharmacokinetic studies completed
`with dapsone gel 5% demonstrated?
`The potential toxicity concerns related to oral
`dapsone use underscored the need for comple-
`tion of careful pharmacokinetic and safety
`analysis with dapsone gel 5% applied twice
`daily. Systemic bioavailability after applica-
`tion of dapsone gel 5% has been evaluated in
`14-day (N(cid:21)18) and 52-week (N(cid:21)340) phar-
`macokinetic studies.6 The mean peak plasma
`dapsone concentration achieved after administra-
`tion of a single 100-mg dose of oral dapsone was
`1375 ng/mL. After topical application of dap-
`sone gel 5%, the mean peak plasma dapsone
`level through day 14 was 19.7 ng/mL (Figure 1).6
`In
`a
`long-term
`safety
`study, 368
`and
`340 actively treated subjects were followed for
`6 months and 12 months, respectively. Contin-
`ued twice-daily application of dapsone gel 5%
`
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`Table 1.
`Success Rate at Week 12*†‡
`
`Study DAP0203
`Dapsone Vehicle
`Gel 5%
`Gel
`44.2
`35.9
`
`Study DAP0204
`Dapsone
`Vehicle
`Gel 5%
`Gel
`36.9
`29.8
`
`Pooled Analysis
`Dapsone
`Vehicle
`Gel 5%
`Gel
`40.5
`32.8
`
`
`
`
`Subjects
`achieving
`GAAS
`success, %
`
`*GAAS indicates Global Acne Assessment Score.
`†Success measured as none or minimal.
`‡Study DAP0203, P(cid:12).001; study DAP0204, P(cid:21).002; pooled analysis, P(cid:12).001.
`
`Data from Draelos et al.7
`
`over 12 months revealed levels ranging from
`7.4 to 11.3 ng/mL, with no increases in plasma
`dapsone concentrations observed over time.6
`Additionally, use of dapsone gel 5% twice daily
`in combination with either benzoyl perox-
`ide 4% once daily or adapalene gel 0.1% once
`daily did not alter the pharmacokinetic profile
`of dapsone as evidenced by measurements of
`plasma concentrations obtained in the dapsone
`gel 5% monotherapy arms and the combination
`therapy groups.7,8
`Based on available pharmacokinetic data, dap-
`sone is minimally absorbed after topical applica-
`tion of the 5% aqueous gel. Systemic dapsone
`exposure is very minimal after repeated topical
`application ((cid:12)1% of the applied dose). Plasma
`dapsone concentrations did not accumulate over
`time with repeated twice-daily applications over
`12 months.6 Continued topical administration of
`dapsone gel 5% produced minimal systemic expo-
`sure with plasma dapsone concentrations remain-
`ing more than 100-fold lower than the mean peak
`plasma dapsone concentration obtained after a sin-
`gle 100-mg oral dose of dapsone. Additionally, in
`the 12-month study, safety analyses demonstrated
`no reports of hemolysis or methemoglobinemia and
`no clinically significant changes in hemoglobin or
`hematocrit values over the duration of the trial.6
`
`What is the efficacy of dapsone gel 5% for
`acne vulgaris?
`In the 2 pivotal phase 3 trials for acne vul-
`garis, pooled results revealed that 3010 subjects
`
`402 CUTIS®
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`(12 years or older) were randomized to use dapsone
`gel 5% (n(cid:21)1506) or vehicle gel (n(cid:21)1504) applied
`twice daily for 12 weeks.7 The gender distribution
`was approximately equal with slightly more than
`50% of subjects being female. Approximately one
`fourth of subjects in both the active and vehicle
`arms were black, Hispanic, Asian, or other. With
`regard to disease severity, approximately 60% and
`33% of subjects in both study arms presented with
`moderate and mild facial acne vulgaris, respec-
`tively. At baseline, a mean of 30.8 and 30.3 inflam-
`matory lesions and 48.2 and 47.8 noninflammatory
`lesions were noted in the dapsone gel–treated
`and vehicle gel–treated study groups, respectively.
`Efficacy parameters included evaluations based
`on investigator static global assessment of none
`or minimal acne at week 12, with results depicted
`in Table 1. The results of percentage reduction of
`inflammatory, noninflammatory, and total lesion
`counts at week 12 compared with baseline are
`reported in Figure 2. Dapsone gel 5% proved
`to be superior to vehicle, both clinically and
`statistically, regardless of the efficacy parameter
`evaluated. Statistically significant greater lesion
`reductions were observed in the dapsone-treated
`subjects compared with the vehicle-treated sub-
`jects and were noted as early as 4 weeks (P(cid:21).008),
`6 weeks (P(cid:21).007), and 8 weeks (P(cid:21).003) for
`inflammatory,
`total,
`and noninflammatory
`lesions, respectively.7
`A subset analysis evaluated the efficacy and safety
`of dapsone gel 5% in adolescents aged 12 to 15 years
`(n(cid:21)176) for up to 12 months, based on the 2 pivotal
`phase 3 trials and a long-term safety study.9 Efficacy
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`Dapsone gel 5% Vehicle control
`
`P(cid:1).0001
`48
`
`40
`
`P(cid:1).0001
`
`P(cid:1).0001
`
`37
`
`29
`
`30
`
`21
`
`50
`45
`40
`35
`30
`25
`20
`15
`10
`
`Total
`Lesions
`
`B
`
`5 0
`
`Infla m m atory
`Lesions
`
`Noninfla m m atory
`Lesions
`
`Reduction in Lesion Count, %
`
`P(cid:2).0302
`
`P(cid:2).0022
`
`P(cid:2).0004
`
`46
`
`42
`
`38
`
`32
`
`31
`
`24
`
`50
`45
`40
`35
`30
`25
`20
`15
`10
`
`Total
`Lesions
`
`A
`
`5 0
`
`Infla m m atory
`Noninfla m m atory
`Lesions
`Lesions
`
`Reduction in Lesion Count, %
`
`Figure 2. Dapsone gel 5% lesion count reductions from 2 pivotal phase 3 trials (study 1, A; study 2, B). Percentage
`lesion count reductions at week 12. Data from Draelos et al.7
`
`Table 2.
`Use of Dapsone Gel 5% in Adolescents With Facial Acne Vulgaris
`(Efficacy Subset Analysis; Mean Percentage Lesion Reduction)
`
`Pivotal Studies
`Dapsone Gel 5%
`Vehicle Gel 5%
`(n(cid:21)569)
`(n(cid:21)544)
`32.0
`31.9
`
`
`P Value
`
`
`Long-term Study*
`Dapsone Gel 5%
`(n(cid:21)176)
`34.5
`
`36.8
`
`15.8
`
`.0006
`
`43.6
`
`.0001
`
`
`
`Efficacy Measure
`Baseline mean
`lesion count
`
`Mean inflammatory
`lesion reduction, %
`
`44.9
`
`Mean noninflammatory 26.9
`lesion reduction, %
`
`*Noninflammatory lesions were not components of entry criteria in the long-term study.
`
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`N(cid:1)301 male or
`female subjects,
`≥12 years of age,
`with facial
`acne vulgaris
`
`n(cid:1)103
`Dapsone gel 5% BID and vehicle daily
`
`n(cid:1)100
`Dapsone gel 5% BID and adapalene gel 0.1% daily
`
`n(cid:1)98
`Dapsone gel 5% BID and benzoyl peroxide 4% daily
`
`Baseline (Day 0)
`W eek 2 Visit
`W eek 4 Visit
`
`W eek 8 Visit
`
`Early Termination
`W eek 12 /
`
`Figure 3. Dapsone gel 5% used in combination with benzoyl peroxide 4%, adapalene gel 0.1%, or vehicle gel for the
`treatment of facial acne vulgaris. BID indicates twice daily. Data from Fleischer et al.8
`
`results from this subset analysis are tabulated in
`Table 2. The conclusion, based on the evaluation of
`efficacy and safety data, was that dapsone gel 5% is
`effective, safe, and well-tolerated.9
`
`What combination therapy data exist with dapsone
`gel 5% for the treatment of acne vulgaris?
`As topical treatment for acne vulgaris commonly
`employs a combination therapy approach, dapsone
`gel 5% twice daily was studied in patients with facial
`acne vulgaris who also were treated with either
`benzoyl peroxide 4% once daily, adapalene gel 0.1%
`once daily, or vehicle gel once daily (dapsone
`monotherapy arm) in a double-blind random-
`ized trial. At study entry, most subjects presented
`with a severity rating of moderate, with baseline
`lesion count characteristics very similar to those
`described above for subjects included in the pivotal
`phase 3 trials.8
`Figure 3 describes the design of this combi-
`nation therapy trial. Efficacy data reported as
`mean percentage reduction in total lesion counts
`are depicted in Table 3, with similar treatment
`responses also observed with inflammatory and
`noninflammatory lesion counts.8 Importantly,
`the efficacy results noted with dapsone gel 5%
`
`404 CUTIS®
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`twice daily used in combination with a vehicle
`gel once daily (essentially reflecting the mono-
`therapy response achieved with topical dapsone)
`were consistent with those observed in subjects
`treated with dapsone gel 5% in the pivotal
`phase 3 studies.7,8
`
`What is the skin tolerability and safety of dapsone
`gel 5% based on available clinical trials?
`Based on clinical studies of more than 2000 sub-
`jects with facial acne vulgaris who were actively
`treated with dapsone gel 5%, skin tolerability
`proved to be favorable.6-9 In these trials, dap-
`sone gel 5% was predominantly used as mono-
`therapy; however, a study of combination use
`with either benzoyl peroxide 4% or adapalene
`gel 0.1% also included tolerability and safety
`assessments.8 The fact that dapsone gel 5% was
`well-tolerated overall may relate to its formulation
`as an aqueous-based gel devoid of ethanol or other
`astringent-type alcohols. Dermal safety studies
`of dapsone gel 5% completed in 385 subjects
`demonstrated no evidence of photoallergy, photo-
`toxicity, or contact hypersensitivity.10
`In the 2 pivotal phase 3 trials, all subjects were
`instructed to use a designated noncomedogenic
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`Table 3.
`Topical Dapsone Combination Therapy Study (Mean Percentage Reduction in
`Total Lesion Counts From Baseline to Week 12)*†‡
`
`Treatment Group
`
`Dapsone Gel 5% (cid:17) Dapsone Gel 5% (cid:17)
`
`Vehicle
`Adapalene Gel 0.1%
`Efficacy
`(n(cid:21)103)
`(n(cid:21)100)
`Measurement
`84.7(cid:22)35.4
`81.4(cid:22)43.4
`Baseline, mean(cid:22)SD
`Mean lesion reduction, % 39.3
`50.6
`
`*Dapsone gel 5% (cid:17) vehicle vs dapsone gel 5% (cid:17) adapalene gel 0.1%; P(cid:21).0041.
`†Dapsone gel 5% (cid:17) vehicle vs dapsone gel 5% (cid:17) benzoyl peroxide 4%; P(cid:21).0564.
`‡Dapsone gel 5% (cid:17) adapalene gel 0.1% vs dapsone gel 5% (cid:17) benzoyl peroxide 4%; P(cid:21).6198.
`
`Data from Fleischer et al.8
`
`Dapsone Gel 5% (cid:17)
`Benzoyl Peroxide 4%
`(n(cid:21)98)
`82.2(cid:22)38.7
`46.4
`
`soap-free liquid cleanser.7 The most commonly
`observed application-site reactions associated
`with use of dapsone gel 5% were erythema and
`dryness.7,9 Based on the 2 pivotal phase 3 trial
`results, erythema and dryness were reported in
`16.3% and 20.0% of dapsone-treated subjects and
`in 16.1% and 18.9% of vehicle-treated subjects,
`respectively, with similar results observed in the
`subset analysis of adolescent subjects.7,9All sub-
`jects were monitored for adverse events at each
`study visit, including specifically being queried
`regarding application-site reactions, with the
`events tabulated irrespective of whether or not
`they were judged by the investigator to be related
`to study medication.7,9 It is important to note
`when analyzing facial skin tolerability results
`that subjects included in the 2 pivotal phase 3
`trials were assessed at baseline regarding signs
`and symptoms, including dryness, erythema, and
`peeling. The baseline evaluations documented
`the presence of erythema, dryness, and peeling in
`14.8%, 2.7%, and 1.3% of subjects, respectively,
`prior to initiation of study drug.7
`Long-term safety analysis demonstrated an
`application-site reaction rate of less than 3.1%.6
`Application-site symptoms such as burning and
`pruritus have been reported in less than 2% of study
`subjects as determined by both spontaneous report-
`ing and elicited responses.6,7
`Clinical and
`laboratory evaluations were
`included in the 2 pivotal phase 3 trials and
`long-term safety study with dapsone gel 5%. In
`
`multiple studies completed with dapsone gel 5%
`to date, there have been no reports of major
`adverse events associated with the use of topi-
`cal dapsone, such as hemolytic anemia, methe-
`moglobinemia, or agranulocytosis, even among
`19 dapsone-treated subjects with documented
`G6PD deficiency.6,7,9 Also, no major safety con-
`cerns emerged during the combination therapy
`trial, and study discontinuations were uncommon,
`with only one subject discontinuing treatment
`because of lack of efficacy.8
`Short-term and long-term pharmacokinetic
`data, including studies of twice-daily application
`of dapsone gel 5% as monotherapy or in combina-
`tion with other topical acne therapies, coupled
`with clinical and laboratory evidence from large
`controlled studies, support that dapsone gel 5%
`is not associated with a risk of systemic tox-
`icities that are sometimes observed with oral
`dapsone therapy.6-9
`
`CLINDAMYCIN PHOSPHATE 1.2% AND
`TRETINOIN 0.025% COMBINATION GEL
`What is clindamycin phosphate 1.2% and
`tretinoin 0.025% combination gel?
`Clindamycin phosphate 1.2% and tretinoin 0.025%
`combination gel is a dual-component combina-
`tion topical formulation.11 This aqueous gel
`contains tretinoin 0.025% that is both solu-
`bilized and crystalline in suspension, in com-
`bination with clindamycin phosphate 1.2%
`in solution. It has been evaluated in several
`
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`Table not
`available online
`
`trials, including three 12-week phase 3 trials and
`a 52-week study. Collectively, 4550 patients were
`enrolled in phase 3 studies that included subjects
`aged 12 years and older with mild, moderate, and
`severe facial acne vulgaris.11-13 The clindamycin
`phosphate 1.2% and tretinoin 0.025% combi-
`nation gel proved superior in efficacy to either
`active component alone and to vehicle, regard-
`less of acne severity.11,13
`
`What is unique about the clindamycin
`phosphate 1.2% and tretinoin 0.025%
`combination gel formulation?
`Unique characteristics of the clindamycin phos-
`phate 1.2% and tretinoin 0.025% patented
`combination formulation are the usage and stabili-
`zation of both solubilized and crystalline tretinoin
`in suspension, the stringent control of tretinoin
`particle sizes, and the use of an aqueous-based
`gel vehicle that also contains clindamycin phos-
`phate in solution.11,14 The ability of the vehicle to
`
`406 CUTIS®
`
`maintain tretinoin stability is believed to allow for
`slow release of the active ingredient.11
`
`What is the efficacy of clindamycin
`phosphate 1.2% and tretinoin 0.025%
`combination gel in the treatment of acne vulgaris?
`In order
`to properly evaluate
`the efficacy
`of the clindamycin phosphate 1.2% and treti-
`noin 0.025% combination gel, this combina-
`tion formulation (n(cid:21)845) applied once daily was
`compared with once-daily monotherapy with treti-
`noin 0.025% aqueous gel (n(cid:21)846), clindamycin
`phosphate 1.2% aqueous gel (n(cid:21)426), and vehicle
`aqueous gel (n(cid:21)423).11,13 The identically designed,
`multicenter, randomized, double-blind, active-
`controlled and vehicle-controlled, parallel-group
`phase 3 studies evaluated treatment response in
`subjects older than 12 years with facial acne vul-
`garis. As mentioned above, the clindamycin phos-
`phate 1.2% and tretinoin 0.025% combination
`gel proved superior in efficacy to either active
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`48
`
`42
`
`39
`
`Clin/Tret gel (n(cid:1)845)
`Clindamycin (n(cid:1)426)
`Tretinoin (n(cid:1)846)
`Vehicle (n(cid:1)423)
`
`36
`
`31
`
`27
`
`26
`
`41
`
`34 34
`
`16
`
`20
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Mean Reduction From Baseline, %
`
`Inflammatory
`Lesions
`
`Noninflammatory
`Lesions
`
`Total
`Lesions
`
`Figure 4. Mean percentage lesion reduction from 2 pivotal 12-week phase 3 trials (pooled data). Clin/Tret indicates
`clindamycin phosphate 1.2% and tretinoin 0.025% combination gel. Data from Schlessinger et al.11
`
`component alone and to vehicle, regardless of
`acne severity, and was shown to be effective in
`reducing both inflammatory and noninflammatory
`acne lesions.11,13 The pooled demographic data
`from subjects enrolled in 2 pivotal phase 3 tri-
`als are tabulated in Table 4, with efficacy data
`reported as mean percentage inflammatory, non-
`inflammatory, and total lesion reductions depicted
`in Figure 4.11
`In a third 12-week phase 3 trial, the efficacy and
`safety of clindamycin phosphate 1.2% and treti-
`noin 0.025% combination gel applied once daily
`(n(cid:21)1088) was compared with clindamycin phos-
`phate 1.2% aqueous gel applied once daily
`(n(cid:21)1002) in subjects with facial acne vulgaris.11
`The demographic data from subjects included in
`this trial were very similar to the data depicted in
`Table 4. At week 12, clindamycin phosphate 1.2%
`and tretinoin 0.025% combination gel was superior
`to monotherapy with topical clindamycin in all
`efficacy parameters. Mean percentage reductions
`in inflammatory, noninflammatory, and total lesion
`counts were 61%, 50%, and 54%, respectively, in
`the combination gel–treated subjects, versus 45%,
`41%, and 47%, respectively, in the clindamycin-
`treated subjects. The differences between groups
`were statistically significant for mean percentage
`
`reduction in inflammatory, noninflammatory, and
`total lesions (P(cid:12).001 for all).11
`
`Did subset analysis of trials evaluating
`clindamycin phosphate 1.2% and
`tretinoin 0.025% combination gel reveal
`any clinically relevant information?
`An unprecedented acne study subset analysis
`derived from 2 pivotal 12-week phase 3 trials
`evaluated acne flares, defined as a 20% or more
`increase in inflammatory lesions, after 2 weeks
`of application of study medication.11,15 The data
`from this subset analysis are tabulated in Figure 5,
`with differentiation based on acne severity rating
`at baseline. Overall, the percentage of subjects
`exhibiting a 20% or more increase in inflam-
`matory acne lesions within the first 2 weeks of
`the study was highest in the tretinoin 0.025%
`aqueous gel and vehicle aqueous gel study
`arms.11 Subjects treated with the clindamycin
`phosphate 1.2% and tretinoin 0.025% combina-
`tion gel exhibited a 30% to 60% lower rate of
`increase in inflammatory acne lesions, which
`was comparable to the rate observed in subjects
`treated with the clindamycin phosphate 1.2%
`aqueous gel alone.11,15
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`
`Figure not
`available online
`
`Figure 5. Subjects with acne flares (20% or more increase in inflammatory lesions) after 2 weeks of application of study
`medication. Clin/Tret indicates clindamycin phosphate 1.2% and tretinoin 0.025% combination gel. Adapted with permis-
`sion from Schlessinger et al.11
`
`It is important to consider that the 20% or
`more increase in inflammatory acne lesions after
`2 weeks of study treatment may actually reflect
`natural disease progression of acne in many of
`these subjects as opposed to a true acne flare.
`Acne lesion counts at baseline are collected
`after defined washout periods from previous acne
`therapies and in subjects who often present with
`acne that is poorly controlled by prior treatments.
`Additionally, enrolled subjects present with an
`acne severity rating that makes them eligible for
`study inclusion based on stringent criteria. It would
`not be unexpected for acne lesions to increase in
`number during the first 2 weeks of a study, at least
`in some subjects, as the onset of activity of study
`medication may not be operative within that ini-
`tial short time frame, thus reflecting natural acne
`progression rather than an actual flare related to
`the study drug itself. Nevertheless, regardless of
`acne severity at baseline, once-daily application of
`clindamycin phosphate 1.2% and tretinoin 0.025%
`combination gel was associated with a markedly
`lower percentage of subjects demonstrating a 20%
`or more increase in inflammatory lesions over
`
`408 CUTIS®
`
`the first 2 weeks of therapy compared with treti-
`noin 0.025% aqueous gel or vehicle aqueous gel. In
`subjects presenting with facial acne vulgaris rated
`at baseline as mild or moderate in severity, the
`percentage of acne flares was approximately two-
`fold lower in the clindamycin phosphate 1.2% and
`tretinoin 0.025% combination gel treatment group
`compared with the tretinoin 0.025% aqueous gel
`treatment group.11
`
`What is the tolerability and safety of
`clindamycin phosphate 1.2% and
`tretinoin 0.025% combination gel
`in the treatment of acne vulgaris?
`In a cumulative irritation study, clindamycin phos-
`phate 1.2% and tretinoin 0.025% combination
`gel alone and its aqueous gel vehicle alone were
`markedly less irritating than conventional tretinoin
`gel 0.025%.14
`In 12-week phase 3 studies, the incidence of
`local tolerability reactions in subjects treated with
`clindamycin phosphate 1.2% and tretinoin 0.025%
`combination gel was minimal or decreased in
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`frequency at study end point compared with base-
`line. Erythema, scaling, pruritus, burning, and
`stinging were reported in 35%, 13%, 10%, 2%,
`and 2% of enrolled subjects at baseline, respec-
`tively, and in 26%, 17%, 4%, 4%, and 2% of
`study subjects at end of treatment, respectively.11
`The adverse reactions noted in all active study
`arms included in the pivotal phase 3 trials were
`consistent with those previously reported for the
`individual ingredients after topical application.
`Study discontinuations due to adverse events were
`less than 1%, and no major adverse events or
`safety concern signals were observed in any of the
`study groups.11,13
`In a 52-week open-label trial, subjects used
`clindamycin phosphate 1.2% and tretinoin 0.025%
`combination gel (N(cid:21)442) for the treatment of
`acne vulgaris as either monotherapy (78%) or in
`combination with other agents (22%). The over-
`all discontinuation rate due to adverse reactions
`was less than 1% in those subjects treated for up
`to 6 months and 0% in those treated for up to
`12 months.12 The combination gel was well-
`tolerated with 91%, 94%, and 92% of subjects
`reporting complete absence of burning, stinging,
`and pruritus, respectively.12
`
`COMMENT
`The pivotal phase 3 trials evaluating dapsone gel 5%
`demonstrate results achieved with monotherapy for
`facial acne vulgaris, predominantly in subjects pre-
`senting with moderate severity. Importantly, data
`from one study suggests that dapsone gel 5% may
`be used in combination with other topical agents,
`such as benzoyl peroxide or a topical retinoid.8 The
`cutaneous tolerability profile of dapsone gel 5%,
`either alone or in combination with benzoyl per-
`oxide or topical adapalene, appears to be very
`favorable based on clinical trials. Importantly,
`both short-term and long-term pharmacokinetic,
`clinical, and laboratory analyses performed to
`date indicate that dapsone gel 5% is devoid of sys-
`temic toxicities associated with oral dapsone use,
`such as hemolytic anemia, methemoglobinemia,
`and agranulocytosis.
`The dual-component combination aqueous
`gel containing solubilized clindamycin phos-
`phate 1.2% and solubilized and crystalline treti-
`noin 0.025% has been shown to be effective,
`well-tolerated, and safe in both 12-week double-
`blind studies and in a 52-week open-label trial. A
`major distinguishing feature of this combination
`aqueous gel formulation is the small particle size
`of tretinoin, which may contribute to reduced skin
`irritation. A clinical concern regarding use of the
`
`Drug Therapy Topics
`
`clindamycin phosphate 1.2% and tretinoin 0.025%
`combination gel for treatment of acne vulgaris
`is the potential for promotion and emergence
`of strains of Propionibacterium acnes that are less
`sensitive to clindamycin. This potential prob-
`lem may be obviated by concomitant use of a
`benzoyl peroxide(cid:13)containing product. Another
`clinical consideration is whether or not a topical
`combination product containing benzoyl perox-
`ide and clindamycin can be used concomitantly
`with clindamycin phosphate 1.2% and treti-
`noin 0.025% combination gel because this would
`result in the clindamycin component being applied
`twice daily. Use of a benzoyl peroxide–clindamycin
`gel combination product once daily in the morn-
`ing and clindamycin phosphate 1.2% and treti-
`noin 0.025% combination gel once daily in the
`evening is a very logical treatment approach.
`Twice-daily application of clindamycin should not
`be a major concern since twice daily use is the
`FDA-approved application frequency with some
`topical clindamycin products.
`
` 2.
`
` 3.
`
`REFERENCES
` 1.
` Gollnick H, Cunliffe W, Berson D, et al. Management
`of acne: a report from a Global Alliance to Improve
`Outcomes in Acne. J Am Acad Dermatol. 2003;49
`(suppl 1):S1-S37.
` Strauss JS, Krowchuk DP, Leyden JJ, et al, American
`Academy of Dermatology/American Academy of
`Dermatology Association. Guidelines for care for acne
`vulgaris management. J Am Acad Dermatol. 2007;56:
`651-663.
` Hall RP, Mickle CP. Dapsone. In: Wolverton SE, ed.
`Comprehensive Dermatologic Drug Therapy. 2nd ed.
`Philadelphia, Pa: Saunders; 2007:239-257.
` 4. Stendahl O, Molin L, Dahlgren C. The inhibi-
`tion of polymorphonuclear
`leukocyte cytotoxicity
`by dapsone: a possible mechanism in the treatment
`of dermatitis herpetiformis. J Clin Invest. 1978;
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` Prendiville JS, Logan RA, Russell-Jones R. A comparison
`of dapsone with 13-cis retinoic acid in the treatment
`of nodular cystic acne. Clin Exp Dermatol. 1988;13:
`67-71.
` Thiboutot D, Sharata H, Taylor S, et al. Pharmacokinetics
`of dapsone topical 5% gel demonstrate minimal systemic
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` 7. Draelos ZD, Carter E, Maloney JM, et al. Two
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`safety of dapsone gel, 5% for the treatment of
`acne vulgaris. J Am Acad Dermatol. 2007;56:
`439-447.
`
` 5.
`
` 6.
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`12.
`
`13.
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` Leyden JJ, Wortzman M, Plott T. Safety of a novel gel
`formulation of 0.025% tretinoin and 1.2% clindamycin
`phosphate: results from a 52-week open-label study.
`Poster presented at: 31st Hawaii Dermatology Seminar;
`March 4-9, 2007; Maui, Hawaii.
` Leyden JJ, Plott T, Wortzman M. A novel gel formulation
`of 0.025% tretinoin and 1.2% clindamycin phosphate:
`efficacy in patients with mild, moderate, and severe base-
`line acne. Poster presented at: 31st Hawaii Dermatology
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`14. Plott RT. Unique aqueous formulation results in reduced
`risk of tretinoin-induced irritation. Poster presented
`at: American Academy of Dermatology 65th Annual
`Meeting; February 2-6, 2007; Washington, DC. P132.
` Leyden JJ, Plott T, Wortzman M. A novel gel for-
`mulation of tretinoin and clindamycin is not associ-
`ated with retinoid induced flaring of inflammatory acne.
`Poster presented at: Hawaii Dermatology Seminar;
`March 4-9, 2007; Maui, Hawaii.
`
`15.
`
`Drug Therapy Topics
`
` 8. Fleischer AB Jr, Abramovits W, Pariser DM, et al.
`Dapsone gel, 5% in combination with adapalene gel,
`0.1%, benzoyl peroxide, 4%, or vehicle gel for treat-
`ment of acne vulgaris: a randomized, double-blind
`study. Poster presented at: American Academy of
`Dermatology 65th Annual Meeting; February 2-6, 2007;
`Washington, DC. P113.
` 9. Taylor S, Raimer S, Lucky AW. Dapsone gel 5% is
`effective and safe fo