STUDY
`
`Hematologic Safety of Dapsone Gel, 5%,
`for Topical Treatment of Acne Vulgaris
`
`Warren W. Piette, MD; Susan Taylor, MD; David Pariser, MD;
`Michael Jarratt, MD; Pranav Sheth, MD; David Wilson, MD
`
`Objective: To evaluate the risk of hemolysis in sub-
`jects with glucose-6-phosphate dehydrogenase (G6PD)
`deficiency who were treated for acne vulgaris with either
`dapsone gel, 5% (dapsone gel), or vehicle gel.
`
`Design: Double-blind, randomized, vehicle-controlled,
`crossover study.
`
`Setting: Referral centers and private practice.
`
`Participants: Sixty-four subjects 12 years or older with
`G6PD deficiency and acne vulgaris.
`
`Intervention: Subjects were equally randomized to 1
`of 2 sequences of 12-week treatment periods (vehicle fol-
`lowed by dapsone gel or dapsone gel followed by ve-
`hicle). The washout period was 2 weeks. Treatments were
`applied twice daily to the face and to other acne-affected
`areas of the neck, upper chest, upper back, and shoul-
`ders as required.
`
`Main Outcome Measures: Results of clinical chemi-
`cal analysis and hematology values; plasma dapsone and
`
`N-acetyl dapsone concentrations; spontaneous reports of
`adverse events.
`
`Results: A 0.32-g/dL decrease in hemoglobin concen-
`tration occurred from baseline to 2 weeks during dap-
`sone gel treatment. This was not accompanied by changes
`in other laboratory parameters, including reticulocytes,
`haptoglobin, bilirubin, and lactate dehydrogenase lev-
`els, and was not apparent at 12 weeks as treatment con-
`tinued. The number of subjects with a 1-g/dL drop in he-
`moglobin concentration was similar between treatment
`groups at both week 2 and week 12. The largest drops
`in hemoglobin concentration were 1.7 g/dL in the ve-
`hicle gel treatment group and 1.5 g/dL in the dapsone
`gel treatment group. No clinical signs or symptoms of
`hemolytic anemia were noted.
`
`Conclusions: After treatment with dapsone gel, 5%, no
`clinical or laboratory evidence of drug-induced hemo-
`lytic anemia was noted in G6PD-deficient subjects with
`acne vulgaris.
`
`Trial Registration: clinicaltrials.gov Identifier:
`NCT00243542.
`
`Arch Dermatol. 2008;144(12):1564-1570
`
`D APSONE IS A SULFONE WITH
`
`both anti-inflammatory
`and antimicrobial prop-
`erties.1-4 Use of oral dap-
`sone may be associated
`with hematologic adverse effects, includ-
`ing dose-dependent hemolysis due to
`
`CME available online at
`www.jamaarchivescme.com
`
`oxidative damage to red blood cells from
`its hydroxylamine metabolite.5,6 Individu-
`als with glucose-6-phosphate dehydroge-
`nase (G6PD) deficiency are more sensi-
`tive to developing hemolytic anemia after
`exposure to hemolytic stressors includ-
`ing dapsone.7 Because the G6PD enzyme
`
`is encoded on the X chromosome, the de-
`ficiency is more common in male pa-
`tients. In the United States, a recent study
`of military personnel reported the preva-
`lence of G6PD deficiency to be 2.5% in men
`and 1.6% in women.8 Among racial groups,
`the prevalence was highest in African
`American men (12.2%), Asian men (4.3%),
`and African American women (4.1%), and
`lowest in white men and women (0.3% and
`0%, respectively). An apparent direct lin-
`ear relationship exists between oral dap-
`sone dose and hemolysis regardless of
`G6PD deficiency status. However, clini-
`cally relevant hemolysis is generally not
`apparent with oral dapsone doses of 50
`mg or less in G6PD-deficient subjects
`compared with 100 mg or less in normal
`subjects.9-11
`
`Author Affiliations:
`John H. Stroger Jr Hospital
`of Cook County, Chicago,
`Illinois (Dr Piette); Society Hill
`Dermatology, Philadelphia,
`Pennsylvania (Dr Taylor);
`Virginia Clinical Research Inc,
`Norfolk (Dr Pariser);
`DermResearch Inc, Austin,
`Texas (Dr Jarratt); University
`Dermatology Consultants Inc,
`Cincinnati, Ohio (Dr Sheth);
`and The Education and
`Research Foundation Inc,
`Lynchburg, Virginia
`(Dr Wilson).
`
`(REPRINTED) ARCH DERMATOL/ VOL 144 (NO. 12), DEC 2008
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`
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`
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`
`Almirall EXHIBIT 2028
`
`Amneal v. Almirall
`IPR2019-00207
`
`

`

`A topical formulation of dapsone was recently devel-
`oped to deliver therapeutic concentrations of dapsone to
`the skin. Clinical studies have shown that dapsone gel,
`5% (Aczone; QLT USA Inc, Fort Collins, Colorado), was
`effective in the treatment of acne vulgaris12 with approxi-
`mately 1% of the systemic exposure that is seen with typi-
`cal oral dapsone treatment.13,14 No evidence of hemo-
`lytic anemia was found in any of the studies. However,
`the small number of subjects with G6PD deficiency in
`those studies precluded definitive conclusions about the
`hematologic effects of dapsone gel in this patient popu-
`lation. The present study was designed specifically to
`evaluate the risk of drug-induced hemolytic anemia from
`dapsone gel used for the topical treatment of acne vul-
`garis in patients with G6PD deficiency.
`
`METHODS
`
`STUDY DESIGN
`
`This was a double-blind, randomized, vehicle-controlled, cross-
`over, postapproval commitment study. Eighteen study cen-
`ters in the United States enrolled patients from November 10,
`2005, to March 29, 2006, and all treatment and follow-up was
`completed by October 13, 2006. Subjects were equally ran-
`domized into 1 of 2 sequences of treatment according to a com-
`puter-generated randomization scheme: dapsone gel followed
`by vehicle gel or vehicle gel followed by dapsone gel. The ve-
`hicle gel consisted of the same inactive ingredients as the dap-
`sone gel. After washing with a standard, nonmedicated cleanser
`(Cetaphil; Galderma Laboratories LP, Fort Worth, Texas), sub-
`jects applied a thin film of the study treatment twice daily (once
`in the morning and once at night) to the entire face and, as re-
`quired, to acne-affected areas of the neck, shoulders, upper chest,
`and upper back. Subjects applied each treatment for a period
`of 12 weeks, with a 2-week washout period between treat-
`ments and a 2-week follow-up period following the last treat-
`ment, for a total study duration of 28 weeks.
`Study center personnel were blinded to the sequence of study
`treatment. As a further precaution, subjects were instructed to
`apply their study treatment at home or away from the study
`center. Two independent physicians, who were specialists in
`hematology and also blinded to the treatment sequence, acted
`as medical safety monitors for the study and reviewed all sub-
`jects’ laboratory data on an ongoing basis. The medical moni-
`tors recommended additional laboratory follow-up tests if and
`when appropriate.
`The study was conducted according to the ethical prin-
`ciples of the Declaration of Helsinki and in compliance with
`good clinical practice guidelines. The protocol was reviewed
`and approved by an institutional review board appropriate to
`each study center. Written informed assent and consent were
`obtained from each subject and from a parent or guardian if
`applicable before the start of study procedures.
`
`SUBJECTS
`
`The main eligibility requirements included age 12 years or older,
`a diagnosis of G6PD deficiency (G6PD enzyme activity below
`the lower limit of normal according to Laboratory and Safety
`Assessments15), and a diagnosis of acne vulgaris (at least 20 in-
`flammatory and/or noninflammatory lesions, 10 or more of
`which were located on the face). Subjects were excluded if they
`had severe cystic acne or acne conglobata; had received treat-
`ment with isotretinoin within 3 months of baseline; or were
`
`using other topical and/or systemic medications for acne at the
`time of study entry. Subjects were also excluded if they had a
`predisposition to anemia for other medical reasons such as gas-
`trointestinal tract bleeding or cancer.
`
`LABORATORY AND SAFETY ASSESSMENTS
`
`Adverse events were collected throughout the study with stan-
`dard interviewing techniques at each study visit. Blood tests
`were scheduled for the baseline, 2-week, and 12-week points
`of each treatment period to measure plasma dapsone and N-
`acetyl dapsone concentrations and evaluate clinical chemistry
`and hematology parameters.
`Blood samples from all subjects were tested for G6PD de-
`ficiency by a central laboratory (ARUP Laboratories, Salt Lake
`City, Utah) using a validated spectrophotometric assay per-
`formed with a commercially available kit (Trinity Biotech PLC,
`Bray, Ireland). The laboratory’s normal reference range for G6PD
`activity was 7.0 to 20.5 U/g hemoglobin (Hb). Plasma dap-
`sone and N-acetyl dapsone metabolite concentrations were mea-
`sured by CANTEST BioPharma Services (Burnaby, British Co-
`lumbia, Canada) using a validated liquid chromatography
`tandem mass spectrometry method. The lower limit of quan-
`tification for this assay was 0.30 ng/mL; levels below the lower
`limit of quantification were assigned a value of 0 for the sum-
`mary analyses. All clinical chemistry and hematology tests were
`analyzed centrally by Quintiles Laboratories (Smyrna, Geor-
`gia), which assigned a high or low flag to any values that were
`determined to be outside of the laboratory normal range.
`
`STATISTICAL METHODS
`
`The planned sample size of approximately 60 subjects was de-
`signed to comply with the US Food and Drug Administra-
`tion’s recommended sample size of approximately 50 evalu-
`able subjects. The intent-to-treat population was defined as all
`randomized subjects; the safety population was defined as all
`subjects who applied dapsone gel or vehicle gel at least once;
`and the safety-evaluable population was defined as all subjects
`who applied at least 50% of the required treatment applica-
`tions and had the week 2 blood draw in the first treatment pe-
`riod. To assess the risk of hemolysis and hemolytic anemia, the
`following laboratory parameters were identified as important
`markers: Hb and bilirubin levels reticulocyte counts, and hap-
`toglobin and lactate dehydrogenase (LDH) levels. For each of
`these parameters, the values at each time point, changes from
`baseline at 2 and 12 weeks, and within-subject between-
`treatment differences in the values and changes from baseline
`were summarized with descriptive statistics (mean, standard
`deviation, median, minimum, and maximum). Two-sided 95%
`confidence intervals were also calculated for the changes from
`baseline and within-subject between-treatment differences in
`the change from baseline. In addition, the number and per-
`centage of subjects with any of the following outcomes were
`determined for the 2-week and 12-week time point of each treat-
`ment period: an Hb concentration shift from normal or high
`to below normal or from low to normal or high; an Hb con-
`centration reduction of 1 g/dL or more; an increase in biliru-
`bin level above the upper limit of normal; an increase in re-
`ticulocyte count above the upper limit of normal; a reduction
`in haptoglobin level below the lower limit of normal; and a re-
`duction of 1 g/dL or more in Hb concentration with concomi-
`tant increase in bilirubin level, increase in reticulocyte count,
`or reduction in haptoglobin level. (To convert Hb to grams per
`liter, multiply by 10.0.) Unplanned correlation analyses be-
`tween the changes in Hb concentration and changes in reticu-
`locyte count or bilirubin, haptoglobin, or LDH level were per-
`
`(REPRINTED) ARCH DERMATOL/ VOL 144 (NO. 12), DEC 2008
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`

`756 Screened for G6PD deficiency
`
`Table 1. Demographic and Baseline Characteristics
`of the Intent-to-Treat Population
`
`686 Not G6PD deficient
`6 Withdrew consent
`
`64 Randomized
`
`32 Vehicle → dapsone gel, 5%,
`sequence (100%)
`
`32 Dapsone gel → vehicle
`sequence (100%)
`
`29 Treatment period 1:
`vehicle completed (91%)
`
`25 Treatment period 1: dapsone
`gel completed (78%)
`
`26 Treatment period 2: dapsone
`gel completed (81%)
`
`21 Treatment period 2:
`vehicle completed (66%)
`
`31 Safety evaluable
`
`25 Safety evaluable
`
`Figure 1. Subject randomization and protocol disposition. G6PD indicates
`glucose-6-phosphate dehydrogenase.
`
`formed with Pearson correlations. A preplanned subgroup
`analysis based on the degrees of G6PD deficiency, which were
`defined as severely deficient (ⱕ2 U/g Hb) and deficient (⬎2 U/g
`Hb up to the lower limit of normal at 7 U/g Hb) was per-
`formed for all variables related to the risk of hemolysis.
`
`RESULTS
`
`SUBJECT DISPOSITION AND
`DEMOGRAPHIC CHARACTERISTICS
`
`A total of 756 subjects were screened for G6PD defi-
`ciency for this study; 64 subjects (8.5%) were identified
`as G6PD deficient and consented to participation
`(Figure 1). Of the 64 subjects in the intent-to-treat popu-
`lation, 63 make up the safety population and 56 make
`up the safety-evaluable population. Seventeen subjects
`did not complete the study, primarily for administrative
`reasons (loss to follow-up, voluntary withdrawal, treat-
`ment noncompliance, urticaria [not related to treat-
`ment], preexisting anemia [protocol violation], or preg-
`nancy), but 1 of these subjects discontinued owing to an
`adverse event (mild contact dermatitis). Baseline demo-
`graphics and characteristics were similar between treat-
`ment groups (Table 1).
`
`PLASMA DAPSONE AND
`METABOLITE CONCENTRATIONS
`
`Dapsone and N-acetyl dapsone levels reached steady state
`within 2 weeks of dapsone gel treatment and fell rapidly
`after the cessation of treatment (Table 2). In addition,
`in subjects who applied dapsone gel in the first treat-
`ment period (n=25), dapsone levels were largely unde-
`tectable by the start of the vehicle treatment period (me-
`
`Characteristic
`Total subjects
`Age, mean (SD) (range), y
`Women
`Ethnic group
`African American
`Asian
`Hispanic
`Otherb
`G6PD enzyme activity, mean (SD), U/g Hb
`Severely deficientc
`Deficientd
`Lesion count, mean (SD) (range), No.
`Inflammatory
`Noninflammatory
`Totale
`
`Valuea
`64 (100)
`28 (10) (12-61)
`35 (55)
`
`56 (88)
`4 (6)
`1 (2)
`3 (5)
`3.8 (1.9) (0.7-6.9)
`15 (23)
`49 (77)
`
`16.2 (12.5) (0-50)
`26.5 (25.4) (0-139)
`42.8 (27.8) (10-162)
`
`Abbreviations: G6PD, glucose-6-phosphate dehydrogenase; Hb,
`hemoglobin.
`aUnless otherwise indicated, data are reported as number (percentage) of
`subjects.
`bThe subjects who identified their ethnic group as other were Middle
`Eastern, mixed race (white black), and Haitian.
`cSeverely deficient is defined as 2 U/g of Hb or lower.
`dDeficient is defined as higher than 2 U/g Hb up to the lower limit of
`normal at 7 U/g Hb.
`eTotal lesion count is the sum of inflammatory and noninflammatory
`lesion counts.
`
`Table 2. Plasma Concentrations of Dapsone
`and N-Acetyl Dapsone for Subjects Treated
`With Dapsone Gel, 5% (Safety Population)
`
`Plasma Concentration,
`Mean (SD) (Range), ng/mL
`
`Measurement Time
`2 wk
`(n=58 for both groups)
`12 wk
`(n=51 for both groups)
`
`Dapsone
`5.63 (6.10)
`(0.00-36.85)
`5.30 ± 6.66
`(0.00-30.58)
`
`N-Acetyl Dapsone
`2.77 (6.75)
`(0.00-48.70)
`2.51 ± 4.79
`(0.00-26.88)
`
`dian dapsone concentration, 0; maximum concentration,
`1.18 ng/mL) and completely undetectable by week 2 of
`vehicle treatment.
`
`HEMOLYSIS-RELATED
`LABORATORY RESULTS
`
`The primary hemolysis-related analysis was performed on
`the safety-evaluable data set (n=56) (Table 3). Both the
`number of subjects who had a 1-g/dL Hb decrease or greater
`and the range of Hb changes from baseline were similar
`between vehicle and dapsone gel treatment regimens at
`weeks 2 and 12, with all of the low Hb values remaining
`close to the normal range. The largest decrease in Hb con-
`centration observed in a safety-evaluable subject oc-
`curred during vehicle treatment (a 1.7-g/dL decrease at
`week 2). Three of 56 subjects (5%) experienced a shift in
`Hb level to below normal during both the vehicle and the
`dapsone gel treatment regimens. The changes in Hb lev-
`
`(REPRINTED) ARCH DERMATOL/ VOL 144 (NO. 12), DEC 2008
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`
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`

`–1
`
`0
`Change in Hb, g/dL
`
`1
`
`2
`
`15
`
`10
`
`5
`
`0
`
`–5
`
`–10
`
`Change in Bilirubin, µmol/L
`
`–15
`
`–2
`
`Figure 2. Correlation analysis of the change in hemoglobin (Hb) concentration
`vs change in bilirubin concentration at week 2 of dapsone gel, 5%, treatment:
`r 2=0.104 (n=52). The mean bilirubin level was 0.58 mg/dL at baseline and
`0.65 mg/dL at week 2. The mean (95% confidence interval) change from
`baseline in bilirubin level at week 2 was ⫹0.06 (⫹0.00 to ⫹0.12) mg/dL.
`(Patient data were collected in SI units and converted to conventional units for
`summary tables. To convert bilirubin to micromoles per liter, multiply by 17.1;
`to convert Hb to grams per liter, multiply by 10.0.)
`
`–1
`
`0
`Change in Hb, g/dL
`
`1
`
`2
`
`1.25
`
`0.75
`
`0.25
`
`0
`
`–0.25
`
`–0.75
`
`Change in Relative Reticulocyte Count, %
`
`–1.25
`
`–2
`
`Figure 3. Correlation analysis of the change in hemoglobin (Hb) concentration
`vs change in relative reticulocyte count at week 2 of dapsone gel, 5%,
`treatment: r 2=0.043 (n=52). The mean relative reticulocyte count was 1.30%
`at baseline and 1.51% at week 2. The mean (95% confidence interval) change
`from baseline in relative reticulocyte count at week 2 was ⫹0.22% (⫹0.11%
`to ⫹0.32%). (To convert Hb to grams per liter, multiply by 10.0.)
`
`laboratory parameters. Two subjects with histories of ane-
`mia completed the study and showed no changes of dap-
`sone-related hemolysis.
`
`ADVERSE EVENTS
`
`No adverse events were reported that were clinical signs
`or symptoms of hemolytic anemia. A total of 27 of 63 sub-
`jects (43%) in the full safety data set experienced an ad-
`verse event regardless of relationship to treatment. Few
`adverse events were considered by the investigators to
`be related to dapsone gel treatment (17 of 44 events), and
`these occurred in only 8 of 63 subjects (13%): 7 during
`the dapsone gel treatment period and 1 during the ve-
`hicle treatment period. Four of these subjects reported
`local application site reactions of burning, dryness, pru-
`
`Table 3. Hemoglobin Concentration, Changes
`From Baseline, and Shifts From Normal
`(Safety-Evaluable Population)a
`
`Treatment Group
`
`Vehicle
`Characteristic
`Pretreatment measurement 13.36 (1.25)
`(n=56)
`
`Dapsone, 5%
`13.44 (1.34)
`(n=53)
`
`Within-Subject
`Differenceb
`−0.06 (0.59)
`(n=53)
`
`−0.24 (0.70)
`(n=52)
`0.32 (0.96)
`(−2.4 to 2.5)
`0.05 to 0.59
`
`NA
`
`NA
`
`2 wk
`13.34 (1.25)
`(n=55)
`0.01 (0.64)
`(−1.7 to 1.4)
`−0.16 to 0.18
`
`4/56 (7)
`
`13.12 (1.36)
`(n=53)
`−0.32 (0.55)
`(−1.5 to 1.5)
`−0.47 to
`−0.17
`6/56 (11)
`
`3/55 (5)
`
`6/52 (12)
`
`Measurement result
`
`Change from baseline
`(range)
`95% Confidence
`intervalc
`ⱖ1-g/dL drop,
`No./No. (%)d
`Shift to below normal,
`No./No. (%)d,e
`
`Measurement result
`
`Change from baseline
`(range)
`95% Confidence
`intervalc
`ⱖ1-g/dL drop,
`No./No. (%)d
`Shift to below normal,
`No./No. (%)d,e
`
`12 wk
`−0.02 (0.64)
`13.42 (1.24)
`13.37 (1.38)
`(n=46)
`(n=50)
`(n=50)
`0.04 (0.91)
`−0.03 (0.59)
`0.01 (0.64)
`(−2.0 to 2.4)
`(−1.5 to 1.4)
`(−1.5 to 1.6)
`−0.18 to 0.19 −0.20 to 0.14 −0.23 to 0.32
`
`4/56 (7)
`
`2/56 (4)
`
`4/50 (8)
`
`3/49 (6)
`
`NA
`
`NA
`
`Abbreviation: NA, not applicable
`SI conversion factor: To convert hemoglobin to grams per liter, multiply by
`10.0.
`aUnless otherwise noted, data are reported hemoglobin concentrations in
`mean (SD) grams per deciliter.
`bDifference is calculated as the vehicle value minus the dapsone gel value in
`the same subject
`cConfidence intervals are for the change from baseline (pretreatment value).
`dNumerators represent the number of affected patients; denominators
`represent the total number of subjects at baseline.
`eBased on observed data.
`
`els observed at week 2 were not correlated with plasma
`dapsone levels, amount of daily dapsone gel use (mean, 1
`g/d), or changes in bilirubin concentration (Figure 2),
`relative reticulocyte count (Figure 3), haptoglobin con-
`centration (Figure 4), or LDH level (Figure 5).
`Two of 56 subjects experienced a change in Hb con-
`centration of 1 g/dL or higher with a concomitant in-
`crease of bilirubin level to above the upper limit of nor-
`mal (1 subject at 2 weeks and the other at 12 weeks of
`dapsone gel treatment) but without any other labora-
`tory changes or clinical signs of hemolytic anemia (4%).
`In addition, the subject with the changes at week 12 had
`similarly high bilirubin levels at week 2 of dapsone gel
`treatment and at week 12 of vehicle gel treatment with
`no concomitant change in Hb level at these time points.
`Changes in hemolysis parameters were similar in vari-
`ous subgroups, including G6PD enzyme activity, race,
`sex, and age. In particular, subjects who were severely
`G6PD deficient (ⱕ2 U/g Hb) did not appear to be at higher
`risk for changes (Table 4). One subject with preexist-
`ing anemia, who should have been precluded from en-
`tering the study, was treated with dapsone gel for 9 days
`before being withdrawn; she showed no change in her
`
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`2, plasma dapsone levels were below the limit of quan-
`tification, even though treatment use was verified by tube
`weights. Furthermore, the low haptoglobin concentra-
`tion was present at the baseline blood test as well as week
`12, and no other changes in the other hematology para-
`meters occurred, so the laboratory adverse events for this
`subject are likely not related to dapsone gel treatment.
`For subject 3, no laboratory or clinical evidence of he-
`molysis or hemolytic anemia accompanied the low white
`blood cell count.
`
`COMMENT
`
`This study was designed specifically to evaluate the risk
`of hemolytic anemia with dapsone gel treatment in sub-
`jects with G6PD deficiency. The study used a crossover
`design to evaluate both dapsone gel and vehicle treat-
`ments within the same subject. Subjects were monitored
`for changes in hemolysis-related laboratory parameters at
`2 and 12 weeks of each treatment and for any clinical signs
`of hemolytic anemia. Because drug-induced hemolytic ane-
`mia is a relatively acute phenomenon, the 2-week time point
`was determined to be the most relevant for observing any
`laboratory evidence of hemolysis or hemolytic anemia,
`while the 12-week time point would allow evaluation of
`any longer-term changes.16
`An evaluation of the laboratory data shows a mean de-
`crease in Hb level from baseline of 0.32 g/dL after 2 weeks
`of dapsone gel treatment, which was not seen at 12 weeks
`even as treatment continued. For several reasons, the de-
`crease in Hb level at week 2 is considered clinically in-
`significant. Most importantly, no mean changes from base-
`line occurred in other laboratory markers of hemolysis
`at either the 2-week or 12-week time point, nor was any
`relationship found between changes in Hb level and these
`other parameters, including bilirubin, haptoglobin, and
`LDH levels and relative reticulocyte count. These find-
`ings strongly argue against the presence of clinically rel-
`evant hemolysis.
`Second, no subjects experienced symptoms of or were
`diagnosed clinically with hemolytic anemia. No therapeu-
`tic interventions or modifications to study treatment were
`required as a consequence of a laboratory finding, even
`for subjects who experienced the largest decreases in Hb
`concentration (−1.7 g/dL and −1.5 g/dL for vehicle and dap-
`sone gel treatment, respectively). Third, no consistent, clini-
`cally meaningful relationship was found between changes
`in Hb level and dapsone gel treatment. The range of Hb
`level changes and percentages of subjects with shifts be-
`low normal or large decreases of Hb level (ⱖ1 g/dL) were
`similar between vehicle and dapsone gel treatments.
`This study also provides substantive data on a sub-
`group of 14 subjects whose G6PD levels were severely
`deficient, within the lower 30% of the G6PD-deficient
`range (ⱕ2 U/g Hb). Results in this subgroup were simi-
`lar to those of the overall population, consistent with no
`difference in risk of hemolysis after dapsone gel treat-
`ment in G6PD-deficient subjects with the lowest en-
`zyme activity. In addition, 1 subject with preexisting ane-
`mia and 2 subjects with histories of anemia participated
`in the study. The subject with preexisting anemia was
`
`–1
`
`0
`Change in Hb, g/dL
`
`1
`
`2
`
`0.75
`
`0.50
`
`0.25
`
`0
`
`–0.25
`
`–0.50
`
`Change in Haptoglobin, g/L
`
`–0.75
`
`–2
`
`Figure 4. Correlation analysis of the change in hemoglobin (Hb) concentration
`vs change in haptoglobin concentration at week 2 of dapsone gel, 5%,
`treatment: r 2=0.027) (n=51). The mean haptoglobin level was 107.9 mg/dL at
`baseline and 109.1 mg/dL at week 2. The mean (95% confidence interval)
`change from baseline in haptoglobin level at week 2 was −0.2 (−5.3 to ⫹5.0)
`mg/dL. (Patient data were collected in SI units and converted to conventional
`units for summary tables. To convert haptoglobin to grams per liter multiply by
`0.01; to convert Hb to grams per liter, multiply by 10.0.)
`
`–1
`
`0
`Change in Hb, g/dL
`
`1
`
`2
`
`75
`
`50
`
`25
`
`0
`
`–25
`
`–50
`
`Change in LDH, IU/L
`
`–75
`
`–2
`
`Figure 5. Correlation analysis of the change in hemoglobin (Hb) concentration
`vs change in lactate dehydrogenase (LDH) level at week 2 of dapsone gel
`treatment: r 2⬍0.001 (n=51). The mean LDH level was 175.0 IU/L at baseline
`and 171.3 IU/L at week 2. The mean (95% confidence interval) change from
`baseline in LDH level at week 2 was −3.3 (−10.0 to 3.4) IU/L. (To convert Hb to
`grams per liter, multiply by 10.0; to convert LDH to microkatal per liter, multiply
`by 0.016%.)
`
`ritus, or contact dermatitis (all mild). The 1 event of con-
`tact dermatitis that led to discontinuation of study treat-
`ment was mild, did not require treatment, and resolved
`within 14 days of study discontinuation. One subject re-
`ported a related adverse event of aggravated acne.
`Three subjects had related adverse events detected by
`laboratory test during treatment, but none of these were
`indicative of hemolytic anemia: elevated bilirubin level
`at 2 weeks and low hematocrit and red blood cell count
`at 12 weeks in subject 1; low haptoglobin concentration
`at 2 weeks and detection of red blood burr cells, poikilo-
`cytosis, and elliptocytosis at 12 weeks in subject 2; and
`low white blood cell count at week 12 in subject 3. In
`subject 1, the elevation in bilirubin level occurred be-
`fore the low hematocrit and red blood cell count and is
`therefore not believed to indicate hemolysis. In subject
`
`(REPRINTED) ARCH DERMATOL/ VOL 144 (NO. 12), DEC 2008
`1568
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`WWW.ARCHDERMATOL.COM
`
`©2008 American Medical Association. All rights reserved.
`
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`Table 4. Values for Hemoglobin (Hb), Bilirubin, Reticulocyte, Haptoglobin, and Lactate Dehydrogenase
`by Severity of G6PD Enzyme Activitya
`
`Parameter
`Hemoglobin, g/dLd
`
`Bilirubin, mg/dL
`
`Reticulocytes, %
`
`Haptoglobin, mg/dL
`
`Lactate dehydrogenase, IU/L
`
`Visit
`Pretreatment
`2 wk
`12 wk
`Pretreatment
`2 wk
`12 wk
`Pretreatment
`2 wk
`12 wk
`Pretreatment
`2 wk
`12 wk
`Pretreatment
`2 wk
`12 wk
`
`Severely G6PD Deficient
`(n=14)b
`
`G6PD Deficient
`(n=42)c
`
`Vehicle Gel
`13.96 (0.80)
`13.91 (0.98)
`13.85 (0.85)
`0.7 (0.3)
`0.7 (0.3)
`0.8 (0.3)
`1.38 (0.42)
`1.31 (0.44)
`1.45 (0.48)
`93.57 (35.86)
`107.86 (29.66)
`95.38 (32.05)
`166.5 (34.5)
`165.1 (40.1)
`165.8 (33.4)
`
`Dapsone Gel, 5%
`13.97 (0.81)
`13.65 (0.79)
`13.86 (1.05)
`0.7 (0.2)
`0.8 (0.3)
`0.7 (0.4)
`1.29 (0.45)
`1.59 (0.57)
`1.38 (0.53)
`99.23 (30.13)
`102.14 (42.82)
`96.43 (30.54)
`162.0 (31.3)
`169.2 (32.1)
`174.1 (43.8)
`
`Vehicle Gel
`13.15 (1.32)
`13.14 (1.28)
`13.21 (1.50)
`0.5 (0.3)
`0.5 (0.2)
`0.6 (0.4)
`1.33 (0.63)
`1.35 (0.55)
`1.39 (0.59)
`118.10 (53.89)
`117.00 (48.42)
`117.03 (53.64)
`177.5 (38.9)
`179.0 (38.3)
`180.5 (36.8)
`
`Dapsone Gel, 5%
`13.25 (1.44)
`12.93 (1.48)
`13.24 (1.28)
`0.5 (0.3)
`0.6 (0.3)
`0.5 (0.3)
`1.31 (0.47)
`1.48 (0.51)
`1.53 (0.61)
`110.75 (48.17)
`111.54 (42.15)
`120.57 (50.11)
`179.6 (35.8)
`172.1 (31.6)
`177.1 (34.2)
`
`Abbreviation: G6PD, glucose-6-phosphate dehydrogenase.
`SI conversion factors: to convert Hb to grams per liter, multiply by 10.0; bilirubin to micromoles per liter, multiply by 17.1; haptoglobin to g/L, multiply by 0.01;
`lactate dehydrogenase to microkatal per liter, multiply by 0.0167.
`aUnless otherwise indicated, data are reported as mean (SD) values.
`bSeverely deficient is defined as 2 U/g Hb or lower.
`cDeficient is defined as higher than 2 U/g Hb up to the lower limit of normal at 7 U/g Hb.
`dPatient data were collected in SI units and converted to conventional units for summary tables.
`
`withdrawn from the study after 9 days of treatment, but
`the other 2 subjects completed the full 28 weeks of the
`study. None of these 3 subjects experienced any changes
`in chemistry and hematology parameters indicative of dap-
`sone-related hemolysis.
`The prevalence of G6PD deficiency in African Ameri-
`can men can be almost 3 times higher than that of African
`American women, consistent with its X-linked transmis-
`sion.8 In this study, the ratio of male to female subjects with
`G6PD deficiency was almost equal. One could speculate
`that because almost 60% of individuals who present at der-
`matologists’ offices for skin concerns are female,17 and at
`least 41% of women will have acne at various times in their
`lives,18 investigators were able to identify a large number
`of female patients with both G6PD deficiency and acne. Sub-
`group analyses of all variables related to hemolysis showed
`no differences between men and women, and findings were
`similar to those in the overall safety-evaluable population.
`Plasma dapsone and N-acetyl dapsone levels were mea-
`sured before any treatment and at the 2-week and 12-
`week time points of each treatment period to assess sys-
`temic exposure. Dapsone and N-acetyl dapsone levels
`reached steady state within 2 weeks of treatment initia-
`tion with dapsone gel and fell rapidly after the cessation
`of treatment. Exposure to dapsone by the termination of
`topical dapsone gel treatment was low, considering both
`the mean (approximately 5-ng/mL) and the maximum (ap-
`proximately 37-ng/mL) exposures in the study (Table 2).
`The level of dapsone exposure observed in this study is
`substantially lower than the levels associated with oral dos-
`ing that would be expected to cause hematologic changes.11
`Data from a previous crossover pharmacokinetic study
`show that systemic dapsone exposure following topical dap-
`sone gel treatment at steady state is approximately 100-
`
`fold lower than exposure to a single 100-mg oral dose of
`dapsone.13 Pharmacokinetic modeling indicates that steady
`state systemic dapsone levels after topical dapsone gel treat-
`ment would still be approximately 35-fold to 63-fold (area
`under the curve) lower than the systemic levels of dap-
`sone following a single 50-mg oral dose. The absence of
`any hemolytic anemia in subjects with G6PD deficiency
`who used dapsone gel for acne was anticipated based on
`the low overall systemic exposure to dapsone observed af-
`ter treatment with dapsone gel.13,14
`The results from this study demonstrate that there were
`no clinically significant effects on chemistry and hema-
`tology parameters or clinical signs of hemolytic anemia
`in subjects with G6PD deficiency following treatment of
`acne vulgaris with dapsone gel. Because G6PD defi-
`ciency represents a highly sensitive marker for the he-
`molytic potential of drugs, this finding can be extrapo-
`lated to patients with acne and normal G6PD enzyme
`activity. Data from this study support the conclusions that
`the safety profile for topical dapsone gel treatment is ex-
`cellent, and that the risk of hemolytic anemia during treat-
`ment with dapsone gel for acne vulgaris is remote for all
`patients, including those with G6PD deficiency.
`
`Accepted for Publication: April 10, 2008.
`Correspondence: Warren W. Piette, MD, John H. Stroger
`Jr Hospital of Cook County, 1900 West Polk St, Chi-
`cago, IL 60612 (wpiette@cchil.org).
`Author Contributions: Acquisition of data: Taylor, Pariser,
`Jarratt, Sheth, and Wilson. Analysis and interpretation of
`data: Piette. Critical revision of the manuscript for impor-
`tant intellectual content: Piette, Taylor, Pariser, Jarratt,
`Sheth, and Wilson. Administrative, technical, and mate-
`rial support: Taylor. Study supervision: Piette.
`
`(REPRINTED) ARCH DERMATOL/ VOL 144 (NO. 12), DEC 2008
`1569
`
`WWW.ARCHDERMATOL.COM
`
`©2008 American Medical Association. All rights reserved.
`
`6 of 7
`
`

`

`Financial Disclosure: Drs Taylor, Pariser, Jarratt, Sheth,
`and Wilson received research support from QLT USA Inc,
`Fort Collins, Colorado. Dr Piette received consulting fees
`from QLT USA Inc. Dr Sheth received an honorarium from
`QLT USA Inc for advisory board participation.
`Funding/Support: This study was funded by QLT USA Inc.
`Role of the Sponsor: The sponsor contributed to the de-
`sign and conduct of the study, analysis of data, and prepa-
`ration and review of the manuscript.
`Additional Contributions: The other investigators and
`study centers who contributed to this study were Mark
`S. Amster, MD, Boston Clinical Trials, Boston, Massa-
`chusetts; Suzanne Bruce, MD, Suzanne Bruce and Asso-
`ciates, PA, Houston, Texas; Julian Mackay-Wiggan, MD,
`MS, Columbia University Medical Center, New York, New
`York; Weldon E. Collins, MD, DiscoveResearch Inc, Beau-
`mont, Texas; Larry I. Gilderman, DO, Uni