CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-794
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`1 of 50
`
`Almirall EXHIBIT 2043
`
`Amneal v. Almirall
`IPR2019-00207
`
`

`

`Clinical Pharmacology/Biopharmaceutics Review
`
`Submission:
`Product Trade Name:
`Product:
`Indication:
`Submission Dates:
`
`Type of Submission:
`Sponsor:
`
`OCPB Reviewer:
`OCPB Team Leader:
`Medical Officer:
`
`NOA 21-794
`Aczone®
`Dapsone 5% Gel
`Treatment of Acne vulgaris
`August 31, 2004; January 14, 2005; January 19,
`2005, February 9, 2005, February 24, 2005,
`February 25, 2005, March l, 2005, March 4, 2005,
`March 7, 2005,, April 7, 2005, April 8, 2005, April
`27, 2005.
`Original NOA (l S)
`Atrix/ QLT
`Fort Collins, CO 80525
`Tapash K. Ghosh, Ph.D. (HFD 880)
`Raman K. Baweja, Ph. D. (HFD 880)
`Brenda Vaughn, MD (HFD 540, ODE V)
`
`I. Executive Summary:
`Dapsone (OAP) is a sulfone with anti-inflammatory and antimicrobial properties. OAP
`oral tablets (25 mg and l 00 mg) have been approved since 1980s to control the
`dermatologic symptoms of dermatitis herpetiformis and for the treatment of leprosy.
`Atrix Laboratories, Inc. (Atrix), submitted NOA 21-794 as a 505(b) (l) application for
`5% OAP Topical Gel (DTG) to be administered twice a day for the treatment of acne
`vulgaris. The gel is intended to be applied to affected areas on the face, chest, back, and
`shoulders twice daily. In 4 clinical pharmacokinetic studies conducted in the intended
`patient population, which employed a range of doses, application areas and durations,
`twice-daily application of 5% DTG resulted in minimal (i.e., only about l % of that from
`the 100 mg oral dose) systemic exposure to OAP and its principal metabolites. A
`dose/formulation was selected based on demonstrntion of maximum skin penetration of
`OAP and its minimal systemic breakthrough. While selection of the bid dosing of 5%
`DTG based on the systemic exposure information is acceptable from a pharmacokinetic
`. point of view, the clinical basis of the selection of the dose and dosing regimen is
`unknown.
`
`OAP absorption after twice daily topical application of 5% DTG in subjects with acne
`vulgaris results in low systemic exposure to OAP and its metabolites, regardless of
`acetylator phenotype, G6PD activity, gram usage or body surface area treated. OAP
`exposure as measured as AUC after topical application of 5% DTG in acne patients
`treated under maximal usage conditions was 415 ± 224 ng·h/mL. In contrast, OAP
`exposure after a single oral 100 rhg OAP dose was 52,641 ± 36, 224 ng·h/mL. The short(cid:173)
`term exposure study indicates that OAP concentrations at steady-state in plasma was
`about 1 % of that observed following a single 100 mg oral dose of OAP. There was no
`apparent evidence of increased exposure or of any relationship between adverse events
`and OAP plasma levels. The long-term study (12-month) also demonstrated low systemic
`
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`

`absorption following topical application and absence of systemic accumulation following
`long-term use. This study also demonstrated no effects of gender, race, glucose-6-
`phosphate dehydrogenase (G6PD) deficiency or acetylator phenotype on the levels of
`OAP in plasma during 5% DTG bid treatment for up to a year.
`
`Given the low systemic absorption ofDAP following topical administration, it may take a
`daily application of 140 to 280 grams to achieve a OAP exposure level similar to a single
`oral OAP dose of 50 and 100 mg, respectively. Since 30 g would typically cover 100% of
`a 70 kg person, application of 140 to 280g of 5% DTG is not feasible. In the 4 clinical
`trials described in this document, the average daily gram use ranged from 1.3 to 2.2
`grams per day, a dose considerably lower than OAP doses needed for hemolytic effects.
`Literature suggests that hemolytic effects are typically associated with OAP doses of
`> l 00 mg per day in normal patients and >50 mg in G6PD deficient patients. Given the
`low absorption profile of OAP after 5% DTG application relative to oral OAP, the
`likelihood of hematologic adverse events is very low, even in patients with G6PD
`deficiency. In fact, patients with high plasma concentrations did not have a change in
`hemoglobin levels and patients with a 2:1 or 2:2 g/dL decrease in hemoglobin did not have
`high plasma OAP levels (Of note, plasma hemoglobin is a very sensitive biomarker for
`OAP toxicity).
`
`A drug-drug interaction study evaluated the effect of the use of 5%DTG in combination
`with double strength (160 mg/800 mg) trimethoprim/sulfamethoxazole (TMP/SMX).
`During co-administration, systemic levels ofTMP and SMX were essentially unchanged.
`However, levels ofDAP and its metabolites increased in presence ofTMP/SMX.
`Systemic exposure (AUC0• 12) of OAP and N-acetyl-dapsone (NAO) were increased by
`about 40% and 20% respectively in presence of TMP/SMX. Notably, systemic exposure
`(AUCo.12) of dapsone hydroxylamine (DHA) was more than doubled in presence of
`TMP/SMX. Given that exposure from the proposed topical dose is only about 1% of that
`from the 100 mg oral dose, the increases in the exposure ofDAP and its metabolites are
`not considered to be clinically relevant.
`
`Overview of Efficacy: The clinical program included 4,622 healthy subjects and
`patients. The 2 pivotal studies (DAP0203 and DAP0204) were identically designed with
`respect to objective, procedures, treatment duration, endpoints, and statistical analyses.
`The objective of both randomized, double-blind, parallel group, 2-arm, vehicle(cid:173)
`controlled, multi-center studies was to evaluate the safety and efficacy of topically
`applied 5% DTG in patients with acne vulgaris compared to a vehicle control (VC).
`Patients applied a thin film of 5% DTG or vehicle to the face twice daily (approximately
`10 to 14 hours apart for 12 weeks). Patients were also allowed to treat other acne affected
`areas; however, these areas were not assessed for efficacy. Patients included males and
`females, 12 years of age or older. The patients had a clinical diagnosis of acne vulgaris of
`the face, with 20 to 50 inflammatory lesions and 20 to 100 non-inflammatory lesions
`above the mandibular line at baseline.
`
`The results of each of the pivotal studies demonstrate that 5% DTG is significantly more
`effective than vehicle control (VC) in each of the populations analyzed.
`
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`

`In Study DAP0203, for the Global Acne Assessment Score, the Week 12/early
`termination success rate for the 5% DTG group was significantly higher than the VC
`group, 44.2% versus 35.9% (p = 0.0003), in the ITT population. The mean percent
`reductions from Baseline to Week 12/early termination were statistically greater in the
`5% DTG group compared with the VC group. In Study DAP0204, for the Global Acne
`Assessment Score, the Week 12/early termination success rate for the 5% DTG group
`was significantly higher than the VC group, 36.9% versus 29.8% (p = 0.0017), in the ITT
`population. For each of the 3 acne lesion types, the mean percent reductions from
`Baseline to Week 12/early termination were statistically greater in the 5% DTG group
`compared with the VC group.
`
`For all analyses of the primary and secondary efficacy variables for the 2 pivotal trials
`and the other large 12-week, vehicle controlled trial, there are statistically significant
`differences in favor ofDTG.
`
`In summary, two identically designed pivotal clinical studies demonstrated that 5% DTG
`is significantly more effective than VC in each of the populations analyzed (see clinical
`review for details).
`·
`
`Overview of Safety: The 5% DTG clinical program included over 4,000 participants and
`5% DTG has been evaluated in more than 2,300 acne patients. No adverse events of
`potential clinical concern were identified in the dermal safety studies and the
`microbiology study in healthy subjects. Although hematological effects such as
`methemoglobinemia and decreased hemoglobin are well known side effects of oral OAP,
`no relationship between these events and 5% DTG treatment was observed. There were
`no clinically important differences between 5% DTG-treated patients and VC-treated
`patients. Length of exposure to 5% DTG did not affect the prevalence of non-application
`site adverse events. No clear trends were identified in the subpopulations. There were no
`deaths in the program and serious adverse events were rare and unrelated to 5% DTG use.
`No agranulocytosis was reported.
`
`A. Recommendations:
`Based on this review, NOA 21-794 is acceptable from a Clinical Pharmacology and
`Biopharmaceutics perspective. A review of the PK data in this submission has resulted in
`certain changes in the appropriate sections of the product label. The suggested changes
`have been incorporated in the section "Labeling Comments".
`
`APPEARS TH1S WAY
`ON ORIGINAL
`
`3
`
`4 of 50
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`

`II. Table of Contents
`Title
`Executive Summary
`Recommendation
`Question-Based Review
`OCPB labeling recommendations
`Appendices
`Appendix A: Package Insert (annotated)
`Appendix B: Individual Study Reports
`Study DAP9903
`Study DAP0 110
`Study DAP0l 14
`Study 03-0-182
`Appendix C: Filing Form
`III. Question-Based Review
`A. General Attributes
`
`Page Number
`l
`3
`4
`17
`19
`20
`29
`30
`32
`41
`47
`54
`
`1. What are the highlights of the chemistry and physical-chemical properties of the
`drug substance, and the formulation of the drug product? What is the proposed
`mechanism of drug action and therapeutic indications? What is the proposed
`dosage and route of administration?
`
`Dapsone (Molecular formula: C12H12N202S; MW: 248.30) is a white to off-white fine
`crystalline powder with the following structural formula:
`
`0
`
`H2N
`
`0
`
`It is very slightly soluble in water, freely soluble in acetone, sparingly soluble in alcohol,
`and dissolves freely in dilute mineral acids. OAP Topical Gel, 5%, is a topical
`formulation containing OAP, USP ( ~ - -~
`diethylene glycol monoethyl ether, NF, (DGME) base as shown in the following table:
`
`4
`
`-0-ll 0-'
`
`S - 1
`
`II _;
`
`NH2
`
`5 of 50
`
`

`

`Component
`
`Dapsonc
`
`Dicthylcne Glycol Monoethyl Erner
`
`Carbomcr 980
`
`Me1hylparabcn
`
`Sodium Hydroxide
`
`Purified Water
`
`Nominal Fill Weight
`
`Quality I
`USP l<
`
`NF
`
`·,
`
`Standard
`
`Function
`
`. )
`
`NF
`
`NF
`
`USP
`
`!
`
`--·-·
`
`Table 3.2.P-l 5% Dapsonc Topical Gel Composition
`
`I P<rcent I Milligrams I
`
`w/w
`
`per gram
`
`---,
`
`,----- ---·.
`
`i !
`
`Pre'-;crimion'
`JO g provided iii a multi-dose rube
`rru(cs,inagl Samnlc: 3 g provided in a multi-dose lube
`
`a. Carbomer 980 oolvmer is nrocc,,ssed bv the man1,fu,,h1n-t'.
`- - - - - - - - - - - - - - - . , s used in the carborner
`940, NI'. Carbomer 980 is understood to he chemically equivalent to caroomer 940,
`NF by FDA.
`
`Oapsone is a sulfone with anti-inflammatory and antimicrobial properties. Its anti(cid:173)
`inflammatory properties include inhibition of neutrophil myeloperoxidase and eosinophil
`peroxidase and suppression of hypochlorous acid production. OAP also scavenges
`reactive oxygen species and minimizes inflammation associated with the generation of
`these highly reactive species. It also suppresses neutrophil recruitment and local
`production of toxic respiratory and secretory products, and inhibits chemoattractant(cid:173)
`induced signal transduction.
`
`Atrix Laboratories, Inc. (Atrix), submitted NOA 21-794 as a 505(b )(I) application for 5%
`OAP Topical Gel (OTG) to be used twice a day for the treatment of acne vulgaris. The
`gel is intended to be applied to affected areas on the face, chest, back, and shoulders
`twice daily.
`
`B. General Clinical Pharmacology
`
`OAP has been recognized since the 1950s as being effective against a number of non(cid:173)
`infectious inflammatory diseases, of which dermatitis herpetiformis is the best known.
`The drug is particularly effective against dermatoses that are characterized by abnormal
`neutrophil accumulation. A considerable number of other inflammatory as well as bullous
`diseases have been reported to respond in varying degrees to OAP. OAP's antimicrobial
`activity is unrelated to its anti-inflammatory activity. Its antimicrobial activity is similar
`to that for other sulfonamides. With dual anti-inflammatory and antimicrobial
`mechanisms of action, topical OAP may be of significant benefit to patients with acne.
`
`1. What is the basis for selecting the dose in dapsone topical gel?
`
`A dose/formulation was selected based on demonstration of maximum skin penetration of
`OAP and minimal systemic breakthrough. The systemic bioavailability at steady-state of
`2 dose formulations (1% and 5% OTG) and 2 treatment regimens (qd and bid) were
`evaluated. OAP exposure (AUC and Cmax) increased less than proportionally (i.e., IO-fold
`increase in dose brought about a 3-fold increase in systemic exposure) over the range of
`doses studied (10 to 100 mg/day). Comparison of qd and bid doses of5% OTG also
`
`5
`
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`

`demonstrated increase in systemic bioavailability with bid dosing compared to qd dosing.
`While selection of the bid dosing of 5% DTG based on these observations is acceptable
`from a systemic exposure perspective, the clinical basis of the selection of the dose and
`dosing regimen is unknown.
`
`2. What is the basis for selecting the response endpoints, i.e., clinical or surrogate
`endpoints, or biomarkers (also called pharmacodynamics, PD) and how are they
`measured in clinical pharmacology and clinical studies?
`
`The primary pharmacodynamic properties that have been summarized and presented are
`anti-inflammatory and immunological activities. Patients were evaluated at Baseline,
`during treatment (Weeks 2, 4, 6, 8), and at Week 12 or end of treatment (ET).
`
`The primary efficacy endpoints at Week 12/ET were the:
`• Incidence of Success obtained from the GAAS (Global Acne Assessment Scale).
`Success was defined as a score of O (none) or l (minimal) on a 5-point static GAAS, and
`• Mean percent reduction in inflammatory, non-inflammatory, and total lesion counts.
`The efficacy endpoints were achieved ifDTG was superior to VC based on the incidence
`of "Success", and the mean percent reduction in 2 of the 3 lesion count parameters.
`
`The 2 secondary efficacy variables were as follows:
`• Mean lesion count at Week 12/ET for inflammatory, non-inflammatory, and total acne
`lesions; and
`• Mean reduction-from-Baseline for inflammatory, non-inflam·matory, and total acne
`lesions.
`
`3. Are the active moieties in the plasma (or other biological fluid) appropriately
`identified and measured to assess pharmacokinetic parameters and exposure
`response relationships?
`
`Yes.
`4. What are the characteristics of the exposure-response relationships (dose-
`response, concentration-response) for efficacy and safety?
`
`The relationship between response in terms of efficacy (reduction in the number and
`severity of inflammatory and non-inflammatory lesions) and systemic safety, and blood
`(plasma) levels ofDAP were not investigated in any of the clinical studies. The 5% DTG
`· formulation was designed to deliver drug directly to areas affected by acne on the skin
`and to avoid systemic effects of both the drug and its metabolites; therefore, a blood level
`response relationship was not anticipated.
`
`5. What are the basic PK parameters?
`
`Cmax, AUC and t 112 values have been used as basic PK parameters.
`
`6
`
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`

`6. Is there any relationship between %BSA and DAP exposure? Also, is there any
`relationship between amount (gm) used and DAP exposure?
`
`%BSA: Plasma OAP levels and their relationship to body surface area were addressed in
`3 pharmacokinetic studies [Studies DAP9903, DAP0l 10, and 03-0-182] which had three
`different fixed body surface treatment areas throughout the study. Patients in these
`pharmacokinetic studies had similar plasma OAP levels after application of 5% DTG to
`body surface areas ranging from ~5% (face only) to ~22.5% (maximum treatment area to
`face, chest, back and shoulders). The difference in exposure between face-only treatment
`(4.5% BSA) at 100 mg/day OAP (DAP9903) and maximum treatment area (22.5% BSA)
`at 110 mg/day OAP (DAP0l 10) was small, suggesting there is little correlation between
`treatment area and OAP exposure for 5% DTG (Table 1).
`
`Amount used: The relationship between individual plasma OAP concentrations and
`product use (dose) was investigated for Study DAP0l 10 and Study 03-0-182. The data
`from both studies show little, ifany, correlation between the amount of product applied
`and OAP concentration between individuals, for product usage ranging from less than 1
`to over 14 g/day (Table 1).
`
`When a range of topical OAP doses (10 to 100 mg/day) was compared (DAP9903),
`plasma exposure to OAP increases less than proportionally, suggesting that there may be
`a reasonably low upper limit to total dermal absorption. Consequently, even excessive
`application of the product would not lead to plasma exposures in the range of that
`observed during oral OAP therapy.
`
`In Study DAP0l 14, the highest OAP concentration (107 ng/mL) during 5% DTG
`treatment occurred in a patient who used over 11 g/day of product (over 550 mg/day of
`OAP) for 12 months. In Study 03-0-182 one patient had a OAP concentration of 112
`ng/mL on Day 35 (the final day of the DTG only treatment) and 120 ng/mL on Day 42
`(final day ofDTG and TMP/SMX treatment). OAP levels in these patients were
`also well below those associated with oral OAP use.
`
`Table 1: Plasma OAP Concentrations in Acne Vulgaris Patients Treated Twice Daily with 5% OAP
`Topical Gel
`
`APPEt,.RS nns WAY
`ON OR\G\NAl
`
`7
`
`8 of 50
`
`

`

`Treatment
`{route!
`5%DTG
`[topicaQ
`
`5%0TG
`[topical}
`
`5%0TG
`[topic,,IJ
`
`Dapsone
`[Oraij
`
`5%0TG
`[topical]
`
`N
`439
`
`12
`
`18
`
`10
`
`20
`
`Dapsone
`Application
`Application (mg/day) Area
`No. Doses
`(¾BSA)
`[frequency] Mean±SO {Range]
`61.5 ± 54.0
`Upto22.5%
`491°
`[0-5511
`[2x!d]
`55
`[2xid]
`
`100 ±0°
`
`4.5%
`
`28
`(2xid]
`
`(single dose j
`
`42
`[2xid]
`
`110 ±60
`[40-275]
`
`100±0
`
`329 ± 197
`[93- B6]
`
`22.5%
`
`NA
`
`20%
`
`C,,,.,.(ng!ml)
`Mean±SD
`{Range]
`7.5 ± 10.1 5
`Fl05-107J
`15.1 ± 7.5
`(2.66- 31.4]
`
`19.7 ± 10.2
`[S.8-48.5]
`
`1375:t517
`[523 - 2353]
`
`26.8 ±23.2
`(5-77-101.3]
`
`AUC(ng•h/ml)
`Mean±SD
`[Range]
`ND
`
`318±159
`[46.0-657]
`
`415±224
`[1e4 -1C67J
`
`52.64 1 ± 35,224
`[23155 - 1378!0]
`
`584.9± 516.1°
`[ 120.2 - 2260]
`
`Study No.
`OAP0I 14
`
`OAP99<33
`
`O.A.P01 IO
`
`DAP01 l0
`
`03-0-182
`
`Values sha,,n are mean± S.D.
`Abbre~iations: BSA=body surface area; C,.,,=Maximum plasma concentration after last dose; AUC=Area under plasma
`concentralion versus time cur,e over 24 hours after last dose; ND=Not determined, NA=No1 applicable.
`• Mean number of applications per patient
`
`" For Study DAPOl 14 a single sarrple for each patient was taken al some time during the day. See Figure 4.
`
`c For study D.A.?9903 DTG was provided in a foil pouch with 1 g of the formulation for each appiicalion.
`
`d For study 03-0-182_. the AUG = 2 x AUC,.12 _
`
`7. Is there any relationship between G6PD deficiency, systemic exposure and
`adverse events from topical 5% DTG applications?
`
`The following sections will discuss this issue:
`
`What is the pharmacological implication ofG6PD deficiency?
`
`Glucose-6-phosphate dehydrogenase (G6PD) plays an important role in preventing
`oxidative injury to red blood cells and preventing lysis. This enzyme catalyzes the
`oxidation of glucose-6-phosphate to 6- phosphogluconate, while concomitantly reducing
`nicotinamide adenine dinucleotide phosphate (NAOP+ to NAOPH). NAOPH is
`particularly important in red blood cell physiology as a necessary co-factor for
`glutathione reduction as reduced glutathione scavenges oxidative metabolites. Patients
`who are G6PO deficient are more sensitive to hemolytic changes associated with
`oxidative stress, which may result from OAP or other drug exposure, infection and
`ingestion of fava beans (favism). Individuals with G6PO deficiency may experience
`adverse effects at lower plasma OAP concentrations than G6PO normal subjects.
`Literature suggests that hemolytic effects are typically associated with OAP doses of
`> 100 mg per day in normal patients and >50 mg in G6PO deficient patients.
`
`What is the possibility of hemolytic effects in normal and in G6PD deficient patients from
`5% DTG exposure?
`
`Based on the following discussion, it appears that the OAP exposure at which normal
`(i.e., exposure equivalent to l 00 mg oral OAP) as well as G6PO deficient patients (i.e.,
`
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`
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`
`

`

`exposure equivalent to 50 mg oral OAP) may suffer from hemolytic adverse events is
`practically unattainable from 5% OTG.
`
`The mean AUCo-24 after topical application was 415 ng·hr/mL and the mean gram usage
`was 2.2 grams per day. The mean AUCo-inf after a single 100 mg oral dose was 52,641
`ng·h/mL. However, we need to keep in mind that systemic exposure from topical
`application does not change linearly with dose (amount) applied because systemic
`exposure from topical application is an interplay between application area and amount
`used. Therefore estimation of systemic exposure from any particular topical dose is
`difficult simply based on systemic exposure data from another topical dose. However, an
`approximate estimation may be made in the following way. In order to achieve a OAP
`exposure level consistent with a l 00 mg oral OAP dose using topical administration of
`5% OTG, 280 grams [(52641 ng·h/mL /415 ng·h/mL)*2.2 g] of 5% OTG would have to
`be applied per day. A similar calculation for a 50 mg oral OAP dose would result in a
`topical administration of 5% OTG of 140 grams per day. Since 30 grams would typically
`cover l 00% of a 70 kg person, application of 140 to 280 grams of 5% OTG is not
`feasible. To put this in perspective, the average daily gram use in the studies presented in
`this NOA ranged from 1.3 grams to 2.2 grams. The highest daily gram use in Study
`OAP0l 14 was l l.0 grams. Concentrations of OAP hydroxylamine, a metabolite
`postulated to be responsible for hematologic effects, including idiosyncratic
`agranulocytosis and dose-dependent hemolysis were measured in study 03-0-182. This is
`a pharmacokinetic drug-drug interaction study with trimethoprim/sulfamethoxazole
`conducted under maximal 5% OTG usage conditions in patients with acne vulgaris. OAP
`hydroxylamine levels were minimal, stable and approximately 12% of the parent
`compound, a ratio similar to oral dosing reported in the literature. Therefore, the
`relationship between oral and topical exposure for the OAP hydroxylamine metabolite is
`expected to be similar to the relationship observed for the OAP parent compound.
`
`Plasma OAP and NAD levels were collected in two studies, OAP0l 10 and OAP0l 14,
`which enrolled a total of six G6PO deficient patients, l patient in OAP0 l l 0 and 5
`patients in OAP0l 14 (Table I). Five patients identified as G6PO deficient were treated
`with 5% OTG twice daily for up to 12 months in Study OAP0l 14. One G6PO patient
`was treated for 2 weeks in Study OAP 0110. The G6PO deficient patients (2 males, 4
`females) ranged in age from 12 to 32 years.
`
`Table I: Number of Patients with G6PD Deficiency in Clinical Studies of DAPTopical Gel
`5% Daosoue Tookal ~I
`Gt>l Vehicle
`SmdvDAPO!lO
`F18
`(5.5%)
`Stndy DAPOl 14
`(1.4%)
`5/360
`57?2
`(0.7%)
`Study DAP0203
`Smdv DAP0204
`14/734 {1_9%)
`Total
`15
`Deuommator represems munber of pallents who had G6PD acunty measured
`t One G6PD deficient patien: (whide group) did not h,,\·c post-ba-seline data
`NA: not applicable
`Overall, plasma concentrations of OAP and NAD in these patients, determined at various
`times after l week to 12 months of treatment, were similar to those in G6PO normal
`patients. This was expected as G6PO deficiency is not supposed to alter systemic
`exposure of OAP. There were no patients (normal or G6PO deficient) with hemolysis or
`
`NA
`7/722
`(L~i>)
`!Si745
`(2-41%)+
`25
`
`9
`
`10 of 50
`
`

`

`hemolytic anemia reported in any studies conducted in support of the acne vulgaris
`development program. There were no patients with methemoglobinemia reported in any
`studies conducted in support of the topical DAP gel acne vulgaris development program.
`
`Was any relationship observed between changes in hemoglobin and plasma DAP levels
`following 5% DTG application?
`
`Fluctuations in plasma hemoglobin is the most sensitive biomarker for hemolytic adverse
`events attributed to DAP toxicity. Overall, hemoglobin values stayed nearly constant and
`did not correlate with plasma DAP levels. Plasma DAP levels were low(< 40 ng/mL) in
`most patients at all time points. Patients with high plasma DAP concentrations did not
`have a change in hemoglobin levels, and patients with a ;;:1 or ;;:2 g/dL decrease in
`hemoglobin did not have high plasma DAP levels, as described in the following section.
`
`The change in hemoglobin versus DAP plasma levels for all patients with DAP blood
`levels from Study DAP0l 14 and the G6PD deficient patients (N=5) from this study is
`shown in Figure I. The negative change in hemoglobin versus DAP plasma levels is
`shown in Figure II.
`
`In Study DAP0l 10, there was no correlation between plasma DAP concentrations and
`changes in hemoglobin. The G6PD deficient patient (Patient 0103) in this study, had a
`1.3 g/dL reduction in hemoglobin, which was comparable to reductions observed in six
`non-G6PD deficient patients and his Cmaxwas 21.82 ng/ml compared to the mean Cmax of
`19.66 ng/ml for all 18 patients in this study. Similarly in Study DAP0l 14 also, there was
`no correlation between plasma DAP concentrations and changes in hemoglobin.
`Fluctuations in hemoglobin values for the G6PD deficient patients in this study were
`similar compared to the non-G6PD deficient patients after long-term treatment. In all
`G6PD deficient patients, hemoglobin levels were generally stable over time. Of note,
`Patient 0317 (patient with severe G6PD deficiency) did not have a reduction in
`hemoglobin of2::l g/dL at any time during the study. Based on data from DAP0l 10 and
`DAP0l 14, there does not appear to be a relationship between plasma DAP levels and
`changes in hemoglobin, regardless of G6PD activity.
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`10
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`11 of 50
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`

`All Values
`
`!(()
`
`100
`
`i BJ
`.s .,
`1i t ..I
`0 "' ~ .. Q .. .!I) e
`"' .. it
`
`<II
`C
`
`(')l)
`
`,o
`
`()
`
`-t
`
`••
`
`G-6.PD Deficient Patients
`
`1/.fJ
`
`na
`
`3
`
`E t ;,o
`~ > " ..I
`I 01
`i Cl ,.
`§
`" ii:
`
`,,o
`
`.w
`
`1 Ni
`~ ~ -· -~
`G
`
`~
`
`N' = 1895
`
`••
`
`N'=·l9
`
`... . . .. ..
`
`• • •
`
`Change In Hl!lllaglobin (g/dL)
`
`Figure I: Change in Hemoglobin vs. OAP Plasma Levels (*N = Number of blood draws)
`
`11
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`12 of 50
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`

`;,:)
`
`~-l
`
`,,
`
`"
`
`N .. :: 1245
`
`Figure II: Negative Change in Hemoglobin vs. Plasma OAP Levels
`
`Clm!g< in Hemoglobwl (g/dl.l
`
`In Studies DAP0203 and DAP0204, no differences were observed in hemoglobin changes
`between 5% DTG treated patients and vehicle treated patients, regardless of G6PD
`activity. The variability of the changes in hemoglobin for the G6PD deficient patients
`was smaller than that of the overall population; the maximum reduction in hemoglobin in
`any G6PD deficient patient was 1.5 g/dL.
`
`Was any relationship observed between changes in hemoglobin and G6PD deficiency
`following 5% DTG application?
`
`There was no relationship between changes in hemoglobin and extent of G6PD activity,
`even in patients with severe G6PD deficiency, as described in the following section.
`
`Changes in hemoglobin were assessed in the patients in the four studies (Studies
`DAP0 110, DAP0 114, DAP0203 and DAP0204) where G6PD activity was measured. A
`summary ofreductions in hemoglobin by G6PD status is provided in the following
`Tables:
`
`Table II: Reduction in Hemoglobin by G6PD Activity in Study DAP0ll0
`
`Reduction iu Hemoglobin
`2 l g:dLReduc!iou
`
`G61'D Deficienr Patients
`n=l
`l
`
`?\on-C.:6PD Deficient Patients
`n=l7
`6
`
`:::: 2 g'dL Reduc1ion
`
`0
`
`1
`
`Table III: Reduction in Hemoglobin by G6PD Activity in Study DAP0114
`
`Reduction in Hemoglobin
`
`G6PD Defidenr Patients
`n=.:::
`
`:Non-Go"PD Deficient Patients
`N=-481
`
`2 1 gidL Reduction
`Overall
`!\-fonth 1
`~ 2 g . .-d.L.Reductiou
`O;·erall
`Month 1
`
`l
`0
`
`0
`0
`
`12
`
`155
`42
`
`16
`3
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`

`Table IV: Reduction from Baseline to End of Treatment in Hemoglobin by G6PD
`Activity in Studies DAP0203/DAP0204
`
`Reduction in
`Hemoglobin
`
`':: 1 g:!dLRed~tion
`
`2: 1 g/dL Redrn:ti=
`
`G6PD Deficieuc Pati.,uts
`Yehide
`5%DTG
`n="~
`n=l9
`5
`
`3
`
`"ou-C:61'D Deficient Patient;
`Vehicle
`5%DTG
`u=l4S7
`n=1479
`152
`
`()
`
`()
`
`10
`
`146
`s
`
`In all studies, the reduction in Hemoglobin in G6PD deficient patients are comparable to
`that from nonG6PD deficient patient. Prolonged use of 5% DTG did not lead to
`differences in reductions in hemoglobin compared to the vehicle controlled Studies
`DAP0203/DAP0204.
`
`8. What is the major route of elimination?
`
`A major pathway of DAP metabolism is the formation ofNAD (NAD) by N-acetyl
`transferase. The acetylation of DAP is reversible, resulting in a relatively constant ratio of
`the N-acetyl metabolite to DAP in plasma during the elimination phase. DAP is also N(cid:173)
`oxidized by CYP2E l and CYP 3A4 to produce OAP hydroxylamine (DHA). The major
`side effects of OAP (methemoglobinemia, agranulocytosis) are linked to the formation of
`OAP hydroxylamine.
`
`Plasma exposure to the metabolite NAD after 5% OTG treatment was approximately 1 %
`to that obtained after oral OAP (Study OAP0I 10) .. After administration of 5% DTG,
`NAD levels remained less than, and declined in parallel with the levels ofDAP in plasma
`observed for oral OAP. Limited data obtained in this study also suggest that urinary
`excretion of OAP hydroxylamine was. also about l % to that that obtained following the
`oral formulation. These data show that 5% OTG treatment is not associated with
`increased DAP metabolite exposure, and that topical administration should not alter the
`metabolism of OAP.
`
`C. Intrinsic Factors
`
`l. What intrinsic factors (age, gender, race, weight, height, disease, genetic
`polymorphism, pregnancy, and organ dysfunction) influence exposure and/or
`response and what is the impact of any differences in exposure on the
`pharmacodynamics?
`I What are the effects of Gender, Race and Age on 5% DTG exposure?
`
`No significant effects of gender or race on the levels of OAP in plasma during 5% OTG
`treatment were apparent in these data. Similarly, OAP exposures are consistent between
`the two age groups (12-15 years vs~ 16 years) indicating no difference in DAP plasma
`levels related to age. Overall, gender, race and age did not demonstrate any clinically
`
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`significant effect on OAP pharmacokinetics following use of 5% DTG in these patient
`populations.
`
`During the clinical development of 5% DTG, OAP pharmacokinetics were monitored in
`studies that enrolled male and female acne patients between the ages of 12 and 77 years,
`and from ethnic groups identified as white, black, Hispanic, Asian, and other. Since the
`greatest number of patients (Study DAP0l 14) had OAP concentration measured at Month
`3, the following tables are based on these data. Data from other time points were
`consistent with Month 3 data.
`
`Table 2: Plasma OAP Concentrations (ng/ml) in Male and Female Acne Patients after 3 Months of Twice-Daily
`Application of 5% OAP Topical Gel (Study OAP0114)
`Female
`N
`216
`8.7 ± 10.0
`Mean±SD
`62
`Median
`0.0-68.5
`Range
`All patients with plasma levels at Month 3 included.
`
`Male
`192
`9.6± ·1·1.9
`6.·1
`0.0- 87.l
`
`Table 3: Plasma OAP Concentrations (ng/ml) by Race/Ethnicity in Acne Patients after 3 Months of Twice-Daily
`Application of 5% DAP Topical Gel (Study OAP0114)
`White
`Black
`Hispanic
`Asian
`28
`N
`321
`35
`8
`9.5 ± "11.4
`6.0 ±6.3
`7.6 ± 8-7
`17.0± 9.9
`Mean± SD
`6.4
`3.4
`14.7
`Median
`4.0
`0.0-87.'I
`0.0- 30.4
`0.0- 24.9
`7.4 - 31.9
`Range
`Includes all patients with plasma levels at Month 3 in the ethnicity groups shown.
`
`Other
`6
`2.5 ± 3.1
`1.7
`0.0- 8.4
`
`Table 4: Plasma OAP Concentrations by Age in Acne Patients after 3 Months of Twice Daily Application of
`5% DAP Topical Gel (Study OAP0114,)
`
`Parameter
`N
`Mean ±SD
`Median
`Range
`
`Plasma Dapsone Level
`12-15 years
`(ng!ml)
`'!55
`8.77 ± 1t5
`5.8
`0.0-87.1
`
`Plasma Oapsone Level
`2'.:16 years
`(ng/rnl)
`253
`9.35 ± 10.6
`6.6
`0.0-82.2
`
`Does genetic polymorphism ( - - - - - - - - - . play any role on clinical outcome
`following 5% DTG application?
`
`< !
`
`(
`!
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`l4
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`____.._/ _ Page(s) Withheld
`
`- - Trade Secret / Confidential
`
`- - Draft Labeling
`
`Deliberative Process
`
`Withheld Track Number: Clin Phann/Bio-_l__
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`{
`
`D. Extrinsic Factors
`
`1. What extrinsic