CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION NUMBER: 20-965
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTICS REVIEW(S)
`
`

`

`.NOV l9 I998
`
`Clinical Pharmacology/Biopharmaceutics Review (Addendum)
`
`
`DUSA Pharmaceuticals Inc.
`Aminolevulinic HCl, 20% Topical Solution
`Valhlla, NY 10595
`Levulan" Kerastickm
`.
`Submission Date:
`Reviewer: A. Noory
`NDA 20-965
`June 29, 1998
`
`
`Addendum
`
`This document is an addendum to the review dated 5-Nov-98 and is addressing the pharmacokinetics and
`dosage and administration section of the package insert for Levulan® Kerastickm.
`
`Comments for Labeling:
`
`Under the “Pharmacokinetics” heading, replace the second and the third sentence with; The oral
`bioavailabilig of ALA was 50-60% with a mean Cmax of 4.65+/-0.94 gym]. Also in the same paragraph
`replace the fourth sentence with; The PQIX concentrations were low and were detectable only in 42% of
`the plasma samples.
`Under the harmacokinetics headin , after the third sentence insert the following two sentences:
`:’____
`Therefore Levulan should
`'6‘ I Be a
`n y
`
`Qplied to the affected skin.
`UnderthfiDOSAGEANDADMDHSTRATIO ” in the second sentence replace “14-1 8 hours”
`I
`
`with ’
`
`
`
`- Assadollah Noory
`Pharmacokineticist
`‘
`-
`(
`Division of Pharmaceutical Evaluation 11]
`Team Leader: E. Dennis Bashaw,Pharm.D.iZ-SZ)/Z ”g ’1
`I
`
`NDA 20-965 (ORIG),
`cc:
`HFD-540/DIV. File
`
`HFD-540/Prj. Mjr/Cintron
`HFD-880 (Noory)
`HFD-880 (Bashaw)
`RFD-880 (Lazar)
`(CDR. Attn. B. Murphy)
`RFD-344 (Viswanathan)
`
`APPEARS THIS WAY .
`0N ORIGINAL
`
`

`

`Nov'91998
`
`Clinical Pharmacology/Biopharmaceutics Review
`———————_—_—“—
`Aminolevulim'c HCl, 20% Topical Solution
`DUSA Pharmaceuticals Inc.
`Levulan" KerastickTM
`Valhlla, NY 10595
`Reviewer: A. Noory
`Submission Date:
`NDA 20-965
`June 29, 1998
`“M—
`
`Review of an NDA
`
`I. Background:
`
`Levulan® Kerastickm is a two component system applicator. The system (shown on Page 8
`of the appendix), consists of two ampoules, one contains the vehicle solution and the other contains
`354mg of Levulan® (aminolevulinic acid I-ICI). Levulan® is mixed with the vehicle solution to
`produce a 20% solution just before application by a health professional by crushing the ampule in the
`applicator. Levulan® photosensitizes actinic keratoses lesions (AK) by inducing the accumulation
`of protoporphyrin IX (PpIX) in cells and tissues for photodynamic therapy with the 4170 Blue Light
`Photodynamic Therapy Illminator (BLU-Um). As part of this NDA, the applicant has submitted the
`results of a pharmacokinetic study using both intravenous and oral closing, a pharmacokinetic study
`,7 WWWmmymmmwmmm absorptionsmdyt Aminolevulinic acid
`HClis a white to off-white crystalline powder, highly soluble in water, sparingly soluble in ethanol
`and methanol, and insoluble in mineral oil or hexane with a molecular weight of 167.59. The
`chemical name of Aminolevulinic acid HCl is 5-amino-4-oxopentanoic acid hydrochloride with the
`following structural formula.
`
`0
`
`0
`
`NH;
`
`or
`
`11. Recommendation:
`
`In support of the human pharmacokinetic and bioavailability portion of this NDA the applicant
`submitted the result ofthree studies. These studies adequately characterized the pharmacokinetic
`and bioavailability ofaminolevulinic acid from the Levulan® Kerastickm. From the
`biopharrnaceutics point of view the NDA 20—965 is approvable.
`
`NDA 20-965. Page ii
`
`

`

`INDEX
`a“
`I. Background
`-
`-
`-
`-
`-
`-
`-
`-
`11. Recommendation
`-
`-
`-
`-
`-
`-
`-
`III. Overview of pharmacokinetic section
`-
`-
`-
`-
`-
`Analytical
`-
`-
`-
`-
`Pharrnacokinetic study (protocol # PK-Ol)
`Phannacokinetic study (protocol # Pharm-03)-
`In Vitro Percutaneous study (Study # ALA-97-l)-
`IV. Conclution
`-
`-
`-
`-
`-
`
`-
`
`-
`
`-
`
`O‘UIAUJNNt—H
`
`-
`
`-
`
`-
`
`111. Overview of pharmacokinetic section/disease:
`
`The human pharmacokinetic and bioavailability section ofthis NDA consists ofthree study
`reports:
`1. Pharmacokinetics of S-Aminolevulinic Acid (ALA) and protOporphyrin IX (PpIX) in healthy
`Volunteers after Intravenous and Oral Dosing, (PK-01)
`2. Pharmacokinetics ofLevulan Induced Protoporphyrin IX in Actinic Keratosis and Adjacent
`Skin, (Pharm-OB)
`3. In Vitro Percutaneous Absorption of [14C]-Aminolevulinic Acid in Human Skin.
`
`Chronic exposure to sunlight may increase the incidence of squamous and basal cell carcinoma
`of the skin in fair, white-skinned persons which is directly related to the amount ofyearly sunlight to
`the exposed area. Precancerous keratotic lesions (actinic keratoses [AK] ) are frequent consequences
`of many years of over-exposure. The keratoses are usually hard and sharp on palpation, and gray to
`dark in color. They differ from warty brown seborrheic keratoses, which increase in number and size
`with age but occur on covered as well as uncovered areas of the body and are not premalignant.
`
`The accumulation of protoporphyrin IX (PpIX) in actinic keratoses and photosensitization of the
`lesion by light of a certain wavelength will result in necrosis of the lesion. Aminolevulinic Acid
`(ALA), an endogenous substance, is an intermediate in the biosynthesis of porphyrins, it induces the
`accumulation of PpIX. Attachment 9 ofthe appendix shows the pathway for the synthesis ofPpIX.
`
`Levulan® Kerastick'm will be applied by a health profetional to assure the proper amount and
`method of application. As mentioned previously the system consists of two ampoules, one contains
`the vehicle solution and the other contains 354mg of Levulan® (aminolevulinic acid HCI). The
`formulation of the vehicle solution is shown in page 10-11 of the appendix.
`
`Analytical:
`
`The analysis ofPpIX in human plasma was carried out by{
`_l
`ased on a method by Meyer and Vogt “Ion-Pair Reversed HPLC
`Determination of Porphyrins from Red Blood Cells” Ch moto
`hia Vol. 16, P190. The assay was
`shown to be(spicific for PpIX and linear over a range ofi
`ig/ml. The lower limit of
`quantitation [Jig/ml. Representative chromatograms are included in the appendix, page 12. The
`analysis of ALA was based on a method by Okayama et a], Clin. Chem. 36: 1494-1497, 1990. The
`
`NDA 20-965, Page #
`
`2
`
`

`

`lug/ml. The lower limit
`assay was shown to be specific for ALA and linear over a range of;
`of quantitation}
`pg/ml. Representative chromatograms are included in the appendix, page 13.
`
`Pharmacokinetic and Bioavailability: Study # PK—Ol
`
`The objective of this study was to determine the bioavailability of S-aminolevulinic
`acid.(ALA). Also the plasma concentrations ofprotoporphryin IX (PpIX) were measured. Six
`healthy male volunteers were enrolled in this crossover study. Each subject received an intravenous
`and an oral dose of 128mg ofALA HCl (equivalent to 100mg ofALA) with a washout period of 6-7
`days. The solution for injection was also used for oral administration. The study design was a two-
`way crossover, and the trial is summarized in the appendix page 14-17. The table below shows the
`AUC and the Cmax for ALA afier Oral and the IV administration.
`
`
`1 SD; N=6
`Pharmacokinetic Parameters for ALA; Mean
`parameter
`a?:73 a tE
`
`7.30 i 1.25
`j
`AUC (0-00) pg‘hr/ml
`;
`
`
`4-65 i 0-94
`
`
`% Bioavailability — 60.3: 13.4
`i
`
`
`
`
`The mean plasma concentration-time curves for ALA are shown below.
`
`ALA: Plasma Levels after the Administration of Levulan
`
`dad—I”#0,“
`Concentration(meglml) 3
`ON‘O’O
`
`
`
`Although the plasma concentration profile for the ALA was determined easily, the plasma”
`concentration profile for the PpIX could not be determined at all. The PpIX concentrations were low
`and erratic. Following the intravenous and oral administration of ALA, the levels of PpIX was only
`detectable in 48% and 38% of the plasma samples respectively. The levels are shown on page 18 of
`the appendix. The results of this study demonstrate that the level of PpIX does not correspond to
`ALA administered. In fact, in one subject (# 4) the concentration of PpIX was similar or higher
`
`NDA 20-965, Page #
`
`J
`
`

`

`before the administration of ALA in both IV and oral dosing. This indicats that the production of
`PpIX could be dependent on the bodies need to maintain homeostasis.
`'
`
`Pharmacokinetic in Aetinic Keratosis: Study if Pharm—03
`
`The objective of—this study was 'tgevaluate the kinetics of PpIX in actinic keratoses and
`adjacent skin on the face and scalp following the application of Levulan using the Levulan"
`KerastickTM for Topical Solution, 20%. PpIX fluorescence was used to follow relative changes in
`PpIX concentration as a function of time (fluorokinetics), following topical application of Levulan.
`Twelve patients were enrolled in this study. Two sequential topical applications of Levulan Topical
`20% solution or Topical Solution Vehicle were made to each skin site using the Levulan Kerastick.
`A' representative fluorokinetics curves for lesional and adjacent skin obtained is shown below.
`
`30000
`
`25000
`
`20000
`
`
`
`
`
`FLUORESCENCE(RELUNITS)
`
`‘a lO‘O ,o 10000
`
`5000
`
`0
`
`0
`
`1o
`
`--~~
`
`20
`
`30
`
`40
`
`so
`
`_
`
`V TIME(HOURS)
`
`. AK LESION
`
`A ADJACENT SKIN
`
`The table‘below contains overall mean peak intensities for lesionaf'anfi adjacent skin
`fluorescence, expressed in arbitrary relative units. The individual data are on page 19 of the
`appendix.
`- *~ -—~-- -
`-
`--‘
`~
`~
`
`
`
`
`
`
`(Mean : SD); (N=12)
`j
`
`
`i——- Plateau Periodmoum
`
`__——_l
`
`——__
`
`
`
`
`
`These data indicate that there was little fluorescence selectivity following Levulan
`administration to AK lesion and adjacent skin sites on the face and scalp. The formation of Z‘pIX in
`healthy skin is similar to that of AK lesion site. Therefore Levulan should only be applied to the
`effected skin.
`
`,,NDA29-?65:P!sst
`
`4
`
`

`

`In Vitro Percutaneous Absorption OF [14C1-ALA in Human Skin:
`
`The study was conducted to evaluate the in vitra percutaneous absorption of ALA 20%
`Levulan Topical Solution in human cadaver skin. A comparison of penetration in intact skin versus
`the “stripped” skin was conducted. The ALA solution was radiolabeled with ALA (aminolevulinic .
`acid hydrochloride,»8-[4-14C]). Theskin was cut into—54 specimens approximately 9 cm2 each.
`Half ofthe skin specimens were tape-stripped to remove the stratum comeum, using up to 22
`sequential strips 05
`)transparent tape until a “glistening” of the skin surface was
`obtained or until e idermal separation started to occur. This skin was placed on the chambers of 54
`;iGlass Chambers. The exposed surface area was] .77 cm2. Two successive
`applications of 8.5 uL (8.5 mg) ofthe test formulation were applied to the skin surface (1.7 cm2) and
`allowed to air dry for 5 minutes before reapplying. This represented a dose of3.4 mg ALA/1.7 cm2
`or 2 mg ALA/cm2 applied to each of the chambers.
`Nine groups were designated according to the following schedule:
`
`l
`
`
`
`Data were analyzed to include all of the DPM data to calculate the percent and micrograms
`recoveries (Analysis I), and after discarding statistical “outlier” values for each compartment
`(Analysis II). The following table provides the results ofthe assays.
`
`r
`
`,
`V
`'
`Txme (hrs)
`
`
`
`a
`
`In Vitro cumulative Penetration of [l4C]-ALA
`
`Intact Skin (Mean 1 SD)
`‘
`STRIPPED Skin (Mean 1 SD)
`--m ug/mcmz --m- Hall-77cm
`
`
` 0.5 i 0.5
`
`15 E 17
`22.3 i173
`757 t 6.5
`0.7 i 0.6
`‘
`25 1 19
`29.2 i 19.8
`
`
`1—- 1.4: 1.0
`47235 n 43.3 :17 2
`
`
`The results also show that the intact stratum comium presents a significant barrier to ALA
`absorption and skin uptake. Many skin diseases, including actinic keratosis, have been reported to
`have a defective skin barrier. Therefore, one can view the results of the present study as
`approximating the range of skin absorption of ALA in intact skin relative to skin in which the barrier
`' has been abrogated by disease.
`
`NDA 20-965, Page 71
`
`5
`
`

`

`IV. Conclusion:
`
`The results ofthese studies demonstrate that the systemic exposure to PpIX following the topical
`application of Levulan® Kereastickm will most likely be undetectable as the body produces about 350mg of
`ALA to maintain the homeostasis. Additionally the topical absoption ofALA is about 2% ofthe applied
`dose, furthermore, for the syntesis of one mole ofPpIX eight moles ofALA is needed. The resulting PpIX
`could practically be indistiguishable fi-om the endogenous production of PpIX
`
`./
`
`/
`
`—
`
`Z §2
`
`Wig/93
`
`Assadollah Noory
`A
`Pharmacokineticist
`Division of Pharmaceutical Evaluation III
`
`Il ”Z ‘71 74
`
`Team Leader: E. Dennis Bashaw, Pharm.D/S/
`
`NDA 20-965 (ORIG),
`CC:
`HFD-S40/DIV. File
`
`HFD-540/Prj. MerCintron
`HFD-880 (Noory)
`m-mashaw) ‘
`HFD-880 (Lazor) /
`(CDR. Arm. B. Murphy)
`HFD-344 (Viswanathan)
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`_,
`
`.
`
`,
`
`NDA 20-965, Puget!
`
`6
`
`

`

`Appendix
`
`
`
`

`

`BEST POSSIBLE COPY
`
`Figure 0.2
`
`Levulan® Kerastick'" and Component Parts
`
`
`
`APPEARS THIS WW
`0" ORIGINAL
`
`

`

`BEST POSSIBLE COPY
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`B-Aminolevulinic Acid
`Synthase
`
`B-Aminolevulinic Acid
`
`Porphobilinogen
`Deaminase
`
`Uroporphyrinogenlll
`Cosynthase
`
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`Decarboxylase
`
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`
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`Oxidase
`
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`on ORIGINAL
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`f3;
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`
`
`KERAsnOK'iv FOR TOPICAL SOLUTION. 20%
`
`
`a ' Theoretical Quantity " Theoretial Quarjm'
`
`
`
`ty’ Theoretical Percent
`(mg/mu
`‘
`(w/v)
`
`
`Table 0.3
`
`'
`
`-l‘‘._.,..
`
`
`
`
`.
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`USP
`
`Vehicle
`
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`STUDY: PHARM-03
`.‘ AOnVAféO LEVULANO KERASTICK'“ FOR TOPICAL SOLUTION, VEHICLE
`
`
`
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`
`
`
`
`Polyethylene Glycol 1
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`
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`(quanmylvlal)
`3(quanlitylmL)
`
`
`
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`
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`

`Volume: 1.23
`
`NDA # 20965
`Study Type:
`Study Title:
`
`Submission Date: June 29, 1998
`Bioavailability
`Study # P1001
`Pharmacokinetics ofS-arninolevulinic Acid (ALA) and protoporphyrin D( in Healthy Human
`Volunteers Afier Intravenous and Oral Dosing
`Clinical Investigator:
`Analytical Investigator: ;
`
`Site:
`Site:
`1/
`‘
`
`/
`
`Study Objective: To describe the bioavailability ofLevulan and the phatmacokinetics ofLevulan and PpIX in the
`plasma of normal volunteers.
`
`Study Design:
`Single Dose: 3.
`Cross-Over: 3
`Fasted: 2g
`Food Study:
`
`'
`
`Multiple Dose:
`Parallel:
`Post Dosing:
`Food Type:
`
`Randomized: X
`Other Design:
`
`Washout Period: One Week
`
`Study Subjects: Six healthy male subjects (5 Caucasian, 1 Black) were enrolled in this study. Allsubjects
`completed the study.
`
`Subject Breakdown
`
`
`1‘
`Weight (range); lb
`Age (range); years
`Number ofSubjects
`i
`Height (range); inches
`
`7 — 7 mum-73m
`.
`
`
`
`
`
`
`
`Drug Products
`”If Drug Product -§I__m Packing L0! #
`
`
`)
`ALA HCl
`l28 mg, (eq. To 100mgALA)
`Injection & Oral
`5l41885
`
`L
`
`Diluent for 5-ALA HCl injection; lOml/vial
`
`
`
`.IIIE-J
`
`Plasma:
`
`‘
`
`Sampling Times
`Blood samples were collected at 0, 0.], 0.25, 0.5, 0.75, I, LS, 2, 3, 4, 5, 6, 7, 8, IO,
`12, and 24 hours afier dose administration. The 0.1 hour was omited for oral
`administration.
`Assay Method: (:18 used for determination ofprotoporphyrin D(.
`Assay Sensitivity:
`10 ng/ml
`Assay Accuracy:
`% Theor. range from
`Assay Precision:
`"/oCV range (to
`
`“
`
`‘
`
`APPEARS THIS WAY
`on ORIGINAL
`
`

`

`ALA: Plasma levels after intravenous Administration
`
`
`
`Concentration(mcglml)
`
`
`
`0123456789101112
`
`Timoihn)
`
`+Subj1 +Sub]2 +Subj3 —)(—Sub]4 +Sub15 +Subj6
`
`ALA: Plasma Levels after Oral Administration
`
`
`
`Conoonmtion(mcglmi)
`
`r'ouauomu
`.L‘
`
`Tim. (hi3)
`
`+Subj1 +Sub12 +Sub33 +Subj4 +Subj5 +Subi6
`
`

`

`
`
`'ll' MEANALA h-...AN HASMA
`
`
` mammmm==mwEW_mmmm==wEmA,Mm—mmmm=_m.Em_m_mmmm_____mmm
`mmmmamEm.=55
`Mammmm==mEm
`NEW.mmmE—mmmm
`
`mammmmE—m_mmm
`
`
`m___mmmm____mm_.mm
`m_m_mmfim_m_mmm
`
`
`___m.mmfm____m,mmm
`_—_mmmm____mWmmm
`
`___mmm_____m_
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`
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`
`

`

`C
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`
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`
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`_ —
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`
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`mllko IBM-mm
`
`TABLE III - SUMMARY OF ALA PLASMA PHARMACOKINETICS
`
`’III' PKIN I ABLE
`
`_
`ISO—M
`mm
`1721!!
`——
`
`“-1-
`Tot. CI.
`1
`Tot. Cl
`mllmln E mllmlnlk
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`
`Page 1
`
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`
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`6 so
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`—
`_
`
`
`

`

`'VII'SUMMARY u.
`
`r’PIX CONC’S
`
`0
`
`__-__m
`__-__m
`
`__mam
`=mW=m
`__mw=m
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`1 2 3
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`Imm—lmmnmmmmummmu-mn—
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`Page 1
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`"annular-elm
`
`Fin-7‘. I”:
`
`Table 2. Summary oprIX fluorokinetics results. When the peak or half-life occurred during a rest
`pa'iod, ranges or estimates are reported in brackets. The error on the peak end plateau time estimates
`is at least :2 hr. and #2000 rcl. units on peak intensity estimates. Values derived fi'om me: where
`peek times are not during the rest period have a smaller error.
`
`
`5n83
`
`aflalaU8a
`
`8a
`
`ed'acem
`
`ed‘acenl
`
`adjacent
`
`
`
`
`
`
`
`
`gE
`
`
`NE
`E
`
`
`
`
`adjacent
`
`sun-
`dama . ed
`
`Irr
`
`not quite
`normal
`
`adjacent
`
`5355S
`
` overall leslon
`
`
`overall adjacent
`
`
`
`average:
`std.dev.. or
`range
`
`average:
`std.dev.. or
`range
`
`peak
`Intensity
`(reL units)
`
`peak
`time
`(no
`
`plateau period
`(ho
`
`t”
`(ho
`
`leslon grade
`and
`assessment
`of adjacent
`skin
`
`='.3.§ea:
`
`not quite
`normal
`
`reddened
`not to - tr
`
`(11000)
`
`III-.-
`
`(2)
`
`est.47-65
`
`A.og (14
`
`13£9
`
`Eélaél
`
`(15000)
`
`(14
`
`(16000)
`
`(10000 :
`4000)
`
`(13000 t
`4000)
`
`(43)
`
`—~____¥
`
`(7 t 1 to
`20 t 2)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`l9
`
`