`
`
`
`
`
`For Reference
`ken from this room ‘
`
`Not to be ta
`
`
`
`
`
`
`
`V AMN1038
`.
`‘
`An1nealv. Al|11irall, LLC
`IPR2018-00608
`
`AMN1038
`Amneal v. Almirall, LLC
`IPR2018-00608
`
`1
`
`

`

`
`
`
`
`
`PDR®
`
`6 I
`
`
`
`PEP PE
`
`EDITION
`
`
`
`
`
`
`
`
`
`
`
`Executive Vice President, PDR: Kevin D. Sanborn
`Senior Vice President, PDR Sales: Roseanne McCauIey
`lice President, Marketing: William T. Hicks
`\
`" ‘
`lice President, Regulatory Affairs: Mukesh Mehta, RPh
`~
`lice President, PDR Services: Brian Holland
`,
`Senior Director,‘Pharmaceutical Solutions Sales: Anthony Sorce,
`’DR Sales Managers: Frank Karkowsky, Elaine Musco,
`Jlarion Reid, RPh
`,
`,
`iational Solutions Manager: Richard Zwickel
`Senior Solutions Managers: Debra Goldman, Warner Stuart,
`,
`Suzanne E. Yarrow, RN
`'
`_
`Solutions Managers: Joseph Gross, Marjorie A. Jaxel, Lois Smith,
`(rista Turpin
`'
`Sales Coordinators: Dawn McPartIand, Janet Wallendal
`
`._
`)irector of Trade Sales: Bill Gaffney _
`Senior Manager, Direct Marketing: Amy Cheong
`
`,
`_
`Directbr,‘Editorial Services: Bette LaGow
`Manager, Professional Services: Michael DeLuca, PharmD, MBA
`Drug Information Specialists: Majid Kerolous, PharmD; Nermin-
`Shenouda, PharmD; Greg Tallis,‘ RPh
`'
`Project Editor: Lori Miirray *
`‘
`Manager, Client Services: Travis Northern
`Customer Service Supervisor: Todd Taccetta
`
`Manager, Production Purchasing: Thomas Westburgh
`PDR Production Manager: Steven Maher
`PDR Index Supervisor: Shannon R. Spare
`,
`Index Editor: Allison O’Hare
`,
`'
`Senior Prdduction coordinators: Gianna Caradonna,
`Yasmin Hernandez
`'
`Production Coordinator: Nick W. Clark
`Traffic Assistant: Kim Condon
`
`Senior Director of Product Management, Electronic Solutions:
`lalerie E. Berger
`.r
`Director of Product Management, Monographs: Jeffrey D. Schaefer
`Senior Marketing Manager: Kim Marich
`
`Production Design Supervisor: Adeline Rich
`,
`Senior Electronic Publishing Designer: Livio Udina
`Electronic Publishing Designers: Deana DiVizio, Carrie Faeth,
`Monika Popowitz
`‘
`'
`- Production Associate: Joan ,K. Akerlind
`Digital Imaging Manager: Christopher Husted
`Senior Director, ClientServices:Stephanie St’ruble
`Digital Imaging Coordinator: Michael Labruyere
`)irector of Operations: Robert Klein
`
`)Irector of Finance: Mark S. Ritchin,
`
`THOMSON > Copyright © 2007 and published by Thomson PDR at Montvale, NJ 07645-1725. All rights reserved. None of the content of this publica-‘
`tion may be reproduced, stored in a retrieval system, resold, redistributed, or transmitted in any form or by any means (electronic, mechan-
`$m
`ical, photocopying, recording, or otherwise) without the prior written permission of the publisher. Physicians‘ Desk Reference”, FDR”,
`PDR
`Pocket PDR", PDR Family Guide to Prescription Drugs®, PDR Family Guide to Women’s Health and Prescription Drug’s®, and PDR Family
`§uide to Nutrition and Health‘9 are registered trademarks used herein underlicense. FDR” for Ophthalmic Medicinesi F’DR“9 for Nonprescription DFUQS, Dietary
`gupplements, and HerbsyPDR‘P Guide to Drug Interactions, Side Effects, and Indications; PDR" Pharmacopoeia; PDRG’ for Herbal Medicines; FDR“ for Nutritional
`gupplements; PDR® Medical Dictionary; PDR® Nurse's Drug HandbookTM; PDR® Nurse’s Dictionary; FDR” Family Guide Encyclopedia of Medical Care; FDR“ Family
`autde to Natural Medicines and Healing Therapies; FDR” Family Guide to Common Ailments; FDR” Family Guide to Over-the-Counter Drugs; PDR® Family Guide to
`\lutritronal Supplements; and PDR" Electronic Library are trademarks used herein under license.
`I
`'
`
`L‘
`
`3:35;: of Thomson Healthcare, Inc.: President and Chief Executive Officer: Bob Cullen; Chief Financial Officer: Paul Hilger; Chief Medical Officer: Rich Klasco, MD,
`, Executive Vice President, Medstat: Carol Diephuis; Executive Vice President, Micromedex: Jeff Reihl; Executive Vice President, PDR: Kevin D. Sanborn; Senior
`V' LP
`‘
`.
`.
`.
`.
`.
`.
`-.
`.
`.
`5Igl‘tfjsresident, Technology: Michael Karaman; Vice PreSIdent, finance: Joseph Scarfone; Vice PreSIdent, Human Resources: Pamela M. Bilash; Vice PreSident, Planning
`“SlneSS Development: Ray Zoeller; Vice President, Product Strategy: Anita Brown; Vice President, Strategic Initiatives: Timothy Murray
`
`ISBN: 1-56363-568—2
`
`2
`
`

`

`
`
`
`
`
`
`
`
`PW
`9.2!,
`
`
`2007
`WPHVSlClAN
`
`DES
`
`E
`
`
`
`REF
`
`
`
`Executive Vice President, PDR: Kevin D. Sanborn
`Senior Vice President, PDR Sales: Roseanne McCauley
`Vice President, Marketing: William. T. Hicks
`\
`"
`Vice President, Regulatory Affairs: Mukesh Mehta, RPh
`-
`Vice President, PDR Services: Brian Holland
`Senior Director, Pharmaceutical Solutions Sales: Anthony Sorce -'
`PDR Sales‘Managers: Frank Karkowsky, Elaine Musco,
`Marion Reid, RPh
`,
`National Solutions Manager: Richard Zwickel
`Senior Solutions Managers: Debra Goldman, Warner Stuart,
`,
`Suzanne E. Yarrow, RN
`'
`.
`Solutions Managers: Joseph Gross, Marjorie A. Jaxel, Lois Smith,
`Krista Turpin
`'
`,
`\ Sales Coordinators: Dawn McPartland, Janet Wallendal
`
`Director of Trade Sales: Bill Gaffney
`Senior Manager, Direct Marketing: Amy Cheong
`SeniOr Director of Product Management, Electronic Solutions:
`-
`Valerie E. Berger
`_
`*
`;
`Director of Product Management, Monographs: Jeffrey D. Schaefer
`Senior Marketing Manager: Kim Marich
`
`_
`Director, Editorial Services: Bette LaGOW‘
`Manager, ProfeSsional Services: Michael DeLuca, PharmD, MBA
`Drug Information Specialists: Majid Kerolous, PharmD; Nermin
`Shenouda, PharmD; Greg rams, RPh
`‘
`-
`'
`Project Editor: L'ori Murray _
`‘
`_
`Manager, Client SerVices: Travis Northern
`Customer service Supervisor: Todd Taccetta
`
`Manager, Production Purchasing: Thomas Westburgh
`PDR Production Manager: Steven Maher
`PDR Index Supervisor: Shannon R. Spare
`Index Editor: Allison O’Hare
`’
`Senior Preduction Coordinators: Gianna Caradonna,
`Yasmin Hernandez
`.
`
`Production Coordinator: Nick W. Clark
`Traffic Assistant: Kim Condon
`
`Production Design Supervisor: Adeline Rich
`,
`Senior Electronic Publishing Designer: Livio Udina
`Electronic Publishing Designers: Deana DiViZio, Carrie Faeth,
`Monika Popowitz
`'
`Production Associate: Joan _K. Akerlind
`Digital Imaging Manager: Christopher Husted
`Digital [Imaging Coordinator: Michael Labruyere
`
`Senior Director,vclient Services: Stephanie Struble
`Director of Operations: Robert Klein '
`Director of Finance: Mark S.» Ritchin,
`.
`
`
`Montvale, NJ 07645-1725. All rights reserved. None of the content of this publica-
`Copyright © 2007 and published by Thomson PDR at
`' THOMSON '
`resold, redistributed, or transmitted in any form or by any means! (electronic, mechan—
`+5 tion may be reproduced, stored in a retrieval system,
`ical, photocopying, recording, or otherwise) without the prior written permission of the publisher. Physicians' Desk Reference®, FDR”,
`PDR
`Pocket PDRQ, PDR Family Guide to Prescription Drugs®, PDR Family Guide to Women’s Health and Prescription Drugs®, and PDR Family
`Guide to Nutrition and Health” are registered trademarks used herein under license. FDR” tor Ophthalmic Medicines; PDFt® for Nonprescription Drugs, Dietary
`Supplements, and Herbs;-PDR” Guide to Drug Interactions,,Side Effects, and Indications; FDR” Pharmacopoeia; PDFI" for Herbal Medicines; PDFl” for Nutritional
`SUPPlementS; FDR” Medical Dictionary; PDR" Nurse's Drug Handbookm; PDRE Nurse’s Dictionary; FDR” Family Guide Encyclopedia of_Medical Care; PDR‘” Family
`Guide to Natural Medicines and Healing Therapies;~PDR® Family Guide to Common Ailments; FDR” Family'Guide to Over-the-Counter Drugs; PDRG’ Family Guide to
`Nutritional Supplements; and PDT-P Electronic Library are trademarks used herein under license.
`,
`‘
`"
`Officers of Thomson Healthcare, Inc.: President and Chief Executive Officer: Bob Cullen; Chief Financial Officer: Paul Hilger; Chief Medical Officer: Rich Klasco, MD,
`FACEP; Executive Vice President, Medstat.‘ Carol Diephuis; Executive Vice President, Micromedex: Jeff Reihl; Executive Vice President, PDR: Kevin D. Sanborn; Senior
`Vice President, Technology: Michael Karaman; Vice President, FInance: Joseph Scarlone; Vice President, Human Resources: Pamela M. Bilash; Vice President, Planning
`and Busmess Development: Ray Zoeller; Vice President, Product Strategy: Anita Brown; Vice President, Strategic Initiatives: Timothy Murray
`'
`’
`“
`lSBN: 1-56363-568-2
`
`3
`
`

`

`.9
`
`
`T‘INF’ORMATIONL“
`
`PRIMARYEFFICACY'ANALYSIS:
`
`Investigators’ Assessment of Treatment Success*At the End of 8 Weeks of Treatment
`
`, GALDERMA/1213
`
`
`
`
`
` v-
`
`7 (1.3>_
`
`:
`
`
`
`.
`
`,
`
`Study No. 2
`
` StudyNo.1 _
`
`
`* Treatment success was defined as melasma severity
`:
`score of Lzero (melasma lesions cleared ofhyperpig'mentation).
`,
`p-value is from Cochran‘Ma'ntel—Haenszel chi-square statistics controlling for pooled investigator and comparing TRI-
`LUMA® Cream to the other treatment grmips.
`'
`‘
`L
`'L “'
`'
`'
`’
`‘
`‘
`'
`j
`
`"
`
`
`' ”
`
`'
`
`
`‘L Investigators' assessmentof Chanéein Melasma Severity from'Ba‘seline to Day 56'
`'L
`‘
`L
`of Treatmenticombined results from studies 1an 2)
`'
`'
`L'
`'
`
`
`
`
`‘ Baseline ,
`
`
`
`gamed... '- ‘NL<%) -__ .
`L
`
`
`TRI-LUMA® ‘
`,
`
`
`
`
`"CreamlN=’l161
`
`
`_- 1 (3%)
`
`Nuniber (“M of Patients at DayL 56‘ ‘
`
`‘_
`
`
`
`2‘Assessment based on patients with severity scores at Day 56. Percentages are based on the total number in thetreatiiient
`b
`grouppopulation. . 1,,
`_
`z.
`,,
`_
`_
`‘ _ . _
`._
`.,
`13.3
`_
`Does not include patients who cleared-before Day'56 or‘were missing from the Day 56 assessment; .,
`
`
`
`4% (HQ) L+ tretinoin‘0.05%’ (RA):_(2)/fluocinolone acetonide ‘V
`0.01%" (FA) + t'retinoin' 0.05% (RA); *(3)*fluocin’o’lone
`acetdnide'0.01% (FA) '+ hydroquinone 4% (HQ)],’ Contained
`in the same vehicle as TRI—LUMA®L Cream. Patients Were
`instructed to apply their study medication each night, after
`washing their face with a mild soapless cleanser, for 8
`weeks. "Instructions were given to' (apply a thin‘ layer of
`study medication to the hyperpigmented lesion; making
`sure to cover the entire lesion including the outside borders
`extending to the normal pigmented skin. Patients were
`provided a mild moisturizer for use as needed. A sunscreen
`Lwith’ SPF‘VBO‘vvas also‘provide'd' with in'structions‘for daily
`L : se: ProtectiVe clothing and avoidance ofSunlight expOsure
`to the face was recommended.
`'
`_
`,
`'
`.,
`'
`Each gram of TRI-LU'MA®J Cream contains Active:
`Patients were evaluated for melas’rnaseverity at Baseline
`fluocinoloneacetonide 0.01% (0.1.,mg), hydroquinone 4% _
`and 'at Weeks 1, 2, 4, and 8 of treatment. Primaiyefficacy
`(40 mg), and tretinoin. 0.05% (0.5nmg); Inactive; butylated
`was based on the. proportion of patients who had an inves-
`hydroxytoluene, cetyl alcohol, citric acid, glycerin, glyceryl
`tigators’ aSsessinent oftreatment success; defined as the
`stearate, magnesium aluminum silicate, methyl gluceth- V
`clearing ofmelasma atthe end ofthe eight7week treat"
`.10; methylparaben, PEG-100* stearate, propylparaben,
`
`period; The majorit
`patients enrolled in 'the‘LtWO st L
`purified water, sodium metabisulfite,~kstearic acid, and
`View :white‘ (appro mately' 66%) and female (approx:-
`mately 98%).‘TRI4LUMA® Creamwas demonstrated tobe
`stearyl alc°h°1"”_l'
`i
`‘
`
`Siefifigagfl? ijfecgjvethe anyéfthemhérceébiea-
`QLINICAL PHARMACOLOGY _ _-
`,,
`,,
`= $25;rsl: tZEfdlggdlegre 1ents.
`I
`One: of
`the
`componentsgin. TRl—LTLMA‘Eijream,
`‘
`hydroquinone, is a depigmenting agent, and mayinten'upt f
`Ill-the Investiga’tors’assessment of melasma seVerity'at
`one. or more steps :in the tyrosine-tyrosinase pathway of
`melanin synthesi‘SuHowever, the mechanism‘of action of
`Day 56 of treatment, the following table shows-the cliniCal '
`the active ingredients in TRI~LUMA® Cream in the treat- ‘
`improvementiprofile for all patients treated ‘Lwit‘h TRl—'
`mentofmelasma is unknown.
`.
`‘
`
`LUMA® Cream based on Severity of theirl‘melasma at the
`start oftreatment.
`'
`'r
`‘
`‘
`‘
`Pharmacokinetics: ,: Percutaneous absorptionsof un-
`changed.
`tretinoin,
`hydroquinone , and,
`fluocinolone
`,
`_
`_,
`[See second table above]
`' Assessment Scale: Cleared (melasma lesions appro -
`acetonide into the systemic "circulation of two groupsof
`healthy volunteers (Total n=59)»was’found to be minimal
`mate‘ly equivalent to surrounding normal skin or with min-
`imal residual hyperpigmentation'); Mild“(sli‘ghtly darker
`than the surrounding normalLSkin); Moderate (moderately
`following 8 weeks ofdaily application 0flg (Group I’ n 2 4?)
`darker than the surrounding normal skin); Severe (mark-
`01? 6g (Gm? H’n“: .14) ofTleLUMA®1CreaniL
`,
`..;
`edlydarker than the Surrounding nor-imal skin):
`_
`-,
`-
`For treti'nom quantifiable plasma concentrations were 'ob-
`Patients‘eiipei-ienced improvement of their melas'n‘ia with
`tt‘imd in‘57.78% (26 (mt °fL45) ofGroup I and57'14% (8 but
`"
`‘
`‘
`of 14) of Group II subjects. The exposure to tretinoin as re— »
`th "
`'
`fTRI—LUMA®C
`‘
`‘L 2:1“ '54 L'e'kLs;Amo '
`.
`,
`.
`.
`e use 0
`ream as e ry a
`we
`’
`ng
`‘flected by the Cmax'valuesranged from 2.01 to 5.34 ng/mL
`‘the 7 patients that» Cleared at the end-cf'4 weeks'Lof-trea‘t-
`.
`,._
`,,
`.
`.
`‘
`,,
`.
`_
`p
`_
`:men’t with‘TRI-LUMA®‘Cream at‘which' timertreatme’nt
`(@011? Band 2-0 t0 4-99 ng/mL‘ (Group '11) Thus (iaflY‘eP- '
`
`‘ was stopped, 3 patientsnfaintai'ri’edrenussion whileL4rpa-
`Phéatlfm 0f.TRI‘LUMA®I Cream ESP-113$? 3mm
`
`tients had-relapse at the final 8th-week evaluation point.
`.
`crease Of normal endogenous .leYels .yo‘ftretmo'ln.‘ Th __
`After 8 weeks of treatment with thestudy drug, patients
`lating tretiraoin levels ’jrepreseht'onl'y‘ a Portion- 9 _, 91331
`L‘entered into an open-label long-term safety studyiin which
`tretinoin-as‘sociat‘ed retinoids, WhiCh W0uld include metab-
`
`TRI-LUMA® CREAM Vvas given on‘ an as—needed basis for
`elites 0f,tr 3min :and 1,511.31? sequestered into Peripheral ti?‘
`the treatment-’ofmelasmawThe objective Wastoprovid'e evi-
`sues; /
`L
`L
`,
`V
`'
`I
`i
`L
`For hydi‘oquinone qliantifiL 1e plasma concentrationswere ‘
`dence of local and’systemicsafety with cumulative User-of
`The expo-
`
`
`obtained 111-18%:(s, out, $44,). Girb'pp I. am _
`.
`_
`TRI}LUMA®‘ Creamfor longer than 6 months, up to one
`
`
`sureto hydroquinoneaS-Lreflecte
`L
`,‘ max. values
`year.
`r.
`_
`»
`.
`.
`_-
`,,
`,
`"‘_
`rangédLfitom125
`$986.52ng/mL1'VAllL
`pAIIsLubjects (6g ,
`Patients were instructed to apply TRLLUMA® Cream
`dose);Lhad'post7dOSe plasma hydroquinone concentrations ,
`once daily at nighttime after washing their face with a mild
`below .thelquantitatiOn limit. For fiuocinolonelacetonide,
`soapless cleanser, also provided a mild moisturizer fornse
`
`Group‘slandrll subjects hadiall post-dose plasma concen—
`as neededsan’d-a sunscreen with SPF 30' for daily use, in
`,t
`'ons below quantitation limit,
`»
`combination withthe use ofiprotective clothing and avoid-
`LCimlcal Studies: , No adequateand wellecontrolled effi«
`anceof sunlight exposure to the face. Patients wereLtreated
`,
`,
`.
`_
`_
`,
`:dailyruntil melasma is resolved,- and then retreated-when
`cacy and safety studieswere conducted infiy41 patients be-
`mel'asma recurred.,.«_The majority of'tpatientsfu‘sed tTRI—
`tween¥.tlfie"ages of 21
`'75, years, having skin phototypes
`
`LI’IV and moderv
`L
`L
`y
`L
`'
`severe ,me'elasma 30fE therfac'e,-3’I‘RI- . LUMA® for. no more than two courses of treatment and
`
`,
`asl'comparedwith 3"pOSLsible. coiribina»
`,
`-
`-
`,
`,
`: >
`'
`‘
`i
`'
`tions: of 2: of the ,3 :active', ingredients -[(1) hydroquinone
`L continued on nextpage
`
`The chemical name for tretin‘oin'is; ( (alle‘)-3, 7¥dimahyl-9-
`(2,6,6-trimethyl-l-cyc'lohexen-_1-yl)-2,4,6,8L'-nonatetraenoic "
`acid;
`L
`,
`,
`-
`.
`30044.
`‘
`L
`i
`'
`L
`The molecular formula is 020H2302 and molecular weight is
`Tretinoinhas the following structural fonnula:
`
`
`
`
`
`4
`
`::*¢<L1n5ult:zoo1 PDR‘ILii supplements and future. editions for: revisions
`
`
`
`
`
`flowing additional adverse experiences have been re- ’
`,3 with the topical use of ' metronidazole: skin ‘
`7
`.
`.
`n transient redness, metallic taste, tingling or
`
`..L'
`
`1311655 of extremities, and nausea.
`
`_
`,._
`\
`VERD05AGE
`,
`.
`,
`
`'
`’ éTeL no reported human experiences with overdosage
`That TROGEL® (metronidazole gel), 1%.,Topically applied
`
`,L W -dazole can be absorbed in sufficient amount to pro-
`eZZystemic efiects-
`r
`,
`*
`w.
`,
`>
`.
`« w ,
`
`.
`SAGE ANDADMINISTRATION
`,,
`
`to be treated should be cleansed beforejapplication of
`aioGELtg (metronidazole gel), 1%. Apply and rub in a
`
`film of METROGEL® (metronidazole gel), 1% onée ‘
`entire affected area(s). Patients may use cosmetics
`
`Yggpucation ofMETROGEL® (metronidazole gel), 1%.
`,
`
`
`
`ube. .
`.
`,
`.
`
`an: tube —_ NDC 0299-3820-60
`
`I, ,.
`,
`‘7
`_
`‘fit’ ofthereach ofChildren;
`‘aconditions: Store at controlled room temperature:
`
`25°C (68° to 77°F), excursions‘permitted between 59° ‘
`35°F(15°-'30°C),
`I,
`.
`,
`,_
`.
`.
`
`ng Informationias of Decembery2005. -
`
`aProduction C
`anada Inc.L
`
`
`Lby: .,-
`,
`
`
`a Laboratories, L.P.
`i
`~ ,
`orth,Texas 76177 USA’ v
`
`
`
`
`;
`
`.
`
`5 available in a 60-
`
`I,
`
`_ n‘olone acetonide._0.01L%,:LLIL1Ydeoquinone 4%, ,f"
`
`
`
`
`'h’eLmical name for fluOCinoIOne’aceto‘n‘ide is&;(fiu,Ilfi,
`
`“)6’97djflu01‘0711, 21-dihydroxy—16,17-[(1-methylethyli— -
`blS<9xy_)J-pregna;1r,-4:diene:3,20-di0ne.‘ :
`:
`'
`
`egficfilar formuiar'is CgHgorgo6 and molecularWeight
`
`“imfldné acetonide- has the following structur'alL
`a;
`,,
`.
`,,*
`:
`‘,
`,3
`
`
`
`
`
`._
`lI'llin‘one is claSsified therapeutically asa depi‘gment- »
`
`magetlt.‘ 'It" is' prepared from the reduction cf p- 3
`
`dl qullionewith sodium bisulfite; It occurs as fin
`bite :
`
`
`
`fl: til-at darken'on exposure to air.
`:
`‘_
`_
`,
`1‘
`‘
`mlcal name for hydroquiilbne is: l,4-benzenediol.,_
`
`
`_ 01%qu formula isCsHeOZ and molecular weight is
`
`
`
`iSall—trans‘metinoic acid formedfrom the inda- '
`he aldehyde. group ofretinene to acarboxyl group.
`.
`3- a‘séyellow’ to light40range crystals, or crystalline
`With a’charact’eristic odorof ensilage. It ishighly .
`
`to light and oisture. :'_I‘r_etinoin is classified ther!
`-
`cale, as-a keratolytic.
`,
`' ~
`’
`«
`
`
`
`
`4
`
`

`

`121L4/GALDERMA
`
`PHYSICIANS’ DESK REFERE
`
`TIitLuma—Cont-
`
`1
`
`
`
`
`
`INDICATIONS AND USAGE
`TRILLUMA® Cream is indicated fortheshort—term inter-
`mittent treatment ofmoderate to severe melasma of the --
`
`1
`
`.
`
`L
`
`1
`
`L
`
`face, in the presence ofmeasures for sun avoidance,includ-
`ing the use ofsunscreens.
`~ ‘-
`-- -
`The following are important statements relating to the indi-
`cation and usage of THI-LUMA® Cream:
`‘
`' TRI—LUMA® Cream, a combination drug product
`L containing corticosterOid, retinoid, andbleaching agent,
`was proven1safe for the intermittent treatment of me-
`lasma, With cumulativetreatment time of at least 180
`. days. Because melasma, usually recurs upondiscontinu-L ,
`ation of TRI-LUMA® Cream, patients can be re—treated
`with TRILUMA® Cream until melasmais resolved Pa-
`Ltients need to avoid sunlight exposure, use sunscreen
`and. _
`with appropriateSPF, wear protective clothing,
`
`
`LLchLange to nonhormonalforms ,of birth control, if ho1 _
`monal methods are used.
`L
`L
`
`- In clinical trials used to supportthe use
`.Creamin the treatment of melasma, patients Were 111-L
`structed to avoid Sunlight exposure to the Lface, wear 11
`protective clothingand use a sunscreen with SPF 30 .1
`Leach day. Theywere toapplythe study medicationeach, .
`1 night, after washing their face with La mild soapless
`cleanser
`' The safetyL and efficacy of TRI-LUMA® Creamin pa-
`, tients of skin types V andVI havenot been studied. Ex— .
`» cessive bleaching resulting ‘ in undesirable cosmetic
`effect in patients with darker skin cannot be excluded.
`' The safetyand' eflicacy ofTRI-LU'MA® Cream in the v, n
`melasma ofthe face:havenot been studied.
`'
`treatment of hyperpigmentation conditions other than
`.9 Because pregnant andlactating womenwere excluded
`from, and women of child—bearing potential had to use
`1.1, birth control measures in theclinicaltrials, the safety
`and efficacy.of TRI-LUMA® Cream'in pregnant women
`
`d nursing mothers have notbeen established (3%
`_._PRECAUTIONS, Pi‘egnancy).
`,,
`s
`.1
`.
`~,
`.
`,
`
`CONTRAle L ATIOLNS
`ted mindividualsWith
`TRI-LUMA® Cream"is contraindi
`a historyofhypersens1t1v1ty, allergy, .or intolerance tothis
`product orany ofits coinponents
`‘WARNINGSL
`
`
`L sodium metabisulfite,LaLsLul-
`TRI-LUMA® Cream cont
`fite thatmay use allergic—Ltype reactions including 3-9231
`phylacticsymptoms and life—thr atoning asthmaticepi—
`sodesin susceptible people.
`L
`Theoverall prevalence ofLsulfite sensitivityinthe general :
`populationisunknown- and probably10W SuIfite sensitivity
`is seenmorefrequentlyinasthmatic,'th
`innon—asthmatic 1
`
`produce exogenous oLchrLonos1s, a gradualblue—black dark—
`,eningof the skin, Whose occurrence should promptdiscon-
`
`this condition are Black, but itmayLal o occurin Cauca-
`sians and Hispanics
`Cutaneous hypersensitivity to the ac
`,L ingredients of L
`
`TRI LUMA® Cream has been reportedin the literature In
`a patch test study to determine sensitization potentialin '
`221 healthy volunteers, three volunteers developed sensi- L
`tivity reactions to TRI-LUMA® Cream or itscomponents. ,
`PRECAUTIONS
`
`General:
`TRI-LUMA®Cream contains hydroqumone and L’
`tretinoin that may:causemild to moder
`1
`\
`irritationss: h as LskinL reddening, peeling, mild burning
`~sensation,dryness1,Land pruritus may be expected at the
`siteof applicationTransient skinreddening or mild burn-
`ing sensation does ot preclude treatment. If a reaction -
`
`suggestshypersenmtivrty or chemical irritation, the,use of
`themedi ationshouldbe discontinued ,.
`,_
`..
`TRI-LUMA® Cream also contains the cort osterLLoLid
`fluocinolone acetonide. systemic absorption Lof topical cor-
`ticosteroids .;can produce , reversible
`hypothalamic- 1
`pituitaryadrenal (IL-IPA) axis suppression, with the poten-
`tial for glucocorticosteroid insufficiency after, withdrawal of
`treatment. , Manifestations ,of. Cushing’s syndrome; hyper—
`glycemia, and glucosuria cai'i‘also be produced bysystemic
`‘_,absorption,:of topical corticosteroid ,while:on,treatment.:lf L
`iI-IPA axis, suppression is noted; the-use of TRI-LUMA® -
`Cream should be discontinued Recovery of HPA axis fImc—
`‘costeroids..
`.
`-
`.
`
`tion generally occurs u on discontinuation oftopicalcorti- ;
`Informationfor Patients: ExposuretoLsunhght, sunlamp,
`.or ultravioletlight should beavoidedPatientswhoarecon-
`sistently. exrmsed to sunlight or' skin-finitantsfeither a
`through their workienvirOnment or habits should exercise '
`particular-a caution.- Sunscreen and~protectiVelzcovering L
`(suchLas the use ofa'hat) over the treated areas should-be
`lused. Sunscreen use isan essential aspect of melasma
`therapy,as even minimal sunlight sustains melanocyticac—
`tivity.
`Information vaillheL’sup'erseded byL supplements and subsequenteditions
`
`
`
`
`
`L teratogenesis ue 0 this exposure Therisk ofteratogene—
`sis due to topital exposure to LTRI-LUMA® Cream may be ‘
`considered low. However,exposure during the period of or- '
`ganogénesis in the first trimester is theoretically more
`.
`likely to produceadverseoutcome than'in later pregnancy.
`
`Theprescribershould havethe followingclinicalconsid- _’
`' erations in making preseribing decisions
`.
`.
`’ The potential developmental effects oftretinoin are se-
`rious but theirisk-from topical administrationiissmall...
`5
`
`Weather extremes, such as ‘heat‘o'rL cold, mayi'be' irritating L
`' Exposure during the'period for orgLaiiogenesIS
`
`$111
`topatients treated'with TRI—LUMA® Cream; Because of
`rimesteris theoreticallymore likely to produe
`9e
`
`
`the drying effect‘ofithis’medic'atiOn; 'a': moisturizer may be L
`
`'outcome thanin laterpregnancy.
`
`' ‘applied‘to‘th‘e face in the morning after washing;
`"
`“0' The risk to the mother for nottreating mela
`thesepatients experienced longerrenuss1ons.LBoth the 1111-
`L
`;’ Application of TRI-LUMA® Cream Lshould be kept away
`ration oftreatment and interval oftime between treatment
`be determined by the physicianWith the is?
`L forms of melasma may not 11 LeSLsarily 1'
`
`’ from the eyes, nose, or angles of the month because the
`courses decreased With increasing number LofL treatment
`mucOsa is much more sensitivethan the skin to the irritant
`treatment. TRILUMA® Crea
`s indica e -.
`courses. Additionally, 24 patients (approximately 8%)
`
`as
`effect. If local irritation persists or becomes severe, appli-
`treatment ofmoderate to severe
`asma.M&1El
`cleared of melasma Without re-occurrence, for a period of
`one year.
`cation of the medication Lshould be discontinued, and the
`
`
`, alsobe managed With other formsoftherapy Sue
`L health care provider consulted Allergic contact dermatitis,
`ical hydroquinonein the presence of sunligtah ‘
`blistering, crusting, andsevere burning or swelling of the .
`/ or stoppingthe use ofhormonalbirth controltmvt’
`
`, skin and irritation of the mucousmembranes of the eyes,
`3
`
`
`:‘possible, delaying treatment with TRI—LUMA®
`' until after delivery should be considered;
`‘
`nose, and mouth require medical attention.
`marked redness,
`L
`If the medication is appliedexcessively,
`There are no adequate and well-controlled
`
`~> peeling, or discomfortmay occur
`pregnant women. TRI—LUMA® Cream Sho
`
`This medicationis to be used as directed by the health care .
`
`during pregnancy only if the potential LbeLLn
`’ the potential risk to the fetus '
`-~ ~
`'
`‘ provider and should notbe usedfor any disorder other than
`
`is
`ssion. Tretirioin'15 con id
`thatfor which itis prescribed.
`'
`
`Laboratory Tests:
`The follownig tests may be helpfulin ‘
`'atOgemc upon systemic administration.
`31 ‘
`., evaluating patientsfor HPA axis suppression:
`tive studies are not available with topical hyqu
`Corticosteroids havebeen shown to be teratogeni
`ACTH or cosyntropin stimulation test
`
`ratory animals whenadministered systemically .
`A.M plasma cortisol testL
`,1 _
`LUrinarLy free cortisol testL
`tively loLWL dosage levels. Some corticosteroids ha:
`Drug Interactions: Patients should avoid medicated or
`
`shown tobe teratogenic after dermal applicati
`tory animals.‘
`abrasive soaps and cleansers, Lsoaps and onsmetics With
`,
`~
`1. Human Data.
`LL
`L
`L
`
`
`1 drying effects, products with high concentration of alcohol
`- In clinical trials mvolvm'gLLTRI—LUMA® CLre
`LL andastringentand other 1111 ants orkeratolytic drugs 1
`treatment offacral melasma, women,ofChildbe .
`L While on TRLLIMA®L Cream treatment Patients are can—
`
`tioLnLedL on concomitant use of medications that are known .1
`1‘ tential initiated treatment only after ham (1
`ative pregnancy test, and used effective blrth ‘
`to be photosensitizing.
`1
`measures during therapy. However, 15 Wom
`Carcinogenesis, Mutagenesis, Impairment of Fertility:
`
`Long-term animal, studies to determine the carcinogenic
`pregnant during treatment with TRIL—LUMA®
`potentialofTRILUMA®Cream havenot been conducted.
`
`Ofthese pregnancies, 6 resulted inheLalthL ba '
`1 Studies of hydroquiiione in animals have demonstrated 1
`and IL caSe was lost to follLo
`comes still unknoWn, 2 L ere reported as ‘
`
`_ some evidence of carcinogenicity Thecarcinogenic poten- 1
`tial ofhydroqumonein humansis unknown.
`_
`.
`' Epidemiologic studies have notLconfirmed an in
`
`birth defects associated With theuse oftopical '
`Studiesin hairless albino mice suggest thatconcurrentex-
`..
`However, there may be limitations to the sens
`,posure to tretinoin may enhance the tumorigenic potential -
`
`of carcinogenic doses ofUVB and UVA light from a solar
`epidemiologic studiesin the detection ofcert
`
`simulator. This effect has been confirmed in a later study L
`
`.
`"
`'
`icits.
`fetal1njury, such as subtle neurologic 01' int"
`1n pigmented mice, and dark pigmentation did not over—
`'
`2. Animal Data.
`- ,come the enhancement of photocarcinogenesis by 0.05% L
`
`_
`_ tretiuo'm. Although the significance ofthesestudies tohu-
`' In a dermal application studyLLusingTRI-LUMA®
`mans is not clear, patients should minimize exposure to .
`in pregnant rabbits, there was an increasein
`
`berof in utero deaths and a L ecrease in fetal W
`sunlight or artificial ultraviolet irradiation sources. ..
`_
`1;-
`.
`the‘dru
`litters from dams treated. pically Wit
`Mutagenicity studies were not conducted with this combi— E
`'
`uct.
`
`nation of active ingredients. Published studies have dem— L
`onstrated that hydroquinone1s a mutagen and aclastogen.
`. In a dermal application studyin pregnant rats treL
`
`with TRI-LUMA®Cream during organogenesis
`Treatment With hydroquin'one has resultedin positive find— L
`was evidence of teratogenicity of the type expect d
`ings for genetic toxicity in the Ames assay in bacterial
`
`strains sensitive to oxidizing mutagens,in in viii-o studies
`tretinoin. These morphological alterations included
`palate, protruding tongue, open eyes, umbili tribe1
`in mammalian cells, andin thein vivo mouse micronucleus
`
`and retinalfolding o'r‘dysplasia’.
`.
`assay. Tretinoin has been shown to be negative for muta—
`
`' In a dermal application study on
`genesis in theLAmes assay. Additional-information regard-
`ing the genetic toxicity potential of -'tret1noin and of
`postnatal effects of a 10—fold dilution L
`fluocinolone acetonide is not available.
`. ‘ ,
`Creamin rats, an increaseinthen
`
`A dermal reproductive fertility study was cdnducted in SD .
`pups, lower pup body weights, and delay'in p p
`rats using a 10-fold dilution of the clinical formulation. No
`separation were observed. Anmcrease in overall L
`L
`effect was seen on the traditional parameters used toas~
`Isess fertility-although prolongationof estrus was observed
`in some females, and there was a trend towards an increase
`in pre-and'post—implantation loss that was-not statistically '
`significant. No adequate study offertility and early embry-
`oni'c toxicity ofthe flilljstrength drug product hasheen per— '
`formed. In a six—month study in minipigs, small testes and
`severe hypospermia were found when males were treated
`
`topically With the full strength drug product.
`1
`.
`_
`Pregnancy: Teratogenic Effects Pregnancy Category C.
`TRI—LUMA® Cream" contains theteratogen,
`tretinoin,
`which maycause embryo-fetal death, altered fetal grthh,
`congenital malformations, and, potential h’eurol‘ogic defi-
`LcitsnIt‘is difficult‘to interpret the animal studies on terato-
`genicity With TRI—LUMA® Cream, because the availability
`of the dermal applications in these studiestcaimo't be’as-
`sored, and comparison with clinical dosing is not possible.
`There are no adequate and’well-controlled-studies in preg—!
`Inant women. TRI—LUlVIA®.LCream should be used during
`tial risk to,thefetus.
`,
`,
`,.
`pregnancy only if the potential benefit justifiesthe poten—
`
`
`Summary Statement on TeratogLeLnLiLc Risk ‘
`1
`, »
`.TRI—LUMA® Cream contains the teratogen; tret'mom,
`which may cause embryo—fetal, death, altered fetal growth,
`congenital malformations, and potential neurologic defi-
`cits However, human data have not confirmed an in- _
`creased risk of these developmental abnormalities when
`tretinoinis administered by the topical route.
`-
`
`clinical considerationsrelevant to actual or potential'm- 1
`,advertent exposure during pregnancy.
`
`In clinical trials involvingTRI—LUMA® CreamLL1n thetreat- 1
`
`merit of facial melasma, women
`hildLbearing potential
`initiated treatment only after havmg Lhad a negative preg—
`nancy test and used effective birth controlmeasures during
`therapy ThuLL safetyLL 1deffioacyofTRILUMA®L Cream
`
`.
`
`
`
`
`
`tionalL andpostnatal effects of the fILLLill-stren
`LUMA® Cream has been performed.
`.,
`' diffi ult to interpret these animalstudie
`
`
`
`L'matLeLs ofL increased fetal risk from LLLdrugexpo
`heavily on animal data. However,animal studies do
`
`ways predict effectsin humans. Even if human dat
`9
`
`available, such data may not be SUfllcient to deteflflm
`
`whether thereis an increased risk to the fetus. Drug BfiLe
`
`on behavior, cogniti
`fimction, and fertility in the 0
`
`spring are particularly difficult to assess.
`Nursing Mothers: Corticosteroids, when systefllicalbgfier
`
`ministered, appear in human milk. Itisnotknown“?hilt in
`t0131C211 application of TRI—LUMA® Cream could 1'95 all
`sufficient systemic absorption to produce detectable q“0111'
`
`tities of fluocinolone acetonide, hydroquinona 01‘ ”Len all ‘
`inhuman milk. Because many drugs are secretediflhu'In
`milk, caution should be exercised when TRIL 111
`taken t
`1 01dcontact between the infant
`TRI—LUMA L Cream.
`_,
`«
`Pediatric Use: Safety and L fi‘ect
`eneLLssL of
`Creamin pediatric patients have not beenLestabliSh
`GeriatricUsLe:Clin1cal studies ofTRILUMA®Ore
`notinclude sufficientnumber Lof subjects aged 6L5
`
`to determine Whether
`they. respond differently
`,
`younger Subjects.In general, dose selec ionfor an e
`patient should be cautious, usually starting at the Iondef
`of the dosing range, reflecting the greater frequency0cofl‘i
`creased hepatic, renal or cardiac function, and of cone
`
`tant disease or other drug therapy.
`'
`ADVERSE REACTIONS
`
`e_
`In the controlled clinical trials,“adverse eventsWeiTLe
`we
`‘torédL inthe 161 patients who usedTRI-LUMA®Gt
`
`once daily during an 8Fweek treatment period. The
`102 (63%) patients who experienced‘at least
`.
`.
`related adverse event during these studies. In Lth ,
`
`
`
`
`
`
`
`'
`
`L
`
`