`
`w3net .- --
`WebIFDAIPrint
`
`.
`
`AMN1039
`-,
`.1
`Amnealv Almirall; LLc
`IPR2018-00608
`
`AMN1039
`Amneal v. Almirall, LLC
`IPR2018-00608
`
`1
`
`

`

`
`
`
`
`
`
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`ISBN: 1-56363-703-2
`
`2
`
`

`

`1942/MEDICIS
`
`
`
`/\
`
`PHYSICIANS' DESK
`
`REFE
`
`
`
`Therapy should be disconti'IIIII-zd’Meh
`
`achieved. Ifnoimprov'ement'is seen WithinOntr01 h
`sessment of diagnosis may be neceSSary 1&2”the:-3-
`" ,.
`
`HOW SUPPLIED '
`'
`W
`VANOSTM (fluocinonide) Cream- 011%;18 s«+5,
`
`’ up!)Pliedi'
`num tubes as follows:
`.
`“a
`30 g (NDC 99207-52530)
`,”ffIt!
`
`60 g (INBC 99207—52560)
`’ ,‘lfi
`120 g (NDC 99207525 10)
`“* ‘ 1,,
`Store at controlled room temperature$15o
`86°F).
`..
`Manufactured for:
`
`.
`
`to 30°C
`
`MEDICIS, The Dermatology Company
`Scottsdale, AZ 85258
`Manufactured by:
`Patheon, Inc.
`Mississauga, Ontario
`Canada L5N 7K9
`Made in Canada
`
`U.S. Patent 6,765,001 and Patents Pending'
`Prescribing information as ofAugust 2006g
`IN-5325/S
`
`K
`
`
`
`
`
`
`
`
`
`
`
`
`
`'
`
`
`ZIANA'T'V‘
`[zee-ah-na]
`(cljndamycgin, phosphate 1.2%,
`
`III I _r l.
`and tretinoi ‘0'025%). GeII
`HIGHLIGHTS OFPRESCRIBING INFORMATION
`
`These highlights do notinclude all the info CC C
`.
`to use ZIANA Gel safely andefiectively. 86621313123:
`'_
`Ia
`-
`information for ZIANA Gel.2“.
`
`ZIANATM (clindamycin phosphate 1.2%
`and Ira! .
`0.025%) Gel
`
`For topical use only
`_
`Initial U.S. Approval: 2006
`
`-
`INDICATIONS AND USAGE
`'
`ZIANA _Gel'IS a lincosamide antibiotic and retinoid ,,I
`
`nation product indicated for the topical treatmento|_
`
`‘
`vulgarisIn patients'1‘2years or older. (1)
`DOSAGE AND ADMINISTRATION
`0 Apply a pea-sized amount to'the entire face‘once
`
`bedtime. Do not apply to 'eyes, mouth, any:
`
`or mucous membranes. (2)
`' ZIANAGelIs not for oral, ophthalmic, or intravagin I
`
`(2)‘
`',
`
`DosAGE FORMS AND ssRENGTgS.If:
`T
`Topical gel: Cliiidamycin phosphate 1.2% arid
`.
`0.025% gel'1n 2,30. and 60 gram tubes.((3)
`,_
`.
`CONTRAINDICATIONS
`
`ZIANA Gel is .contraindica
`,1 , 111ml
`terltis, ulcerative colitis, or his fyIO
`
`colitis. (4)
`I
`H
`WARNINGS ANsPRECAUTIG‘NS
`
`.' Colitis:Clindamycin can cause severecolitis.dimly ”
`result1ndeath D1a1'rhea,, bloody diarrhea, Cgen.
`
`cludingr,pseudomembranous coiyitiSJJ'haVeu1d ho.
`with-the,useof clindamycin. ZIANA 019115;“)
`
`tinned if significant diarrhea occurs..(5)Exposlm;
`
`' Ultraviolet Light andipEnvironmental
`suns
`
`exposure.»to sunlight and sunlalmps we”
`
`(5.2)
`
`16
`Observed local adverse reactions 1“
`ZIANAGelwere skin erythema scalingen
`
`only rep0or
`and stingingaOther most,00mm ZIANZX
`
`event'sI(> 1%IinpatientsitreatedWiltpain: dry
`
`.
`.
`sopharyn'giti‘s, pharyngolaryngea
`REACTIONS‘
`'
`and sinusitis:1(6.__1)
`i1
`
`To report SUSPECTED ADVERSE
`-
`Medicis,
`The Dermatology Company
`
`at 1-800-900-6389
`
`
`.
`
`I
`
`I,
`or FDA at 1-800-FDA-1088£ l1 I
`or www.fda. ov/medwii 0
`g DRUGINTEERAS:
`'_ Concomitant useI of topi,
`ing effect can increase Skin
`(7 1)
`be
`° ZIANA Gel should not
`erythromycin-containing 1;
`clindamycin component (7
`See 17 for PATIENT CO
`and FDA-approved labeling-
`
`use
`edcgs
`
`
`
`
`
`FULL PRESCRIBING INFO
`1
`INDICATIONS AND U56
`
`' 2 DOSAGE AND ADMIN'sA
`DOSAGE FORMS AND5
`III-PAW
`
`CONTRAINDICATIONS
`l/VARNINGS AND PREc
`5 1
`Colitis
`
`5.2 Ultraviolet Light and
`6 ADVERSE REACTIONS
`
`6.1
`Clinical StudieS
`
`
`i
`
`
`
`Vanos—Cont.
`
`
`
`daily with VANOSTM Cream. The first cohort of“ 31 p'atients
`(mean 36.3% BSA) 12 to < 18'years old; the second cohort
`included 31 patients (mean 39.0% BSA) 6 to < 12 years old;
`the third cohort included 30 patients (mean 346% BSA) 2 to
`< 6 years old; the fourth coh'prt included 31 patients (mean
`40.0% BSA) 3 months to < 2years old. VANOSTM Cream
`ca'used HPA axis suppression in 1 patient'in the twice daily
`group in Cohort 1, 2patients in thetwice daily group in
`Cohort 2, and 1 patient'In the twice daily group in Cohort 3.
`Follow--up testing 14 days after treatment discontinuation,
`available forall4 suppressed patients, demonstrated a nor-
`mally responsive HPA-axis. Signs of skinIatrophy were pres-
`cutat.baseline and severity was not determined making it
`difficult to assess local skin safety. Therefore, the safety of
`VANOSTM Cream'in patients younger than 12 years-of age
`has not been demonstrated
`,1
`Because of a higher ratio of skin surfacearea to body mass,
`pediatric patients are at a greater risk than adults of HPA-
`| axis suppression and Cushing’s syndrome when they are
`treated with topical corticosteroids. They are therefore also
`at'greater risk ofadrenal insufficiency during or after with-
`drawal of treatment Adverse eflects includingvstriae have
`been reported withinappropriate use of topical corticoster-
`oidsIn infants and childreni
`‘*
`HPA axis suppression, Cushing’s syndrome, linear growth
`retardation: delayed weight gain—and intracranial'hyper-
`tension have been reported in children receiving ‘topica'l
`corticosteroids. Manifestations of adrenal suppression in
`
`children include low plasma cortisol levels and absence of
`
`response to 'cosynt'ropin(ACTI-I'1‘)
`' Cmulation. Manifest'a—
`tions of intracranial"hypertension '1 bliide bulging'fonta-
`nel'les, headaches,I diid bilateral p9pi‘lle‘dema”L.
`J ~
`Geriatric Use. Clinical studies of VANOSTMCream did not
`include sufi‘ic‘ient numbers 01 subjects aged 65‘ and over to
`determine whether they respond differently from younger
`subjects. In generai, dose selection for an elderly patient
`should be cautious: C
`
`I
`
`
`
`
`
`l
`‘
`
`'
`
`If irritation‘develops, VANOSTM Cream should'be discontin
`ued arid appropriate-therapy instituted. Allergic: contact
`dermatitis with'sortieo'steroids is usually"diagnosed by 015-
`serving faIIure to, heal rather than noting a clinical
`exacerbation as withvmost' topical products ndt (Entainingm
`corticosteroids. Such an observation should be corroborated
`with apprbpriate diagnostic patch testing.
`If concomitant skin infectibns are present or develop, an ap-
`pnrppriarjie antifungal 9r antibacterial agent should be used.
`If a favorable response does not occur promptly, use of
`VANOSTM Cream should be discontinued until theinfectiou
`has been adequately controlled.
`VANOSTM Cream should not be used in the treatment of ro-~
`sacea or perioral dermatitis, and should not be used on the
`face; groin, or axillae.
`.
`Information for the Patient: Patients using VANOSTM
`Cream should receive the following information and in-
`structions. This information is'int'ended to aid in the safe
`andsefl'ective use of this medication. It is not a disclosure of
`all possible adverse or unintended effects:
`I) VANOSTM. Cream is to be‘ used as directed by the phy'si-
`cian. It is for external useonly. Avoid contact with”the
`arms.
`"
`eyes. It should not be used on the face, groin and under-
`2) VANOSTM Cream should not be used for anydisorder
`other than that for whichit was prescribed.
`'
`'
`_
`3) The treated skin area should not be bandaged or‘ other-
`wisecovered or wrapped, so as to be occlusive unless 'di-
`rected b'y-‘thé?physician.
`,1)
`4) Patients should report ‘to theftphysician ari‘yzsighs of lo-
`cal adverse reactions.
`n. A
`I;
`5) Other corticosteroid-containing products shou d not be
`IiSed With‘V CS 016th Without first talking to the phy-
`s'Iic'idi‘iF'
`‘r
`3
`-
`AEV'ERSE REACTIONSW
`6)As withQOther:cort1coster01dsEthé‘rapy should be distn-
`In clinical trials, atotal‘of 443 adult patients with atopic
`tinned when”edntrol 'is achieved.Tf no improvement is
`dermatitis or plaque—type psorgasis were treated once daily
`seen in 2 weeks, the patient should be instructed to con-
`or twice daily with VANOSTM Cream for 2 weeks. The most
`tact _a physician The safety of the :iise of VANOSTM
`commonly observed adverse events in these clinical trials
`Cream for longer than 2 Weekshas fiot been established
`were as follows:
`7) Patients should be informedto rot use more than 60 g
`[See table 3 below]
`per weekof VANOSTM Cream Do not use more than half
`No other adverse events were reported by more than 1 sub-
`of the 120 g tube per week.
`ject receiving active treatment. The incidence of all advers 1
`8) Patients should inform their physicians that they are us;
`events was similar between the active treatment'groups
`ing VANOSTM Cream 1fsurgery is contemplated.
`and the vehicle control groups. Safety in patients 12 1:0117
`tion.
`years fofla'gé‘éwas similar to that observed .in adults.
`9) Patients should w‘ash’ their handsafter applying med1c'a’-
`The‘follbw 'g additional local adverse reactions have been -
`Laboratory Tests: The cosyntropin (ACTH1_24);s 'I‘nulation
`reported with topical corticosteroids, and they may occur
`test may be helpful in evaluating patientzs5 for yi-IgA-axis
`.-
`(m 3 ‘2
`.
`more? equéntly with theuse of oc‘clusive dressings. and
`
`
`hIgheroplotencycorticosteroids. These reactions are listedIn
`Mutagenesis, and Impair'i'nent of Fe I Ity:
`an approximate decreasing order of occurrence. burning,
`Long--term animal studies have not been performedtoeval’
`itching, irritation, dryness,folliculitis, hypertricnosis, acne-
`uate the carcinogenic potential or the efiect on fertility of
`
`fluocin‘onide.
`,
`_n
`.
`.
`,
`. ..
`,
`5;“
`iform eruptions, hypopi'gmentation, peIioraldermatitis", alli
`Iergi contact dermatitis, maceration ofthe skin, setondary
`Fiuocinonide revealed no ev ence of mutage131'c or clasto-
`genie potentialbasedon th results of two in vitro genotox-
`infection skinatrophy,str'iae, and miliaria 9" , C
`“5 U.
`
`
`icityl tests;,(Ames test and
`;i_n vitro chromosomal aberra-
`Systemic absorption of topical corticosterui s 133‘s. produced
`hpothalamic—pituitaryadrenal (I-IPA’) ax1§rIsiippr
`'s'i,"
`tion assay'in human lymphocytes).However, fluocinonide
`Iii.
`ifestations of Cushing’s syndrome, hyperg'iycemlr,
`'
`
`
`was positiv'e- for clastogenic potential whenytested'1n the in
`J
`glucosuria1'11 some patients.
`"
`viva mouse micronucleus assay.
`,
`_
`+
`OVERDOSAGE
`Pregnancy Category, C. Teratogenic ,Effects; Corticosteir;
`oids have/been shown to be teratogenic in laboratory ani-
`Topically applied VANOSTM Cream canbe absorbedin suf-
`Inalswhen,admi131'stered systemicallynat relatiyelylow dos.-
`ficientamounts to producesysteml-i'efl'ect's (seePRECAU-
`age levels S
`_e,,corticosteroids have beenjs ow .to be
`TIONS)
`tr?
`2')
`
`
`;
`er dermal application'in laborat
`_
`DOSAGE AND ADMINISTRATION
`
`
`There are. no-adeqnateandwell-controlled slim _s in preg-
`
`nant women. Therefor . ANOSW‘ Cream ehouldlbe used
`For psoriasis,_.applya thin layer. of VANOSTM Cream once or
`during pregnancy onlyrif the, potential benefit justifies the
`twice daily tothe afl‘ected,skin areas as directed bya phy-
`potentialrisk to the fetus.
`7
`,
`sician.’1\vice daily application for the treatment of psoriasis
`NursingMothers: Systemicallyadmmistered corticoster-
`haszbeen shown‘to be more-effective1n achievmg treatment
`oidsI. appear in human Inilkand, could suppress growtth
`successduring}2 weeks. of treatmenton
`{or
`.
`
`III Foratopic dermatitis,Japplya thin layer ofVAN0SCream
`terfere with endogenou cort1coster01d,productlon, or cause
`other untowa.rd,eii‘ectsr
`not known whetheritopical ad-
`1; on daily to the affected skin;areas as directed byza physi-
`ministration of cqrticostero s,couidresultIn sufl‘icient sys-
`cia Once daily application forlthetreatment of atopicder-
`
`matitis has been shown to becas: effective as twice daily
`temic absorptiontoproducedetectable quantities in breast
`treatment'in achieving treatment success duringI2 weeks of
`milk. Neverthele ,uadecision should be made.whether to
`treatment (SeeCLlNICAL STUDIES).
`discontinuegnursmg or to discontinue the drug,taking into
`account the importance of the drug to the mother.
`,
`-
`For corticosteroid responsive dennatoses,other thanpsori»
`' asis or atopic dermatitis, apply a thin!layer of 1VAN0STM
`Pediatric Use: Safety and efficacy of VANOSTM Cream in
`pediatrlc patients younger than 12 years of age havenot
`Cream once or twice daily to theiafl‘ectedVareasas directed
`by_-a physician. ,
`I
`been established;
`therefore;-use in pediatric patients
`Treatmengmith VANOST'V' Cream should be limited to 2
`yOunger than 12 years of age is not recommended.
`consecutiIIe weeks, and no more than 60 g/week should be
`HPA axis suppressionwas studied'In 4 sequential cohorts of
`used.Do not use more than half of the 120 g tube'per
`pediatric patients With atopic dermatitis covering at least
`week.
`I;
`20% of the body surface area, treated once daily or twice
`
`Table 3: Most Commonly OSservéd Adverse Events in AdiIlt' Cl's'lical Trials
`AdverseEvent
`-
`VANOSTMi Cream,
`VANOSTM Cream,
`Vehicle Cream,
`once daily
`twice daily
`once or twice daily
`
`
`(11:216)
`(11:227),
`(n=211)
`
`
`Headache
`-
`8/216 (3.7%) '.
`9/227 (4.0%)
`6/211 (2.8%)
`.
`I
`J:
`l—-—--
`
`Application Site Burning
`5/216 (2.3%)
`,4/227 (1.8%)
`14/211 (6.6%)
`,
`1
`,
`——-?",'—"'———_C—
`
`Nagopharyngitis
`‘2/216 (0.9%)
`3/227 (1.3%)
`i
`3/211 (1.4%)
`Nasal Congestion
`3/216 (1.4%)
`11227 (0.4%)
`l
`0
`Unspecified Application Site Reaction
`1/216 (0.4%)
`15227 (034%)
`1
`3/211 (1.4%)
`
`3
`
`

`

`ME DIClS/e’l 943
`
`
`
`.l'? at Least Thief
`Table 1: Adverse'RLeactions Report
`Patients Treated 'with ZIANA Gel: 12-Week Studies
`ZIANA
`Clinda-
`Trétinbin l Vehicle
`Gel
`mycin
`_
`.-
`
`N=1853
`N=1428
`In}???
`Nit/2?).
`
`N 1%)
`N 1%)
`-.
`.
`.“
`
`
`
`
`
`
`
`
`'1
`
`|
`
`i
`I
`
`Clindamycin
`Teratology (Segment II) studies using clindamycin were per-
`formed orally in rats (up to 600 mg/kg/day) and mice (up to
`..
`100 mg/kg/day) (583 and 49times amount of clindamycin1n
`the recodiniended clinical dose based ona body Surfacearea 4
`comparison, respectively) or; with subcutaneous doses of
`.L-
`
`clindamycin up to 180'mg7kg/d-
`175:(a'n‘d 88 times the
`amount of clindamycin1n the-recommended cliiiié‘al dose _.
`based on a body surfacegagea comparison, respectiveIJQ get
`1111.5:
`vealedi no evidence of teratogenicitytj m a
`Thetinoin
`
`In oral Segment III studies in rats with tretinoin, decreased
`survival of neonates and growth retardation were observed
`at doses1n excess of 2 mg/kg/d’ay (N 78 times the recom-
`mended clinical dose assuming 100% absorption and based
`on body surfacé area comparison).
`With widespread use of any drug, a small number of birth
`defect reports associated temporally with the administra-
`tion of the-drug wouldbe expected by 'chance a1.one Thirty
`cases of temporally associated congenital malformations
`have been reported during two decades of clinical use of an-
`other formulation of topical tretinoin. Although no definite
`pattern‘bf teratogenicity and no, causal association have
`been established from these3cases, 5 of the reports describe
`the rare birth“defe'ct-.category,"holoprosencephaly (defects
`' asso iated with incomplete midline development of the fore-
`terms of risk to the? fetusis not known.
`brain). The significance of these spontaneous reports in
`DermalI tretinoin has been shown to be fetotoxic1n rabbits
`whensadministeredin doses 40 times the-recommended hu—
`man ol-inica'l dose based on a body surface aivea comparison.
`Oral tretinoin has been shown to be fetotoxic in rats when
`administered in doses 78 times the recommended clinical
`dose based \on aabody surface area comparison.
`le
`8.3 Nursing Mothers
`It is not known whether clindamycih is excreted in human
`milk followingmse of ZIANAGel. However, orally and par—
`enteral-1y administered. clin‘damycinihas been reported to
`appearrin breast milk. Because'of the potentialeor serious
`adverse‘reactions in nursing infants, a decision should be
`made whether to discontinue nursing or; to discontinuefithe
`drug, taking into account the importance of thefdrug to the
`mother? It is not known whether tretinoin is excreted in hu-
`man'milk. Because many drags are.excreted inhuman
`milkgzcaution should berexercised when ZIANA Gel is _ad—
`ministered to a nursing woman.
`8.4 Pediatric Use
`
`Safety‘and effectiveness of ZIANA Gelin pediatric patients
`under the
`5 f 2 have not been established.
`Clinical trials of ZIANA Gelincluded patients 12—17 years
`ofage.[See Clinical Studies (114)]
`8.5 Geriatric Use
`
`i
`
`
`
`Melecular Weight; 50497
`
`The chemical .name for tretigoin is 3,7-Dimethyl-9-(2,6,6-
`trimethyl- 1-cyclohexen-l-y1)-24,6[8-nonatetraenoic acid
`(all-trans form). The structural formulafor tretinoinis rep-
`‘1
`resented below.
`Tretinoin:
`
`H50 » CH3
`
`CH3
`CH3
`\’ \ \ \
`
`to
`
`OH
`
`CH3
`
`-
`
`,
`
`Molecular, Formula: 0291123025 J,
`Molecular Weight: 300.44
`
`Continued on next. page
`
`
`
`’PATIEHNTS
`
`-
`WITH AT
`
`LEAST
`497 (27)
`342 (_24)
`225 (27)
`_ 91 (22)
`ONE AR
`
`
`Nasopharyn—
`.~
`-
`'
`
`
`gitis
`65 (4)
`64 (5)
`16 (2)
`5 (1)
`Pharyn-
`..
`.
`.
`
`golaryn-
`29 (2)
`18 .(1).
`.
`geal pain
`
`5 (1)
`
`7 (2)
`
`
`23 (1)
`0:.(0)
`Dry skin
`
`
`Cough
`19 (1)
`2 (1)
`
`Siddéitis
`19 (11‘,
`4 (1)
`
`Note: Formulations usedin all treatment arms were in
`the ZIANA vehiclegel
`
`-
`
`
`
`
`
`I'tEnd‘of Treatment
`Local Reaction '
`‘
`'
`1N=J614
`
`:1
`N l-%l
`
`'
`
`Erythema
`Scaling
`
`‘
`
`237 (13’)
`
`416 (26),
`280(1‘7?
`
`
`
`
`111111111
`1
`I
`189 (10)
`7o (4)
`
`Burning
`.38 (2) .
`56‘ (4)
`—
`
`Stinging
`
`33 (2)
`
`27 (32);“qu
`“,2
`1
`
`
`At each study visit application site reactiolns on a scale of 0
`Clinical studies of ZIANA Geldid not include suficient
`(none), 1_(mild), 2 (moderate),and3,(severe), and the mean
`numbers ofsubjects aged 65 andovertodetermme whether
`_scores were calculatedfore .ch (ifthe local'skin reactions. In ,
`A
`1
`gen subjects.
`they respond difi‘erentlyfrom yo I . ”
`.
`
`
`i
`libjects enrolled With moderate to
`11 DESCRIPTION
`’i‘ tis
`.
`severe acne, 854subjectstreated withZIANA Gel and 423
`ZIANA (clindamycin phosphate 1:2% and tretinoin 0.025%)
`treatedwith vehicle. Analysis;over thetWelve week period
`demonstli'atedthat cutaneous irritationscores for erythema,
`Gel, is an antibiot1c and retinoid combination ge'l‘prod'uct
`scaling,_itching, burning, and stingingpeaked at_tWoweeks
`
`with tWo active ingredients. Clindamycin phosphate is‘ka
`
`of therapy, and were slightly higher,
`1‘ the ZIANA—-treated
`Water-soluble’éster of the semi--synthetic antibiotic p'ro-
`group, decreasing thereafter.~i__,._
`,.
`1...M
`2 A
`
`ducedilb,
`a -7(S)-€hloro substitution of the 7(R)—hydroxyl
`One open-label 12-month safety study for ZI’AEAR.Gel
`group of-theeparent antibiotic lincomycin.
`showeda similar adverse reactionprofileas.seen in the 12-
`.. The
`chemical name for
`clindamycin phosphate is
`week studies. Eighteen out of 442 subjects (4%) reported
`. Methyl 7—chloro—o‘,7,8—ti-ideoxy-6-(1-methyl tracs-4-propyl
`!
`gastrointestinal symptoms.
`-
`L-2-pyrrol1d1necarboxam1do)1-thio-L-threo—“a—D-galacto—
`7 DRUG INTERACTIONS
`E octopyrahoside 2-(dihydrogen- lph_1')s_phat1-‘z). The structua1
`7.1 Concomitant TopicalMedication
`.. 1
`“s
`.,-
`..
`formula for clindamycin phosphate15 representedbelow:
`Concomitant topical medication, medicated or abrasive :
`Ciindamycin phosphate.
`lsoaps and cleansers,soaps”alnd cosmeticsthat have a strong
`ldrying-g effect, andproductswith h1g1i concentrations of alco-
`hol, astringe’nts spice‘sofllimeshould be used with caution.
`When usedWith- ZIANAGel, there’ may beincreased skin
`irritation.
`i‘ ‘~ 1.
`‘
`
`
` _ , ,f.
`7-.2Er'ythrdicini .
`.
`‘
`«ZIANA Gel' should not be‘lusedg' in combination“with j
`erythromycin——co‘ntaining products due to its clindamycin
`component. In vitro. studies have showniantagonism be-
`;
`tween these two antimicrobials. The clinical significance of
`thisin vitro antagonism is not known.
`"1’
`7.3 Neuromuseular Blocking Agents
`Clindamycin has been shown to have neuromuscularblock-
`ing properties that may enhance the action of other neuro-
`muscular blocking agents. Therefore,ZIANA Gel should be
`used with cautionin patients receiyi'ng such agents
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Pregnancy Category C. There are no well‘controlled trialsin
`pregnant women treated with ZIANA Gel. ZIANA Gel
`should'be used during pregnancy orfly‘if the potential ben-
`efit justifies the potential risk to the fetus. ZIANA Gel was
`tested for maternal and developmental toxicity in New
`Zealand White Rabbits with topical doses of 60,180 and
`600 mg/kg/day. ZIANA Gel at 600 mg/kg/day (approximately
`12 times the recommended clinical dose assuming 100% ab-
`sorption'and' based on body surface area comparison) was
`considered to be the no--observed-adverse-efl‘ect
`level
`(NOAEL) for maternal and developmental toxicityfollowing
`dermal administration of ZIANA Gelfortwo Weeks prior to
`artific1al insemination and continuing until gestation day
`18, inclusive. For purposes of comparisons of the animal ex-
`posure to human exposure, the recommended clinical dose
`is defined as 1 g of ZIANA Gel applied daily to a60 kg
`person.
`4
`
`Impairment of
`
`1p!“ ‘
`
`
`DIIE
`no IIANDLING
`RAGE A
`
`'3’:th INFoRMATION -.
`
`1101100115 for Use
`I
`‘._ngmtation
`
`Ifveg Patienthabeling
`Mew-0,15 omitted from the full prescribing
`5511
`
`
`are 1105 listed.
`
`I
`1331116 INFORMATION
`ONS AND USAGE
`dicated forthe topical treatment of winevul-
`
`_-'en‘ts 12 years or- 011de'r.
`,,
`ANT) ADM¥NISTRATION
`
`eeze a pea——sized amount of medication onto
`2;; onto the chin, cheeks, nose, and forehead
`
`_b safer the entire face ZIANA Gel should be
`m tse eyes the mouth, _angles of the nose, and
`
`. raues.
`
`15 not for oral, ophthalmic,orJ‘mtravag'ihaluse
`
`
`tains, clindamycin phosphate. 12% and
`1 5%, fogmulated as altopi‘qal gel. Each gram of
`
`1 \ta'insr as dispensed, 10 mg (1%)'clinda.mycin
`
`a [1.25 mg (0.025%) tretinoin in an aqueous
`AGel is available in 2 gram, 30 gram, and
`
`1
`l1]
`
`IIIEATIONS
`
`_ ontraindicatedin patients With regional en-
`ive colitis, orhistory of antibiotic—associated
`
`ICOLOGY
`M11utagenesis,
`
`1"
`
`It.
`
`
`
`airfares
`
`4
`
`

`

`1944/:MESICIS
`
`
`PHYSICIANSIIDES
`
`
`
`
`(2) Percent of subjects who cleared or almost cleared at
`Week 12 as judged by an Evaluators Global Severity
`(EGS) score.
`The EGS scoring scaleius'ed in all of the clinical trials for
`ZIANA Gel is as follows':
`
`Grade Description
`
`Clear
`
`Normal, clear skin with no evidence of acne
`"f
`vulgaris
`Rare non—inflammatory lesions present, with
`rare min-inflamed papules (papules must be
`resolving and may be hyperpigmented,
`‘
`
`though not pink-red)
`
`Almost
`Clear
`
`Mild
`
`Moderate
`
`Some non-inflammatory lesions are present,
`with few inflammatory lesions (papules/
`pustules only; no nodulocysti: lesions)
`Non—inflammatory lesions predominate, with
`“multiple inflammatory lesions evident
`several to many comedones and papules/
`pustules, and there may or may not be one
`small nodulo-~cystic lesion
`
`Severe
`
`Inflamniatory lesions are more apparent
`many comedones and papules/pustules, there
`may or may not be a few nodulocystic lesmns
`
`Very
`'Severe
`
`highly inflammatory lesions predominate
`variable nuinber of comedones, many
`papules/pustulesand many nodulocystic
`
`lesions
`
`:
`
`
`Clinda-
`ZIANA
`
`Tretinoin Vehicle
`mycin
`
`N=846
`
`Evaluators GlobaIISevgrityi N (%),
`
`Ejfiigfifng
`succesé,
`
`34
`122~
`70
`180
`
`(11%), 18%) (16%) (14%)
`
`
`Inflammatory Lesion Count (% reduction‘from' baseline)
`
`
`
`
`
`
`
`I"
`
`31%
`27%
`36% I
`16%
`Total LesionCount (% reduction from‘ baseline)
`Mean
`41% f
`34%
`34%
`
`"20%
`
`
`
`*Success was defined as clearedror almost cleared at Week I'
`12.
`r I
`I
`
`Ziana—j-Cont.
`
`-
`
`I.
`
`ZIANA Gel contains the following inactive ingredients: pu-
`rified water USP, glycerin USP, carbomer- 981 NF, methyl—
`paraben NF, polysorbate 80 NF, edetate disodium-USRncit-
`ric acid USP, propylparaben NF, butylated hydroxytoluene
`NF, and tromethamine USP.
`12 CLINICAL PEARMACOLOGY
`12.1 Mechanisms of Action
`Clindamycin
`[see Microbiology (12.4)].
`TI‘etinoin
`Although the exact mode of action of tretinoin is unknown,
`curren evidence suggests that topical tretinoin decreases
`cohesiveness of follicular epithelial cells withidecreased Ini-
`crocomedo formation.
`J 1
`.
`Additionally, tretinoin stimulates mitotic activity and in-
`creased turnover of follicular epithelial cells causing extru—
`sion of the comedones.
`12.3 Pharmacokinetics
`In an Iopen-label, multiple-dose study treating 12, subjects
`with moderate to severe acne, thezp'ercutaneous absorption
`of tretinoin following 14 consecutive daily applications of
`approximately 4 g of ZIANA Gel was minimal;rQuantifiable
`tretinoin plasma concentrations ranged from 1.0 to 1.6 ng/
`mL, with unquantifiable plasma concentrations in 50% to
`92% of subjects at any given timepoint following adminis-
`tration. The plasma concentrations oféthe key tretinoin me—
`tabolites, 13-cis-retinoic acid and 4-oxo-13-cis—retinoic acid,
`ranged=from 1.0 to 1.4 ng/mL and from 1.6 to 6.5 ng/mL, re-
`spectively. Plasmarconcentrations for clindaniycinzgenerally
`did not exceed 3.5 ng/mL, with the exception ofsone subject
`whose plasma concentration reached 13.1 ng/mll:
`12.4 Microbiology
`Clindamycin binds to the 50S ribosomal subunitsof suscep-
`tible bacteria. and prevents elongation of peptide chains 'by
`interfering with peptidyl transfer, thereby suppressing bac— '
`terial protein‘ synthesis. Clindamycin has been shown to
`have in vitro activity against Propionibacteriumcones; an
`organism whichIhas been associated with acne vulgaris;
`however, ,.the clinical, significance of this activity againstvfl
`acnes was not examined in clinical trialswith ZIANA Gel. P.
`acnes resistance to clindamycin .has been documented. Re—
`sistance to clindamycin1's often associated with resistance
`to erythromycin.
`_.
`..
`138
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenésis, Impairment 6? Fe
`Iity
`
`Carcinogenicity, mutagemmty andi‘IISpairment of fer
`ity
`cies.
`testing of ZIANAG‘el havenot been performedIn any spe-
`Clindamycin
`The carcinogenicity ofa 1% clindaniycin phosphate gel sim-
`ilar to ZIANA Gel was evaluated by daily application to
`mice for two years. The daily doses usedin this study were
`approximately 13 and 72 times higher than the human'dose
`of ,clindamycin phosphate froerIANA Gel, assuming corn-
`plete absorption and based on a,body surfacearea compar-
`ison..fNo significant increase in tumors was noted in the
`treated animals. For purposes of comparisons of the animal
`exposuretohuman exposure, the recommended human top-
`ical clinical dbseis defined as 1 g ofZIANA Gel applied daily
`to a60 kg person.
`. Fertility (Segment 1)studiesIn ratstreated orally with up
`to. 3Q0 mg/kg/day of clindarnycln (approximately 290 times
`the amount ofclindamycindelivered from the recommended
`clinical dgse for ZIANA Gel, based on a body surface area
`comparison) revealed no eifects on fertility or mating ability _
`Tretinoin
`
`In two independent studies with longterm topical applica-
`tion of tretinoin in mice, carcinogenicity was not observed.
`In both studies,
`tretinoin was‘ administered topically
`(0.025% or 0. 1%) three tiines per week for up to two years.
`No carcinogenicity was observed with maximum efi‘ects of
`dermal amyloidosis1n the basal layer of the skin.
`photoco-
`Tretinoin has
`been
`shown
`to
`enhance
`carcinogenicity in properly performed specific studies, em-
`ploying concurrent or intercurrent exposure to the drug and
`UV radiation. The contribution of ‘clindamycin to that effect
`is unknown. Although the significance of these stadies to
`humans is not clear, patients should minimize exposure to
`sun.
`
`The genotoxic potentialof tretinoinwas evaluatedIn an in
`vitro Ames Salmonella reversion test and an in vitro chro-
`mosomal aberration assay inChinese hamster ovary cells.
`Both tests werenegative.
`In oral Segment1 studiesIn rats treated with tretinoin, the
`no--observed-efi‘ect—level Was 2 mg/kg/day (~78 tiines the
`reCommended clinical dose assuming 100% absorption and
`based on- body surface area comparison).
`14 CLINICAL STUEIES
`The safety and efficacy of once daily use of ZIANA Gel for
`treatment of acne vulgaris were assessed in three 12 week
`prospective, multi—center, randomized, blinded studies in
`patients 12 years and older. Studies 1 and 2 were of identi-
`cal design, and compared ZIANA Gel to clindamycin in the
`vehicle gel, tretinoin in the vehicle gel, and the vehicle gel
`alone. Patients With mild, moderate, or severe acne were en-
`rolled in the studies. The co-primary efficacy variables were:
`(1) Mean percent change from baseline at Week 12 in
`0 inflammatory lesion counts,
`' non-inflammatory lesion counts, and
`I total lesion counts
`
`
`
`.
`
`16 HOW SUPPLIED/STORAGE
`ZIANA (clindamy
`
`NDC 99207. 0
`2 gram tube
`NDC 99- 01300‘0
`30 gram tube
`NDC 99207_30030
`60 gram tube
`Storage and Handling
`060
`- Store at 25°C (77"F); excurTSiOns
`(59—86°F) [see USP ControlledJ5R0011;peTmiltte8d
`“3 15‘
`0 Protect from light.
`InmTe111p
`0 Protect from freezing
`Bram-1%
`- Keep out of the reach of children
`0 Keep away from heat.
`' Keep tube tightly closed.
`
`as erythenaa. :*
`
`
`
`.17 PATIENT COUNSELING INFOR
`
`See FDA-A roved Patient
`”MAT
`17.1 lnstruftibns for Use
`Labeling (17-4). 0N
`- At bedtime, the face should be
`g9ntlyw
`soap and Warm Water. After
`Patting ‘35}?sh“! we,
`
`ZIANA Gel as a thin layer 0v
`errthe entirget: I]: ,Kc
`the eyes and lips).
`- Patients should be advised not to011
`ommended pea sized amount and n5: more
`
`than once daily (at bedtime) as to. tea
`faster results and may increase irritlst'WII
`0 A sunscreen should be applied evera mn'
`plied over the course ofthe day as nezdmommg and m
`
`be advised to avoid exposure to sunli fid'aPattlenls I”:
`violet light, and other medicines tht
`I SuMiamp,
`tivity to sunlight
`at maylncrease a;
`‘17.2 Skin Irritation
`ZIANA Gel may cause irritation-such
`
`itching, burning, or stinging
`17.3 Colitis
`
`
`
`is
`In the event apatient treated withZIANA Gel “PE”My“
`seve’re diarrhea or gestrointestinal d
`shodl‘dbe discontinued and a physician:hlélfiétbezgstu
`17.4 FDA-Approved Patient Labeling 9 f- ’
`
`-
`'
`PATIENT INFORMATION
`"
`ZIANA (ZEE-AH-NA)
`(clindamycin phosphate 1.2%and tr‘etinoin 0.025%) Gd I
`
`IMPORTANT. Not for mouth, eye, or vaginal use. T
`Read the Patient Information that comes with ZIANA"
`
`
`before you start using wands-ach- tir‘n‘e yea go; II
`This leaflet does no:
`There may be new iriforinat‘io
`
`the’jp'lace‘ r'of t