deeiYiy10):
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`awww.nPLOFynet
`. aleea8
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`ree senilebd
`ccAeAlmirall,‘LLC
`
`AMN1039
`Amneal v. Almirall, LLC
`IPR2018-00608
`
`1
`
`

`

`
`
`
` PDR
`63
`
`2009
` Pets JAN
`Soa58ca
`IKEFERENCE
`
`xecutive Vice President, PDR.vias r. KICe
`ice President, Finance, PDR: Donna Santarpia
`ice President, Product Management: Cy Caine
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`Copyright © 2008. Published by Physicians’ Desk Reference Inc. at Montvale, NJ 07645-1725.All rights reserved, None of the content of this publication may be
`reproduced, stored in a retrieval system, resold, redistributed, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise)
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`ISBN: 1-56363-703-2
`
`2
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`

`
`
`|
`
`1942/MEDICIS
`
`Vanos—Cont.
`
`igiewe
`
`abea
`
`tinued wheneontrol 'is’ achieved!Tf no ‘improvement is
`seen in 2 weeks, the patient should be instructed to con-
`tact a physician, The’ safety of the ‘use of VANOS™
`Créamn fr longer than 2 weeks'fasfiot been eétablished:
`7) Patients: should beinformedto ot use more than*60 ¢
`per week’of VANOS™Cream. Do not use more than half
`of the 120 ¢ tube per’ week.
`8) Patients should inform their physicians‘that théy are us-
`infVANOS™Cream if’‘surgery is contemplated.
`9) Patients should wash their amesie applying medica*
`tion.
`Laboratory Tests: The Anau (ACTH,oastimulation
`test. may be helpful in evaluating patients.for, HBA-axis
`
`
`S, |‘Mutagenesis, and Impairment of Felrti ity:
`Long-term animal studies have not been performned’+6éval
`
`uate the carcinogenic Peas or the effect’ on’ fertility:of
`fluocinonide,
`.
`42).
`,
`F
`:
`#
`Fluocinonide- revealed no evidence of mutagenic or..clasto;
`genic potential.based.on the results of twoa, vitro genotox-
`
`igity: tests;(Amestest and:
`aniin vitro chromosomal jaberra-
`tion assay ‘in human ‘lymphocytes),-However, fiuocinénide
`was positive: for clastogenic potential when;tested-in the in
`vivo mouse micronucleus assay.
`’
`>
`lashpet
`Pregnancy Category,C:
`,TeratogenicEffects:
`,Corticoster:
`oids have-been shownto be teratogenic in laboratory anit
`
`malg.when; administered systemicallysat relatively low dos;
`age Jevels. Si
`.e,corticosteroids have been,shown. to ‘be
`
`teratogeni
`er dermal application.in laborat
`
`There are.no,adequate;and,well-controlled stuc
`nant women.., Therefore,
`IANOS™-‘Cream ‘should ibe used
`during pregnancy only-if the,Potential benefitjustifies the
`potentialrisk to the fetus:
`Nursing.‘Mothers: Systemically ¢administered‘corticoster:
`east
`oids,Appear in“human.milk‘and, could suppress,growth, in:
`terfere with endogenous corticosteroid;prodnetion, or cause
`
`other‘untowardeffects:iI
`not known whethertopical ad:
`ministration. of cortivostero s,could.result, jin sufficient sys-
`
`temic absorption‘to-producedetectable quantities in breast
`+8decision should: be made,whether fo
`discontinue.jnursing or to discontinue the drug:taking.into
`account the importanceof the drug to the mother...
`,
`.-
`Pediatric Use: Safety and efficacy of.VANOS™ Cream in
`pédiatne patients younger than 12wears of age have“not
`been, “established;
`therefore,;use ‘in pediatric patients
`younger than 12 years of age is not recommended.
`HPAaxis suppression was studied in 4 sequential cohorts of
`pediatric patients with atopic dermatitis covering at least
`20% of the body surface area, treated once daily or twice
`e
`
`Unspecified Application Site Reaction
`
`0
`
`|
`|
`
`3/211 (1.4%)
`
`The‘followirig additional local adverse reuictidns have been |
`
`daily with VANOS™‘Cream.‘Thefirst cohort of 31 phtients
`(mean 36.3% BSA) 12 to < 18years old; the second cohort
`included 31 patients (mean 39.0% BSA) 6 to < 12 years old;
`the third cohort included 30 patients (mean 34.6% BSA) 2 to
`If irritation‘develops, VANOS™ Cream shouldbe disvontin
`<6 years old; the fourth cohort included 31 patients (mean
`ued anid appropriate-therapy instituted. Allergic contact
`40,0% BSA) 3 months to < 2-years old- VANOS™ Cream
`dermatitis with corticostéroids is usuallydiagnosed by ob-
`caused HPAaxis: suppression in 1 patient in the twice daily
`serving failure to heal rather than noting a clinical
`group in Cohort-1, 2-patients in the.twice daily group-in
`exacerbation as withmost topical products not containing™~
`Cohort 2, and 1 patientiin the twice daily group.in Cohort 3.
`corticosteroids. Such an observation should be corroborated
`Follow-up testing 14 days after treatment, discontinuation,
`with appropriate diagnostic patch testing.
`|. available for.all_4 suppressed patients, demonstrated a nor-
`If concomitant skin infections are present or develop, an ap-
`
`mally responsive HPA-axis. Signs of skin,atrophy were pres-
`propriate antifungal or antibacterial agent should be used.
`ent.at.baseline and severity was not determined making rt
`If a favorable response does not occur promptly, use of
`difficult to assess local skin safety. Therefore, the safety of
`VANOS™Cream should bediscontinued until theinfection.
`VANOS™Cream in patients younger than 12 years.of age
`has not been demonstrated.
`tds
`has been adequately controlled.
`VANOS™ Gream should not be used in the treatment ofro--
`Because of a higher ratio of skin surface-area to body-mass,
`sacea or perioral dermatitis, and should not be used on the
`pediatric patients are at a greater risk than adults of HPA-
`face, groin, or axillae.
`i
`| axis suppression and Cushing’s syndrome when they are
`treated with topical corticosteroids. They are therefore also
`Information for the Patient:
`‘Patients using VANOS™
`Cream should receive the following information and-in-
`at’greater risk of-adrenal insufficiency during or after with-
`structions. This information isinténded to aid in the safe
`drawal of treatment. Adverse effects including-striae have
`and-effective use of this medicationIt isnot a disclosure of
`been reported with-inappropriate use-of topical ComCDser:
`all possible adverse or unintendedeffects:
`oids in infants and children{
`HPA-axis suppression, CusHing’s syndrome,linear doe
`1) VANOS™Cream is to be used as directed by the physi-
`retardation; delayed weight gain;-and-intracranial-hyper-
`cian. Itis for external use~only, Avoid contact withthe
`eesee
`tension have been reported in children receiving topical
`eyes. It should not be used on the face, groin, and under-
`aris.
`rare
`
`corticustertids. Manifestations of adrenal suppression in
`children include low plasma cortisol levels and absence of
`2) VANOS™ Cream should not be used for any|disorder
`response to cosyntrépin:(ACEH. }
`stithulation. Manifesta-
`other than that for whichit was prescribed.
`|
`i
`
`tions of intracranial®‘hypertension include bulging’fonta!
`3) The treated skin area should not bebatidaged ’or‘éther-
`wisé’covered or Wrapped, so asto be occlusive unless ‘di-
`nellés, headaches! &hd bilateral papilledemat'SE
`em
`Geriatric Use: Clinical studies of VANOS™Gieam did not
`tected bythe?‘physician.
`.
`thy?
`4) Patientsshotild-reporttétheitphysician ee oflo-
`include sufficient naimbers ‘of subjects’ aged 65‘anhd over to
`cal adverse reactions.
`7
`determine whether they respond differently from younger
`5) Other corticosteroid:containing products ate tr not be
`subjects. In general, ‘dose selection for an elderly patient
`should be cautious: ©
`“used with'VAD ‘OS Creayythoutfirst talking to,thephy-
`see‘sician.
`ae
`6)As withother:Scuba‘therapy’ should be discon:
`
`
`EFER iBN
`Therapy’ should bei discontinued ‘whan
`+
`
`achieved. If noimprovenient is seen wiithetro] h
`sessment ofdiagnosis may be necessary. aiauesi
`HOW SUPPLIED "
`~
`ef
` Swatpgigig
`
`VANOS™.. (fluocinonide) ‘Cream:0,15
`num tubes as follows:-:
`“thre edin,aly
`
`30 g (NDC 99207-525-30)
`aks
`
`60-g (NBC99207-525-60)
`“ty
`120 g (NDC 99207-525-10)
`on
`
`Store at’controlled room temperature: 15°
`
`86°F).
`Manufactured for:
`
`MEDICIS, The Dermatology Company
`
`Scottsdale, AZ 85258
`Manufactured bj:
`
`Patheon, Inc.
`
`Mississauga, Ontario
`Canada L5N 7K9
`Made in.Canada
`
`U.S. Patent 6,765,001and Patents Pending
`Prescribing information as ofAugust 2006"
`IN-5325/S
`.
`
`ZIANA™
`[zee-ah-na]
`
`(clindamycin, phosphate 1.2%,
`
`and eneee Gel-
`HIGHLIGHTS. OF,PRESCRIBINGINFORMATION
`
`These Tiphlights do not-includeall. the information
`to use ZIANAGel.safely and.effectively, Seefull
`oa
`
`information for ZIANA:Gels,
`am
`and on n
`ZIANA™ (clindamycin phosphate 1,2%
`
`0.025%) Gel
`For topical use only
`Initial U.S. Approval: 2006
`INDICATIONS AND USAGE
`ZIANA Gelis a lincosamide antibiotic ‘andretinoid ep
`
`nation product indicated for the topical treatmentof
`
`9
`vulgaris in patierit’s!19years or older. (1)
`DOSAGE AND ADMINISTRATION ~
`
`* Apply a pea+sized amount to'the entire ‘faceonce
`of thi
`bedtime. Do not apply to éyes, mouth, angies
`
`ae
`or mucous membranes. (2)
`* ZIANAGelis notfor.oral,, ophthalmic, oF intravagin !
`
`Op
`
`DOSAGE FORMS AND STRENGTa
`4
`Topical gel: Clindamycin phospliate 1.2% and
`treve
`0.025% gel in 2, 30, and60 gram tubes. (3)
`
`CONTRAINDICATIONS ;
`ZIANA Galiis.contraindicat
`
`teritis, ulcerativecolitis, or his
`
`bit
`golitis. (4),
`‘WARNINGS AND;BREGAUTIONS
`
`# Colitis:Clindamyein can, cause severe|colitis: a if
`regultin.death, Diarrhea,bloodydiarrhea;wens
`
`cluding’,pseudomembranous colitis)-haveould be
`with:the,use-ofclindamyein.ZIANA cli
`tinuedif significant diarrhea“occurs,(6DExposres
`
`sunsereel
`* Ultraviolet Light and,Environmmental
`
`exposure,to sunlight and sunlamps. Wear
`(5.2)
`
`ADVERSE REACTIONS
`Observed local adverse reactions 19 patie
`ZIANAGelwere’ skin erythema, sealrt
`and. stinging.,Other. most comme punncal
`exentsi(=:1%tinpatients:treated-wit Na
`
`sopharyngitis; phanjngolaryneeepa
`and sinusitis;.(6:1)
`To report SUSPECTED ADVERSE RE
`
`Medicis,
`j
`
`The Dermatology Company
`e
`at 1-800-900-6389
`;
`
`rig
`or FDA at 1-800-FDA-1088
`PONS 5 any
`or www.fda.govimedwatch _
`
`DRUGINTER:ions Wiwit?
`
`a
`* Concomitant use,oftopical™Peitation- Use
`ing effect can increase §
`avin s
`71
`in © oa
`. Ne Gel should not be veces bee
`
`I
`‘erythromycin-containing o
`clindamycin component. G. gELING
`
`See 17 for PATIENT CO
`Table 3: Most Cornmonly Observed Adverse Events in AdultClinical Trials
`and FDA-approved labeling-
`
`Revised: 11/2006
`Adverse Event
`VANOS™Cream,
`VANOS™Cream,
`Vehicle Creani,
`con
`
`once daily
`twice daily
`once or twice daily
`FULL PRESCRIBING INFORMATIO':my
`
`
`(n=216)
`(n=227),
`(m=211)
`INDICATIONS AND USAG™ow
`1
`
`
`Headache
`8/216 (3.7%) .
`9/2277, (4.0%)
`6/211 (2.8%)
`"2 DOSAGE AND ADMINISTR
`*
`eRe
`arco
`3 DOSAGE FORMS AND
`
`5/216 (2.3%)
`412.27 (1.8%)
`14/211 (6.6%)
`Application Site Burning
`olesikerermeceesseekShak
`4 CONTRAINDICATIONS
`
`3/2217 (1.3%) 3/211 (1.4%)
`Nagopharyngitis
`2/216 (0.9%)
`5 WARNINGS AND PRE
`itis
`1/227 (0.4%)
`—
`3/216 (1.4%)
`Nasal Congestion
`1/216 (0.4%)
`gar (04%)
`
`
`
`ADVERSE REACTIONS;,;
`In clinical trials, a total“of 443 adult patients with atopic
`dermatitis or plaque-type psoriasis were treated once daily
`or twice daily with VANOS™ Cream for 2 weeks. The most
`commonly observed adverse events in theseclinical trials
`were as follows:
`[See table 3 below]
`Noother adverse events were reported by more than 1 sub-
`ject receiving active treatment. The iticidence of all advers> |
`events was similar between the active treatment’groups
`and the vehicle control groups. Safety in patiénts 12 to217
`years-of.dgéswas similar to that observed‘in adults.
`
`reported with topical corticosteroids, and they-may occur
`morefrequéntly with the°use of occlusive dressings. and
`highérpotency:corticosteroids. These reactions are listed in
`an approximate decreasing order of occurrence: burning,
`itching,irritation, dryness, .folliculitis, hypertricnosis, acne-
`iform eruptions, hypopigmenitation, perioraldermatitis’ alt
`
`érgi contact dermatitis; ‘maceration ofthe skin,gotondaty
`
`infection, skinatrophy, striae, and miliaria,?”
`.
`lined
`Systemic absorption of topical corticosterui is“hasprodiiéed
`hypothalamic-pituitary-adrenal’ (HPA) “axia’):isuppr didn
`
`ma
`ifestations of Cushing's syndrome, hypetalyeetmia, 5
`gluosuia iin somepatients.
`‘
`OVERDOSAGE
`Topically applied.‘VANOS™. Crean can ‘be absorbed iin suf:
`ficient.amounts to ‘produce*ratedéffects (see-PRECAU:
`TIONS). -
`af
`“29
`DOSAGE AND ADMINISTRATION
`For psoriasis,-apply-a thin layer,“ofVANOS™ Cream once.or
`twice daily.to.the affected,skin, areas,as, directed by-a phy-
`sician. Twice daily application for the treatment of psoriasis
`has-been shown:to be more.effective in achieving treatment
`success,; during22 weeks. of treatment.,on
`eT
`|
` Eor,atopic dermatitis,sapply.2a thin layer ofVANOST¥Cream
`\ onee,daily. to theaffected skin‘areas as directed by physi-
`cian. Oncedaily‘application for;the.-reatmeht ofatopic der:
`matitis has, been:shown to:bevas:effective as twice. daily
`treatmentin achieving treatment successduring2 weeksof
`treatment-(See,CLINICAL STUDIES).
`For corticostervid responsive dermatoses, other than.spsori-
`| asis or atopic, dermatitis, apply a thin,layer of VANOS™
`Cream onceor twice daily to the. affected,areas,as directed
`by.a physician, »
`5
`Treatment,with VANOS™ Cream should _be limited to 2
`consecutive weeks, and no more than 60 g/week should be
`used.Do not.use more. than half ofthe 120 g tube: per
`week.
`
` J
`
`PHYSICIANS’ DESK R
`
`=
`
`:
`
`to 802%
`
`|
`
`
`
`
`
`s: Golem Light a"
`
`6 ADVERSE REACTIONSa
`
`6:1
`Clinical Studies
`
`r
`
`3
`
`

`

`js not for oral, ophthalmic,Shintravdeiisaluse:
`
`
`Clindamycin
`
`Table 1: Adverse Reactions Report
`in at Least 7%of
`Teratology (SegmentII) studies using clindamycin wereper-
`Patients Treated With ZIANA Gel: 12-Week Studies
`formedorally in rats (up to 600 mg/kg/day) and mice (up to
`100 mg/kg/day) (583 and 49times amountof clindamycin in
`
`oe, sockingAgen
`aie Se Tretinoin | Vehicle,
`the recomended clinical dose based ona body surface-area
`6ae
`=
`=
`Ss
`oeseuleCULATIONS:
`
`N=1853|N=1428 Nee ds
`comparison, respectively) ow with subcutaneous doses of
`.;
`C
`
`clindamycin ‘up. to 180:ing/Kg/da:
`lisvand 88 tithes the
`
`
`N(%)|N(%) oo ae
`amount of clindamycin in the"‘recommended. clitiiéal “dose
`
`PATIENTS
`based on a body surface:area, comparison, respectively) ree
`:
`WITH AT
`vealed:no evidence of teratogenicity. we
`feaa
`Tretinoin
`
`
`ease 497 (87)|842 (24)|225 7)|91 (22)
`In oral Segment III studies in rats with tretinoin!Meefeaned
`ONE AR
`
`
`survival of neonates and growthretardation were observed
`at doses in: excess of ‘2 mg/kg/day (~ 78times the, recom-
`
`Nasopharyn-
`©
`7
`mended clinical dose assuming 100% absorption and based
`gitis
`65 (4)
`64 (5)
`16 (2)
`5 (1)
`
`on: body surfacetarea comparison).
`
`With widespread use of any drug, a amall. numberof birth
`Pharyn-
`te
`resi
`29 (2)
`18 (1),
`5 (1)
`7 (2)
`golaryn-
`defect reports asséciated temporally with the administra-
`tio of the-drug would'be expected by chance:alone. Thirty
`geal pain
`
`cases of temporally associated congenital malformations
`have been reported during two decadesofclinical use of an-
`
`23 (1)
`0,(0)
`Dry skin
`other formulation of topical tretizioin..Although:no) definite
`pattern.of teratogenicity and no. causal association have
`
`
`2(1)
`Cough
`19 (1)
`been:established from these:cases,'5 of the reports describe
`
`19,(1),
`Sinusitis
`the: rare: birth: defect: category, holoprosencephaly (defects
`| assotiated with incomplete midline developmentof the fore-
`Note: Formulations usediin all treatment, arms were in
`brain). The: significance of these spontaneous reports in
`terms of risk to theifetus.is not: known.
`the ZIANA vehicle,gel.
`Dermal: tretinoin has ‘been shown to be fetotoxic in rabbits
`when-administered in dosés'40 times the:recommended hu-
`man clinical dose based on a body surface afea comparison.
`Oral tretinoin has been shownto ‘be fetotoxic in rats when
`administeréd in doses°78 times the recommended clinical
`dose based.on a ‘body surface area comparison:
`’
`ses
`8.3 Nursing Mothers
`It is not known whether:clindamyein is excreted in human
`milk following:use of ZIANA Gel. However, orally and :par-
`enterally administered: clindamycin *has been’ reported to
`appeartin breast milk. Because of the potentialfor serious
`adversereactions ‘in nursing ‘infants, a decision should be
`madeiwhether todiscontinue nursing or to discontinue:the
`drug, taking into account the importance of the:arug'to the
`mother? It is.not known whethertretinoin-is exereted in hu-
`man'milk. Because many/drugs are-excreted in human
`milkizcaution should be-exercised when ZIANA Gel is ad-
`ministered to a nursing woman.
`8.4 Pediatric Use
`'
`Safety.and effectiveness of ZIANA Gel in pediatric patients
`
`under. the:
`1
`f'
`12 have not, been established,
`aT ty TNE
`27 (2)
`Clinical trials of ZIANA Gel.included patients 12-17 years
`Ont
`of|age.[See Clinical Studies (14)
`8.5 Geriatric Use
`At each study visit, application site reactions on a scale of 0
`Clinical studies of ZIANA Gel.did.‘notAnelude sufficient
`(none), I(mild), 2 (moderate),aand3,(severe), andthe mean
`numbers of‘subjects aged 65 andover‘todetermine whether
`Scores weré calculated‘fore veht6éfthe local’skin reactions. In |
`they respond differently,from jyo
`gi
`
`( upjects enrolled with moderate to
`
`11 DESCRIPTION
`PY bane
`severe acne, 854°“subjectstitreated’ withJZIANA Gel and 423
`ZAANA (cliidamycin phosphate 12% and tretinoin 0;035%)
`treatedwath wehicle. Analysis,over the,twelve week period
`demonstrated’that cutaneous irritation¢scores for erythema,
`| Gel, is an antibiotic: and retinoid’ combination gel'préduct
`scaling,itching, burning, and stingingpeaked attwo weeks
`with:twoactive ingtédients. Clindamycin phésphate- isa
`
`
`of therapy, and were slightly higher,
`Tr the ZIANA+treated
`Water-soluble”S8ter of the semi-synthetic antibiotie _pro-
`group, decreasing thereafter,__
`duced”)
`a 7S).chloro-substitution of the ‘7(R)-hydroxyl
`One open-label 12-month safety study. ‘for ZIANA,Gel
`
`
`Zroup oftheié parent antibiotic lincomycin.
`showed.a similar adverse reaction‘profile.as.seen in the 12-
`The chemical name for
`clindamycin Phosphate:
`is
`week studies. Eighteen out of 442: euiets (4%) reported
`‘
`‘Methyl 7-chloro-6,7,8-trideoxy-6-(1-methyltra’.s-4-propy]
`gastrointestinal symptoms.
`7 Le-2!pyrtolidinécarboxamido):1-thio-L-¢hreo-a-D:-galacto-
`7, DRUG INTERACTIONS
`i octopyrahoside 2-(dihydrogeh:phosphate). The‘structii-al
`7.1 Concomitant TopicalMedication
`formula for clindamycin:pioepliatenis representedinlorge
`ei
`Concomitant topical medication, medicated or abrasive :
`Clindamyein snoaehate:
`soaps and cleansers,SOAPS|and cosmetics.that have a strong
`drying éffect? and’‘products!With high‘concehtrations of dlco-
`hol, astringents, spices‘OPlithé'sshould betiked with caution.
`When used*with ZTANA‘Gel, there’may be’intreased skin
`igritation.
`esouy!
`
`7:2-Erythtomyéini =:
`ZIANA Gel should not Be'lused: in ‘combination-with -
`erythromycin-containing. products dueto its clindamycin |
`component. In vitro, studies have 'shown:antagonism be-
`:
`tween these two antimicrobials. The clinical significance of
`this in. vitro. antagonism is not known,
`re
`73. Neuromuscular Blocking Agents
`Clindamycin,has been shownto.have neuromuscularblock-
`ing properties that may enhance the action of other neuro-
`muscular blocking agents. Therefore,|ZIANAGel should be
`used with caution in patients receiving such agents..
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Pregnancy Category C. There are no well-controlled‘trials:in
`pregnant women treated with ZIANA Gel- ZIANA Gel
`shouldbe uséd during pregnancy orily‘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. ZIANAGelat 600 mg/kg/day‘(approxifnately
`12 times the recommendedclinical dose assuming 100% ab-
`sorptionand"based on body surface avea comparison) was
`considered to be the no-observed-adverse-effect evel
`(NOAEL) for maternal and developmental toxicityfollowing
`dermal administration of ZIANA Gel’fortwo weeks prior to
`artificial insemination and continuing until gestation day
`18, inclusive. For purposes of comparisonsof the animal ex-
`posure to human exposure, the recommendedclinical dose
`is defined as-1 g of ZIANA Gel applied daily to a1’ 60 ke
`person.
`4
`
` oawaTlon a
` .oricalMedicationis
`
`
`
` aeOLOGY
`“sic Aosta Mutagenesis, Impairment of
`
`
`:
`
`
`oprovel PatientiLabeling:
`ad
`, ections omitted from the full prescribing
`
`; ad f
`
`are nob listted.
`
`meric INFORMATION
`TON!Ns AND USAGE
`indicatedfor’the topical treatment ofacne-vul-
`
`wients 42 years or older.
`B
`
`
`gg AND ADMENISTRATION
`
`queen, axpea--sized amount of medication onto
`“dot onto the chin, cheeks, nose, and forehead,
`
`ab ever the entire face: ZIANA.Gel should be
`
`m the eyes, the mouth, angles.of the nose, and
`
`
`aeness
`moranes.
`
`'FORMS.AND, STRENGTHS sioome
`
`ibination.of a lincosamide antibiotic and 2
`
`tains, clindamycin phosphate. 1.2% and
`
`025%, formulated as a topical gel. Each gram of
`él contains, as dispensed, 10 mg (1%):clindamycin
`
`d 0.25. mg (0.025%) tretinoin in an aqueous
`4AGelis available in 2 gram, 30 gram, and
`
`4
`Ny
`IDICATIONS
`i
`
`‘contraindicated in patients with regional en-
`ive colitis, orhistory of antibiotic:associated
`
`te
`
`iifeis?
`
`Le
`
`MEDICIS/1943
`
`
`
`
`
`
`
`
`
`
`
`
`
`= VsEnd ‘of Treatment
`Local Reaction «
`‘N=1614
`at
`N(%)
`
`
`416 (26).
`Erythema
`280(17)
`287 (13)
`Scaling
`&
`Itching |
`189 (10)
`70 (4)
`
`‘Burning
`88 (2)
`56(4)
`
`Stinging
`
`33 (2)
`
`
`
`
`
`HC
`
`Melecular Weight: 504.97
`
`The chemical name for tretimoin is 3,7-Dimethyl-9-(2,6,6-
`trimethyl-1-cyclohexen-1-ylJ-2,4,6,8-nonatetraenoic acid
`(all-trans form). The structural formula’‘for. tretinoin iis rep-
`resented below:
`53
`Tretinoin:
`
`HC. - CHy
`
`CHs
`CH,
`SEWERS
`
`.0
`
`‘OH
`
`CHa
`
`ae
`
`Molecular, Formula: CopHesO2, X
`Molecular Weight: 300.44
`
`Continued on nextpage
`
`4
`
`

`

`pustules only; no nodulocystic lesions):
`
`
`
`Inflammatory Lesion Count(% reductionfrom baseline)
`
`
`
`
`PHYSICIANS":DES REREER
`EN
`16 HOW SUPPLIED/STORAGR.
`(2) Percent of subjects who cleared or almost cleared at
`Ziana—Cont.
`Week 12 as-judged.by an Evaluator’s Global Severity
`
`ZIANA(clindamy:~phosphate 129; ,
`(EGS)score.
`Gel is supplied as follows:
`° 8nd tr, Ung
`ZIANA Gel contains the following inactive ingredients: pu-
`2 gram tube
`NDC 99207.300
`tapi
`ia
`The EGS scoring scale‘used-in all of the clinical trials for
`tified: water USP, glycerin USP, carbomer 981 NF, methyl-
`30 gram tube
`NDC 99297.-309-02
`ZIANA Gel is as follows:
`paraben NF, polysorbate 80 NF, edetate disodium: USP;cit-
`60 gram tube
`NDC 99997-3020
`ric acid USP, propylparaben NF, butylated hydroxytoluene
`Storage and Handling ¢
`Grade Description
`
`NF, and tromethamine USP.
`© Store at 25°C (77°F); excursj
`12 CLINICAL PHARMACOLOGY
`
`¢ Protect from light.
`oleRooms Bi te le,
`Clear
`Novatel, flea aki with no evidence of acne
`(59-86°F) [see USP Contr,
`12.1 Mechanismsof Action
`vulgaris
`Clindamycin
`* Protect from freezing.
`takure hry
`be
`:
`[see Microbiology (12,4)).
`* Keep out of the reach of children,
`Tretinoin
`* Keep away from heat.
`Although the exact mode ofaction of tretinoin-is unknown,
`* Keep tubetightly closed.
`curren’ evidence suggests that topical tretinoin decreases
`cohesivenessoffollicular epithelial cells witmdecreased mi-
`17 PATIENT COUNSELING INF
`crocomedo formation.
`ha
`TIO)
`See FDA-Approved Patient
`:
`17.1 iatnctions for Use Mabeling (17.4)
`Additionally, tretinoin: stimulates mitotic activity and in-
`ereaséd turnoveroffollicular epithelial cells causing extru-
`* At bedtime, the face should be gently w
`sion of the comedones.
`
`soap and warm Wwattér. After Patting iashe wig
`12.3 Pharmacokinetics
`ZIANAGal as a thin layer over the
`the skining
`
`© entire® face (exe4
`the eyes and lips).
`In an ‘open-label, multiple-dose study treating 12, subjects
`with moderate to severe acne, the:percutaneous ‘absorption
`* Patients should be advised not to use
`of tretinoin following 14 consecutive daily applications of
`ommendedpea sized amount and notiintSre than the
`than once daily (at bedtime) ag thi toi more tt
`approximately 4 g of ZIANA Gel was minimal.Quantifiable
`faster results and may increase re Not make
`tretinoin plasma concentrations ranged from 1.0 to 1.6 ng/
`mL, with unquantifiable plasma concentrations in 50% to
`* A sunscreen should be applied eveee
`&
`plied over the course ofthe day ag ‘rymori
`92% of subjects at any given timepoint following adminis-
`And regesei
`tieentsgl
`be advised to avoid exposure to sunliy aePat
`tration. The plasmia concentrations ofithe key tretinoin me-
`unamp,=May increCAG
`violet light, and other medicines thanehee
`tabolites,. 13-cis-retinoic acid and 4-oxo-13-cis-retinoic acid,
`
`tivity to sunlight.
`ranged-from 1.0 to 1.4 ng/mb and from 1.6 to 6.5 ng/mL,re-
`17.2 Skin Irritation
`spectively. Plasmarconcentrations for clindamycin:generally
`ZIANA Gel maycause irritation.
`did nét éxceed 3:5 ng/mL, with the exception éfone subject
`itching, burning, or stinging.
`eha rythema,‘lag
`whose plasma-concentration reached 13.1 ng/mL»
`17.3 Colitis
`12.4 Microbiology
`
`Clindamycin bindsto the 50S ribosomal subunits.of suscep-
`In the event a patient treated with. ZIANA Gel
`severe diarrhea or gastfointestinal disdomfért, Zineiy
`tible bacteria and prevents elongation of peptide chains by |
`should'be discontinued and a physicianshould be ANAGe
`interfering with peptidyl transfer, thereby suppressing bac-
`|
`terial protein: synthesis. Clindamycin has been shown to
`17.4 FDA-Approved Patient Labeling’® 0: |
`
`have:in vitro activity against Propionibacterium-acnes;. an
`PATIENT INFORMATION
`at
`organism which.has been associated with acne vulgaris;
`ZIANA (ZEE-AH-NA)
`wm
`however, the clinicalsignificance of this activity against-P.
`
`
`(clindamycin phosphate1.2%-andtfetinoin 0.025%)Gel
`acnes was not examined in clinical trials-with ZIANA Gel. P.
`IMPORTANT: Notfor mouth;eye, or vaginaluse,
`
`-|Zana|Clinda-
`aenes resistance to clindamycin has been documented. Re-
`Read the Patient Information’that comes with ZIANATS
`
`mycin|Tretinoin|Vehicle
`sistance to clindamycin is often associated with Reece
`
`before you start using it and’eachtime you get a pull
`to erythromycin.
`4
`N=426
`N=846
`N=423
`
`
`13NONCLINICAL TOXICOLOGY
`s
`THere may be new iiformatio
`This leaflet does ne©
`
`theplace Of talking with your’ doctor about your:ane
`Evaluator’s Global Severity: N (%)
`
`treatment.
`BB
`13.1 Carcinogeriesis, Mutagenésis,Inipairment,‘of Fertil
`Whatis ZIANA Gel?
`
`Carcinogenicity, mittagenicity and‘i hpairment of fer
`ZIANAGel is an antibiotic and retinoid combination ~
`84
`eae 2
`180
`70
`122-|
`testing of ZIANA'Gel havenot been performediin any'spe-
`
`cies.
`cine used for the skin treatment of acnein patients ilpe
`pee @i%)|Gem|a4%|8%
`
`and older.
`Clindamycin
`Whoshould not use ZIANA Gel?
`‘The carcinogenicity of a 1% clindaniycin phosphate gel sim-
`Do not use ZIANAGelif you:
`ilar to ZIANA Gél was evaluated by daily application to
`¢ have Crohn’s Disease’
`mice for two years. The daily doses used in this study were
`* have Ulcerative Colitis
`approximately 13 and 72 times higher than the human‘dose
`
`of clindamycin phosphate from.ZIANAGel, assuming com-
`* haye developed colitis with past antibiotig use
`Tell your doctor: ..
`° ifyouarepregnantor.planningto,‘becomecr
`plete absorption, and based on a,body surface area compar-
`ison.,;No: significant increase in tumors was noted in the
`
`treated animals. For purposes of comparisons of the animal
`not known if ZIANA Gel may: harm your un! s
`exposureto;human exposure, the recommended human top-
`° if you are breastfeeding.:»ZIANA Gel may P¥
`ical clinicaldose is defined as 1g ofZIANAGel applied daily
`
`your milk and may harm your baby.
`ts you se
`to a.60 kg person.
`* aboutall the medicines and skin produc
`rthhroare”
`* ZIANA.Gel should not beused with &
`_ Fertility (Segment 1).studiesin rats.treated orally with up
`0.300 mg/kg/day of clindamycin. (approximately: 290 times
`containing produets-
`the amountofclindamycindelivered from, the recommended
`* Avoid medicated or abrasive 80aP8
`:
`andcosmeticsthathaveastronsom
`clinical dose for ZIANAGel, based on a body surface area
`producté that, contain: alcohol®aeal ia
`comparison) revealed noeffects on fertility or matingability.
`
`Tretinoin
`=
`lime. Thesetproducts mayécaus
`In two independent studies with long--term topical applica-
`tion if used with ZIANA-GEL.
`, It ngae
`tion of tretinoin in mice, carcinogenicity was not observed.
`In both studies,
`tretinoin’ was’ administered topically
`Use’ ZIANA Gel exactly as presctio™ seno Wl Gal
`time for you to see improvementt ofO usea iw
`(0.025% or 0.1%) three tines. per week for up to two years.
`No carcinogenicity was observed with maximurh effects of
`Gel. Your doctor will tell you !how long
`d
`dermal amyloidosis in the basal layer of the skin.
`At bedtime:
`« Wash your face gentlywith a mild e
`photoco-
`Tretinoin has
`been
`shown
`to
`enhance
`on an
`out
`carcinogenicity in properly performed specific studies, em-
`: a to vou
`* Pat the skin dry.
`* Apply apea-size amount’cdf ZANT moothf
`ploying concurrentor intercurrent exposureto the drug and
`UV radiation. The contribution of clindamycin to that effect
`and spread it over‘yourface. fnyou yes ©
`is unknown. Although the significance of these studies to
`skin. Do not get. ZIANA Geli youyp n0s®
`humansis not ¢lear, patients should minimize exposure to
`sun.
`your lips, on the’ corners: o
`wounds.
`a
`In the’morning:
`jy dur ig
`* Applya sunscreen and reapP ‘thanaoe ack v
`* Dé not apply ZIANA Gel He, Cel.00 ™
`* Do not use too much
`oe
`mayirritate your skin:
`than”inet f
`* Do not wash your face mo" or scrub
`Washing your face too ©
`x
`wité.
`40nd
`your acne worse.
`Avoid:
`ei cold: re
`* excessiveexposuretotheasone<
`extremes ‘can dry,an!
`sk .g ba
`screen -onZIANA Gel treat
`.Use other protectiveveclothing §
`6
`in the-sun.
`in i
`nr
`"A
`* the use of sunlamps and ta
`oa
`GeA
`If your face becomes sun ur
`218
`ki” in
`4
`ts
`skin has healed.
`Whatarepossible side tel7ay cate
`© Skinirritation. Z:
`ing, pur
`as dryness, redness, pee
`
`
`
`Almost
`Clear
`
`Rare non-inflammatory lesions present, with
`rare non-inflamed papules (papules must be
`resolving and may be hyperpigmented,
`
`though not pink-red)
`
`me
`
`Mild
`
`Some non-inflammatory lesions are present,
`with few inflammatory lesions (papules/
`
`Moderate
`
`Severe:
`
`Non-inflammatory lesions predominate, with
`‘multiple inflammatory lesions evident.
`séveral to many comed