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`For Reference >
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`AMN1040
`Amneal v. Almirall, LLC
`IPR2018-00608
`
`1
`
`

`

`
`
`CEO: Edward Fotsch; MD
`:
`President: David Tanzer
`Chief Medical Officer: Christine Coté, M
`Chief Technology Officer: Nick Krym
`Chief Financial Officer: Dawn Carfora .
`
`Vice President, Product Management & Operations: Valerie Berger
`Vice President, Emerging Products: Debra Del Guidice
`Vice President, Corporate Development, Copy Sales & -
`General Counsel: Andrew Gelman
`Vice President, Sales: John Loucks
`Vice President, Marketing: Julie Baker
`Vice President, Business Development: Tom Dieker
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`:
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`Senior Manager, Client Services: Lisa Caporuscio
`Manager, Clinical Services: Nermin Kerdlous, PharmD
`Senior Drug Information Specialist,
`Database Management: Christine Sunwoo, PharmD
`Senior Drug Information Specialist,
`:
`Product Development: Anila Patel, PharmD
`Drug Information Specialists: Peter Leighton, PharmD;
`Kristine. Mecca, PharmD; See-Won Seo, PharmD
`Manager, Editorial Services: Lori Murray
`Associate Editor: Jennifer Reed
`Manager, Art Department: Livio Udina
`Electronic Publication Designer: Carrie Spinelli Faeth
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`Director of Sales: Eileen Bruno
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`Business Manager: Karen Fass
`: Senior Account Executives: Marjorie A. Jaxel: Philip Molitiaro
`Account Executives: Nick W. Clark, Carlos Cofnejo, Caryn Trick
`Associate Account Executives: Carol Levine, Janet Wallenda
`Sales Coordinator: Dawn McPartland
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`Senior Director, Operations & Client Services: Stephanie Struble
`Senior Director, Editorial & Publishing: Bette Kennedy
`Director, Clinical Services: Sylvia Nashed, PharmD
`Director, Marketing: Kim Marich
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`Director, PDR Production:Jeffrey. D.:Schaefer
`Associate Director, Manufacturing & Distribution: Thomas Westburg
`Production. Manager, PDR:.Steven Maher.
`Cee,
`Operations Database Manager: Noel Deloughery
`Senior Index Editer: Allison O’Hare
`Index Editor: Julie L. Cross’
`Senior Production Coordinator: Yasmin Hernandez
`Production Coordinators: Eric. Udina, Christopher Whalen
`Format Editor: Dan Cappello.
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`Manager, Customer Service: Todd Taccetta
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`Copyright © 2010 PDR Network, LLC. Published by PDR Network, LLC at Montvale, NJ 076451725.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)
`withoutthe prior written permission of the publisher. Physicians’ Desk Reference® and PDR®are registered trademarks of PDR Network, LLC. PDR® for Ophthaimic Medicines;
`PDR® for Nonprescription Drugs, Dietary Supplements, and Herbs; PDR® Pharmacopoeia; and PDR® Electronic Library are trademarks of PDR Network, LLC.
`
`ISBN: 978-1-56363-780-3
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`2
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`
`
`jimentary CMEforPDR-listed products at PDR.net
`
`
`“ay stoP taking Soriatane, your psoriasis may return,
`
`ytreat this new psoriasis withleftoverSoriatane.It is
`ant to'see your prescriber again fortreatment recom:
`
`
`008 because your situation may have changed.©
`
`ant
`jould Favoid while taking Soriatane?:
`
`pregnancy. See “Whatis the most important infor:
`a I should know about Soriatane?”, ‘and “What‘are
`
`nportant vwarnings and instructions for femalestak-
`oriatane?”,.
`
`preast feeding. See“Whatare the important warn-
`d instructions for females taking Soriatane?”
`id: alcohol. Females-must avoid. drinks, foods, medi-
`
`0" and over-the-counter: products that contain alcohol.
`9 risk of birth defects. may continue for longer:than-3
`
`g if you. swallow any form of alcohol during Soriatane
`tment and for 2: months after stoppitig Soriatane (see
`
`pat are the importantwarnings and instructions for fe-
`
`es taking Soriatane?”). °
`id givingblood. Do- not donate blood while you‘ are
`
`
`3 g Soriatane and for at least3years.after stopping
`sane treatment. Soriatane in your blood canharm an
`
`“ibaby if yourblood is given to a pregnant woman,
`jatane doesnot affectyour ability to. receive. ablood
`
`1 fusion.
`Ls
`progestin-only birthcontrol pills (“minipills). This.
`
`of birth control pill may not work while you take
`atane. Ask your prescriberif you are not. sure what
`
`eof pills you are using:
`|. --
`
`sid: night. driving if you develop any. sudden vision
`
`blems. Stop taking Soriatane'and call your prescriber
`occurs (see “Serious side-effects”).
`
`non-medical ultraviolet (UV) light. Soriatane can
`your skin more sensitive to-UV light. Do not use
`
`ips, and avdid sunlightas much as possible. If you
`
`aking light. treatment (phototherapy), your pre-
`er may. need to. change your light ‘dosages to avoid
`
`id © dietary supplements- containing vitamin A
`is related to vitamin A, Therefore; do not take
`
`ents. containing.vitaminA, becausethey may,add
`unwanted:effectsofSoriatane: Checkwithyour pre-
`
`eror:pharmacist ifyou have any.questions:about vi-
`in: supplements.
`NOT: SHARESoriatane with anyone else, even if they
`
`he'same symptoms: Your medicinemayharmthem
`ir unbornchild:
`:
`.
`
`are the possible side effects of Soriatane?:
`
`atane can causebirthdefects. See “Whatis the most
`
`information: I should:‘know about Soriatarie?”
`“Whatare the important. warnings and instructions
`
`ales taking. Soriatane?”
`asis ‘gets .worse. for some patients-when they first
`
`Soriatane treatment: Some-patients have mire red-
`itching. Ifthis happens;tell your:prescriber: Thesé
`ptoms‘usually get better.as' treatment continues; but
`
`rescriber may need to change the amount:of your
`
`
`contain gelatin,iron oxide (yellow, black, and red), andtita-
`nium dioxide. Theymayalso contain benzyl alcohol, carboxy-
`methylcellulose sodium, edetate calcium disodium.
`General_information: about the safe and effective.use. of
`Soriatane _-
`Medicines are sometimes prescribed forpurposes other.than
`thoselisted in aMedication Guide..Do not use Soriatane for
`a condition for which it was not prescribed. -Do. not. give
`Soriatane to other people, even if they have the samesymp-
`toms that you have.
`This Medication.Guide summarizes themost:jmportentiin-
`formation about Soriatane. If you wouldlikemoreinforma-
`tion, talk with your prescriber. You can ask your pharmacist
`- or prescriberfor information about Soriatanethatiiswritten,
`for health professionals.
`This Medication Guide has.beenapprovedby:theUS.Food
`and Drug Administration.*
`Tegison® is aregistered trademark ofHoffimann-La Roche
`Tne.
`Do Your PA.R.. is a trademark, SORIATANE, STIEFEL,
`and STIEFEL & Design areregisteredtrade narksofStiefel
`Laboratories, Ine. .
`©2009Stiefel.Laboratories,Inc.
`|
`
`STIEFEL® 2...
`ond
`Manufactured for.
`Stiefel Laboratories, Tne:
`Coral Gables, FL33134USA |
`Faly 2009
`
`303795... ee oa
`a
`Shown inProductentiation Guide,page319.
`
`do not happen often, but they ceanni Tead to permariént , VELTIN © STIEFEL/3145
`trin. (a mixture.of polysaccharides). Gelatin capsule ‘shells __
`
`or-rarely, to death. Stop taking Soriatane and call
`
`rescriber right away if you get the following signs or
`tas:
`mas
`.
`
`
`headaches, nausea, vomiting, blurred vision. These
`toms can be signs ofincreased, brain pressure that
`
`lead to blindness or even death.
`eased vision inthe dark (night blindness). Since this
`tart suddenly, you should be very careful when driv-
`
`at-night. This problem usually goes away when
`natane treatment-stops. Ifyou develop any vision prob-
`
`benor eye pain stop taking Soriatane and call your pre-
`pression. There have been some repérts ofpatientsde:
`ly ling mental problemsincluding a depressedmood,
`
`ssive feelings, or thoughtsofendingtheir own life
`de), These events, including suicidalbehavior, have
`reportediin patientstaking’ other’ drugs”‘similar‘to
`
`
`VELTIN™| arr OR
`aneas well ‘as patients taking Soriatane: Sinca.
`
`[vel-tin] ES seca
`3
`ony
`er things may have contributed to these problems,itis
`(clindamycin phosphate and tretinoin)
`known if they are related‘to Soriatane. Itis very in-
`:
`t INDICATIONSAND USAGE
`
`
`
`
`ant to.stop taking Soriatane and call your prescriber
`VELTIN™ (indamycin, hosphate.-‘and tretinoin), Gel,
`ht away if you develop such problems.
`Fer.topical,use only" wos
`
`1.2%/0.025%is indicatedfor thetopical treatment: of,acne
`‘Swing of your. skin or the whites of youreyes, nausea
`HIGHLIGHTS:OF PRESCRIBING INFORMATION| oe
`
`vulgaris ‘in patients.12.years:orolder. ..:
`-
`vomiting, loss of appetite, or dark urine. These.can
`sf],"AySigns of serious liver damage.
`These highlights do not include all-the information’needed
`
`2°.°DOSAGE AND ADMINISTRATION: :
`hes or pains in your. bones;joints,muécles; or‘back:
`to use VELTIN Gel safely and effectively. See full,Preserib-
`
`VELTIN Gel shouldbe applied’ once daily iin the evening,
`ing information for VELTIN Gel.)2*:
`le moving; loss of feeling in yourhands ‘or feet.
`VELTIN™ (clindamycin PhosphateandtretinoinGel 1
`
`gently rubbing the medicationto lightly cover the entire af.
`
`&secanbe signs‘ofab iormal’changesto your bonesor
`
`
`
`fected area. Approximately: pea’sized; amount’ will. bé ~
`0.025%|
`:
`eas
`.
`:
`needed.for eachapplication:‘Avoid the:eyes, tips, and mu-
`‘(uent urination; ‘great thirst or hunger. Soriatane can
`For topical useonly eG
`Loses OS
`
`cous‘membranes:
`Q
`
`Sct blood sugar control; even if‘youdo not alreadyhave
`VELTINGeliis notfororal;ophthalmic oriittavaginalase,
`initialU.S.‘Approval: 2006..
`Sey
`:
`
`-INDICATIONS AND USAGE———___
`tes. These are someofthe’signs of!high blood sugar.
`
`Ottnassof breath, dizziness,nausea, chest pain, weak:
`e.°.VELTIN Gel is‘alincosamide-antibiotic andretinoid con:
`3 DOSAGE FORMS AND STRENGTHS|
`
`trouble Speaking, or swelling of a leg. Thesemay
`VELTIN:Gel; containing clindamycin“phosphate.1.2%: and
`bination. product indicated for: the:topical treatment’of
`
`Signs of a heart attack, blood clots, or. stroke.
`acne vulgaris in patients 12-years'‘or‘older::(1):::
`:
`tretinoin 0.025%, is a-yellow, opaque ‘opicalgel. Hach gram
`_oVisitPDRinat to register:forProductSafetyAlerts and to download:mobilePDR® .-free to.U.S.prescribers:
`
`
`
`
`
`
`
`Soriatane can cause serious changes in bloodfats (lipids)..
`It is possible for thesechanges to cause blood vessel block-
`ages that lead to‘heart attacks, strokes, or.blood clots,
`Commonside effects.
`Ifyou develop anyof these side effects or any unusual reac-
`tion, check with your prescriber to find out if you. need to.
`change the.amountof Soriatane you take. These sideeffects
`usually get better if the Soriatane dose is reduced or
`Soriatane is stopped.
`© Chappedlips; peeling fiingertips, palms, and ‘soles; iteh-
`ing; scaly skin all over; weak nails; sticky or fragile (weak).
`skin; runnyor dry nose,or nosebleeds. Your prescriber or
`~ pharmacist can. recommenda lotion or cream to help treat
`drying or fapping.
`* Dry mouth
`¢ Joint pain
`® Tight muscles~
`:
`® Hair loss. Most patients have some hairloss, but this ¢con-
`dition varies among patients: No one can‘ tell if you will”|:
`lose hair, how much hairyou may lose or if and when it
`”
`thay grow back.
`© Dry eyes: Soriatane may dry your eyes. Wearing contact
`lenses may be ‘uncomfortablé during and‘after treatment ‘|
`with. Soriatane-because of the dry feeling in your eyes. If--
`this happens, remove your contact lenses and call your
`prescriber. Also read the section aboutvision under “Seri:
`ous side effécts”.
`® Rise in blood fats (lipids). Soriatane can cause your blood
`fats (lipids) to-rise. Most of the time this is not serious,
`But sometimes the increase can beedmea serious problem
`(see information under “Serious side effects”). You should
`have blood tests as directed by your prescriber:
`These are not all thé possible side effects of Soriatané. For
`more information, ask your prescriber or pharmacist.
`Howshould I store Soriatane?
`Keep Soriatane away from sunlight, high temperature, and‘ |:
`humidity. Keep Soriatane awayfrom children.
`Whatare the ingredients in Soriatane?
`Activeingredient:
`acitretin
`microcrystalline cellulose, sodium
`Inactive ingredients:
`ascorbate, gelatin, black monogramming ink and maltodex- a
`
`DOSAGE AND ADMINISTRATION-—___—
`. Apply a pea size amount once dailyin the eveninglightly.
`covering the entire affected area. Avoid the eyes,lips, and
`_ Mucous membranes.(2)
`® Not fororal, ophthalmic, or intravaginaluse. (2)
`DOSAGE FORMS AND. STRENGTHS———_
`* Topical gel:
`clindamycin phosphate. 1.2%andtretinoin
`0.025% in 30 gram and 60 gram tubes.(8)
`—__-__CONTRAINDICATIONS-——_____
`* VELTIN Gelis contraindicated in patients. with.regional
`enteritis,. ulcerative -colitis,. or history. of antibiotic-
`associated colitis. (4)
`———-WARNINGS AND. PRECAUTION:s—
`¢ Colitis:’.\Clindamycin can cause severecolitis, which may.
`result in death. Diarrhea, bloody diarrhea, andcolitis (in-
`cluding: pseudomembranouscolitis):have.been: reported
`~with the use-of clindamycin. VELTIN Gel should he dis-
`continued if significant diarrhea occurs: (5.1)
`:
`* Ultraviolet Light and Environmental Exposure:
`‘Avoid
`exposure to sunlight, sunlamps, and weather extremes.
`' Wear stinscreen daily. (5.2)
`ADVERSE REACTIONS———————
`* Observed local: treatmént-rélated “adverse ‘reactiotis
`(2.1%) in-elinical studies with VELTIN Gel-were applica-
`tion site reactions, including dryness, irritation, exfolia-
`“tion; erythéma;’ pruritus,”and dermatitis. Sunburn’was
`-also reported. (6.1).
`To report SUSPECTED ADVERSE REACTIONS,contact
`~ Stiefel Laboratories, Inc, at 1-888-784-3335 or FDAat 1-800-
`FDA-1088 or www.fda.gov/medwatch.
`—_—__—-_—_DRUG INTERACTIONS
`‘® VELTIN Gel should not be used in combination with
`_ erythromycin-cotttaining “ products ~ becausé Of“its
`clindamycin component.(7.1)
`os
`USE IN SPECIFIC POPULATIONS———__-
`* Pediatric Use: The efficacy and safety have not been
`established in pediatric patients below the age of 12
`years. (8.4)
`See 17 for PATIENT COUNSELING INFORMATION.
`Revised: 07/2010
`_ FULL PRESCRIBING INFORMATION: CONTENTS*.
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`DOSAGE FORMS AND STRENGTHS.
`» CONTRAINDICATIONS
`be
`
`WARNINGSAND PRECAUTIONS
`5.1
`Colitis
`5.2 Ultraviolet Light andEnvironmentalExposure
`6». ADVERSE .REACTIONS::.:..:
`“@.1::.. Adverse Reactions:in Clinical:Studies =
`7 DRUG INTERACTIONS
`71>
`Erythromycin.
`-,
`as
`7.2.
`.-NeuromuscularBlocking‘Agents’
`8. USEIN SPECIFIC POPULATIONS
`
`BLE: “Pregnancy.
`nse
`wddn
`
`8.3.
`“Nursing Mothers *.
`84. Pediatric Use
`i
`“8.5. GeriatricUse
`:
`ore
`11. DESCRIPTION *
`oe
`12.CLINICAL PHARMACOLOGY_aS
`. 12:1. MechanismofAction
`"12.3" Pharmacokinetics
`;
`
`2A. Microbiology
`18 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis,Mutagenesis,Impairment,ofFer-
`|
`tility
`14, CLINICAL STUDIES
`16. HOW.SUPPLIED/STORAGEAND HANDLING *
`17PATIENT COUNSELING. INFORMATION©
`“17.1 “Instructionsfor:Use. a
`“17.2 SkinTeritation
`17.3),. Colitis...
`:
`ve
`*Sections,or subsections.omitted from thefullprescribing
`
`: FULL PRESCRIBING INFORMATION.informationare not listed. = f
`
`OreOOD
`
`weet
`
`Gel 1.2%/0.025%.... SteetsFa kests
`
`:
`
`
`
`3
`
`3
`
`

`

`3146/STIEFEL ¢ VELTIN
`
`Table 1: Treatment-Related Adverse Reactions Reported by =1% of Subjects ~
`VELTIN Gel
`Clindamycin Gel
`N=1091
`N=1104.
`n{(%)
`1 (%)
`
`Patients with at least one adverse
`reaction
`
`’ Tretinoin Gel
`N=1084
`n (%)
`
`.
`
`Applicationsite dryness
`
`Application site irritation
`
`Application site exfoliation
`
`Application site erythema
`
`Application site pruritus
`Sunburn
`
`Application site dermatitis
`
`Table 2: VELTIN GEL-Treated Patients with Local Skin Reactions
`
`“Vehicle Gel
`N=652
`n (%)
`
`_
`
`17 (8)
`
`3)
`5a).
`<1)
`3 (1)
`
`6)
`
`3)
`1(<1)
`
`IMPORTANT NOTICE: ‘Updated-drug information is sent bi-monthly via the PDR®UpdateInsert: For:monthly email-updates, register at PDR?
` Tretinoin.
`
`ie :
`of VELTIN Gel contains, asdispensed, 10 mg (1%)
`| and were treated once daily in the evelting for 12 weeks.
`clindamycin as clindamycin phosphate, and 0:25 mg
`Adverse reactionsthat were reported in. =1% of patients
`(0.025%) tretinoin ‘solubilized in an aqueousbasedgel.
`treated with VELTIN Gel are presented iin Table 1 :
`:
`[See table 1 above]
`4
`..CONTRAINDICATIONS
`Local'skin ‘reactions actively assessed at baseline and endof
`VELTIN Gel is contraindicated.inpatients withregional en-
`treatment with a score > 0 aré presentediin Table 2:
`[See ‘table 2 above] °
`teritis, ulcerative ‘colitis, or history of. antibiotic:associated
`colitis.
`During the twelve weeks of treatment, each local skin reac-
`5 WARNINGSAND PRECAUTIONS|:
`tion’peaked at week 2 and gradually reduced thereafter.
`:
`5.1
`Colitis
`~
`7. DRUG INTERACTIONS
`Systemic absorption of clindamycin has been demonstrated
`7.1
`Erythromycin
`following topical use. Diarrhea, bloody diarrhea, andcolitis
`VELTIN Gel should not be used ia “combination:with |
`(including pseudomembranouscolitis)have been reported
`erythromycin--containing ‘products due to possible antago-
`with the use oftopical clindamycin. If significant diarrhea
`nism to the clindamycin component. Invitro studies have
`occurs, VELTIN Gel should be discontinued...
`°
`._.
`shown antagonism: between these 2 antiniicrobials. The
`Severe colitis has occurred following oral or parenteral ad-
`clinical’ significance of this in vitro antagonism is* not
`ministration of clindamycin with anonset ofup'to several
`known.
`weeks. following cessation of therapy. Antiperistaltic agents
`7.2°-Neuromuscular Blocking Agents
`such as opiates and diphenoxylate with atropine may pro-
`Clindarnycin has been shownto have neuromuscular block:
`long and/or worsen severe colitis.Severe colitis mayresult
`ing properties that may enhancetheaction of other neurd-
`in death.
`muscular blocking agents. Therefore, VELTIN‘Gel should
`Studies indicate a toxin(s) prodticedby clostridia is one pri-
`be used with caution in patients receiving such agents: ©
`:
`mary cause of antibiotic-associated colitis. The colitis is usu-
`8
`USE IN SPECIFIC POPULATION‘Ss :
`ally. characterized by severe persistent diarrhea andsevere
`8.1
`Pregnancy
`abdominal ramps and may beassociated with the passage
`Pregnancy Category.C. There are no well-controlled studies
`of blood aiid mucus. Stool cultures’for Clostridium difficile
`in pregnant womentreated with VELTIN Gel. VELTINGel
`and stool assay for C..difficiletoxin may be helpful diagnos-
`tically.
`shouldbe used during pregnancy only if the potential ben-
`efit justifies thepotential risk to the fetus.A limit teratology
`5.2. Ultraviolet Light and Environmental Exposure |
`study performed in Sprague Dawley rats treated topically
`Exposure :to ‘sunlight;
`including sunlawips; should’ bé
`with VELTIN Gel or 0.025%. tretinoin. gel at a. dose of
`avoided during the use of VELTIN’Gél,: and patients with
`2 mL/kg during gestation days 6 to 15 did not result in ter-
`sunburn should be advised not.to.use the product until fully
`atogenic effects. Although no systemic levels of tretinoin
`recovered because of heightened ‘susceptibility. to ‘sunlight
`were detected, craniofacial and heart abnormalities were
`as a result of the: use of tretinoin.Patients who may be re-
`described. in drug:treated ‘groups. These abnormalities’ are
`quired to have considerablesun exposure due to o¢cupation
`consistent with retinoid effects and occurred at 16 times the
`and those with inherent’ sensitivity to the sun should exer-
`recommendedclinical dose assuming100% absorptionand
`cise particular ‘caution:Dailyusé'of Sunscreen products and
`based on body. surface. area. comparison. For purposes of
`protective apparel (e.g:; a hat) ‘aré réecominéended! Weather
`comparison oftheanimal exposure to human exposure, the
`extremes, such as wind or.cold, also may be irritatingto pa-
`tients under treatment withVELTIN,Gel...
`.
`récommendedclinical dose isdefined as i g:ofVELTIN Gel
`applieddaily to’a 50'kg person. . -‘
`‘ADVERSE REACTIONS-
`:
`. .1
`“:. Adverse Reactions.in.Clinical ‘Studies
`Clindamycin
`:
`,
`Reproductive developmerital toxicity studies perforined iin
`Becauseclinical studies are conducted.underwidely varying
`rats and mice using oral doses of ‘clindamycin up to
`conditions, adverse reaction rates observed:in-clinical stud-"
`600 mg/kg/day (480 and 240 times the recommended clini-
`ies ofa.drug carinot bedirectly compared to.rates.in theclin-
`eal dose based on body surface area-: comparison,
`jeal studies. of another drug and maynotreflect the, rates
`respectively) or subcutanéous‘doses: of ‘clindamycinup to
`observed in clinical practice.
`°°“
`180mg/kg/day (140-and’70.times the recommended ¢linical
`Thesafety data reflect exposure to VELTIN Gelin 1104 pa:
`dose ‘based ‘on body ‘surface: area comparison; respectively)
`tients with acne vulgaris: Patients were 12 years or older
`revealed no eéviderice of teratogenicity...
`.
`
`' For-the latest PDR product information,visi; Pop
`Oral tretinoin has. been shown’ to. be terato,
`rete
`rats, hamsters, rabbits,.and primates. It was
`aove
`and fetotoxic in ,Wistar rats.when given oral
`greater than 1-mg/kg/day (32 timesthe: recommen,Ya
`cal dose. based'on body surfacearea comparison)" Ted:a
`variations in teratogenic doses aMONg varioys
`ave
`rats have been reported. In the cynomologoyg ° 2
`species in which tretinoin metabolism is close; ti 0
`than in other species examined, fetal malfor
`. h
`reported at oral dosesof 10 mg/kg/day or gre;ater,son,
`were observed at 5 mg/kg/day (324timesthevq,
`bu
`clinical ‘dose based on body surface: area: comps
`though increasedskeletal variations were obgg,ationaes
`doses..Dose-relatedteratogenic effects“and=<nedat
`tion'rates were reported in pigtail macaques,
`With widespread. use of any drug, a small num
`defect reports associated temporally with the©ade
`int
`tion of the drug would be expected by chance‘alone.
`©. Thing
`cases of temporally associated. congenital malfy
`have beenreported during two decades ofclinical Maton
`other formulation of topical tretinoin. Although ng € ofan.
`patternof teratogenicity and no causal associato° defn
`beenestablished from these cases, 5 ofthe reports Ae
`the rare birth defect’ category, holoprosencephaly (4
`associated with incomplete midline development;
`brain). The significance ‘ofthese’spontaneous
`Srepo
`_ terms of risk to fetus is not’ known.
`8.3.
`--- Nursing Mothers
`:
`It is not known whether clindamycin is excreted ;inh
`milk following-use ofVELTIN Gel. However, orallyani
`enterally administered clindamycin has been repior
`appear in breast milk. Because of thepotential -for
`adverse reactions in nursing infants, a decision. §
`made.whether to. discontinue ‘nursingor to diseonti;
`drug, taking into account the.importanceof the drug
`mother.It is not known whethertretinoin is excreé
`man milk.Because many drugs areexereted in hy
`milk, caution shouldbe éxercised when VELTIN |
`ministered to a nursing woman.
`8.4" Pediatric Use __
`et
`, Safety ‘and: effectiveness. of VELTIN-Gel inpedi
`tients belowthe age’of 12 years have not been’e: ab
`Clinical trials of VELTIN Gel included 2,086 patients
`years of'age: with-acne vulgaris: [See Clinical ‘Studi
`8.5
`Geriatric Use
`gs
`Clinical. studies. of VELTIN: Gel did: not includé
`sufi
`numbers of subjects aged 65 and over to determine w
`they respond differently from younger subjects.
`11
`DESCRIPTION
`VELTIN (clindamycin phosphate arid’ tretinoi
`0.025%, is‘a fixed: cdmbination ‘of two‘solubilized’
`gredients iin an aqueousbased gel. Clindamycinphos
`is a water soluble ester of the semi-synthetic antibiotic
`duced. by''a'7(S)-chloré-substitution: of the: TR) re
`group ofthe parent antibiotic: lincomycin:
`‘The -chemical-name for-clindamycin. phosphate is m
`7-chloro-6,7,8-trideoxy-6-(1-methyl-trans-4-propyl-L-
`rolidinecarboxamido)-1-thio-L-threo-a-D-galacto-oct
`noside 2-(dihydrogen phosphate). The structural formula
`clindamycin phosphate is represented below:,.
`Clindamycin phosphate: :
`.
`
`activ
`
`‘
`
`oP
`- HO ie
`Molecular Formula: AeNORRS
`Molecular Weight: 504.97
`(2,6,6--trimethyl-L-cye
`-
`acid. It is a member of theretino family 0
`The structural formulafor tretinoinis representedbe
`Tretinoin:
`
`Molecular Formula: CogHygOo,-
`Molecular Weight:. 300.44
`VELTIN- Gel contains the following inactive in
`butylated hydroxytoluene, carbomer 940, anby
`acid, edetate disodium, methylparaben; ‘Jaureth
`lene glycol, tromethamine, and purified water.-
`12 CLINICALPHARMACOLOGY
`12.4:
`-Méchanism:of Action
`Clindamyein::::
`»
`[See Microbiology (12.4).]
`
`VEHICLE GEL
`"Endof Treatment
`5
`N= 209
`N(%)
`- (BB%
`"12%
`“18%
`
`Local Reaction
`
`Erythema
`
`Scaling _
`Dryness
`Buining /
`ltching
`
`Lo.
`
`VBLTINGEL
`
`Endof Treatment
`/ N= 409 |
`N (%)
`
`
`
`4
`
`

`

`
`
`Mean percentage (%) reduction: (48.3%
`
`
`5 ranged from 1,19 to 1.23 ng/ml compared‘with the
`
`in
`-
`sy
`
`finnthe.exact mode ofaction oftretinoin iis unknown,
`
`
`
`Skin almostclear; rare non~inflammatory lesions: present; with rarenon-“inflamed
`eat evidence suggests that topical tretinoin. decreases
`
`siveness of follicular. epithelial célls‘with decreased mi-
`papules (papules must be resolving and may be hyperpigmented, though not...
`
`pmedone formation: Additionally; tretinoin ‘stimulates
`
`
`“| pink-red) requiring no further treatment in the Investigator’s opinion. :
`
`zc activity and increased turnover of. follicular epithe-
`Some non-inflammatory lesions are present, with few inflammatory Tesions
`
`sells causing extrusion of the comedones.
`Pharmacokinetics
`;
`
`(papules/pustules:‘only, no nodulo--cystic lesions).
`
`i “open-label study of17, patients with moderate-to-
`
`Moderate:
`
`
`Non-inflammatorylesionspredominate, with multiple inflammatory lesions
`acne vulgaris, topical administration ‘of approxi-
`
`:|evident;‘several to many comedones and papules/pustules, andthere may or may_
`aly 3 grams-.ofVELTIN Gel once, daily for 5. days,
`
`
`
`| not be 1.‘small nodulo-cystic lesion.
`:
`amycin. concentrations, were quantifiable in. all 17
`
`
` Severe
`ents starting from: 1,hour post..dose. All. plasma
`Inflammatory lesions‘are more apparent; many comedones and papules/pistules, :
`
`
`damycin concentrations were <5:56 ng/ml on day.5,
`-| theremay or may not be afew nodulo-cystic lesions.
`
`
`
`amthe exception of one subject, who had a:maximum
` Very: Severe
`
`Highly. inflammatory lesidns predominate; variable nurabers‘ofcomedones, many
`damycin:concentration of:8.73 ng/mL at:4 hours. post-
`
`.There was no appreciable increase insystéemic:expo-
`papules/pustules and nodulo-cystic lesions.
`
`
`jo tretinoin, as compared to the baseline valué. The av-
`
`
`@ tretinoin concentration’ across all sampling times on °
`
`
`Table 3: Efficacy Results at Week 12
`vresponding baseline:mean‘tretinoin’concentration range
`
`74.16 to.1.30 ng/mL.
`, Clindamycin Gel
`Tretinoin Gel
`Vehicle Gel
`_|).VEETIN Get
`“" Viicrobiology
`N=476
`. N=467-
`Study I
`N=464
`ih
`N=242
`microbiology.studies were conducted in theclinical trials
`Investigator’s Global Assessment
`‘this product.”
`wg ee
`,
`
`
`janism ofAction.
`;
`
`*
`7+
`.
`~
`i
`:
`|
`.
`om
`4
`i
`
`damycin bindsto, the 50S,ribosomal‘subunit,of suscep-
`- 36.8%
`Improvement,
`deo 26.6% a
`: 20.2%
`Percentage of subjects achieving Two Grade
`a
`.
`
`‘bacteria and prevents elongation ofpeptide chains by
`fering with peptidyl transfer, thereby suppressing pro-
`
`9990%
`Percentageof subjects achieving an‘IGA of0
`24.0%
`178%
`syothesis. Clindamycin.has been shown to have in vitro
`or 1 with a Two Grade Improvement
`
`
`ity against Propionibacterium acnes (P. aches), an or-
`
`that has been associated with. acne vulgaris;. how-
`Inflammatory Lesions:
`
`the clinical significancéof this ‘activity against P. acnes
`not examined in clinical studies with VELTIN Gel. PB
`Mean absolute reduction
`Ma:
`3resistance to clindamycin has been doctimented.
`
`
`cible Clindamycin Resistance’
`*
`
`
`‘reatment of acne with antimiérobials is associated
`Non-inflammatory Lesions:
`the development of antiniicrobial’resistancein P.acnes
`
`ell as otherbacteria (e.g. Staphylococcus:aureus, Strep-
` 17.0
`
`' Mean absolute reduction
`us pyogenes). The use of.clindamycin may resultiin de-
`
`ing inducible resistance in these organisms. Thisresis-
` 86.0%
` Mean percentage (%) reduction
`e is not detected by routine susceptibilitytesting.
`
`Total Lesions:
`tance to clindamycin iis oftenassociatedwith resis-
`
`
`Mean,absolute reduction::
`:
`to erythromycin.: .
`:
`3
`
`.NONCLINICAL TOXICOLOGY.
`o
`
` “Mean percentage (%) reduction.
`
`Carcinogenesis, Mutagenesis,Impairment.‘of Fer-
`
`
`
`term animel studieshave:‘notbeen performed|to eval-
`clindamycin tretinoin. combination: 3is ‘unknown, Atehouigh
`16.
`“HOWSUPPLIED/STORAGE‘AND HANDLING..
`thecarcinogenic potential ofVELTIN Gel or the effect
`
`the significance ofthese studies-to’humansiis not clear,> Par
`How Supplied
`LTIN. Gel. on fertility.. VELTIN:Gel:was, negative for
`
`tients should: avoid exposureto'sun.
`*”
`VELTIN Gelis supplied as:follows;. -.:...-;
`genic potential. when evaluated:in an’in’ vitro Ames
`The genotoxi¢ potential of tretinoin wasevaluatedin ‘aii in
`
`30-g aluminum tubesNDC. 0145-0071-30.
`orella reversion assay. VELTIN, Gel was equivocal for
`vitro Ames Salmonella reversion ‘test- and ‘an in vitro chro-.
`60 g aluminum tubes NDC 0145-0071-60
`
`astogenic potential in the-absence’of-metabolic activation
`mosomal aberration assay'in Chitiese hamsterovary”cells.
`Storage and Handling
`
`-tested in an‘in:vitrochromosomal aberrationassay.
`« Store. at 25°C. (TTF); excursionsspeedto,15-30°C__
`Bothtests were négative::
`
`indamyein
`
`~ 69-86°F):..
`In oral fertility studies in rats tréated with‘tretinoin, the
`ce ‘daily dermal:administrationof 1% clindamycin‘as
`no-observed-effect-level-was'2 mg/kg/day (64 times theree-
`: . Protect from. heat::
`lamycin phosphate in.the’:VELTIN’ Gel. véliicle
`ommendedclinical dose based onbody surface areaa compar:
`
`
`© Protect fromlight.
`
`ison).
`ig/kg/day; 13 times-the reeommended clinical dose
`© Protect from freezing...
`
`¢,Keep.out.ofreach ofchildren.
`sed on body. surface atea'comparison) to micefor up to 2
`14° CLINICAL STUDIES —
`
`ars did not produce evidence oftumorigenicity:-
`Thesafety-and efficacy. of VELTIN: Gel, applied «once daily
`« Keep tube:tightly closed.
`
`
`lity. studies.in-rats. treated ..orally. with up to
`
`for the treatment of acne vulgaris, was evaluated. in.-12-
`17 PATIENT COUNSELING INFORMATION
`g/ke/day of clindamycin, (240times therecommended
`week. multicentér, randomized, blinded studies in, subjects
`cal dose. based:on body. surface:area comparison) Te-
`12 years and older.
`[See FDA-approved. Patient Labeling].
`_
`d
`
`Treatment:response:was definedas.s the percent of subjects .
`17.1
`Instructions for, Use
`
`© At bedtime,the face should be.gently washed with amild
`etinoin e
`:
`whohad a two.gradeimprovement from basélineto Week 12
`htwo independent mouse studies,wheretretinoin was ad-
`soap andwater, After patting the skin dry, apply.VELTIN
`based: on the Investigator’s: Global-Asséssment (IGA) and a
`Ninistered topically: (0.025%: or: 0.1%)three times per week
`Gel as athin.layerooverthe entire affected area(excluding
`meanabsolute charige from: basélizie’to. Week. 12 ‘in:two out
`the-eyes.and lips)...
`5
`‘t'up to two years-no. carcinogenicity.-was observed, with
`of three (total, inflammatory and non-inflammatory)lesion
`*. Patients should be advised not to use mote:than. a-pea
`aximum effects of dermal amyloidosis. However, in a
`counts. The-IGA‘scoring scale used:in all:the: clinical trials
`feral carcinogenicity‘studyiin mice, tretincin-applied at a
`sized amountto cover the face and not to applymoreoften.
`for VELTIN. Gel:is as‘follows:
`|...
`° «.
`than.once daily (at.bedtime) as this: will not. make, for
`[See first table above]
`wld
`"Se of 5.1pg: (14timesthe ‘récommended’ clinical dosé
`InStudy.1,.1649 subjects, were randomizedto VELTIN Gel,
`faster results and may. increaseirritation:
`“sed. on, body surface, area comparison) three times per
`* ‘A sunscreen should be applied every morning: and. reap-
`Clindamycin. gel;, Tretinoin gel, and:vehicle gel. ‘The:median
`ee for20weeksacted asa‘weak prosioterof skin tumor
`pliedover.the course ofthe day as needed. Patientsshould
`nation following-a. single -applicationof!Senethyt.
`age.of subjects was 17 years.old.and-58% were females. At
`baseline, subjects had an-average-of.71.total: lesions. of
`be advised: to avoid exposure to sunlight, sunlamp; ultra-
`Tyvtlanthracene (DMBA).”
`“violet light;.and-other-medicines.that:may increasé sensi-
`which:the mean ‘numberof inflammatory lesions-was 25.5
`di“A.study.in, female SENCAR mice,‘papillomas were in-
`tivity to sunlight:
`‘
`lesions and the mean numberof non--inflammatory. lesions
`Need by. topicalexposure.to DMBAfollowedby. promotion
`© Othertopicalproductsswitha‘strong.dryingeffect; such,as
`was. 45.1 lesions... The.majority:of‘siibjects enrolled with a
`12-0-tetradecanoyl-phorbol 18-acetate or mezerein for
`abrasivesoaps or cleansérs, may. cauise.anincrease in. skin
`baselineIGA.score of8.The efficacy resultsat weelks 12.are
`Dio 20.weeks. Topical,applicationoftretinoin prior to each
`irritation with: VELTIN Gel::
`presentedin Table 3.;
`:
`:
`qulication,ofpromoting agent