EDITION-r“,
`«02":
`
`For Reference '
`Not to be taken fromvthisroomv
`
`‘
`
`7
`
`.
`
`,
`
`_,
`
`,
`
`_
`
`.
`
`,
`
`.
`
`, PDR net
`
`,
`
`..
`
`,.
`
`Onlme Updateso: FDA—approvedDrug Aleflsa CME
`
`.
`1
`
`,
`
`,
`
`p
`
`'
`
`'
`
`'
`
`,
`
`.
`
`,
`
`‘
`
`,
`
`,
`
`,
`
`~
`
`A
`
`_
`
`,
`
`,
`
`AIVIN1040
`,
`. Amnealv.AlmiraIl, LLC
`'-
`IPR2018-00608
`
`AMN1040
`Amneal v. Almirall, LLC
`IPR2018-00608
`
`1
`
`

`

`
`
`
`
`CEO: EdWard Fotsch, MD
`-
`President: David Tanzer
`Chief Medical Officer: Christine Cété, 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 8:
`General Counsel: Andrew Gelman
`Vice President, Sales: John Loucks
`Vice President, Marketing: Julie Baker
`Vice President, Business Development: Tom Dieker
`
`-
`
`’
`
`Senior Manager, Client seNices: Lisa Caporuscio
`Manager, Clinical Services: Nermin Kerolous, 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 ServicesrLori Murray
`Associate Editor: Jennifer Reed
`,
`Manager, Art Department: Livio Udina
`Electronic Publication Designer: Carrie Spinelli Faeth
`
`Director of Sales: Eileen Bruno
`._
`Business Manager: Karen Fass
`' Senior Account Executives: Marjorie A. Jaxel, Philip Molin'aro
`Account Executives: Nick W. Clark, Carlos Cornejo, Caryn Trick
`As50ciate Account Executives: Carol Levine, Janet Wallenda
`Sales Coordinator: Dawn McPartIand
`'
`
`,
`
`Senior Director, Operations 8: Client Services: Stephanie Struble
`Senior Director, Editorial &‘Publisl1ing: Bette Kennedy
`Director, Clinical Services: Sylvia Nashed, PharmD
`
`Director, Marketing: Kim Marich '
`
`Director, PDR Productionueffrey D.’-Schaefer
`Associate Director, Manufacturing & Distribution: Thomas westburgh
`Production Manager, PDR: Steven Maher
`‘
`Operations Database Manager: Noel Deloughery
`Senior Index Editor: AllisonO’Hare
`Index Editor: Julie L, Cross
`'
`Senior'Production Coordinator: Yasmin Hernandez
`Production Coordinators: Eric’ Udina, Christopher Whalen
`Format Editor: Dan Cappello
`L
`.
`Fulfillment Management Specialist: Gary Lew,
`Manager, Customer Service: Todd Taccetta
`
`Copyright © 2010 PDR Network, LLC. Published by PDR Network, LLC 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 omen/vise)
`withoutthe prior written permission of the publisher. Physicians’ Desk Reference® and PDFl® are registered trademarks of PDR Network, LLC. PDR® for Ophthalmic Medicines;
`PDH® for Nonprescription Drugs, Dietary Supplementsand Herbs; PDR? Pharmacopoeia; and PDR® Electronic Library are trademarks of PDR Network, LLC.
`
`ISBN: 978—1—56363-780-‘3
`
`
`
`
`
`
`2
`
`

`

`
`
`
`
`'“mentary CME forPDR-listed products at PDR.net
`
`VELTIN . STIEFELI3145
`
`Soriatane can cause serious changesin blood fats (lipids)
`Itis possible for thesechanges to cause blood vessel block-
`Common side effects.
`ages that lead toheart attacks, strokes, or blOod clots.
`If you develop any of these side effects or any unusual reac-
`tion, check withyour prescriber to find out if you need to
`change the amount of Soriatane you take Theseside effects
`usually get better if the Soriatane dose is reduced or
`Soriataneis stopped.
`I Chapped lips, peeling fingertips, palms, and soles; itch-
`ing; scaly skin all over; weak nails; sticky or fragile (weak) .
`skin; runny or dry nose, or nosebleeds. Your prescriber or
`pharmacist can recommend a lotion or cream to help treat
`drying or chapping
`0 Dry mouth
`0 Joint pain
`.
`"
`*
`0 Tight muscles
`' Hair loss. Most patients have some hair loss, but this con-
`dition varies among patients. No one can tell if you will” »,
`lose hair, how much hair you may lose or if and when it
`' may grow back.
`'
`' Dry eyes: Soriatane may dry your eyes Wearing contact
`lenses may be uncOmertable during and afler treatment '
`with Soriatane because of the dry feelingin your eyes. If-
`this happens, remove your contact lenses and call your
`ous side efi'écts”.
`prescriber. Also read the section about vision under “Seri-
`0 Rise'In blood fats (lipids). Soriatane can cause your blood
`fats (lipids)to rise. Most of the time thisis not serious.
`Butsometimes theincrease can becomea serious problem
`(see information under “Serious side Vefl'ects”) You should
`have blood tests as directed by your prescriber.
`These are not all the possible side effects of Soriatane; For
`more information, ask your prescriberVor pharmacist.
`HOw should I store Soriatane?
`
`V
`
`———__DOSAGE AND ADMINISTRATION_————-
`0 Apply a pea size amount once dailyin the evening lightly
`covering the entire afi‘ected area. Avoid the eyes, lips, and
`mucousmembranes. (2)
`V - Not for oral, ophthalmic, or intravaginalVuse (2)
`-—-—-VDOSAGE FORMS AND STRENGTHS——
`0 Topical gel:
`clindamycin phosphate 1.2% and tretinoin
`0.025%'in 30 gram and 60 gram tubes. (3)
`.
`C0NTRA]NDICAT]ONS—————V—
`0 VELTIN Gel1s contraindicated1n patients withregional
`enteritis, ulcerative colitis or history of antibiotic-
`associated colitis. (4)
`WARNINGS AND PRECAU'ITONS—V—-V
`0 Colitis: Clindainycin can cause severe Cohtis, which may
`resultin death. Diarrhea, bloody diarrhea, and colitis (in—
`cluding pseudomembranous colitis) have been reported
`with the use of clindaniycin. VELTIN Gel should be dis—
`.
`continued if significant diarrhea occurs. (51)
`'
`- Ultraviolet Light and Environmental Exposure: AvOid
`exposure to sunlight, sunlamps, and weather extremes
`Wear sunscreendaily. (5.2)
`ADVERSE REACTIONS——-‘———
`' Observed local treatment-related adverse reactions
`(> 1%)'inclinical studies with VELTIN Gel were applica-
`tion site reactions, including dryness, irritation, exfolia-
`tion, erythVVema, pruritus’, and dermatitis. SunburnWas
`also reported. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact
`,, Stiefel Laboratories, Inc. at 19888-784-3335 or FDA at 1-800-
`FDA-1088 or www.fda.gov/medwatch.
`V—-————-DRVUG INTERACTIONS———‘—-—'
`" VELTIN Gel should not be used in combination with
`VV erythromycin-containing ’ products
`because j of,
`'its
`clindamycin compdnent. (7.1)
`'
`'
`V
`'
`1‘
`(-——-—USEVIN SPECIFIC POPULATIONS——
`‘ t Pediatric Use.
`The efficacy and safety have not been
`establishedin pediatric patients below the age of 12
`years. (8.4)
`See 17 for PATIENT COUNSELING INFORMATION
`Revised: 07/2010
`
`Keep Soriatane away from sunlight, high temperature, and I
`humidity. Keep Soriatane awayfrom children.
`What are the ingredients'In Soriatane?
`Active ingredient: acitretin
`Inactive ingredients:
`microcrystalline cellulose, sodiumVV
`ascorbate, gelatin, black monogramming ink and maltodeX-g ..
`contain gelatin, iron oxide (yellow, black, and red), and tita-
`nium dioxide. They may also contain benzyl alcohol, carboxy-
`methylcellulose sodium, edetate calcium disodium.
`Soriatane .
`.,
`General information about the safe and effectiveuse of
`Medicines are sometimes prescribed for purposes otherthan
`those listedin 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 MedicationGuide summarizes the inosVVtV-importantin-
`formation about Soriatane. lfyou would like, more informa-
`tion, talk with your prescriber. You can ask your pharmacist
`- or prescriber for information about Soriatanethatiswritten
`for health professionals.
`This Medication Guide has. been approvedbythe US.Food
`and Drug Administration.’
`’
`Tegison®1s a registered trademark of HolfniannLa. Roche
`Inc.
`Do Your RAHR-T. is a trademark, SOVRIATANE, STIEFEL,
`and STIEFEL & Design are registered trade VarksofStiefel
`Laboratories, Inc '
`.
`,
`,
`,
`©2009 StiefelLaboratories Inc.
`STIEFEL®,
`._
`.
`,_
`Manufactured for,
`V
`Stiefel Laboratories, Inc. V
`Coral Gables, FL 33134 USA
`July 2009 _V
`'
`
`
`,
`__
`,_.\
`393795 1
`_
`*
`'
`Shownm; Product Identification Guide,page, 319
`
`tfin (a mixture of polysaccharides). Gelatin capsule shells _
`
`progestin-only birthcontrol pills ("minipills"). This .
`
`
`011 Stop taking Soriatane, your psoriasis may return
`treat this new psoriasis with lefiover Soriatane. It'IS
`silt to see you prescriber again fortreatment recom-
`
`fions because your situation may have changed
`damhould lavoid while taking Soriatane? ,_
`V
`‘
`
`pregnancy See “What'is the most 11nportant infor-
`I, 1 should know about Soriatane?”, and “What are
`
`, portant warnings and instructions for females tak—
`Oflatan'e?”
`breast feeding. see“What are the important warn-
`d instructions for females taking Soriatane?” .. .
`
`idalcbhOI- Females must avoid drinks, foods, medi—
`
`° and over--the-counter products that contain alcohol.
`91.15]; of birth defects may continue for longerthan -3
`
`sifyou swallow any form of alcohol during Soriatane
`351116111; and for 2 months afier stopping Soriatane (see
`' at are the important warnings and instructions for fe~
`és taking Soriatane?”).
`-
`id giving blood. Do not donate blood while you are
`
`gsoriatane and for at least 3 years after stopping
`gage treatment. SoriataneIn your blood can harm an
`
`rfi' baby if yourbloodis given to a pregnant Woman
`-atane does not aifectVyour ability to receive a blood
`‘ fusion.
`-,
`
`V'f birth control pill may not work while you take
`
`atane- Ask your prescriber if you are not sure what
`eof pills you are using.
`,
`.
`'
`
`id night driving if you develop any sudden vision
`
`bl-emS Stop taking Soriatane and call your prescriber
`occurs (see “Serious side effects”).
`non--medical ultraviolet (UV) light. Soriatane can
`
`your skin more sensitive toUVlight Do not use
`
`‘ps, and avoid sunlight as much as possible If you
`
`aking light treatment (phototherapy), your pre-
`1‘ may need to change your light dosages to avoid
`
`id " dietary supplements containing vitamin A.
`e is related to vitamin A. Therefore, do not take
`
`ents containingvitaminA, becausethey may add
`unwantedeffects of Soriatane. Check with your pre-
`
`er’orpharmacist if you have any questionsabout vi-
`' supplements.
`NOT SHARE Soriatane with anyone else, even if they
`
`he same symptoms. Your medicinemay harmthem
`
`._ 1r unborn child ..
`
`
`
`“What are the important warnings and instructions
`ales taking Soriatane?”
`.
`asis gets worse for some patientsthen they first
`Soriatane treatment. SOme patients have more red-
`itching Ifthis happens, tellyour prescriber. These
`ptomsusually get better astreatment continues, but
`rescriber may need to change the amount of your
`
`do not happen often, but they canlead to permanent V
`or rarely, to death. Stop taking Soriatane and call
`
`cased vision in the dark (night blindness). Since this
`tan suddenly,you should be very careful when driv-
`at night This problem usually goes away when
`Hatane treatment stops. Ifyou develop any vision prob~
`er.
`1) or eye pain stop taking Soriatane and call your pre-
`Mission There have been some reperts of patientsde-
`1°,Ing mental problems including a depressed mood,
`SsiVye feelings, or thoughts ofending their own life
`d8). These events, including suicidalbehavior, have
`reportedin patients taln'ng other drugssimilar to
`fine as well as patients taking, Soriatane. Since
`er things may have contributed to these problems, itis
`Own if theyare related to Soriatane. It'is very im-
`V3111: to stop taking Soriatane and call yOur prescriber
`‘3 away if you develop such problems
`k“Wing of your skinor the whites of youreyes. nausea
`“.Vomiting, loss of appetite, or‘ dark urine. These can
`S1311s of serious liver damage.‘
`““35 0r pains in your bones,joints. muscles; or back;
`Is moving; loss of feeling in your hands or feet.
`
`ése can be signsofab ‘ rmalchangesto your bonesor
`Went urination, great thirst or hunger. SoriataneVcan
`Eel: blood sugar contra; even ifyoudo not already have
`tes. These are some ofthesigns ofhigh blood sugar.
`“Mess of breath, dizziness,nausea, chest pain, weak-
`‘IOuble speaking, or swelling of a leg Thesemay
`s'Sns' ofVa heart attack, blood clots, or stroke.
`
`
`
`
`
`, FULL PRESCRIBING lNFORMATlQN: CONTENTS" _
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`DOSAGE FORMS AND STRENGTHS
`__ CONTRAINDICATIONS
`»
`'
`WARNINGSAND PRECAUTIONS
`51
`Cohtis
`5.2 Ultraviolet Light and Enwronmental Exposure
`ADVERSE REACTIONS V
`-,
`,
`,
`- 6.1 Adverse Reactionsin ClinicalStudies
`7 DRUG INTERACTIONS
`.
`_
`7.1
`Erythromycin'
`,»
`7.2 Neuromuscular Blocking Agents
`8 __USEIN SPECIFIC POPULATIONS
`
`,,8.V rVPregnancy ,.
`,.
`V
`8.3 Nursing Mothers ,
`_
`
`: ,4 Pediatric Use
`’ 8.5 Geriatric Use
`,
`VVV
`11, DESCRIPTION
`12 CLINICAL PHARMACOLOGYV
`‘_ 12.1V Mechanism ofAction ,
`‘
`.
`12.3 Pharmacokinetics
`V
`,
`
`, V12.4 Microbiology .,
`_
`” ‘
`13 NONVCLINICVALEVyTOIHVCOLOGYV
`13.1 Carcinogenesis, Mutagenesis,ImpairmentofEer-
`V
`tilitVy
`»
`-
`14,0LINICALSTUDIES
`'
`‘
`‘
`“ ‘V
`16; HOW SUPPLIED/STORAGEAND HANDLlNG
`17",PATIENT COUNSELING INFORMATION
`‘V 17.1 Instructions forUse V
`V
`17.2 Skin Irritation VVV
`~~
`-
`-
`17.3Cohtis _-.
`,
`,
`,
`*Sectionsor subsectionsomitted from the fullprescribing
`informationare not listed.
`-
`,
`
`"
`VELTINTM
` FULL PRESCRIBVING lNFORMATlON
`,
`"
`V
`V
`VV
`,_VV,V
`[vel-VtirVL],
`(clindamycin phosphate and tretmoml
`1V
`INDICATIONSAND USAGE?
`Gel1.2%/0.02,5%.
`,
`_
`,
`.
`VELTIN"M (clindamycm hosphateand tretin’oViiVVi) Gel,
`FortopIcal use only _
`1.2%l0.025%is indicated, for the topical izeatment of acne
`HIGHLIGHTSOF PRESCRIVBING lNFORMATlON
`vulgarisin patients 12 years or older. I.
`_
`.
`.
`_
`2 - DOSAGEANDADMINISTRATION
`These highlights do not, include all the informationheaded
`to use VELTIN Gel safely and effectively. See fullprescrib-
`ing information for VELTINGel.
`VELTIN Gel should be applied once dailyin the evening,
`gently rubbing the medication to lightlycover the entire af-
`VELTIN“, (clindamycin phosphateand tretinoin)Gel V1
`
`
`fected area Approximately a peasized amount will be '
`0.025% .‘
`__
`,
`.,
`,
`,.
`,
`cousmembranes '
`needed for eachapplication’;Avoid theeyes, lips; and mu-
`For topical use only .~
`:
`
`
`‘
`,
`~.-._,
`initial u.sApproval: 2606
`VELTIN Gelis not fororal, ophtha1m1c ormtravagmaluse,,
`INDICATIONS AND USAGE——-——-——
`3V 1
`V DOSAGE FORMSAND STRENGTHS
`0VVELTIN Gel'1s alincoSaniide antibiotic andretinoid com-
`bination product indicated for the topical treatmentof
`VELTIN Gel, containing clindamycin phosphate 1.2%, and
`tretinoin 0.025%,'1s a yellow, opaque topical.gel Each gram
`acne vulgarisin patients12 yearsorolder (1)
`'
`Visit PDR.net to registerforProduct SafetyAlerts and to dOWnloadmobilePDR®-free toU.S. prescribers
`3
`
`MIROOMI—I
`
`c:
`
`,
`
`
`
`,,
`
`,,
`
`V
`
`V
`
`.
`
`V
`
`'V
`
`v
`
`.
`
`
`
`,
`
`(E
`
`'
`
`'-
`
`'
`
`"
`
`3
`
`

`

`"e
`_,
`
`_
`
`Patients with at least one adverse
`reaction
`
`Application, site dryness
`
`Application site irritation
`
`Applicationsite exfoliation
`
`Application site erythema
`
`Application site pruritus
`Sunburn
`
`Application site dermatitis
`
`—__
`
`———
`
`_
`
`L
`
`L,
`
`3(1)
`
`5(1) L
`21(<1)
`
`3(1)
`
`L 6(1) -
`
`. 3(1)
`
`1(<1)
`
`_
`
`
`
`
`,For, the latest-FDR product information. visit LPLD
`Detinoin
`_
`,
`_
`Oral tretinoin has been shown to be teratogé .
`rats, hamsters, rabbits, and primates. It wash? 111%
`and fetotoxic in ;Wis_tar rats when given gran erato
`ed
`greater than lmglkg/day (32 times the rectum11ey at
`cal dose based on body surfacearea comparisOmild
`variations in teratogenic doses among val-mus However
`rats have been reported. In the cyrnomologmls
`111s
`>
`species in which tretinoin metabolism is CIDSe‘r film
`than in other species examined, fetal malformatl) h
`reported at oral doses of 10 mg/kg/day or green“
`were observed at 5 mg/kg/day (324‘ times the rec-0’ 1’
`clinical dose based on body surface area- 96mm .
`though increased skeletal Variations were 013581.31
`dosesDose-related teratogenic eifects’and increa ‘1
`tion rates were reported in pigtail macaques.
`se
`.
`With widespread use of any drug, a small Rumba
`"
`defect reports associated temporally with the a r Sikh-t}:
`tion of the drug would be expected by chance floimImStra.
`cases of temporally associated congenital mam) 6‘ Tlurty
`have been reported during two decades of Clinical lfmations
`other formulation of topical tretinoin; Although nose“ 31% L
`pattem7Lof teratogenicity and no causal associati-d flm
`been‘established from these cases, 5 of the I‘epbrtsg
`the rare birth defect category, holoprosencephaly 6
`associated with incomplete midline development -
`brain). The significance 'of 'theSe"spontaneous~ mm)
`, terms of risk to fetus is not known.
`.
`*
`8.3 ’ Nursing Mothers
`It is not known whether clindamycin is excreted in h
`milk following use ofVELTIN Gel. However, orally an
`enterally administered clindamycin has been i‘epo‘
`appear in breast milk. Because of the potential for s
`adverse reactions in nursing infants, a decisions
`made whether'to discontinue nursing or to disConm'1
`drug, taking into account the importance of the drug
`mother. It is not known whether tretinoin is excrete
`’
`man milk. Because many drugs'are'excreted in 5
`milk, caution should'be exercised When VELTIN
`ministered to a nursing woman,
`' 8L4’ '
`‘
`Pediatric Use ,
`‘
`( safety and: efi‘ecti'veness of VELTIN‘Gel in'Lpedi
`tients below-(the ag'e'of 12 years [have not been e ab
`Clinical trials of VELTIN Gel included 2,086 patlent's
`years of'age with acne vulgaris. [See Clinical LStud’
`.
`Geriatric Use
`,
`_
`Clinical studies of VELTIN Gel did not includ sufii
`numbers of subjects aged 65 and over to determinew
`they respond difi‘erently from younger subjects.
`11
`DESCRIPTION
`>
`VELTIN (clindamycin phosphate and tretino'
`0.025%, is a fiXed combination ’of two solubr zed
`gradients in an aqueous‘based gel. Clindajnycin' phos
`is a water soluble ester of the semi-synthetic antibiotic
`duced by‘a 7(S)—chlor0‘-substitution ’of the17(‘R)-
`'L
`group of‘the parent antibiotic lincomycin;
`'
`.
`,
`The chemical name for clindamycin phosphate ism
`7—chloro—6,7,8-trideoxy-6:(1-methyl-tmns—4—propyl~L1
`rolidinecarboxamido)—1-thi0eL-threo-oc-D-galizcto—oct _
`noside 2-(dihydrogen phosphate). The structural formula
`clindamycin phosphate is represented below; ,
`Clindamycin phosphate: 2
`
`3146/STIEFEL O VELTIN
`
`,
`
`Table 1: Treatment-Related Adverse Reactions Reported by 21% of Subjects "
`VELTIN Gel
`Clindamycin Gel
`N=1091
`N=1104
`n (%)
`'n (%)
`
`’
`
`' Tretinoin Gel
`N=1084
`
`'
`
`n (%l
`
`'- Vehicle Gel
`N=552
`n (%)
`
`‘
`
`,
`
`17 (3) ,
`
`~
`
`Table 2: VELTIN GEL-Treated Patients with Local Skin Reactions
`
`,
`
`.
`
`.
`
`,
`
`.
`
`VELTINGEL
`
`VEHICLE GEL
`
`Local Reaction
`
`End of Treatment
`L N: 409 ,
`,
`N (%)
`
`Erythema
`
`Scaling "
`Dryness
`
`Burning ,
`
`Itching »
`
`
`
`18%
`
`‘_ 12%
`
`,1
`
`,:13,%_
`
`14% -_
`
`j 'End'of Treatment
`"
`N: 209 __
`-
`N_(%)
`'J35% "
`
`of VELTIN Gel contains, as dispensed, 10 mg (1%)
`clindamycin as clindamycin phosphate, and 0.25 mg
`(0.025%) tretinoini‘solubilized in‘ an aqueous based gel.
`4
`CONTRAINDICATIONS
`,_ ,p
`:6
`.
`VELTIN Gel is contraindicatedin patients with regional en-,
`teritis, ulcerative colitis, or history of antibiotic—associated
`colitis.
`1'
`'
`-
`
`,
`
`_,
`,
`5 WARNINGS AND PRECAUTIONS L
`,
`_
`f
`5.1
`Colitis
`‘
`.
`:LL
`.
`,_
`V
`-,
`'
`Systemic absorption of clindam'ycin has been demonstrated
`following topical use. Diarrhea, bloody diarrhea, and colitis
`(including pseudomembranous colitis)‘have been reported
`with the use of topical clindamycin. If significant diarrhea
`occurs, VELTIN Gel should be discontinued:
`’
`.
`.
`_
`1
`Severe colitis has occurred following oral or parenteral ad-
`ministration of clindamycin With ,an‘ onset ofup 7toseveral
`weeks following cessation of therapy. Antiperistaltic agents
`such as opiates and diphenoxylate with atropine may pro—
`long and/or worsen severe colitis. Severe colitis may result
`indeath.
`_,
`'
`,
`,
`‘
`Studies indicate a toxin(s) produced by clostridia is one pri-
`mary cause of antibiotic-associated colitis. The colitis is usu-
`ally characterized by severe persistent diarrhea andjsevere
`abdominal Cramps and may be, associated with the passage
`of blood and mucus. Stool cultures'for Clostridium difl‘z'cile
`and stool assay for C. difi‘icile toxin may be helpful diagnos-
`tically.
`'
`'
`'
`I,
`‘_
`5.2 __ Ultraviolet Light and Environmental Exposure ‘
`Exposure to sunlight,
`including sunlamp‘s, should be
`avoided during the use of VELTIN Gel, and patients with
`sunburn should be advised not touse the product until fully
`recovered because of heightened su'sceptibilityto sunlight
`as a result of the use of tretinom.nyatients who may be re-
`quired to have considerable sun exposure due to occupation
`and thuse with inherent‘s’ensitivity to the sun should exer-
`cise particular caution. Daily use of sunscreen products and
`protective apparel (e.g., La hat) are‘ recommended: Weather
`extremes, such as wind orcold, also may be irritating to pa-
`tients under treatment withLVELTINGel.
`_
`'
`6*; ,_ ADVERSE REACTIONS, .
`:
`-
`,
`,
`- 6.1
`'- Adverse Reactionsin Clinical Studies
`BecauSe‘clinical studies are conductedunder widely varying
`condititms, adverse reaction rates observed in clinical stud:'
`ies ofa’drug cannot bedirectly compared torates in the dim
`'ical studies of another drug and may not reflect theyrates
`observed in clinical practice.
`L,
`’
`'
`'
`-
`'
`L
`The safety data reflect eXposure to VELTIN Gel in 1,104 pa4
`tients with acne vulgar-is. Patients were 12 years or older
`
`, ,
`
`‘
`
`i and were treated once daily inthe evening for 12 weeks.
`AdVerse reactions that were re'portediin 21% of patients
`treated with VELTIN Gel are presented in Table 1‘
`L
`'L
`[See table labove]
`_
`r
`v
`‘\
`-
`"
`Local skin reactions actively assesSed at baseline and end of
`treatment with a score > 0 are presented in Table 2.
`'
`[See table 2 above] ,
`’
`-
`L
`,
`During the twelve weeks of treatment, each local skin reac-
`tion‘p'eaked at week 2 and gradually reduced thereafter.
`«
`7‘; _
`; DRUG INTERACTIONS
`'
`’
`7.1'
`i' Erythromycin
`VELTIN Gel Should not be usedLinLcombinationL‘with '
`erythromycin-containing products due to possible antago-
`nism to the clindamycin component. In' uitr‘ov studies have
`shown antagonism between these 2LLantimicrobials. The
`clinical significance of this in vitro antagonism is not
`known:
`_
`_
`p
`.
`_
`7.2
`.Neuromus’cular Blocking Agents '
`Clindamycin has been shownto have neuromuséular block:
`ing properties that may enhance the action of other ‘n‘euro’:
`muscular blocking agents. Therefore, VELTIN Gel should
`be used with caution in patients receiving such agents." '
`8
`USE IN SPECIFIC POPULATIONS _
`_
`‘
`,
`_
`8.1
`Pregnancy
`‘
`p
`_
`’y
`Pregnancy Category C. There are no well-controlled studies
`in pregnant women treated with VELTIN Gel. VELTIN Gel
`shouldvbe used during pregnancy only if the potential ben-
`efit justifies the'potential risk to the fetus. Alimit teratology
`study performed in Sprague Dawley rats treated topically
`with VELTIN Gel or 0.025% tretinoin gel at a dose of
`2 mL/kg during gestation days 6 to 15 did not result in ter-
`atogenic effects. Although no systemic levels of tretinoin
`were detected, craniofacial and heart abnormalities‘were
`described in drug-treated groups. These abnormalities are
`consistent with retinoid eifects and occurred at 16 times the
`recommended clinical dose assuming 100% absorptionand
`based on body surface area comparison, For purposes of
`comparison of theanimal exposure to human exposure, the
`recommended clinical dose isd'efined as 1 g-of VELTIN Gel
`applied'daily to'a 50kg person. 1 f '
`‘
`j
`/
`’
`_
`,_
`__
`,
`Cllndamycin
`,
`L
`'
`'
`Reproductive develOpmental toxicity studies performed in
`rats and mice using oral doses of 'clindamycin up to
`600 mg/kg/day (480 and 240 times the recommended clini-
`cal dose based on body surface area comparison,“
`respectively) or subcutaneous doses of ‘clindamyciniiup to
`180*mg’lkg/day (140 and 70. times the recominended clinical
`dose based on body surface area comparison, respectively)
`revealed no evidence of teratogenicity.’ _
`'
`'
`'
`'
`
`
`
`Molecular Formula: 0201712302. ,L L.‘_
`.
`,
`'
`Molecular Weight:,300.44
`_
`'
`VELTIN Gel contains the following inactive 111
`butylated hydroxytoluene, carbomer 940, anhy
`acid, edetate disodium, methylparaben, laureth
`lene glycol, tromethamine, and purified water} .
`12 ' CLINICAL 'PHARMACOLOG
`_
`12:1
`Mechanism of Action
`:
`Clindamycin ,, ..
`«.
`[See Microbiology (124).]
`
`‘
`
`,
`
`IMPORTANT NOTICE: Updateddrflg informatibn‘ is sent bi-mOnthly via the PDR®"Updat‘e Insert. For‘monthly em‘ail‘u‘pdates, register at FDR-"g
`
`4
`
`

`

`
`
`‘-
`7min,
`
`
`#011311 the exact mode of action of tretinoinis unknown
`
`ennt evidence suggests that topical tretinoin decreases
`
`Skin almost clear; rare non—inflammatory lesions present, with rarenon-inflamed
`
`siveness of follicular epithelial cells with decreased mi-
`
`papules (papules must be resolving and may be byperpigmented, though not
`
`' pink-red) requiring no further treatmentin the Investigator’s opimon ’
`omedone formation. Additionally, tretinoin stimulates
`
`tic activity and increased turnoverof follicular epithe-
`
`09115 causing extrusion of the comedones
`
`Some non-inflammatory lesions are present, with few inflammatory lesions
`
`
`3 Fharmacokinetics
`(papules/pustulesonly, no nodulo--cystic lesions).
`Moderate
`
`’
`‘open—label study of 17 patients With moderate—to-
`
`
`Non-inflammatory lesionspredominate, with multiple inflammatory lesions
`acne vulgaris, topical administration of approxi-
`ely 3 gramsofVELTIN Gel oncedaily for 5 days,
`evident; several to many cemedones and papules/pustules, andthere may or may
`
`
`
`
`
`’ not be 1small nodule—cystic lesion
`amycin concentrations were quantifiable in all 17
`
`Severe
`entS starting from 1 hour post dose. All plasma
`
`
`
` Inflammatory lesionsare more apparent; many comedones and papules/pustules, 'L
`damyCin concentrations were <556 ng/mL on day 5,
`, there may or may not be afew nodulo—c'ystic lesions.
`
`
`all;the exception of one subject who had a maximum
`
`
` Very Severe
`damycinconcentration of 8.73 ng/mL at 4 hours post—
`Highly inflammatory lesions predominate;va1iable numbersofcomedones, many
`_ There was no appreciableincrease in systemic expo-
`
`
`papules/pustules and nodule-cystic lesions.
`to .tretinoin, as compared to the baseline value. The av-
`
`e tretinoin concentration across all sampling times on '
`
`
`Table 3: Efficacy Results at Week 12
`rreLspoiiding baseline meantretinoin concentration range
`'16t0130ng/mL
`"‘
`*
`~
`
`,
`,
`Tretinoin Gel
`Vehicle Gel
`
` . ' VELTIN Gel ' Clindamycin Gel
`L Microbiology
`L
`N=476
`N=467
`.L_..
`Study 1
`N=464
`.
`,
`N=242
`microbiologystudies were conductedin theclinical trials
`
`this pruduct
`,
`,
`~
`-
`
`lnvestigator's Global Assessment
`‘
`_
`.
`hanism ofAction -
`.
`.
`’
`Percentage ofsubjects achieving Two Grade "
`L2'0L2% L
`.
`36.3%
`
`damycin binds to the 50S ribosomalsubunitof suscep—
`
`26.6% -_
`.
`Improvement,
`
`bacteria and prevents elongation of peptide chains by
` 24.0%
`rferiug with peptidyl transfer, thereby suppressing pro-
`Percentage of subjects achieving anLIGA of 0
`17.8%
`
`332%
`or 1 with a Two Grade Improvement
`
`
`Inflammatory Lesions:
`L ,, 11:1: :
`
`Mean absolute reduction
`
`
`
`Mean percentage (%) reduction ' 43.3%;
`
`
`
`LL Non-inflammatory Lesionsi
`
`L Mean absolute reduction
`‘
`
` 17.0 ,
` Mean percentage (%) reduction
` "36-01:;
`Total Lesions:
`
` * 28:1- : r
`
`. Mean: absolute reduction LL
`
`LMean percentage (%) ieduction LL
`L
`
`1st
`clindamycin tretinoin combinationis unknown. Although
`LLHOWL SUPPLIED/STORAGE AND HANDLING
`How Supplied
`the significance of these studies tohumansis not clear, pa-
`tients should avoid exposure to sun.
`L
`VELTIN Gel'1s suppliedasfollows
`The genctoxicpotential of tretinoin was evaluatedm an in
`30g aluminum tubes NDC 0145—0071-30
`vitro Ames Salmonella reversion test andan in vitro chro-p
`60 g aluminum tubes NDC 0145-0071—60
`Storage and Handling
`
`mosomal aberration aSsa’y in Chinese hamsterovarycells.
`Both tests were negative.
`. Store at 25°C (77°F); excursions permittedto 15—30L°C
`, (59—86°F)
`, the
`In oral fertility studiesIn rats treated with tretino’
`0 Protect from heat
`no-observed-efl‘ect-levelwas 2 mg/kg/day (64 timesthe rec-
`ommended clinical dose based on body surface area compar:
`
`
`' Protect from light
`-_
`ison).
`'
`.
`-
`- Protect from freezing
`0 Keepout of reach of children.
`_
`.
`,
`»
`y
`.
`0 Keep tubetightly closed
`17 L ' PATIENT COUNSELING INFORMATION
`[See FDA-approved Patient Labeling].
`17.1
`Instructions for Use
`' At bedtimie,the face should begently washed with aLLmild
`soap andwater. Aflzer patting the skin dry, applyVELTIN
`Gel as a thin layeroverthe entire affected area(excluding
`the eyes and lips)
`.,
`,
`0- Patients should be adviSed not to use more than a pea
`sized amount to cover the face and not to applymore often
`than once daily(at bedtime) as this Will not make for
`faster results and may increase imitation.
`0 'Asunscreen should be applied every morning and reap-
`plied over the course ofthe day as needed. Patients should
`be advised to avoid exposure to sunlight, sunlamp, ultra-
`violet light, and other medicinesthatmay increase sensi—
`tivity to sunlight.
`-
`,
`-
`-.
`- Other topical productswithaLLsti'ongdrying effect, suchas
`abrasive soaps or cleansers, may. cause an increase in skin
`irritation with VELTIN Gel. =
`17.2
`Skin Irritation -
`-
`L
`‘
`“
`VELTIN Gelmay causeirritation such as Lerytbema, scal-
`iug, itching, burning, or stinging.
`,
`17.3
`Colitis
`‘
`'
`In the event a patient treatedWith VELTINGel experiences
`severe diarrhea or gastrointestinal discomfort, VELTIN Gel
`should be discontinued and a physician should be‘contacted
`VEL:P12
`"~ _.
`.
`,
`..
`,,
`.
`.
`
`14" CLINICAL STUDIES
`
`The safety and eflicacy of VELTIN Gel, appliedonce daily
`for the treatment of acne vulgaris, was evaluated'In 12-
`week multicenter, randomized, blinded studies in subjects
`12 years and older
`Treatment responsewas definedasthe percent of subjects ,
`who had a two gradeimprovement from baselineto Week 12
`based on the Investigator’s GlobalAssessment (IGA) and a
`mean absolute change from baseline'toWeek 12in two out
`of three (total, inflammatory and non-inflammatory)lesion
`counts. TheIGAscoring scale usedin all the clinical trials
`for VELTIN Gel1s as follows:
`-
`, s
`.
`,
`[See first table above]
`_.
`'
`In Study 1,1649 subjects were randomizedto VELTIN Gel,
`Clindamycin gel, Tretinoin gel and vehicle gel Themedian
`ageof subjects was 17 years old and 58% were females. At
`baseline, subjects had an average of 71 total lesions of
`whichthe mean number of inflammatory IesibnsWas 255
`lesions and the mean number of non--inflammat0ry lesions
`was 45.1 lesions.-The majority of subjectsenrolled With a
`baselineIGA score of 3The efficacy results at week 12are
`presentedIn Table 3.
`.
`-
`.
`,
`[See table 3 above]
`The safety and eflicacy ofclindamycin-tretinoin gelwasalso
`e'Valuatedin two additional 12-week multi-centered,-ran-
`domized, blinded, studiesin patients12 years and older. A
`total of 2219 subjects with mild—to—moderate acne vulgaris
`were treated once daily for 12weeks. Of the 2219 subjects,
`634subjects weretreated with clindamycin—tretinoin gel
`These studies demonstrated consistent outcomes
`
`5 ranged from 1.19 to l.23 ng/mL‘ compared with the}
`
`
`tbe clinical significance of this activity against P. times
`
`not examinedin clinical studies with VELTIN Gel. P.
`
`treatment of acne with antimicrobials1s associated
`the development of antimicroblalresistancein P. acnes
`
`
`
`
`to erythromycin.
`.
`NONCLINICAL TOXICOLOGY
`
`
`Carcinogenesis. MutageneLSi's,ImpairmentLLof Fer-
`
`
`the carcinogenic potential of VELTIN Gel or the effect
`
`
`
`astogenic potentialIn the absence ofmetabolicactivation
`
`testedm anin vitro chromosomal aberrationassay.
`Lndamycin
`’
`~
`
`
`tejdaily dermal administration‘of 1% ‘clinLdamycinas
`amycin phosphate in the ’- VELTIN ’ Gel» vehicle
`g/kg/day, 13 times the recommended clinical dose
`
`ed on body surface areacemparison) tomice for up to 2
`firs did not produce evidence of tumorigenicity
`_
`,
`
`lity studies in rats treated orally with up to
`g/kg/day of clindamycin (240 times the recommended
`Cal dose baSed on body surface:area comparison) re-
`
`
`d no effects onfertility or mating ability.
`_
`, linoin ,~
`,1“ l5W0 independent mouse studies where tretinoin was ad-L
`miniSllcred topically (0.025% or 0.1%)three times per week
`0111p to two years no carcinogenicitywas observed, With
`max11mm effects of dermal amyloidosis. However, in a
`dam“1181 carcinogenicitystudyin mice, tretinoin applied at a
`dosé
`0f 5.1 pg (1.4 times the recommended clinical dose
`filled on body surface area comparison) three times per
`foefik for 20 weeks actedas a Weak promoter of skin tumor
`hemfifion followinga singleapphcationofdimethyl-
`Innzlulanthracene (DMBA).
`'L
`.
`d“.aStudym female SENCAR mice,papillomas were in-
`Wi°°d by topicalexpoSureto DMBAfolloWed by promotion
`11th 12-0--te1n‘adecanoyl-pborbol 13-acetate or mezerein for
`M0 20weeks.