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`EDITION
`
`2012
`
`DFS
`RFFFi2F
`
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`Copyright © 2011 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
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`
`ISBN: 978-1-58363-800-8
`
`1 of 4
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`Almirall EXHIBIT 2031
`Amneal v. Almirall
`IPR2018-00608
`
`

`

`REPORT SUSPECTED ADVERSE DRUG EVENTS NOW at RxEvent.org
`
`DUAC = STIEFEL/2765
`
`¯
`
`Table g. Summary of Efficacy Data"
`
`Study I
`
`Study 2
`
`Zevaltn
`therapeutic regimen
`N : 54
`
`Zava0n
`therapeutic regimen ,
`N = 64
`
`Dverall Response Rate ~%)~
`
`Complete Response Rate~ (%1
`
`74
`
`15
`
`~ 83
`
`38
`
`"
`
`Median DRY,~
`[Months)
`
`[Rang~I
`
`I
`
`6.4
`[0.5-49.9+1
`
`i
`M~aa TTP~,~(1Hontks)
`[Range’J} .......
`
`6,8
`|1,1-50.9+]
`
`14.3
`[1.8-47.6+]
`
`i2.1
`[2,1-49.0+]-
`
`1WRC: International Workshop Response Criteria
`~L CRu and CR: Unco~ed and coniirm complete response
`Estinmted with observed range
`§ Duration of resppnse: interval from the onset of response to disease progression
`¶ %" indicates !m ongoing response
`# Time rn Disease Progression; interval from the first infasion to disease pl:ograssion
`
`’
`
`’
`
`¯
`
`’
`
`Rituximab
`N = 66
`
`¯
`
`55
`
`-
`
`18
`
`1L5 ,
`[L2-49.7+]
`
`10.1
`[0,7-51.3+]
`
`Ftgum 1. Study 4: Kaplaa-Meier Estimator for Investigator-
`A~eesad Proglasslon Free Sul~tval Time
`
`PFS !Tree from Racdomizalioe IMonlhs)
`
`men (83% vs. 55%, p<0.0Ol). T’ime-to-disease~pregression
`Was not significantly different between study arms, Table 9
`summarizes efficacy data from Study 2.
`[See table 9 above]
`Stu[iy 3 was a single arm study of 30 patients of whom 27
`had relapsed or refractory low-grade, follicular NHL and a
`pintelct count 100-000 to 149,000/mm3. Patients witti a 25%
`lymphomntaus marrow involvement, prior myeioablative
`therapy with st ..... ll support, prior external beam rndia-
`Lion to > 25% of active marrow or neutrophi] count
`<LSOO/mma we]~a ineligible for Study 3. All patients re-
`ceived Y-90 Zevalin 10.3 mCi per kg t11.1 MBq per kg)l. Ob~
`iective, durable clinical responses were observed [89% ORR
`(95% CI: 7I)-97%] with a median duratieu ef response of 1L6
`months (range: 1,0-42.4+ months)].
`14.2 Follicular, B-Cell NHL Upon Completion of First;
`Line Chemotherapy
`Study 4 was a multi~center, randomized, open-label stmdy
`conducted in petiente with fellieniar NHL with a partial
`3. One (11 Formulation Buffer Vial containing~ 750 mg
`(PR) ar samplers response (CPJCRu/upon completion of
`Albumin (Human), 76 mg Sodium Chloride, 28 mg
`first-line chemotherapy. Randomization was stratified: by
`Sodimn Phosphate Dibasic Dadecahydrale, 4 mg Pantetic
`center and response to first-line therapy (Ca or PR), Key
`Acid, 2 mg Potnssinm Phosphate M0nobasi~ and 2 mg Po:
`eligibility criteria were <25% bone marrow involvement, no
`thssium Chloride in 10 mL Water for InjeL~on, pH 7.1 as
`prior external beam radintiu .... ye!oablative therapy, and
`a clasr yellow to ambei" celared selation.
`recovery of plateleLs te normal levels. Patients were ran-
`4. One (1) empty Reartion Vial .
`damlzod to.receiv~ Zevalin tn~208) or uo fia~her therapy
`Indium4It Chloride Sterile Solution fIn-lll Chloride) must
`(n=206). Y-90 ZevaIin was administered at least 6 weeks,but
`be= ordered separately from either GE Healthcare, or
`no more then.12 weeks following the last dose of chemother- M~ckrafit/Covidiun.
`spy. The main efficacy outcome measure was pregreesian~ Yttrium-90 Chloride Sterile Sulutian is shipped directly
`free survival iPFS) assessed by study investigators using
`from the supplier upon piaceumnt of an order for the Y-90
`the International Workshop to Standardize Response Crite-
`Zevalla kit.
`ria for non-Hedgkin’e Lymphoma {1999L
`Ritmdmab (Rito_xa~, Biogen Idec and Genentech USA}
`Among the 414 patients, 49% were male. 99% were Canoe- must be ordered separately,
`mas, 12% weft, _>65 years old, 83% had a WHO pertbrmance
`Storage
`status of 0, and 65% had Stage IV disease. Thirtymine
`Store k~ts at. 2-8~(~ (364(~F). Do not freeze,
`(9.5%) patients received single agent chlorambucll, 22 (5%)
`patients received fludarabine er a fludtu~abine-cantaining
`rogimea. 294 (71%) patieute received eyclephcsphamide:
`containing combination chemotherapy ICHOP- 131%);
`CHOP-like 115%); CVP/COP (26%)1 and 59 (14%) petiants
`received ritmximab-cnntaining comblnatieu chemotherapy
`as first-line troatment,
`Progression-free surviva! was significantly prolonged
`among Zevalln-treated patients compared to those receiving
`an !’urther treatment [median PFS 38 months vs. 18
`months; HR 0.46 (05% Ck 0.35, 0,60) p<O.O001 Cox model
`stratified by response to first-line therapy and initial ~aL-
`meat strategy(immediate vs. watch*and-wait)l, The num~
`bar of pntients who died was too small to permit a reliable
`comparison on survival,
`The results for PFS are presented in Figla’e 1.
`[See figure 1 at top of nsxL columzfl
`
`Stiefel Laboratories. Inc.
`Research Triangle Park, NC 27709
`
`Direct Inquiries to:
`ProLhssioual Services Department
`1-888-STIEFEL 11-888-784-3335,
`
`DUAC®
`{dFz-(tk]
`(olindamycin phosphate, 1% - henzoyl peroxide, 5%)
`Topical Gel
`For Dermatological Use Only,
`Not for Ophthalmic Use.
`Rx Only
`
`I}
`
`DESCRIPTION
`Dune® Topical Gel contains clindamycin phosphate. (7(S)-
`chlora-7-deexylincemycin.2-phasphate), equivalent to 1%
`clindamycin, and 5% benzoyl peroxide.
`Clin@~vin phosphate is a watex soluble ester of the semi-
`~ynthetic antibiotic produced by a 7(S]-~oro-substitution
`of the 7(R)-hydroxyl group of the parent antibiotic liucomy-
`cin.
`Clindamycin phosphats is C1sH~4CINsOsl~. The structural
`formula far clindamycin phasphate is sepresented below:
`
`i~’
`~,,
`¢~:’~.q
`:~!2~
`J’~ -~"-"
`~
`"l~-j ~’~,/--~\--
`|
`~" N
`[
`?~ .
`
`° .....
`~
`
`Clindamy~ phosphate has a mo}e~Jer weight of 504.97
`and its chemical name ia methyl 7-chlero*6,7~8-trideox3"-6-
`(1-methyl-trans-4-propyl-L-2-pyrrotidinecarboxamido).l.
`thio-L-thrse~a-D-galocto-ectopyrannside 2-(dihydrogen
`phosphate).
`Benzoy! peroxide is C14HloO4. IL has the following struc-
`tur~ formula:
`
`c ~-~
`~;’~ ~t-°o--o- ~°’’~
`
`~
`
`Benzeyl peroxide has a moieca]ar weight of 242.23,
`Each gram~ of Duac Topical Gel contains 10 mg ’(1%)
`ctindamyciu, ae phosphate, and 50 m’g (5%) benzoyl
`peroxide in a base consisting of:carbomar homepotymer
`(type C), dimethicone, disedi!~m leery] sulfesascinate, ede-
`tale di~odium, glycerin, meLhytpsra~n, peloxamer 182, pu~-
`rifled water, silicon dioxide, and sodium hydroxide.
`
`CLINICAL PttAB_MACOLOGY
`17 PA22Ea’wr COUNSELING INFORMATION
`Acomparative stiidy of the pharmacekinetics of Dune® Top
`Advise patients:
`teal Gel and 1% ~’lindamydn solution alone in 78 patient~
`¯ To contact a healthcars professional for severe signs and
`symptoms vflnfusiaa reactions,
`indicated that mean pinsmu clindamy~.ln levels during the
`four week dosing period were < 0.5 ng/ml for both troatmeat
`¯ To take pramedications as pres~bed [see Dr~age pad Ad.
`ministration (2.2) and Warnings and Precautions (5.1)1,
`groups.
`Ben’zoyl peroxide has been shown ta be abaci’bed by the skin
`¯ ’Ib rcpert any signs or symptoms of cytepenias (blceding,
`easy bruising, petechiae or purpura, pallor, weaknsfia dr where it is cem;~rted to beaz0ic acid. Less Lhan 2% sf th~
`dose enters systemic circulation a~ benzoic acid,
`fatigne),
`¯ To avoid medications that interfere with plata!eL function. Microbiology
`except as directed by a hsalthcare professional [see Warn- Mechanism of Action
`Clindamycin binds to the.5OS ribosomal subanits of snseep~
`ings and Precautions (5.2)L
`¯ To seek prompt medical uvaltaation for diffaee rash, hellas,
`tible bacteria and p~ants eloagatiort" of peptide chains by
`interfering:wit~ poptidyl transfer, thereby Suppressing pro~
`or desquamaticn ef the skin or oral musesa,
`rein synthesis.
`* To immediately report symptoms of infection te.g. pyrexia)
`Benzoyl peroxide is a potent o~ddizing agent.
`[see Adverse Reactions (6.3)].
`¯ That immunization with live viral vaccines is not resem-
`In Vivo Activity
`No microbiology studies were conducted in the clinical trials
`mended for 12 months following the Zevulin therapeutic
`with this product.
`regimen [see Warnings and Predautions (ff.8)].
`in Vitro Activity
`* To ass effective contraceptive methods during treatment
`The clindamycln and beazoyl peroxide compor~ents individ-
`und for a minimum of 12 months following Zevalin tiler-
`ualty have been shown to have in vitro activity against Prm
`apy.
`¯ TO discontinue nursing during and after Zevalin treatmont
`pionibaeterium aches, an organism which tms been asseci~
`ated with none vulgarisl however, the clinical significance of
`Isee Use In Special Populations (8.3)].
`© 2009 Spectrum Pharmaceuticals. Ins
`this is not known.
`Drug Resistenca
`[rvine, CA 92618
`There are reports of an increase of R acnss resistance to
`U.S. License No. 1832
`Protected by U.S. Patent Nos. 5,736,137. 5,776,456,
`ctindamycin in the treatment of ache. In patients with R
`aches resistant to ehndamycin, the clindamycin component
`5,843,439, 6,207,858, 6,399,06!, 6,682,734, 6,994,840,
`7,229,620, 7,381~560, 7,422,739 and other patents and pat, muy provide no additional benefit beyond benzoy! peroxide
`eats pending,
`aloue.
`
`16
`
`HOW SUPPLIED~’ORAGE AND ttANDLING
`
`There are ~we kits necesoary for preparation of the Z~valin
`therapeutic regimes: one for preparation of In-lll radicle-
`beted Zevalin CNDC 68152-104-04) and one for preparation
`of Y-90 radiolabeled Zevalln {NDC 68152-106-03), The corn
`tents of all vials are sterile, pyrogen-frec, contain no preser-
`vatives, and are not radioactive. Each kit contains four
`idon~ifieatien labels and the following four vials:
`1. One H) Zevalin vial containing 3.2 mg ibritumomab
`tiuxeisu in 2 mL 0.0% Sodium Chloride as a c~ear, coloP
`less solution.
`2. One ill 50 mM Sadinm Acetate Vial containing 13.6 mg
`Sodium Acetate trihydrate in 2 mL Water for Injection,
`USP as a clear, c~lorless solution,
`
`RECEIVE FDA REQUIRED DRUG ALERTS INSTANTLY ONLINE, REGISTER at PDR.net
`
`2 of 4
`
`

`

`2766/STIEFEL ¯ DUAC
`
`FIND PATIENT SUPPORT RESOURCES at PDR.net
`
`Mean percent reduction in inflammatory lesion counts
`
`DuacCTopiealGel
`
`Benzeyi Peroxide
`
`Clindamyein
`
`Vehicle
`
`Study t
`(n=1201
`
`65%
`
`36%
`
`34%
`
`19%
`
`Study 2
`(n=273)
`
`56%
`
`37%
`
`30%
`
`~0.4%
`
`Study 3
`{n=2801
`
`Study 4
`(n=28B}
`
`Study 5
`(n=358)
`
`.
`
`42%
`
`32%
`
`38%
`
`29%
`
`57%
`
`57%
`
`49%
`
`I
`
`52%
`
`41%
`
`83%
`
`29%
`
`Local reactions with use of Ouac® Topical Gel % of patients using Duac® Topical Gel with symptom present Combined
`results from 5 studies [n--397}
`
`Before Treatment (Baseline)
`
`During Treatment
`
`Erythema
`
`Peeling
`
`Burning
`
`Dryness
`
`’
`
`Mild
`
`28%
`
`6%
`
`3%
`
`6%
`
`Moderate
`
`Severe
`
`3%
`
`<1%
`
`<1%
`
`<1%
`
`0
`
`O
`
`0
`
`0
`
`’
`
`Mild
`
`26%
`
`17%
`
`5%
`
`15%
`
`Moderate
`
`Severe
`
`’
`
`.
`
`5%
`
`2%
`
`<£%
`
`t~-
`
`O
`
`0
`
`o O
`
`O
`
`’
`
`~
`
`in transgealc TgAC mice in a study using 20 weeks of topi-
`cal txeetment. The clinical significance of this is u~own.
`[n a 2*year dermal rercinogenisity study in mice, treatment
`with Duac® Topical Gel at doses up to 8900 mg/kg/day 116
`times the fdghast recommended adult human dose of 2.5 g
`Dnac® Topical Gel. based on mgim~l did not cause an in-
`crease in skin tumors. However, tog}eel treatment with an=
`other tbrmulation containing 1_% clindamycin and 5%
`benzoy! peroxide ac doses of 100, 500, or 2000 mg/kg/day
`caused a dose-dependent increase in the incidence of kera-
`ioacauthoma at the treated skin site of male rats iv. a 2-year
`dermal carinogealeity study in rats.
`In a 52-week phstocareinogenicity study in hairless mice
`C4O weeks of treatment followed by 12 weeks of obeerva-
`}ion), the median time to onset of skin tumor formation de*
`creased sad the number of tumors per mouse increased rel-
`ative to controls following chronic concurrent topical
`treatment with Duuc® Topical Gel and exposure to ultravi-
`plat radiation.
`Genotexicity studies were not eonductsd with Duas@ Topical
`Gel. Clindamycin phosphate was not geuotexic in Saline-
`aella typhimurium or in a rat. micronucleus test. Benzoyl
`peroxide has been fonnd to cause DNA strand breaks in a
`vm’iety of mammalian ceil types, to be mutagenic in Salute:
`nelfa typhimurium teef~ by some but not all invsstiga~ere~
`and to cause sister chromatid exchanges in Chinese ham-
`ster ovary cells.
`Studies have not been performed with Daac~ Topical Gel or
`benzoyl peroxide to evaluate the effect on tbrtility. Fertility
`studies in rats ~reamd orally with up to 300 mgtkg/day of
`clindamycin (apprommately t20 times the amount of
`clindamydn in the highest recommended adulthuman dose
`CLINICAL STUDIES
`CONSIDERED TO ESTABLISH h DEFINITIVE DIAGNOSIS IN
`of 2.5 g Duac® Topical Gel. based on ra!!mS) revealed up el-
`CASES OF SEVERE DIARRHEA, ANTIPERISTALTIC AGENTS
`In five randomized, double-blind clinical studies of 1.319 pa-
`tecta on }hrtllity or muli~ ability.
`SUCH AS OPIATES AND DIPHENORYLATE WITH ATROPINE
`}tents, 397 used Duac® Topical Gel, 396 used benzeyl
`Pregnancy
`MAY PROLONG AND/OR WORSEN THE CONDITION~ DIAR-
`p~roxide, 349 used dindamycin and 177 used vehicle. Duae®
`Teratogenia Effects
`RHEA. COLITIS AND PSEUDOMEMBRANOUS COLITIS
`Topical Get applied once dally for 11 weeks was significantly
`Pregnancy Category C
`HAVE BEEN OBSERVED TO BEGIN UP TO SEVERAL
`more effective than vehicle, bensoyl peroxide, and
`A.~mul reproduction studies have not been conducted with
`clindamycin in the treatment of inflammatory lesions of WEEKS FOLLOWING CESSATION OF ORAL AND PAREN-
`Dust® Topical Gel or bensoyl peroxide. It is also not known
`TERAL THERAPY WITH CLINDAMYCIN.
`moderate to moderately severe facial acne vulgaris in three
`whether Duac~ Topical Gel can cause fetal harm when ad-
`Mild cases of pseudomembrunous colitis usually respond to ministered to a pregnant woman or c~ aflhct reproduction
`of the five studies (Studies 1, 2, and 5).
`drug discontinuation alone. In moderate to severe cases,
`Patients were evaluated and acae lesions counted at each
`capacity. Duac® Topical Gel should be given tea pregrm~t
`consideration should be given to management with fluids
`clinical visit: weeks 2, 5, S, 11, The primary efficacy men-
`woman only ff clearly needed.
`and electrolytes, protein supplementatiau and treatment
`sures were the lesion spouts and the investigator’s global
`Developmental toxicity studies performed in rats and mice
`assessment evaluated at week 1L Patients were insh’ucted with an antibacterial drug elinlca]ly effective against Clos-
`using oreI doses of clindamycin up to 600 mg!kgiday (240
`to wash the face. wait 10 to 20 minutes, and then apply
`Iridium difficile colitis,
`and 120 times the amount ofclindamycin in the highest rec-
`medication to the entire face, once daily, in the evening be-
`ammended adult human dose b~ed ou mg/m2, respectively)
`PRECAUTIONS
`fore retiring. Percent reduetious in inflammatory lesion
`or suhcataneous doses of clindamyein up to 250 mgikgiday
`Genera~
`counts m~er treatment for 11 weeks in these five stadiea are
`tlOO and 50 dmee the amount of clindamycin in the highest
`For dermatological use only; no~ for ophth~e use, Con-
`shown in the thllo~ng table:
`recommended ~idult human dose based on mg/m2, respec-
`semi}ant tspical scan therapy should be used with can}ion
`[See first table above]
`tlvely) raw,sled no evideuce of teratogonicity.
`because a possible cumulative irritancy effect may occur, as-
`The Du~c® Topical Gel group showed greater overall ira- pecinUy with the use of peeling, desquamating, or abrasive Nnrslng Women
`®
`provemeuc in the investigator’s global assessment titan the
`It is nat known whether Duac Topical Gel is secreted into
`agents.
`henzoyl peroxide, cliadamycin and vehicle groups in three of
`famlen milk- after, topical applicatisn~ However, oi’al]y and
`The use of antibiotic agents may be associated with the
`the five stedie~ ~Studice L 2. and 5).
`parenterally adds}prod elindamychi has been reported to
`overgrowth of nonsuseeptible organisms; including fuagL If
`Clinical studies have not adequately demonstrated the of-
`appear-in breast milk# Because of the potential fi)r serious
`this ~urs, discontinue use of this medication and take ap-
`fectiveuess of Duac® Topical Gel versus benzoyl peroxide
`adverse reactions in nursing infants, a declsian ehauld be
`propriate measures,
`alone in the treatment of non-inflammatory lesions of ache.
`made whether to discontinue nursing or to discontinue the
`Avoid contact with eyes and mucous membranes,
`drug, takisg into account the importance of the drug to the
`INDICATIONS AND USAGE
`CIindomycin and erythromycln eantaining prdducts should
`mother.
`Duac® Topical Gel is indicated for the topical treatment of
`net be used in combination. In vitro studies have shown an~-
`Pediatric Use
`iIffiammatery ache vulgar}s,
`ragonism between these two antimierobiale. The clinical sig-
`Safhty and effectiveness of ~s product in pediatric patients
`Duac® Topical Gel has not been demonstrated to have any
`alficance of this in eitro aategenism is not k~mwn.
`below the age of 12 have net been established,
`additional benefit when compared to benzoyl peroxide alone
`Information for Patients
`in the same vehicle when used for the treatment of nun* Patients using Duac~ Topical Gel should receive the ibnow- ADVERSE ~CTIONS
`inflammatory ache.
`ing information and instructions:
`During clinical trials, all patients were graded fo~ facial er-
`1. Duac® Topical Gel is to be used as directed by the physi-
`ythema, peeling, burning, and dryness on the following
`stale: O = absent, 1 = mild, 2 ÷ moderate, and 3 = severe.
`The percentage of patients that had symptoms present be-
`fore treatment (at baseline) end during treatment were ~s
`}bllows:
`[See second table above]~
`(Percentages derived by # subjects with symptom score/#
`enrolled Duac® rlbpical Gel subjects, n = 397).
`Anaphylaxls, as well as allergic reactians leading to hospi-
`talizatian, has been reported in post-marketing use. with
`Duac~ Topical Gel. Because theee reactions ore reported col.
`untarlly from a population of uncertain size, it is not always
`possible to reliably estimate their frequency or establisli o
`causal relationship Lo a drug exposure
`
`CO~ICATIONS
`®
`Duac Topical Gel is contraindicated in those individuals
`who have shown hypersensitivity ro any of its components
`or to lincomyrin. It is also contraindicated in these having a
`history of regional enteritis, ulcerative colitis, pseudomem-
`b~anens ~)litis, or" antibiotic-aesseiated colitis,
`
`WARNINGS
`ORALLY AND PARENTERALLY ADMINISTERED
`CLINDAMYCIN HAS SEEN ASSOCIATED WITH SEVERE CO-
`LITIS WHICH MAY RESULT IN PATIENT DEATH. USE OF THE
`TOPICAL FORMULATION OF CL1NDAMYCIN RESULTS I1~
`ABSORPTION OF THE ANTIBIOTIC FROM THE SKIN SUR-
`FACE. DIARRHEA, BLOODY DIARRHEA. AND COLITIS (IN-
`CLUDING PSEUDOMEMBRANOUS COLITIS} HAVE BEEN
`REPORTED WITH THE USE OF TOPICAL AND SYSTEMIC
`CLINDAMYCIN. STUDIES INDICATE A TOXIN(S} PRO-
`DUCED BY CLOSTRIDIA IS ONE PRIMARY CAUSE OF
`ANTIBIOTIC-ASSOCIATED COLITIS. THE COLITIS tS USU-
`ALLY CHARACTERIZED RY SEVERE PERSISTENT DIAR-
`RHEA AND SEVERE ABDOMINAL CRAMPS AND MAY SE
`ASSOCIATED WITH THE PASSAGE OF BLOOD AND MU-
`CUS. ENDOSCOPIC EXAMINATION MAY REVEAL PSEUDO*
`MEMBRANOUS COLITIS. STOOL CULTURE FOR ClostrM.
`ium difflcile AND STOOL ASSAY FOR Clostridlum difficile
`TOXIN MAY BE HELPFUL DIAGNOSTICALLY. WHEN SIG-
`NIFICANT DIARRHEA OCCURS, THE DRUG SHOULD BE
`DISCONTINUED. LARGE BOWEL ENDOSCOPY SHOULD BE
`
`clan. It is for external use only. Avoid contact with eyes,
`and inside the nose, mouth and all mucous membranes.
`as this product may be irritatiug
`2. This medication should net be used for any disucder other
`than that for which it was prescribed.
`3. Patients should net use any other topi~ ache prepare-
`}ion unless otherwise directed by their physician,
`4. Patients should report any signs of local adverse roac-
`}ions to their physician. Patients who develop allergic
`symptoms such as severe swelling uc shot}aces uf breath
`should discontinue use and contact their physidun imme-
`diate~.
`5. Duac~Topical Gel may bleach hair or colored fabric,
`®
`6. Duac Topical Gel can be stored at room temperature up
`to 25°C (77~F) fur up to 2 montb~. Do not freeze. Keep DOSAGEt*~TD~[[N[STP~TION
`®
`tube tighlly clesed~ Keep out of the reach of small chil-
`Duns Topical Gel should be applied en.ce daily, in the eve-
`dren. Discard any unused product aRer 2 months,
`nmg or as directed by the physician, te affected areas aider
`7. Before applying Duns@ Topical Gel to affected areas, wash
`the skin is gently washed, rinsed with warm water and pat.
`the skin gently, rinse with warm water, and pat dry.
`ted dry.
`8, Excessive er prolonged exposure to sunlight should be
`HOW SUPPLIED
`limited. To minimize exposure to sunlight, a hat or ether
`clothing shauld be worn.
`Dune~ (clindamycin, 1% - benzoyl peroxide, 5%) ’Ibpical Gel
`Carcinogenesis, Mutagenesls, Impairment of Fertility
`is available in:
`* 45 gram tube NDC 0145-2371-05
`Bonzoyl peroxide has been shown to be a tumor promoter
`and progression agent m a number of animal studies.
`Prior to Dispensing: Stere in a cold place, preferably m a
`refrigerator, between 2°C and 8°C (36°F and 46°F), Do not
`Benzoyl peroxide in acetone at doses of 5 end 10 mg admin-
`istered twice per week induced squamous cd] skin minors freeze,
`
`FREE CME AND LIABILITY REDUCTION SERVICES at PDR,net
`
`3 of 4
`
`

`

`REPORT SUSPECTED ADVERSE DRUG EVENTS NOW at RxEvent.org
`
`EVOCLIN * STIEFEL/2767
`
`Dispensing instructions for the Pharmacist; Dispense
`Duac~ Topical Gel with a 60 day expiration date and specify
`"Stare at room temperature up to 25"C 1770F), Do not
`freeze."
`Keep tube tightly closed. Keep out of the reach of small chit-
`dran,
`~72010 Stieihl Laboratories, Inc.
`Stiofal Laboratories, Inc.
`Research Triangle Park. NC 27709
`DUA:3PI
`Ray, February 2011
`DUAC is a registered trademark of Stiefel Laboratories,
`Inn
`
`EVOCLIN®
`[~-vS-kl~n]
`{elindamyoin phosphate) Foam, 1%
`For Topical Use
`
`t~
`
`HIGHUGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed
`to use EVOCLIN Foam safely and affecttvely. See full pre-
`scribing information for EVOCLtN Foam,
`EVOCLIN® lelindamycin phosphate) Foam; 1%
`For Topical Use
`initial U.S. Approval: 1970
`
`17
`
`14 C~(cid:128)AL STUDIES
`16
`HOW SLiP.D/STORAGE AND HANDLING
`How Supplied
`16.!
`16.2
`Storage and Handling
`PATIENT coLrNsEIANG INFORMATION
`17.1
`Instructions for Use
`Sldu Irritation
`17.2
`17,3
`Colitis
`* Sections or subsections omitted from the full prescribing
`information are not listed
`
`Application silo
`reaction, not
`otherwise specified
`
`3 (1%)
`
`4 (3%)
`
`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`EVOCLtN Foam is=indicated for topical application in the
`treatment of aene vulgaria in patients 12 years and older,
`
`In a canta~ sensitization study, none of the 203 subjects de-
`ycleped evidence of allergic contact sensitization to
`EVOCLIN Foam.
`6,2 Postmarketing Experience
`q~e following adverse reactions have been identified during
`post approval use of EVOCLIN Foam: application site
`pain, application site orythema, diarrhea, urtiem’ia, abdom-
`inal pain, hypersensitivity, rash, abdominal discomfort,
`nausea, eeborrbea, application site rash, dizziness, mad pain
`of skin. Because those reactions ore reported voluntarily
`from a population of uncertain size, it is not always possible
`to reliably estimate their frequency or establish a causal re-
`2 DOSAGE AND ADMINISTRATION
`lationship to drug exposure.
`EVOCLIN Foam is for topical use only, and not fbr oral, oph-
`Abdominal pain and gastrointestinal disturbances, as well
`thalmic, or intravaginal use.
`as gram-negative folfiealitis, have also been reported in ac-
`Apply EVOCLIN Foam ance dafly to affected areas al%ec the
`sectarian with the usa of topical formulations of
`skih is washed with mild soap and allowed to fully dry. Use
`clindamyein. Orally and perenterally administered
`enough to cover the entire affected area.
`clindamycin have been associated with severe colitis, which
`The contents of EVOCLIN Foam are flammable; avoid fire, may end fhtaUy.
`flame and]or smoking during and immediately following ap-
`plication.
`
`DRUG INTERAETIONS
`7
`Erythromycin
`7.1
`3 DOSAGE FORMS AND STRENGTHS
`EVOCIAN Foam should not be used in combination with
`White to off=white thermelabile foam. Each gram of
`topical or oral erythr0mycin-con~ing products due to poll:
`INDICATIONS AND USAGE ~ EVOCLIN Foam contains, as dispensed, 12 mg (1.2%) of sible antagonism to its clindamycin component. In eitro
`EVOCLIN Foam is a lincasamide product indicated for
`clindamycin phosphate, equivalent to 10 mg (1%) ~ff
`acns vnlguris in patients 12 years and older. (1)
`dindamycim
`
`studies have shown antagonism between these two ansimi-
`crsbials. The clinical significance of this in ultra antagonism
`is not known.
`4 CONTRAINDICATIONS
`7.2 Neuromuscular Blosking Agents
`EVOCL~ Foam is contraindicated in individuals with a
`history of regional enteritis or ulcerative colitis, or a history Clmdamyein has been shown to have neuromuscular blsck~
`tag properties that may enhance the action of other neuro-
`of antibiotic-associated colitis,
`muscular blocking agents. Therefore, EVOCLIN Foam
`should be used with caution in pat2enLs receiving such
`agents.
`
`DOSAGE AND ADMINISTRATION
`
`¯ Far topical use only; net ibr oral, ophthalmic, or intravag-
`inal use. (2)
`¯ Apply EVOCLIN Foam once daily to affected areas. (2)
`
`¯ Flammable; avoid firs~ flame and]ar smoking during and
`immediately following application. (2)
`
`DOSAGE FORMS AND STB~NG~S
`1% cllndamycin as clindamycin
`
`Foam containing
`phosphate, (31
`
`CONTRA.INDICATIONS
`
`EVOCLIN Foam is contraindicated in individuals with a
`history efreginsal enteritis er ulcerative colitis, or a histary
`of antibiotic-associated colitis. (4)
`
`5 WARNINGS AND PRECAUTIONS
`5.1
`Colitis
`Systemic absorption of cliedamycin has been demonstrated
`8 USE IN SPECIFIC POPULATIONS
`following topical use of this product. Diarrhea, bloody diar*
`8.1 Pregnancy
`rhea, andcolitisiiacludingpoeudomembranouscolitis)have
`Pregnancy Category B: There are uo adequate and wd~r
`been reported with the use of topical elindamydn. If eignif-
`controlled studies in pregnant women treated with
`leant diarrhea occurs, EVOCL]N Foam shoold be diecontin-
`EVOCLIN F0am..EVOCLJN Foam should be used during
`ned. [See Adverse Reactions (6.21.]
`pregnancy only if the potential benefit Ciearty outweighs the
`Severe coli~ has occurred follmving oral or parenterai ad-
`potential risk to the fetus.
`ministration of clindomycin with an onset of up to several
`Reprnduction s~xallas have been perform’ned in rats and mica
`weeks tbllowing cessation of therapy. Antiparistaltic agents
`using subeutandanS and oral’ doses of cllndainycin
`WARNINGS AND PRE~UTIONS such as npiates and diphenoxytate with atropine may pro-
`phosphate, dindamyein hydrechloride and elindaraycin pal-
`long and]or worsen severe calitis. Severe colitis may result mitate hydrsehloride. These studies revealed no evidence Of
`¯ Colitis: Clindamyc’m can cause severe colitis, which may
`in death,
`result in death. Diarrhea, bloody diarrhea, and colitis (in-
`fetal harm. The highest dose used in the rat and mouse tee-
`Studies indicate a tsxin(s) produced by Clestr~ia is one pri-
`eluding pseudomembranous colitis) have been reported
`atagenieity etudiee was equivalent; to a elindamycm
`with the use of clindamyein. EVOCLIN Foam should be mary cause of antibistic-assoeiatsd colitis. The ca!iris is usu-
`phosphate dose of 432 mgikg. For a ra~, this dose is 84 fold
`ally characterized by severe persistent diarrhea and severe
`discontinued if significant diarrhea occurs, (5.11
`higher, and for a mouse 42 fold higher, than the anticipated
`abdominal cramps and may be associated with the pasesge
`human dose, of clindamyein phosphate from EVOCLIN
`.ADVERSE REACTIONS of blood and mucus. Stool cultures for Clnstridium diffieile" Foam based on a mg]ms comparison.
`and stool assay for C, diffieile toxin may be helpful dingoes-
`The most common adverse reactions (>1%) are headache
`tieally.
`and application site reactions including burning, pruritus,
`5.2 Irritation
`and dryaaess. (6.1)
`EVOCLIN Foam can cause irritation,
`To report SUSPECTED ADVERSE REACTIONS, contact
`Avoid contact of EVOCLIN Foam with eyes. If contact oe:
`Sttefel Laboratories, inc. at 1-888-784-3335 11-S88-STIEFEL)
`curs, rinse eyes thoroughly with water,
`or FDA at 1-800-FDA-1088 or w~.fda.gov/medwatch,
`EVOCLIN Foam shuuld be prescribed with caution in utopia
`Sea 17 for PATIENT COUNSELING INFORMATION
`individuals,
`and ~A-approved patient labeling
`
`Revised: 0712011
`
`6
`
`7
`
`8
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`INDICATIONS AND USAGE
`I
`2
`DOSAGE AND ADMINISTRATION
`3
`DOSAGE FORMS AND STRENGTHS
`4
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5
`5.1 Colitis
`5.2 Irritation
`ADVERSE REACTIONS
`Climcol Trials Experience
`6.1
`6.2
`Posteaarketing Experience
`DRUG LNTERACTIONS
`Erythrsmycin
`7.1
`Neuromuscular Blocking Agents
`7.2
`USE IN SPECIFIC POPULATIONS
`Pregnaocy
`8,1
`Nursing Mothers
`8.3
`Fediatric Use
`8,4
`8.5
`Geriattic Use
`DESCRIPTION
`11
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2
`Pharmacodv’anmics
`Pharmacokinetics
`12.3
`h~[icrsbiology
`I2.4
`13 NONCLINICAL TOXICOLOGY
`Carcinogenesis, Mutagenesis, Impairment
`13.1
`of Fertility
`
`8.3 Nursing Mothers
`It is not known whether clindamycin is excreted in haman
`milk following use of EVOCLh’~ Foam. However, orally and
`parenterally adminietered ellndamyrin has been reported to
`appear in breast milk. Because of the potential for serious
`adverse reactions in nursing infants, a decision should be
`made whether to discontinue nursing or to discontinue the
`drug, taking into account the importance of the drug m the
`mother.
`6
`ADVERSE REACTIONS
`6.1
`Clinical Trials F.xperiense
`Lr used during lactation and EVOCLIN Foam is applied to
`the cheat, emre shonld be taken