PDR®
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`EDITION
`
`2012
`
`PHYS CANS'
`DESK
`REFERENCE@
`
`CEO: Edward Fotsch, MD
`President: Richard C. Altus
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`
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`
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`Senior Director, Operations & Client Services: Stephanie Struble
`Director, Cllnlcal Services: Sylvia Nashed, PharmD
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`Client Services Manager: Kathleen O'Brien
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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
`reproduced, stored in a retrieval system, resold, redistributed, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise)
`without the prior written permission of the publisher. Physicians' Desk Reference® and PDR"' are registered trademarks of PDR Network, LLC. PDR® for Ophthalmic Medicines;
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`
`ISBN: 978-1-56363·800-B
`
`1 of 4
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`Almirall EXHIBIT 2040
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`IPR2019-00207
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`

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`
`DUAC • STIEFEL/2765
`
`Table 9. Summary of Efficacy Data•
`
`Study 1
`
`Study 2
`
`Zevalin
`therapeutic regimen
`N = 54
`
`Zevalin
`therapeutic regimen
`N:64
`
`Overall' Response Rate (.% )'
`
`Complete Response Ratel(%)
`
`Median DR',1
`(Months)
`[Rangel]
`
`Median TTPl,'(Months)
`[Rangel]
`
`74
`
`15
`
`6.4
`(0.5-49.9+]
`
`6.8
`[l.1-50.9+]
`
`83
`
`38
`
`14.3
`(1.8-4 7 .6+ J
`
`12.1
`(2.1-49.0+]
`
`* IWRC: International Workshop Response Criteria
`t CRu and CR: Unconfirm~d and confirm complete response
`i Estima.ted with observed range
`.
`,
`§ Duration of resp9nse: interval from the onset o{ response to disease progression
`~ "+" indicates an ongoing response
`# Time. to Disea.se Progression; interval from the fir~t infusion to disf!a.s.e progression
`
`Rituximab
`N :66
`
`55
`
`18
`
`11.5
`(1.2-49.7+]
`
`10.1
`[0.7-51.3+]
`
`men (83% vs. 55%,' p<0.001). Time-to 0disease-progression
`was not significantly different between study arms. Table 9
`summarizes ·efficacy data from Study 2.
`[See table 9 aliove]
`·
`Study 3 was a single arm study of 30 patients of whom 27
`had relapsed dr refractory low-grade, follicular NHI.i ind a
`platelet count 100,000 to 149,000/min3. Patients with;,, 25%
`lymphomatous marrow involvement, prior myeloablative
`therapy with stem cell support, prior external beam radia(cid:173)
`tion to > 25% of active marrow o·r neutrophil count
`<l,500/mma. were ineligible for Study 3. All patients re(cid:173)
`ceived Y-90 Zevalin [0.3 mCi per kg (11.1 MBq per kg)]. ObL
`jective, durable clinical responses were observed [89% ORR
`(95% CI: 70-97%) with a median duration of response of 11.6
`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 study
`conducted in patients with follicular· NHli with a partial
`(PR) or complete response (CR/CRu) upon completion of
`first-line chemotherapy: Randomization was stratified, by
`center ·and response to·first-line therapy (CR or PR). Key
`eligibility criteria were <25% bone marrow involvement; no
`prior external beam radiation or myeloablative therapy, and
`recovery of platelets to normal levels. Patients were ran•
`domized· to· receive Zevalin (n=208). or no further therapy
`(n=206). Y-90 Zevalin was administerecl. at least 6 weeks.but
`no more than,12 weeks following, the last dose of chemother,
`apy. The main efficacy outcome measure was, progressioµ,
`free survival (PFSJ assessed by study investigators using
`the International Workshop to Standardize Response Crite(cid:173)
`ria for non-Hodgkin's Lymphoma (1999) ..
`Among the 414 patients, 49% were male, 99% were Cauca·
`sian, 12% were ;,,65 years old, 83% had a WHO performance
`status of 0, and 65% had .Stage, IV disease. Thirty-nine
`(9.5%) patients received single agent chlorambucil, 22 (5%)
`patients received fludarabine or. a flud!U'abine-containing
`regimen, 294 (71 %) patients received cyclophosphamfde'
`containing· combination chemotnerapy [CHOP, (31%);
`CHOP-like (15%); CVP/COP (26%)] and 59 (14%) patients
`received rituximab-containing combination chemotherapy
`as first-line treatment.
`Progression-free survival was significantly prolonged
`among Zevalin-treated patients compared to those receiving
`no further treatment [median PFS 38 months vs. 18
`months; HR 0.46 (95% CI: 0.35, 0.60) p<0.0001 Cox model
`stratified by response to first-line therapy and initial treat·
`ment strategy.(immediate vs. watch-and-wait)]. Thenum,
`her of patients who died.was too small to permit a reliable
`·
`·
`comparison on survival.:
`The results for PFS are presented in Figure 1.
`[See figure 1 at top of next column]
`16
`HOW SUPPLIED/STORAGE AND HANDLING
`There are two kits necessary for preparation of the Zevalin
`therapeutic regimen: one for preparation of In-111 radiola(cid:173)
`beled Zevalin (NDC 68152-104-04) and one for preparation
`of Y-90 radiolabeled Zevalin (NDC 68152-103-03) .. The con,
`tents of all vials are sterile, pyrogen-free, contain no preser(cid:173)
`vatives, and are not radioactive. Each kit contains four
`identification labels and the following four vials:
`·
`1. One (1) Zevalin vial containing 3.2 mg ibritumomab
`tiuxetan in 2 mL 0.9% Sodium Chloride as a clear, color(cid:173)
`less solution.
`2. One (1) 50 mM Sodium Acetate Vial containing 13.6 mg
`Sodium Acetate trihydrate in 2 mL Water for Injection,
`USP as a clear, colorless solution.
`
`Figure 1. Study 4: Kaplan-Meler Estimator for Investigator(cid:173)
`Assessed Progression Free Survival Time
`l"1•=•~----~~--~-----~---
`E
`!I .. ".
`0 j ?~
`£1,60
`al"'
`:go.so
`
`S 80
`
`DD D ·coi,/rol
`e e e Z&valin
`
`¥2 40 130
`
`E 20
`~ 10 ConllOf:20fJ
`t
`143~ 116
`90,
`74
`38
`23
`0
`13 1 6
`~O~b-,~~,~~r'~M~·~mr·~1M~,m~rnr .. r'~'~~~r"~~'=rl'
`00 ~ n
`1~. ~ ® ~ ~ ~ M
`6
`12
`' PFS Time from Randomization (Months)
`
`3. One (1) Formulation Buffer Vial conta.ining. 750 mg
`Albumin (Human), 76 mg Sodium Chloride, 28 mg
`Sodium Phosphate Dibasic Dodecahydrate, 4 mg Pentetic
`Acid, 2 mg Potassium Phosphate Monobasic and 2 mg Po:
`tassium Chloride in 10 mL Water for Injection; pH 7.1 as
`a clear yellow to amber colored soltition,
`4. One (1) empty Reactioi} Vial:
`Indium-111 Chloride Sterile Solution (In-111 Chloride) must
`be, ordered separately from. either GE Healthcare, or
`Mallinckrodt/Covidien ..
`Yttrium-90 .Chloride Sterile. Solution. is shipped directly
`from the supplier upon placement of an order for the· Y-90
`Zevalin kit.
`,
`. ,
`,
`.
`.
`.
`Rituximab (Rituxan®, Biogen Idec. and Genentech. USA)
`must be. ordered separately,
`Storage
`. .
`· ·
`'
`Store kits at 2-8°C (36-46"F). Do not freeze.
`17
`PATIENT COUNSELING INFORMATION
`Advise patients:
`• 'lb contact a healthcare professional for severe signs and
`symptoms of infusion reactions.
`• 'lb take premedications as prescribed [see Dosage and Ad(cid:173)
`ministration (2.2) and Warnings and Precautions (5.1)].
`• 'lb report any signs or symptoms of cytopenias (bleeding,
`easy bruising, petechiae or purpura, pallor; weakness cir
`fatigue).
`• 'lb avoid medications that interfere with platelet function,
`except as directed by· a healthcare professlonal [see Warn(cid:173)
`ings and Precautions (5.2)].
`• 'lb seek prompt medical evaluation for diffuse rash, bulfae,
`or desquamation of the skin or oral mucosa;
`• 'lb immediately report symptoms of infection (e.g. pyrexia)
`[see Adverse Reactions (6.3)].
`• That immunization with live viral vaccines is not recom(cid:173)
`mended for 12 months following the Zevalin therapeutic
`regimen [see Warnings and Precautions (5.8)].
`• 'lb use effective contraceptive methods during treatment
`and for a minimum of 12 months following Zevalin ther(cid:173)
`apy.
`• 'lb discontinue nursing during and after Zevalin treatment
`[see Use In Special Populations (8.3)].
`© 2009 Spectrum Pharmaceuticals, Inc.
`Irvine, CA 92618
`U.S. License No. 1832
`Protected by U.S. Patent Nos. 5,736,137, 5,776,456,
`5,843,439, 6,207,858, 6,399,061, 6,682,734, 6,994,840,
`7,229,620, 7,381,560; 7,422,739 and other patents and pat(cid:173)
`ents pending.
`
`Stiefel Laboratories, Inc.
`Research Triangle Park, NC 27709
`
`Direct Inquiries to:
`Professional Services Department
`1-888-STIEFEL (1-888-784-3335)
`
`DUAC®
`[du-akl
`(clindamycin phosphate, 1 % - benzoyl peroxide, 5%)
`Topical Gel
`'
`For Derm.atological Use Only.
`Not for Ophthalmic Use.
`Rx Only
`
`~
`
`DESCRIPTION
`Duac® Topical Gel contains clindamycin phosphate, (7(8)(cid:173)
`chloro-7-deoxylincomycin-2-phosphate), equivalent to 1%
`clindamycin, and 5% benzoyl peroxide.
`·
`Clindamycin phosphate is a water soluble, ester of the semi(cid:173)
`synthetic antibiotic produced by a 7(8)-chloro-substitution
`of the 7(R)-hydroxyl group of the parent antibiotic lincomy~
`cin~
`Clindamycin phosphate is C18H34CIN20 8PS. The structural
`formula for clindamycin phosphate is represented below:
`
`Clindaniycin phosphate has a molecular weight of 504.97
`and its chemical name is methyl 7-chloro-6,7,8-trideoxy-6,
`(1-methyl-traris-4-propyl-L-2-pyrrolidinecarboxamido)-l(cid:173)
`thio-L-threo-a-D-galacto-octopyranoside
`2-(dihydrogeri
`phosphate).
`Benzoyl peroxide is C14H 100 4i It has the following struc:
`tural formula:
`-
`
`Benzoyl peroxide has a molecular weight of 242.23.
`Each gram of Duac® Topical Gel contains 10 mg '(1 %)
`elindamycin, as phosphate, and 50 mg (5%)
`lienzoyl
`peroxide in a base consisting, of. carbomer homopolymer
`(type C), dimethicone, disodium lauryl sulfosuccinate, ede(cid:173)
`tate disodium, glycerin, methylpara!Je'.1, poloxamer 182, pu:
`rifled water, silicon dioxicl.e, and sodiu1;;\ hydroxide.
`CLINICAL PHARMACOLOGY ,
`A comparative study of the pharmacokinetics of Duac® Top(cid:173)
`ical Gel and 1 % clindamycin solution alone in 78 patients
`indicated that mean plasma clindamypin levels during the
`four week,~osing period were 1 0.5 ng/ml for both tr~atment
`groups,, · ·
`·
`. , . ·.
`Benzoyl peroxide has been sho.wn to be ab~orbed by t~e skin
`where it is converted to benzoic acid. Less than 2% of the
`dose enters systemic circulation as benioic acid,
`Microbiology
`·
`Mechanism of Action
`Clindamycin binds to tl1e ·508 ribosomal subunits ofsuscep,
`tible bacteria- and prevents elongation· of peptide chains by
`interfering with peptidyl transfer; thereby suppressing prof
`tein synthesis·.
`Benzoyl peroxidfr is a potent oxidizing agent.
`In Vivo Activity
`No microbiology studies were conducted in the clinical trials
`with this product.
`In Vitro Activity
`The clindamycin and benzoyl peroxide components individ,
`ually have been shown to have in vitro activity against Pro,
`pionibacterium acnes, an: organism which. has been assoch
`ated with acne vulgaris; however, the clinical significance of
`this is not known.
`Drug Resistance
`There are reports of an increase of P.: acnes resistance to
`clindamycin in: the treatment of acne. In patients with P.
`acnes resistant to clindamycin,,the clindamycin component
`may provide no additional benefit beyond benzoyl peroxide
`alone.
`
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`
`2 of 4
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`

`

`2766/STIEFEL • DUAC
`
`FIND PATIENT SUPPORT RESOURCES at PDR.het
`
`Mean percent reduction in inflammatory lesion counts
`
`Study 1
`(n:120)
`
`Study 2
`(n:273)
`
`Study 3
`(n=280)
`
`Study 4
`(n=2BB)
`
`Study 5
`(n:358)
`
`Duac® Topical Gel
`
`Benzoyl Peroxide
`
`Clindamycin
`
`Vehicle
`
`65%
`
`36%
`
`34%
`
`19%
`
`56%
`
`37%
`
`30%
`
`-0.4%
`
`.
`
`42%
`
`32%
`
`38%
`
`29%
`
`57%
`
`57%
`
`49%
`
`52%
`
`41%
`
`33%
`
`29%
`
`Local reactions with use of Duac" Topical Gel o/o of patients using Duac" Topical Gel with symptom present Combined
`results from 5 studies (n:397)
`
`Before Treatment (Baseline)
`
`During Treatment
`
`Mild
`
`28%.
`
`6%
`
`3%
`
`6%
`
`Moderate
`
`Severe
`
`3%
`
`<1%
`
`<1%
`
`<1%
`
`0
`
`0
`
`0
`
`0
`
`Mild
`
`26%
`
`17%
`
`5o/r
`
`15%
`
`Moderate
`
`Severe
`
`5%
`
`2%
`
`<1%
`
`1%
`
`'
`
`0
`
`0
`
`0
`
`0
`
`Erythema
`
`Peeling
`
`Burning
`
`Dryness
`
`CLINICAL STUDIBS
`In five randomized, double-blind clinical studies of 1,319 pa(cid:173)
`tients, 397 used Duac® Topical Gel, 396 used benzoyl
`peroxide, 349 used clindamycin and 177 used vehicle. Duac®
`Topical Gel applied once daily for 11 weeks was significantly
`more effective than vehicle, benzoyl peroxide, and
`clindamycin in the treatment of inflammatory lesions of
`moderate to moderately severe facial acne vulgaris in three
`of the five studies (Studies 1, 2, and 5).
`Patients were evaluated and acne lesions counted at each
`clinical visit: weeks 2, 5, 8, 11. The primary efficacy mea(cid:173)
`sures were the lesion counts and the investigator's global
`assessment evaluated at week ll. Patients were instructed
`to wash. the face, wait 10 to 20 minutes, and then apply
`medication to the entire face, once daily, in the evening be(cid:173)
`fore retiring. Percent reductions in inflammatory lesion
`counts after treatment for 11 weeks in these five studies are
`shown in the following table:
`[See first table above]
`The Duac® Topical Gel group showed greater overall im(cid:173)
`provement in the investigator's global assessment than the
`benzoyl peroxide, clindamycin and vehicle groups in three of
`the five studies (Studies 1, 2, and 5).
`Clinical studies have not adequately demonstrated the ef(cid:173)
`fectiveness of Duac® Topical Gel versus benzoyl peroxide
`alone in the treatment of non-inflammatory lesions of acne.
`INDICATIONS AND USAGE
`Duac® Topical Gel is indicated for the topical treatment of
`inflammatory acne vulgaris.
`Duac® Topical Gel has not been demonstrated to have any
`additional benefit when compared to benzoyl peroxide alone
`in the same vehicle when used for the treatment of non(cid:173)
`inflammatory acne.
`CONTRAINDICATIONS
`Duac® Topical Gel is contraindicated in those individuals
`who have shown hypersensitivity to any of its components
`or to lincomycin. It is also contraindicated in those having a
`history of regional enteritis, ulcerative colitis, pseudomem(cid:173)
`branous colitis, or antibiotic-associated colitis.
`WARNINGS
`ADMINISTERED
`PARENTERALLY
`ORALLY
`· AND
`CLINDAMYCIN HAS BEEN ASSOCIATED WITH SEVERE CO·
`LITIS WHICH MAY RESULT IN PATIENT DEATH. USE OF THE
`TOPICAL FORMULATION OF CLINDAMYCIN RESULTS IN
`ABSORPTION OF THE ANTIBIOTIC FROM THE SKIN SUR'
`FACE. DIARRHEA, BLOODY DIARRHEA, AND COLITIS UN·
`CLUDING PSEUDOMEMBRANOUS COLITIS) HAVE BEEN
`REPORTED WITH THE USE OF TOPICAL AND SYSTEMIC
`CLINDAMYCIN. STUDIES INDICATE A TOXIN(S) PRO(cid:173)
`DUCED BY CLOSTRIDIA IS ONE PRIMARY CAUSE OF
`ANTIBIOTIC-ASSOCIATED COLITIS, THE COLITIS IS USU(cid:173)
`ALLY CHARACTERIZED BY SEVERE PERSISTENT DIAR·
`RHEA AND SEVERE ABDOMINAL CRAMPS AND MAY BE
`ASSOCIATED WITH THE PASSAGE OF BLOOD AND· MU·
`CUS. ENDOSCOPIC EXAMINATION MAY REVEAL PSEUDO·
`MEMBRANOUS COLITIS. STOOL CULTURE FOR C/ostrld•
`/um difflcl/e AND STOOL ASSAY FOR C/ostrldlum dlfflc//11
`TOXIN MAY BE HELPFUL DIAGNOSTICALLY. WHEN SIG•
`NIFICANT DIARRHEA OCCURS, THE DRUG SHOULD BE
`DISCONTINUED. LARGE BOWEL ENDOSCOPY SHOULD BE
`
`CONSIDERED TO ESTABLISH A DEFINITIVE DIAGNOSIS IN
`CASES OF SEVERE DIARRHEA. ANTIPERISTALTIC AGENTS
`SUCH AS OPIATES AND DIPHENOXYLATE WITH ATROPINE
`MAY PROLONG AND/OR WORSEN THE CONDITION. DIAR·
`RHEA, COLITIS AND l"SEUDOMEMBRANOUS COLITIS
`HAVE BEEN OBSERVED TO BEGIN UP TO SEVERAL
`WEEKS FOLLOWING CESSATION OF ORAL AND PAREN(cid:173)
`TERAL THERAPY WITH CLINDAMYCIN.
`Mild cases of pseudomembranous colitis usually respond to
`drug discontinuation alone. In moderate to severe- cases,
`consideration should be given to management with fluids
`and electrolytes, protein supplementation an.d treatment
`with an antibacterial drug clinically effective against Clos(cid:173)
`tridium difficile colitis.
`PRECAUTl9NS
`Genera(
`.
`. .
`.
`For dermatologicaj 11se only; not for. ophthalmic. use, Con(cid:173)
`comitant topical acne therapy should be used with caution
`because a possible cumulative irritancy effect may occur, es(cid:173)
`pecially with the use of peeling, desquamating, or abrasive
`agents.
`The use of antibiotic agents may be associated with the
`overgrowth of nonsusceptible organisms, including fungi. If
`this occurs, discontinue use of this medication and take ap(cid:173)
`propriate measures.
`Avoid contact with eyes and mucous membranes.
`Clindamycin and erythromycin containing prddu~ts should
`not be used in combination. In vitro studies have shown an!
`tagonism between these two antimicrobials. The clinical sig(cid:173)
`·
`nificance of this in vitro antagonism is not known.
`Information for Patients
`Patients using Duac® Topical Gel should receive the fo.llow.
`ing information and instructions.: -
`.
`.
`.,
`1. Duac® 'lbpical Gel is to be used as directed by the physi(cid:173)
`cian. It is for external use only. Avoid contact with eyes,
`and inside the nose, mouth, and all mucous membranes,
`as this product may be irritating.
`2. This medication should not be used for any disorder other
`than that for which it was prescribed.
`3. Patients should not use any other topical acne prepara(cid:173)
`tion unless otherwise directed by their physician.
`4. Patients should report any signs of local adverse reac(cid:173)
`tions. to their physician. J?atients )Vho develop !l,llergic
`symptoms such as sevJ!re .swelling or shortness_ of breath
`should discontinue use and contact their physician i.mme-
`diatei,
`: ·-
`. .,
`5. Puac Topical Gel, may bleach hair or, colored f!lbric,., · .
`6. Duac~ Topical Gel can pe stored 11,t room temperature up
`to 25'C (77~F) for up to 2 months. Do not freeze.- Keep
`tuqe tightly closed •. Keep out of the reach of small chi!,
`,
`dren. Djscarc! any unused product after 2 months.
`7. Before applying Duac® Topical Gel to affected areas, wash
`the akin gently, rinse with warm water, and. pat dry.
`8. Excessive or prolonged exposure to sunlight should be
`limited. To minimize exposure to sunlight, a hat or other
`clothing should be worn.
`Carcinogenesis, Mutagenasls, Impairment of Fertlllty(cid:173)
`Bertzoyl peroxide has been shown to be a tumor promoter
`and progression agent in a number of animal studies.
`Benzoyl peroxide in· acetone at doses of 5 and 10 mg admin(cid:173)
`istered twice per week induced squamous cell akin tumors
`
`in transgenic TgAC mice in a study using 20 weeks of topi(cid:173)
`cal treatment. The clinical significance of this is unknown.
`In a 2-year dermal cercinogenicity study in mice, treatment
`with Duac® Topical Gel at doses up to 8000 mg/kg/day (16
`times the highest recommended adult human dose of 2.5 g
`Duac® Topical· Gel, based on mg/m2) did not cause an in(cid:173)
`crease in skin tumors. However, topical treatment with an(cid:173)
`other formulation containing 1 % clindamycin- and 5%
`benzoyl peroxide at doses of 100, 500, or 2000 mg/kg/day
`caused a dose-dependent increase in the incidence of kera(cid:173)
`toacanthoma at the treated skin site of male rats in a 2-year
`dermal carinogenicity study in rats.
`In a 52-week photocarcinogenicity study in hairless mice
`( 40 weeks of treatment followed by 12 weeks of observa(cid:173)
`tion), the ·median time to onset of skin tumor formation de(cid:173)
`creased and the number of tumors per mouse increased rel(cid:173)
`ative to controls following chronic concurrent topical
`treatment with Duac® Topical Gel and exposure to ultravi(cid:173)
`olet radiation.
`Genotoxicity studies were not conducted with Duac® Topical
`Gel. Cliridamycin phosphate was not genotoxic in Salmo·
`nella typhimurium or in a rat· micronucleus test. Benzoyl
`peroxide has been found to cause DNA strand breaks in a
`variety of mammalian cell types, tb be mutagenic in Salnio'
`nella typhimurium tests by some but not all investigators,
`and to· cause sister chromatid exchanges in Chinese ham(cid:173)
`ster ovary cells.
`Studies have not been performed with Duac® Topical Gel or
`benzoyl peroxide, to evaluate the effect on fertility. Fertility
`studies in rats treated orally with up to 300 mg/kg/day of
`clindamycin (approximately 120 times the amount of
`clindamycin in the highest recomm.ended adult.human dose
`of 2.5 g Duac® Topical Gel, based on mg/m2) revealed no ef(cid:173)
`fects on fertility or mating ability;
`Pregnancy
`Teratogenic Effects
`Pregnancy Category C
`Animal reprodu.ction studies have not been conducted with
`Duac® Topical Gel or benzoyl peroxide. It is also not known
`whether Duac® Topical. Gel can cause fetal harm when ad(cid:173)
`ministered to a pregnant woman or can affect. reproduction
`capacity. Duac® Topical Gel should be given to,a pregnant
`woman only. if clearly needed:
`Developmental toxicity studies performed in rats and mice
`using oral doses of clindamycin up to 600 mg/kg/day (240
`and 120 times the amount of clindamycin in the highest rec,
`ommended adult human dosebased,on mg/m2, respectively)
`or subcutaneous doses of clindamycin up to 250 mg/kg/day
`(100 and 50 times the amount of clindamycin in the highest
`recommended adult human dose based on mg/m2, respec(cid:173)
`tively) revealed no evidence of teratogenicity.
`Nursing Women
`It is not known whether Duac® 'Topical Gel is secreted into
`human milk aften topical application. However, o·rally and
`parenterally administered clindamycin has been reported to
`appear·in breast milki 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 to the
`mother.
`Pediatric Use
`Safety and effectiveness of this product in pediatric patients
`below the· age of 12 have not been established;
`ADVERSE REACTIONS
`During clinical trials, all patients were graded for facial er(cid:173)
`ythema, peeling, burning, and, dryness on the following
`scale: 0 = absent, 1 = mild, 2 = moderate, and 3 = severe.
`The percentage of patients that had symptoms present be(cid:173)
`fore treatment (at baseline) and during treatment were as
`follows:
`[See second table above J'
`(Percentages derived by # subjects with symptom score/ii
`enrolled Duac® Topical Gel subjects, n = 397).
`Anaphylaxia, as well as allergic reactions leading to hospi(cid:173)
`talization, has been reported in post-marketing usei·with
`Duac® Topical Gel. Because these reactions are reported vol(cid:173)
`untarily from a population of uncertain size, it is not always
`possible to reliably estimate their frequency or establish a
`cau~al relations!¥p to ~ flrug .expqs!ll'.e, ·
`DOSAQE AND ADMINISTRATION
`Dunc® Topical Gel should be applied once daily, in the· eve(cid:173)
`ning or as directed by the physician, to affected-areas after
`the akin is gently washed, rinsed with warm·water and pat(cid:173)
`ted dry.
`HOW SUPPLIED
`Duac® (clindamycin, 1 % • benzo;J -perdxide, 5%) Topical Gel
`is available in:
`NDC 0145-2371-05
`• 45 gram tube
`Prior to Dispensing: Store in a cold place, preferably in a
`refrigerator, between 2'C and S'C (36'F and 46'F). Do not
`freeze.
`
`FREE CME AND LIABILITY REDUCTION SERVICES at PDR.net
`
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`REPORT SUSPECTED ADVERSE DRUG EVENTS NOW at RxEvent.org
`
`Dispensing Instructions for the Pharmacist: Dispense
`Duac® Topical Gel with a 60 day expiration date and specify
`"Store at room temperature up to 25'C (77'F). Do not
`freeze."
`Keep tube tightly closed. Keep out of the reach of small chil(cid:173)
`dren.
`©2010 Stiefel Laboratories, Inc.
`Stiefel Laboratories, Inc.
`Research Triangle Park, NC 27709
`DUA:3PI
`Rev. February 2011
`DUAC is a registered trademark of Stiefel Laboratories,
`Inc.
`
`EVOCLIN""
`[e-vii-klrn]
`(clindamycin phosphate) Foam, 1%
`For Topical Us~
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed
`to use EVOCLIN Foam safely and effectively. See full pre-
`scribing information for EVOCLIN Foam.
`.
`·
`EVOCLIN9 (clindamycin phosphate) Foam; 1%
`For Topical Use
`Initial U.S. Approval: 1970
`
`INDICATIONS AND USAGE
`EVOCLIN Foam is a lincosamide product indicated for
`acne vulgaris in patients 12 years and older. (1)
`- - - DOSAGE AND ADMINISTRATION - - -
`• For topical use only; not for oral, ophthalmic, or intravag(cid:173)
`inal use. (2)
`• Apply EVOCLIN Foam once daily to affected areas. (2)
`• Flammable; avoid fire, flame and/or smoking during and
`immediately following application. (2)
`
`- - DOSAGEFORMSANDSTRENGTHS ~ (cid:173)
`Foam containing 1 % clindamycin as clindamycin
`phosphate. (3)
`
`CONTRAINDICATIONS----(cid:173)
`EVOCLIN Foam is contraindicated in individuals with a
`history ofregional enteritis or ulcerative colitis, or a history
`of antibiotic-associated colitis. (4)
`
`- - - WARNINGS AND PRECAUTIONS - - -
`• Colitis: Clindamycin can cause severe colitis, which may
`result in death. Diarrhea, bloody diarrhea, and colitis (in(cid:173)
`cluding pseudomembranous colitis) have been reported
`with the use of clindamycin. EVOCLIN Foam should be
`discontinued if significant diarrhea occurs. (5.1)
`
`ADVERSE REACTIONS•----(cid:173)
`The most common adverse reactions (>1 %) are headache
`and application site reactions including burning, pruritus,
`and dryness. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact
`Stiefel Laboratories, Inc. at 1-888-784-3335 (1-888-STIEFEL)
`or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`See 17 for PATIENT COUNSELING INFORMATION
`and FDA-approved patient labeling
`
`Revised: 07 /2011
`
`6
`
`7
`
`8
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`INDICATIONS AND USAGE
`1
`2
`DOSAGE AND ADMINISTRATION
`3
`DOSAGEFORMSANDSTRENGTHS
`4
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5
`5.1
`Colitis
`5.2
`Irritation
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`DRUG INTERACTIONS
`7 .1
`Erythromycin
`7.2
`Neuromuscular Blocking Agents
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`12.4 Microbiology
`NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment
`of Fertility
`
`11
`12
`
`13
`
`17
`
`14
`16
`
`CLINICAL STUDIES
`HOW SUPPLIED/STORAGE AND HANDLING
`16.1
`How Supplied
`16.2
`Storage and Handling
`PATIENT COUNSELING INFORMATION
`17 .1
`Instructions for Use
`17.2
`Skin Irritation
`17.3
`Colitis
`* Sections or subsections omitted from the full prescribing
`information are not listed
`
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`EVOCLIN Foam is• indicated for topical application in the
`treatment of acne vulgaris in patients 12 years and older.
`2
`DOSAGE AND ADMINISTRATION
`EVOCLIN Foam is for topical use only, and not for oral, oph(cid:173)
`thalmic, or intravaginal use.
`Apply EVOCLIN Foam once daily to affected areas after the
`skin is washed with mild soap and allowed to fully dry. Use
`enough to cover the entire affected area.
`The contents of EVOCLIN Foam are flammable; avoid fire,
`flame and/or smoking during and immediately following ap(cid:173)
`plication.
`3
`DOSAGEFORMSANDSTRENGTHS
`White to off-white thermolabile foam. Each gram of
`EVOCLIN Foam contains, as dispensed, 12 mg (1.2%) of
`clindamycin phosphate, equivalent to 10 mg (1 %) of
`clindamycin.
`4
`CONTR.Ai:NDICATIONS
`EVOCLIN Foam is contraindicated in individuals with a
`history ofregional enteritis or ulcerative colitis, or a history
`of antibiotic-associated colitis.
`5 WARNINGS AND PRECAUTIONS
`5.1
`Colitis
`Systemic absorption of ~lindaniycin has been demonstrated
`following topical use of this product. Diarrhea, bloody diar(cid:173)
`rhea, and colitis (including pseudomembranous colitis) have
`been reported with the use of topical clindamycin. If signif(cid:173)
`icant diarrhea occurs, EVOCLIN Foam should be discontin(cid:173)
`ued. [See Aduerse Reactions (6.2).)
`Severe colitis has occurred following.oral or parenteral ad(cid:173)
`ministration of clindamycin with an onset of up to several
`weeks following cessation of therapy. Antiperistaltic agents
`such as opiates and diphenoxylate with atropine may pro(cid:173)
`long and/or worsen severe colitis. Severe colitis may result
`in death.
`Studies indicate a toxin(s) produced by Clostridia is one pri,
`mary cause of antibiotic-associated colitis. The colitis is usu(cid:173)
`ally characterized by severe persistent diarrhea and severe
`abdominal cramps and may be associated with the passage
`of blood and mucus. Stool cultures for Clostridium diffecile·
`and stool assay for C. diffecile toxin may be helpful diagnos(cid:173)
`tically.
`Irritation
`5.2
`EVOCLIN Foam can cause irritation.
`Avoid contact of EVOCLIN Foam with eyes. If contact oc:
`curs, rinse eyes thoroughly with water.
`EVOCLIN Foam should be prescribed with caution in atopic
`individuals.
`6
`ADVERSE REACTIONS
`6.1
`Clin.ical Trials Experience
`Because clinical trials are conducted under widely varying
`conditions, adverse reaction rates observed in tbe clinical
`trials of a drug cannot be directly compared to rates in the
`clinical trials of another drug and may not reflect the rates
`observed in clinical practice.
`A total of 439 subjects with mild to moderate acne vulgaris
`were treated once daily for 12 weeks with EVOCLIN Foam.
`The incidence of adverse reactions occurring in <!l % of the
`subjects in clinical trials comp¢ng EVOCLIN Foam, ang.
`its vehicle is presented in Table 1.
`Tabla 1: Adverse Reactions Occurring ln·<!1o/o of SubJects
`
`Adverse Reactions
`
`Number (o/o) of SubJects ,
`
`/
`
`EVOCLIN Foam
`N = 439
`
`Vehicle Foa'1'1 ..
`N = 154
`
`12 (3%)
`
`27 (6%)
`
`1 (1%)
`
`14(9%)
`
`5 (1%)
`
`5 (3%)
`
`4(1%)
`
`5(3%)
`
`Headache
`
`Application site
`burning
`
`Application site
`pruritus
`
`Application site
`dryness
`
`Application site
`reaction, not
`otherwise specified
`
`3 (1%)
`
`EVOCLIN • STIEFEL/2767
`I
`
`4 (3%)
`
`I
`
`d
`
`,,,
`
`In a contact sensitization study, none of the 203 subjects de(cid:173)
`veloped evidence of allergic contact sensitization to
`EVOCLIN Foam.
`6.2
`Postmarketing Experience
`The following adverse reactions have been identified during
`post approval use of EVOCLIN Foam: application site
`pain, application site erythema, diarrhea, urticaria, abdom(cid:173)
`inal pain, hypersensitivity, rash, abdominal discomfort,
`nausea, seborrhea, application site rash, dizziness, and pain
`of skin. Because these reactions are reported voluntarily
`from a population of.uncertain size, it is not always possible
`to reliably estimate their frequency or establish a causal re(cid:173)
`lationship to drug exposure.
`Abdominal pain and gastrointestinal disturbances, as well
`as gram-negative folliculitis, have also been reported in as(cid:173)
`sociation with the use of topical formulations of
`clindamycin. Orally and parenterally administered
`clindamycin have been associated with severe colitis, which
`may end fatally.
`7
`DRUG INTERACTIONS
`7 .1
`Erythromycin
`EVOCLIN Foam should not be used in combination with
`topical or oral erythromycin-containing products due to pm!'
`sible antagonism to its clindamycin component. In uitro
`studies have shown antagonism between these two an