PDR®
`5
`2011
`
`EDITION
`
`PHYS CANS'
`DESK
`REFERENCE®
`
`CEO: Edward Fotsch, MD
`President: David Tanzer
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`
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`
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`
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`
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`
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`
`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 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: 978-1-56363-780-3
`
`1 of 4
`
`Almirall EXHIBIT 2039
`
`Amneal v. Almirall
`IPR2019-00207
`
`

`

`Complimentary CME for PDR-listed products at PDR.net
`
`BENZACLIN • SANOFI-AVENTIS/2967
`
`Chemically, clindamycin phosphate is (C 18H34C!N20 8PS).
`The structural formula for clindamycin is represented
`below:
`
`Debossing
`
`Bottle of 30
`
`Bottle of 90
`
`Bottle of 500
`
`Blister of 100
`
`75mg
`
`2771
`
`0087-2771-31
`
`0087-2771-32
`
`150mg
`
`2772
`
`0087-2772-31
`
`0087-2772-32
`
`0087-2772-15
`
`0087-2772-35
`
`300mg
`
`2773
`
`0087-2773-31
`
`0087-2773-32
`
`0087-2773-15
`
`"
`
`s
`
`In addition, the following potentially important events
`occurred in less than 1 % of the 1965 patients and at least 5
`patients (0.3%) receiving irbesartan in clinical studies, and
`those less frequent, clinically significant events (listed by
`body system). It cannot be determined whether these events
`were causally related to irbesartan:
`fever, chills, facial edema, upper extrem(cid:173)
`Body as a Whole:
`ity edema
`flushing, hypertension, cardiac murmur,
`Cardiovascular:
`myocardial infarction, angina pectoris, arrhythmic/conduc(cid:173)
`tion disorder, cardio-respiratory arrest, heart failure, hyper(cid:173)
`tensive crisis
`Dermatologic: pruritus, dermatitis, ecchymosis, erythema
`face, urticaria
`Endocrine/ Metabolic/ Electrolyte Imbalances: sexual dys(cid:173)
`function, libido change, gout
`·
`Gastrointestinal: constipation, oral lesion, gastroenteritis,
`,
`flatulence, abdominal distention
`Musculoskeletal/ Connective Tissue: extremity swelling,
`muscle cramp, arthritis, muscle ache, musculoskeletal chest
`·
`pain, joint stiffness, bursitis, muscle weakness
`Nervous System: sleep disturbance, numbness, somno(cid:173)
`lence, emotional disturbance, depression, paresthesia,
`tremor, transient ischemic attack, cerebrovascular accident
`Renal I Genitourinary: abnormal urination, prostate
`disorder
`Respiratory: epistaxis, tracheobronchitis, congestion, pul(cid:173)
`monary congestion, dyspnea, wheezing
`Special Senses: vision disturbance, hearing abnormality,
`ear infection, ear pain, conjunctivitis, other eye disturbance,
`.
`eyelid abnormality,. ear abnormality
`Nephropathy in Type 2 Diabetic Patients
`,
`In clinical studies in patients with hypertension and type 2
`diabetic renal disease, the adverse drug experiences were
`similar to those seen in patients with hypertension with the
`exception of an increased incidence of orthostatic symptoms
`(dizziness, orthostatic dizziness, and orthostatic hypo'
`tension) observed in IDNT (proteinuria 2:900 mg/day,, and
`serum creatinine ranging from 1.0,3.0 mg/dL). In this trial,
`orthostatic symptoms occurred more frequently in the
`AVAPRO group (dizziness 10.2%, orthostatic dizziness 5.4%,
`orthostatic hypotension 5.4%) than in the placebo group
`(dizziness 6.0%, orthostatic dizziness 2. 7%, orthostatic
`hypotension 3.2%).
`Post-Marketing Experience
`The following have been very rarely reported in post(cid:173)
`marketing· experience: urticaria; angioedema (involving,
`swelling of the face, lips, pharynx, and/or tongue); increased
`liver function tests; jaundice; and hepatitis. Hyperkalemia
`has been rarely reported.
`Rare cases of rhabdomyolysis have been reported in pa(cid:173)
`tients receiving angiotensin II receptor blockers.
`Laboratory Test Findings
`Hypertension
`In controlled clinical trials, clinically important differences
`in laboratory tests were rarely associated with administra(cid:173)
`tion of AVAPRO.
`Creatinine, Blood Urea Nitrogen: Minor increases in blood
`urea nitrogen (BUN) or serum creatinine were observed in
`less than 0.7% of patients with essential hypertension
`treated \vith AVAPRO alone versus 0.9% on placebo. (See
`PRECAUTIONS: Impaired Renal Function.)
`Hematologic: Mean decreases in hemoglobin of 0.2 g/dL
`were observed in 0.2% of patients receiving AVAPRO com(cid:173)
`pared to 0.3% of placebo-treated patients. Neutropenia
`( <1000 cells/mm3) occurred at similar frequencies among
`patients receiving AVAPRO (0.3%) and pla~ebo-treated pa(cid:173)
`tients (0.5%).
`Nephropathy in Type 2 Diabetic Patients
`'
`In IDNT (proteinuria 2:900 mg/day, and
`Hyperkalemia:
`serum creatinine ranging from 1.0-3.0 mg/dL), the percent
`of patients with hyperkalemia (>6 mEq/L) was 18.6% in the
`AVAPRO group vs. 6.0% in the placebo group. Discontinua(cid:173)
`tions due to hyperkalemia in the AVAPRO group were 2.1 %
`vs. 0.4% in the placebo group.
`OVERDOSAGE
`No data are available in regard to overdosage in humans.
`However, daily doses of 900 mg for 8 weeks were well(cid:173)
`tolerated. The most likely manifestations of overdosage are
`
`expected to be hypotension and tachycardia; bradycardia
`might also occur from overdose. Irbesartan is not removed
`by hemodialysis:
`To obtain up-to-date information about the treatment of
`overdosage, a good resource is a certified regionai Poison
`Control Center. Telephone numbers of certified Poison Con(cid:173)
`trol Centers are listed in the Physicians' Desk Reference
`(PDR). In managing overdose, consider the possibilities of
`multiple-drug interactions, drug-drug interactions, and un(cid:173)
`usual drug kinetics in the patient.
`Laboratory determinations of serum levels of irbesartan are
`not widely available; and such determinations have, in any
`event, no known established role in the management of
`irbesartan overdose.
`.
`Acute oral toxicity studies \vith irbesartan in mice and rats
`indicated acute lethal, doses were in excess of 2000 mg/kg,
`about 25- and 50-fold the maximum recommended human
`dose (300 mg) on a mg/m2 basis, respectively.
`DOSAGE AND ADMINISTRATION
`AVAPRO may be administered with other antihypertensive
`agents and with or without food.
`Hypertension
`The recommended initial dose of AVAPRO (irbesartan) is
`150 mg once daily. Patients requiring further reduction in
`blood pressure should be titrated to 300 mg once daily.
`A low dose of a diuretic may be added, if blood pressure is
`not controlled by AVAPRO alorie. Hydrochlorothiazide has
`been shown to have an additive effect (see CLINICAL
`PHARMACOLOGY: Clinical Studies). Patients not ade(cid:173)
`quately treated by the maximum dose of 300 mg once daily
`are unlikely to derive additional benefit from a higher dose
`or twice-daily dosing;
`No dosage adjustment is necessary in elderly patients, or in
`patients with hepatic impairment or mild to severe renal
`impairment.
`Nep,hropathy in Type 2 Diabetic Patients
`The recomme11ded target maintenance dose is 300 mg once
`daily. There are no data on the clinical' effects oflower doses
`of AVAPRO on diabetic nephropathy (see CLINICAL
`PHARMACOLOGY: Clinical Studies).
`Volume' and Salt-depleted Patients
`A lower initial dose of AVAPRO (75 mg) is recommended in
`patients w.ith depletion ofintravascular.volume or salt·(e.g.,
`patients treated vigorously \vith diuretics or on hemodialy(cid:173)
`sis) (see WARNINGS: Hypotension in Volume- or Salt(cid:173)
`depleted Patients).
`HOW SUPPLIED
`AVAPRO® (irbesartan) is available as white to off-white bi(cid:173)
`convex oval tablets, debossed with a heart shape on one side
`and a portion of the NDC code on the other. Unit-of-use
`bottles contain 30, 90, or 500 tablets and blister packs con(cid:173)
`tain 100 tablets, as follows:
`[See table above]
`Storage'
`Store ·at 25° C (77° F); excursions·permitted to 15° C-30° C
`(59° F-86° F) [see USP Controlled Room Temperature].
`Distributed by:
`Bristol-Myers Squibb Sanofi-Synthelabo Partnership
`New York, NY 10016
`Bristol-Myers Squibb Company
`1192328A2
`1192327A2
`S~own in Product Identification Guide, page 318 '
`
`sanofi aventis
`· · Revised April 2007
`
`BENZACLIN® TOPICAL GEL
`[ben-zA-clin]
`(cllndamycin • benzoyl peroxide gel)
`Topical Gel: Clindamycln (1%) As Clindamycin
`Phosphate, Benzoyl Peroxide (5%)
`For Dermatological Use,Only - Not for Ophthalmic Use
`*Reconstitute Before Dispensing*
`
`ij
`
`DESCRIPTION
`BenzaClin19 Topical Gel contains clindamycin phosphate,
`(7(S)-chloro-7-deoxylincomycin-2-phosphate). Clindamycin
`phosphate is a water soluble ester of the semi-synthetic an(cid:173)
`tibiotic produced by a 7(8)-chloro-substitution of the 7(R)(cid:173)
`hydroxyl group of the parent antibiotic lincomycin.
`
`Me
`I
`N
`
`n-Pr
`
`0 -··"'-N
`
`Cl
`o
`II H
`
`H
`
`SMe
`
`Clindamycin phosphate has molecular weight of 504.97
`and its chemical name is Methyl 7-chloro-6,7,8-trideoxy-
`6-(l'methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-1-
`thio-L-threo-alpha-D-galacto-octopyranoside 2-(dihydrogen
`phosphate).
`Be~zaClin Topical Gel also contains benzoyl peroxide, for
`topical use.
`Chemically, benzoyl peroxide is (C14H100 4). It has the fol(cid:173)
`lowing structural formula:
`
`Benzoyl peroxide has a molecular weight of 242.23.
`Each gram of BenzaClin Topical Gel contains, as dispensed,
`10 mg.(1%) clindamycin as phosphate and 50 mg (5%)
`benzoyl peroxide in a base of carbomer, sodium hydroxide,
`dioctyl sodium sulfosuccinate, and purified water.
`CLINICAL PHARMACOLOGY
`An in uitro percutaneous penetration study comparing
`BenzaClin Topical Gel and topical 1 % clindamycin gel alone,
`demonstrated there was no statistical difference in penetra(cid:173)
`tion between the two drugs. Mean systemic bioavailability
`of topical clindamycin in BenzaClin Topical Gel is suggested
`to be less than 1 %.
`Benzoyl peroxide has been shown to be absorbed by the skin
`where it is converted to benzoic acid. Less than 2% of the
`dose enters systemic circulation as benzoic acid. It is sug(cid:173)
`gested that the lipophilic nature of benzoyl peroxide acts to
`concentrate the compound into the lipid-rich sebaceous
`follicle.
`Pharmacokinetics
`The pharmacokinetics (plasma and urine) of clindamycin
`from BenzaClin Topical Gel was studied,in male and female
`patients (n=l3) with acne vulgaris. BenzaClin Topical Gel
`( ~2g) was applied topically to the face and back twice daily
`for four and a half(4.5) days. Quantifiable (>LOQ=lng/mL)
`clindamycin plasma concentrations were obtained in six of
`thirteen subjects (46.2%) on Day 1 and twelve of thirteen
`subjects (92.3%) on Day 5. Peak plasma concentrations
`( Cm"') of clindamycin ranged from 1.4 7 ng/mL to 2. 77 ng/mL
`on Day 1 and 1.43 ng/mL to 7.18 ng/mL on Day 5. The AUC
`(0-12h) ranged from 2.74 ng.h/mL to 12.86 ng.h/mL on Day
`1 and 11.4 ng.h/mL to 69.7 ng.h/mL on Day 5.
`The amount of clindamycin excreted in the urine during the
`12 hour dosing interval increased from a mean (SD) of 57 45
`(3130) ng on Day 1 to 12069 (7660) ng on Day 5. The mean
`% (SD) of the administered dose that was excreted in the
`urine ranged from 0.03% (0.02) to 0.08% (0.04).
`A comparison of the single (Day 1) and multiple (Day 5) dose
`plasma and urinary concentrations of clindamycin indicates
`that there is accumulation of clindamycin following multi(cid:173)
`ple dosing of BenzaClin Topical Gel. The degree of accumu(cid:173)
`lation calculated from the plasma and urinary. excretion
`data was ~2-fold.
`Microbiology
`The clindamycin and benzoyl peroxide components individ(cid:173)
`ually have been shown to have in vitro activity against
`Propionibacterium acnes an organism which has been asso(cid:173)
`ciated with acne vulgaris; however, the clinical significance
`of this activity against P. acnes was not examined in clinical
`trials with this product.
`CLINICAL STUDIES
`In two adequate and well controlled clinical .studies of 758
`patients, 214 used BenzaClin, 210 used benzoyl peroxide,
`168 used c!indamycin, arid 166 used vehicle. BenzaClin
`applied twice daily for 10 weeks was significantly more
`effective than vehicle in the treatmep.t of moderate to mod(cid:173)
`erately severe facial acne vulgaris. Patients were evaluated
`aqd acne lesions counted at each clinical visit; weeks 2, 4, s;
`8 and 10. The primary efficacy measures were the lesion
`counts and the investigator's global assessment evaluated
`at week 10. Patients were instructed to wash the face with a
`mild soap, using only the hands. Fifteen minutes after the
`face was thoroughly dry, application was made to the entire
`face. Non-medicated make-up could be applied at one hour
`after the BenzaClin application. If a moisturizer was
`required, the patients were provided a moisturizer to be
`
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`
`2 of 4
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`

`2968/SANOFI-AVENTIS • BENZACLIN
`
`For the latest PDR product information, visit PDR.net
`
`used as needed. Patients were instructed to avoid sun expo-
`sure. Percent reductions in lesion counts after treatment for
`10 weeks in these two studies are shown below:
`
`Si
`ze
`
`(N w · h I
`et
`eig t
`
`NDC 0066-
`
`Benzoyl Peroxide Gel Active Cllndamycin Powder Purified Water To Be
`(In plastic vial)
`Added to each vial
`
`Study 1
`
`BenzaClin
`
`n=120
`
`Benzoyl
`peroxide
`n=120
`
`Clindamycin
`
`Vehicle
`
`n=120
`
`N=l20
`
`Mean percent reduction in inflammatory lesion counta
`
`0494-25
`
`0494-35
`
`0494-50
`
`0494-55
`
`0495-55
`
`-
`
`19.7g
`
`27.6g
`
`39.4g
`
`39Ag
`
`39.4g
`
`25 grams
`
`35 grama
`(pump)
`
`50 grams
`
`50 grams
`(pump)
`
`BenzaClin Care Kit:
`50 grams
`BenzaC!in (pump)
`with 20 ampoules
`Viscontour Serum
`
`·-·
`
`0,3g
`
`0.4g
`
`0.6g
`
`0.6g
`..
`
`0.6g
`
`•·
`
`5mL-
`
`7mL
`
`'.,
`
`lOmL ..
`
`lOmL,
`
`lOmL
`
`46%
`
`32%
`
`16%
`
`I
`
`I +3%
`I +.1%
`
`Mean percent reductfon in non-inflammatory lesion coullts
`
`22%
`
`22%
`
`9%
`
`36%
`
`Mean percent reduction in total lesion counts
`1- 0.2%.
`
`I . 15%
`
`28%
`
`Study2
`
`BenzaC!in
`
`n=95
`
`Be11zoyl'
`peroxide
`n=95
`
`Clindamycin
`
`Vehicle
`
`n=49
`
`N=48
`
`Mean percent reduction in inflammatory lesion counts
`
`63%
`
`1
`
`53%·
`
`45%
`
`1
`
`42%
`
`Mean percent reduction in non-inflammatory lesion counts
`
`54%
`
`50%
`
`39%
`
`1
`
`36%
`
`i.
`
`.·r:.··
`
`..
`
`The BenzaCiili group showed greater overall improvemen~
`than the benzoyl peroxide, clindamycin and vehicle grotipii
`as rated by the inve~tigator. '
`: , ·
`·
`INDICATIONS AND USAGE
`BenzaClin Topical Gel is indicated for the topical treatment
`of acne vulgaris,,,
`CONTRAINDICATIONS'
`BenzaClin Topical Gel is contraindicated in those individu(cid:173)
`als who have shown hypersensitivity to any of its compo(cid:173)
`nents or to lincomycin. It is also contraindicated in those
`having ii history of regiomtl enteritis, ulcerative colij;iil, or
`antibiotic-asliociilted·i:olitili. ·,j
`·
`"
`·
`w.ARNINos ..
`: . ~
`,.,;. : =. ,;;
`ADMINISTERED
`/ AND ; PARE;ii!TERALLY
`ORALLY
`CUNDAMYCIN HAS BEEN ASSOCIATED WITH SEVERE
`COLITIS WHICH MAY RESUl,T IN. PATIENT DEATH. USE'OF
`THE TOPICAL FORMULATION OF CUNDAMYCIN RESULTS
`IN ABSORPTION OF THE ANTIBIOTIC FROM THE SKIN
`SURFACE. DIARRHEA, BLOODY DIARRHEA, AND COLITIS
`(INCLUDING PSEUDOMEMBRANOUS COLITIS) HAVE
`BEEN REPORTED WITH , THE USE OF TOPICAL AND
`SYSTEMIC CLINDAMYCIN: STUDIES INDICATE A TOXIN($)
`PRODUCED BY CLOSTRIDIA IS ONE PRIMARY CAUSE OF
`ANTIBIOTIC-ASSOCIATED'COLITIS. THE COLITIS IS USU;
`ALLY CHARACTERIZED BY SEVERE PERSISTENT DIAR:
`RHEA AND SEVERE ABDOMINAL CRAMPS AND MAY BE
`ASSOCIATED• WITH THE PASSAGE OF BLOOD AND
`MUCUS. ENDOSCOPIC EXAMINATION MAY REVEAL
`PSEUDOMEMBRANOUS COLITIS. STOOL CULTURE FOR
`Ciostridium Dffflclle AND STOOL ASSAY FORC. difficile
`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 PSEUDOMEMBRANOUS COLITIS
`HAVE BEEN OBSERVED TO,BEGIN UP TO SEVERAL
`WEEKS FOLLOWING CESSATION OF ORAL AND PAREN·
`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 supplementatio11 and treatment
`with an antibacterial drug clinically effective against C. dif-
`ficile colitis.
`·
`· ·
`·
`PRECAUTIONS
`General,·
`For dermatological use only; not for ophthalmic use. Cons
`comitant topical acne therapy should be used with caution
`
`because a possible cumulative itritancy effect may occur, es'
`pecially'With the use of peeling; dasquamating, or abrasive
`agenta,;
`·
`·
`,,, ·" ·" ·
`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 products should
`not be used in combination. In vitro studies have shown an(cid:173)
`tagonism between these two antimicrobials, The clinical sig(cid:173)
`nificance of this in vitro antagonism is not known:
`Information for Patients
`,
`,,
`Patients using BenzaClin Topical Gal should receive the fol-
`lowing information and instructions:
`"
`1. BenzaClin Topical Gel is to be used as directed by the
`physician. It is for external use only. Avoid contact with
`
`:~:l! ~;!Ju:';~;~!~:::4·:riiko: inem-
`
`2. This'medication should not be tised for any disorder other
`thii)i that for which it was preilctjtied. '.
`': ' ' : . ..
`. .
`3. Patiei>.ta should not use any' other topica:l acne prepata.
`tion'tinlese otherwise directed by physicjlui. ,·.
`· .. .
`.
`4. Patients should minimize or avoid exposlin!, to natural or
`artificial sunlight (tanning beds or uvAJB·treatment)
`while using BenzaClin Topical Gel. To minimize exposure
`to sunlight, a wide-brimmed hat or other protective cloth(cid:173)
`ing should be worn, and a sunscreen with SPF 15 rating
`or higher should be used,
`'
`5. Patients who develop allergic symptoms .such as severe
`swelling or shortness of breath · should discontinue
`BenzaClin Topical Gel and contact their physician imme-
`diately.
`.
`. .
`,
`6. BanZliClin Topical Gel may bleach hair or colored fabric.
`7. BenzaClin Topical Gel can be stored ilt roomte)!ijierature
`.. up to.25'C (77'F) for 3 moriths;,Do'not li'e~ze. Discard
`.· any unused product after 3 months.
`,, . • . . . ... ·.
`.
`.
`,
`8. Before applying BenzaClin. Topical Gel. to affected areas
`wash. the skin gently, then rinlle with warm water and
`patdry.
`- - '
`·.
`· ·
`·
`.··
`: ··
`,
`Carcinogenesis, Mutagenesis, Impairment of Fartillty
`Benzoyl peroxide has been shown to be a tumor promoter
`and progression agent in a number of ~al studies. The
`clinical significance of this is unknown. '
`.
`Benzoyl peroxide in acetone at doses of 5 and 10 mg admin(cid:173)
`istered twice per week induced skin tumors in transgenic
`Tg.AC mice in a study using 20 weeks of topical treatment.
`In a 52 week dermal photocarcinogenicity study in hairless
`mice, the median time to onset of akin tumor formation was
`decreased and the number of tumors per· mouse in,creased
`following chronic concurrent topical administration of
`BenzaClin Topical Gel with exposure to wtraviolet radia.
`tion ( 40 weeks of treatment followed by 1~ weeks of
`observation).
`In a 2-year dt!rmal carcinogenicity study in rats, treatment
`with BenzaC!jn, Topical Gel at doses of 100, 500 aniJ
`2000 mg/kg/day caused a dose-dependent increase in the in•
`cidence of keratoacanthoma at the treated skin site of male
`rats, The incidence of keratoacanthoma at the treated site
`of males treated with 2000 mg/kg/day (8 times the highest
`recommended adult human dose of 2.5 g BenzaClin Topical
`Gel, based on mg/m2) was statistically significantly higher
`than that in the sham- and vehicle-controls.
`Genotoxicity studies were not conducted with BenzaClin
`Topical Gel. Clindamycin phosphate was not genotoxic iii
`Salmonella typhimurium or in a rat micronucleus · test.
`Clindamycin phosphate swfoxide, an oxidative degradation
`product of clindamycin phosphate and benzoyl peroxide,
`was not clastogenic in a mouse micronucleua test. Benzoyl
`peroxide has been found to cause DNA strand breaks in a
`variety of mammalian cell types, to be mutagenic in S. ty(cid:173)
`phimurium tests by soms but not all investigators, and tq
`cause sister chromatid exchanges in Chinese hamster ovary
`cells, Studies have not been performed with BenzaClln
`
`. "
`
`...
`Topical Gel or benzoyl peroxide'to evaluate the effect oncer:
`tility. Fertility studies in rata treated orally with tip to
`300 mg/kg/day ofclindamycin (approximately 120 times the
`amQunt 11£,cliodamycin .in the highest recommended adult
`human_ dose. of 2.5 g BenzaC!in Topics! Gel, based on ?llf/m~)
`revealed no effects on fertility or mating ilbility.
`Pregnancy , .,· .,..
`, .. , , ., .
`Teratogenic Effeats
`...
`Pregnancy Category C
`.
`.
`,
`Animal· reproductive/developmental toxicity studies have
`not been conducted with BenzaClin Topical Gel or benzoyl
`peroxide. Developmental toxicity studies performed in rats
`and mice using oral doses of clindamycin ·up
`to
`600 mg/kg/day (240' and 120 times amount of clindamycio in
`the highest recommended adult human dose based 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. ~n mg/m~,.respectiv_ely}revealed no evidence oftera;
`, . ·,<a., .
`togematy.
`,;, .. ,;.,,. ,.,
`,. .
`.,_ -
`-
`, ,
`There are no well-controlled trials in pregnant wome11
`treated. wi~ B,11~aClio. Topical Gel. It lllso_ is not known
`whether BenzaClin TopiciiLGal can cause fetal hHl'Dl. wh8'1
`administered to-~ p1'1;1iP.J,_aii~ ·wom~:- --
`·
`Nursing Wilin!!it
`;' ',
`·' , : .
`·
`. .
`. . , .,
`It is not known whether BanzaClin Topical Gel is excreted in
`human milk after topicai' application. However, orally and
`parenterally administered clindamycin has been reported tli
`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 to the
`mother.
`Pediatric Use
`,.·,,,
`,
`, ,
`Safety anll effectiveness of~hi,s product in pediatric patients
`below t;he age,~,( 1-2 have not been establiahed.
`ADVERSE REACTIONS,
`· -,, '.!. ·
`During clinical j;nalii, the ino~t frequently reported ad\ierse
`event in the BenzaC!in treatment grouji was dry skin (1291,)
`The Table below lists local adverse events reported by, ·a
`least 1 % of ~a,~~~ta i,11 ~-e BenzaClin and v~~e grc>~ps'.,:
`' ' ! L~cll ;Adva~ •• ·E~i!~ts .. all ~a~~alities
`' in >/"i' 1% of patients
`
`1
`·_..·:,·: .~:::;:
`
`BenzaC~
`'n = 420
`
`Vehicle
`n = 168
`
`Application site reaction
`
`13 (3%)
`
`D!'Y s!qn.,,
`
`,, ,
`
`50 (12%)
`
`led%)'' -
`
`10(6%)
`
`Pruritus
`
`Pe~ling
`
`Erythema
`
`Sunburn
`
`8(2%)
`
`. 1(<1%)
`
`9(2%)~
`
`6 (1%)'·' .;
`.. , .
`~ ! ...
`5(1%),
`
`1(<1%)
`
`The actual incidence of dry skin might have been greater
`were it not for the use of a moisturizer in these studies.
`Anaphylaxis, as well as allergic reactions leading to hospi
`talization, have been reported during post-marketing use of
`clindamycin/benzoyl peroxide products. Because these reac
`tions are reported voluntarily from a population of uncer(cid:173)
`tain size; it is not always possible to reliably estimate their
`li.iiquencror establiah a causal relatioilship to drug expo-
`sure.
`,,
`.
`
`DOSAGE AND ADMINISTRATION'
`BenzaClln Topical Gel should be applied twice daily, moms
`ing and evening, or as directed by a physician, to affected
`areas after the skin is gently washed, rinsed with warm wa-
`ter and patted dry,
`,
`
`IMPORTANT NOTICE: Updated drug information is sent bi-monthly via the PDR® Update Insert. For monthly email updates, register at PDR.net.
`
`3 of 4
`
`

`

`Complimentary CME for PDR-listed products at PDR.net
`
`CARAC • SANOFI-AVENTIS/2969
`
`HOW SUPPLIED AND COMPOUNDING INSTRUC(cid:173)
`TIONS
`[See table at top of previous page]
`Prior to dispensing, tap the vial until powder flows freely.
`Add indicated amount of purified water to the vial (to the
`mark) and immediately shake to completely dissolve
`clindamycin. If needed, add additional purified water to
`bring level up to the mark. Add the solution in the vial to
`the gel and stir until homogenous in appearance (1 to l'/2
`minutes). For the 35 and 50 gram pumps only, reassemble
`jar with pump dispenser. BenzaClin Topical Gel (as recon(cid:173)
`stituted) can be stored at room temperature up to 25"C
`(77"F) for 3 months. Place a 3 month expiration date on the
`label immediately following'mixing.
`Store at room temperature up to 25"C (77"F) {See USP].
`Do not freeze. Keep tightly closed. Keep out of the reach of
`children.
`Prescribing Information as of June 2010.
`Dermik Laboratories
`a business of sanofi-aventis U.S. LLC
`Bridgewater, NJ 08807
`©2010 sanofi-aventis U.S. LLC
`
`CARAC® CREAM, 0.5%
`[ca-rack]
`·
`(fluorouracil cream)
`FOR TOPICAL DERMATOLOGICAL USE ONLY {NOT
`FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE)
`
`~
`
`DESCRIPTION
`Carac® (fluorouracil cream) Cream, 0.5%, contains
`fluorouracil for topical dermatologic. use. Chemically,
`fluorouracil is 5-fluoro-2,4(1H, 3H)-pyriinidinedione. The
`molecular formula is C4H3FN20 2• Fluorouracil has a molec(cid:173)
`ular weight of 130.08.
`
`Carac Cream contains 0.5% fluorouracil, with 0.35% being
`incorporated
`into a patented porous microsphere
`(Microsponge®)1 composed of methyl methacrylate/glycol
`dimetbacrylate crosspolymer and dimethicone. The cream
`formulation contains the following other inactive ingredi'
`ents: Carbomer Homopolymer Type C, dimethicone, glyc(cid:173)
`erin, methyl gluceth-20, methyl methacrylate/glycol
`dimethacrylate crosspolymer, methylparaben, octyl hydroxy
`stearate, polyethylene glycol 400, polysorbate 80, propylene
`glycol, propylparaben, purified water, sorbitan monooleate,
`stearic acid, and trolamine.
`
`1 Microsponge is a registered trademark of Cardinal Health,
`Inc. or one of its subsidiaries:
`
`CLINICAL PHARMACOLOGY
`There is evidence that the metabolism of fluorouracil in the
`anabolic pathway blocks the methylation reaction of deox(cid:173)
`yuridylic acid
`to
`thymidylic acid. In this manner;
`fluorouracil interferes with the synthesis of deoxyribotm(cid:173)
`cleic acid (DNA) and to a lesser extent inhibits the forma(cid:173)
`tion of ribonucleic acid (RNA). Since DNA and RNA are es(cid:173)
`sential for cell division and growth, the effect of fluorouraci!
`may be to create a thymine deficiency that provokes unbal(cid:173)
`anced growth and death of the cell. The effects of DNA and
`RNA deprivation are most marked on, those cells that grow
`more rapidly and take up fluorouracil at a more rapid rate.
`The contribution to efficacy or safety of individual compo-
`nents of the vehicle has not been established;
`·
`Pharmacokinetlcs
`A multiple-dose, randomized, open-label, parallel study was
`performed in 21 patients with actinic keratoses. 'l\venty pa(cid:173)
`tients had pharmacokinetic samples collected: 10 patients
`treated with Carac, and 10 treated with Efudex®2 5%
`Cream. Patients were treated for a maximum of 28 days
`with Carac, 1 g once daily in the morning; or Efudex® 5%
`Cream, 1 g twice daily, in the morning apd evening. Steady(cid:173)
`state plasma concentrations and the amounts offluorouracil
`in urine resulting from the topical application of either
`product were measured.
`Three patients who received Carac and nine patients who
`received Efudex® 5% Cream had measurable plasma
`fluorouracil levels; however, only one patient receiving
`Carac and six patients receiving Efudex® 5% Cream had a
`
`sufficient number of data points to calculate mean pharma(cid:173)
`cokinetic parameters.
`
`Plasma Pharmacokinetic Summary
`
`Percentage of Subjects with at Least 75% Clearance
`
`~%~----------------,
`
`60% - j - - - - · - - - - , c ;= ; - - - - - - - i
`
`PK Parameter
`
`Carac
`n:1
`
`Efudex (Mean± SDI
`n:6
`
`Cmax
`Tmax
`AUC (0-241
`
`0.77 ng/mL
`1.00 hr
`2.80 ng• hr/mL
`
`11.49 ± 8.24 ng/mL
`1.03 ± 0.028 hr
`22.39 ± 7.89 ng•hr/mL
`
`60%+-----;
`50%+-----<
`40%
`30%
`
`20%
`10%
`
`0%
`
`a Study 9721
`1i1Sludy 9722
`
`Five of 10 patients receiving Carac and nine of 10 patients
`receiving Efudex® 5% Cream had measurable urine
`fluorouracil levels.
`
`Urine Pharmacokinetic Summary
`
`PK Parameter
`
`CumAe*
`(min-max)
`Max excretion
`rate
`(min-max)
`
`Carac
`(Mean± SD)
`(Rangel
`n:10
`
`Efudex
`(Mean± SDI
`(Rangel
`n:10
`
`119.8± 94.80 mcg
`2. 7 4± 5.22 mcg
`(0-329.87)
`(0-15.02)
`0.19 ± 0.52 mcg/hr 40.27 ±47.14 mcg/hr
`
`(0-1.67)
`
`(0-164.5)
`
`* Cumulative urinary excretion
`
`Both Carac and Efudex® 5% Cream demonstrated low mea(cid:173)
`surable plasma concentrations for fluorouracil when admin(cid:173)
`istered under steady-state conditions. Cumulative urinary
`excretion of fluorouracil was low for Carac and for Efudex®,
`corresponding to 0.055% and 0.24% of the applied doses, re(cid:173)
`spectively.
`
`2Efudex is a registered trademark of ICN Pharmaceuticals,
`Inc.
`Clinical Trials
`Under the experimental conditions of the topical safety
`studies, Carac was not observed to cause contact sensitiza(cid:173)
`tion. However, approximately 95% of subjects in the active
`arms of the Phase 3 clinical studies experienced facial irri(cid:173)
`tation. Irritation is likely and sensitization is unlikely based
`on the results of the topical safety and Phase 3 studies.
`'l\vo Phase 3 identically designed, multi-center, vehicle(cid:173)
`controlled, double-blind studies were conducted to evaluate
`the clinical safety and efficacy of Carac. Patients with 5 or
`more actinic keratoses (AKs) on the face or anterior bald
`scalp were randomly allocated to active or vehicle treatment
`in a 2:1 ratio. Patients were randomly allocated to treat(cid:173)
`ment durations of 1, 2, or 4 weeks in a 1:1:1 ratio. They ap(cid:173)
`plied the study cream once daily to the entire face/anterior
`bald scalp. Each patient's clinical response was evaluated 4
`weeks after the patient's last scheduled application of study
`cream. No additional post-treatment follow-up efficacy or
`safety assessments were p