PDRo
`
`EDITION
`
`2011
`
`CEO: Edward Fotsch, MD
`President: David Tanzer
`Chief Medical Officer: Christine C6t~, MD
`Chief Technology Officer: Nick Krym
`Chief Financial Officer: Dawn Carfora
`
`Vice President, Product Management & Operations: Valerie Berger
`Vice President, Emerging Products: Debra Del Guidice
`Vice President, Corporate Development, Copy Sales &
`General Counsel: Andrew Gelman
`Vice President, Sales: John Loucks
`Vice President, Marketing: Julie Baker
`Vice President, Business Development: Tom Dieker
`
`Director of Sales: Eileen Bruno
`Business Manager: Karen Fass
`Senior Account Executives: Marjorie A. Jaxel, Philip Moiinaro
`Account Executives: Nick W. Clark, Carlos Comejo, Caryn Trick
`Associate Account Executives: Carol Levine, Janet Wallendai
`Sales Coordinator: Dawn McPartland
`
`Senior Director, Operations & Client Services: SLephanie Struble
`Senior Director, Editorial & Publishing: Bette Kennedy
`Director, Clinical Services: Sylvia Nashed, PharmD
`Director, Marketing: Kim Marich
`
`Senior Manager, Client Services: Lisa Caporuscio
`Manager, Clinical Services: Nermin Keroious, PharmD
`Senior Drug Information Specialist,
`Database Management: Christine Sunwoo, PharmD
`Senior Drug Information Specialist,
`Product Development: Ani[a Patel, PhermD
`Drug Information Specialists: Peter Leighton, PharmD;
`Kristine Mecca, PharmD; See-Won See. PharmD
`Manager, Editodal Services: Loft Murray
`Associate Editor: Jennifer Reed
`Manager, Art Department: Livio Udina
`Electronic Publication Designer: Carrie Spineili Faeth
`
`Director; PDR Production: Jeffrey D. Schaefer
`Associate Director, Manufacturing & Distribution: Thomas Westburgh
`Production Manager, PDR: Steven Maher
`Operations Database Manager: Noel Deloughery
`Senior Index Editor: Allison O’Hara
`Index Editor: Julie L Cross
`Senior Production Coordinator: Yasmin Hern~ndez
`Production Coordinators: Eric Udina, Christopher Whalen
`Format Editor: Dan Cappello
`Fulfillment Management Specialist: Gary Lew
`Manager, Customer Service: Todd Taccetta
`
`Copyright @ 2010 PDR Network, LLC Published by PDR Network, LLC at Montvale, NJ 07645-1725, All rights reserved. None of the content of this publication may be
`reproduced, stored in a retrieval system, resold, redistributed, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise)
`without the prior written permission of the punisher. Physicians’ Desk Reference® and PD R® are registered trademarks of PDR Network, LLCo PDR® for Ophthalmic Medicines;
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`
`ISBN: 978-1-56363-780-3
`
`1 of 4
`
`Almirall EXHIBIT 2030
`Amneal v. Almirall
`IPR2018-00608
`
`

`

`Complimentary CME for PDR-listed products at PDR.net
`
`BENZACLIN ¯ SANOFI-AVENTIS/2967
`
`Debossing
`
`Bottle of 30
`
`Bottle of 90
`
`Bottle of 500
`
`Blister of 100
`
`75 mg
`
`2771
`
`0687~2771-31
`
`0087-2771-32
`
`150 mg
`
`2772
`
`300 mg
`
`2773
`
`Chemically, etindamyoin phosphate is (CI~H~4C1N~OsPS).
`The structural formula for elindamycin is represented
`heiow:
`
`0087-2772~31
`
`0687-2773.31
`
`~I8
`
`’~’~ OH
`
`0087-2772-32
`
`0087-2773*32
`
`0087-2772-15
`
`0087-2773-15
`
`008%2772-35
`
`, OH
`
`sMe
`
`expected to be hypotension and tachycardia; brodycardia
`In addition, the following potentially important events
`occurred in lose than 1% of the 1965 patients and at least 5 might also occur from overdose. Irbesartan ia not removed
`patients (0.3%1 receiving irbosartan in clinical studies, and
`by hemedialysis:
`those less frequent, tiinieally significant evenr~ (listed by
`To obtain up-to-date intbrmalion about the treatment of
`overdasagn, a good resource is a certified regional Poison
`body system/, tt cannot be dete~ed whether these events
`were causally related to irbesar~a:
`Control Center. Telephone numbers of certified Poison Con-
`~rol Centers are listed £a the Physicians’ Desk Reference
`Body as a Whole:
`fever, chills, facial edema, upper extrem~
`(PDR). In man~g overdose, consider the possibilities of
`ity edema
`
`Ca~dila~:ff.~hm~hyper~e~si~di~r~nnltip~drngl~tera~tl~drag.d~u~ioterecti~s,a~d~ ...... ...... .....
`myocardial infarction, angina peetorls, arrhythmidcenduc-
`usual drug kinetics in the patient.
`lion disorder, card:o-respiratory arreso~ heart thiinre, hyper-
`Laboratory determinations of serum levels of irbasartaa are
`teasive crisis
`not widely avallable~ and such determinations have, in any
`Dermatotogic: pru~tus, dermatitis, ecchymesis, erythema
`event, no known established role in the management of
`irbesza~tan overdose.
`face, urticaria
`Endocrine/Metaboliclgleetrolyte Imbalances: sexual dye-
`Acute oral toxicity studies with irbesartml in mice and rats
`function, libido change, gout
`indicated acute lethal doses were in excess of 2000 rag/kg,
`Gastrointestinal: constipation, oral lesion, gastxoentsrlhs,
`about 25- and 50-fold the maximum recommended human
`dose (300 rag) on a mgim2 basis, respectively,
`flatulence, ahdominal distention
`Museu!osheletal/Connect:as 2qssue: extremity swelling,
`muscle cramp, arthritis, m~sde ache, musculosknletal chest
`pain, joint stiffness, bureitis, muscle weakness
`Nervous System: sleep disturbance, numbness, semen,
`lance, emotional disturbanas, depression, paresthasia,
`tremor, transient ischemic attack, cerebrevaccular accident
`Renal[Genitourinary: abnormal urination, prostate
`disorder
`Respiratory~ epistaxis, traeheobronchltis, cengesfion, pal-
`monary congestion, dyspnea, wheezing
`Specia! Senses: vismn disturbance, hearing abnormality,
`ear infection, ear pain, conjunctivitis, other eye disturbance,
`eyelid abnarmali~y~ ear abnormality
`Nephropathy in Type 2 Diabetin Patients
`In cIinical studies in patients with hypertension and type 2
`diabetic renal disease, the adverse drug experiences were
`similar to those seep in patients with hyperteusion with the
`exception of an increased incidence of orthosta~ic symptoms
`(dizziness, orthostatie dizziness, nnd orthostatic hyp~
`tension) observed in IDNT (protainurin ~900 mg]day, and
`serum croat:nine ranging from 1.0;3.0 mgidL). In this trial,
`orthostatic symptoms occurred more frequently in the
`AVAPRO group (dizziness 10.2%, or~ostatie dizziness 5.4%,
`orthostatic hypetensien 5.4%} than in the placebo group
`~dizzinass 6.0%, orthostatie dizziness 2.7%. orthostatic
`hypotensien 3.2%)~
`Poet-Marketing ~Dadence
`The following have been very rarely reported in post-
`marketing experience: urticaria; angioedema (involving
`swelling afthe face, lips, pharynx, and]or tongue); increased
`liver bract:on tests; jaundice; and hepatitis. Hyperkalemia
`AVAPRO@ (h’beasr~un) is available as white to off=white hi-
`has been rarely reported,
`convex oval tablets, debassed with n heart shape pc one side
`Rare cases of rhabdomyolysis have been reported in pa-
`and a portion of the NDC code on the other. Unit-of-ase
`tients receiving angiotenein II receptor blockers,
`bottles contain 30. 90, or 500 tablets and blister packs con-
`Laboratory Test Findings
`rain 100 tablets, as follows:
`Hypertension
`[See table above]
`In cnnixelled clinical trials, elinlcally important differences
`Storage
`in laboratory ~es~s were rarely associated with admiaistra-
`Stere at 25~ C 177" F); excursions permitted to :t5~ C-30~ C
`lion of AVAPRO.
`(59° F-86° F) [see USP Controlled Ro(im Temperatare].
`Croat:nine. Bl~ Urea Nitrogen: Minor increases in blood Distributed by:
`ur.a nitrogen (RUN) or serum croat:nine were observed in
`Bristol-Myers Squibb Sanofi-Synthelabo Partnership
`leas than 0.7% of patients with essential hypertension
`New York. ~NrY 10016
`treated with A~:a.PRO alone versus 0.9% on placebo. (See
`Bristol-Myers Squibb Company
`PRECAUTIONS: impaired Renal Function.)
`1192328A2
`HsmotoIogie: Mean decreases in hnmaginbin of 0.2 g]dL
`1192327A2
`were observed in 0.2% of patients receiving AVAPRO corn-
`Shown ia Product Identification Guide. poge 318
`pared to 0.3% of placebo-treated patients. Nentropenia
`(<1000 cells]mmSl occurred at similar frequencies among
`patients receiving AVAPRO (0.3%) and placebo-trea~ed pa-
`tiants (0.5%).
`Nephropathy in Type 2 Diabetic Patients
`Hyperkalemia: In IDNT (proteinuria ~900 mgiday, and
`serum croat:nine ranging from 1.0-3.0 mg]dL)~ ~he percent
`of patients with hyperkalemia (>6 mEqiL) was 18.6% in the
`AVAPRO group vs. 6.0% in the placebo group. Discontinue-
`lions due to hyperkalemia in the AVAPRO group were 2.1%
`vs. 0.4% in the placebo group,
`
`DOSAGE AND ADMINISTRATION
`AVAPRO may be administered with other ahtihypertensive
`agents and with or without food.
`Hypertension
`The recommended in:tie! dose of AVAPRO (irbeaartaa) is
`150 mg once daily. Patients requiring fiarther reduction in
`biped pressure should be Litrated to 300 mg once daily,
`A low dose of a diuretic may be added if blood pressure is
`oat controlled by AVAPRO alone. Hydroehlarbthiazide has
`been shown to have an odditive effect /see CLINICAL
`P~4RMACOLOGY: Clinioal Stud:as:. Patients no~ ado-
`quately treated by the m~mum 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
`pat:acts with hepatic impairment or mild to severe renal
`impairment,
`Nephropathy in Type 2 Diabetic Patients
`The recommended target maintena~oe dose is 300 mg once
`daily. ~ere are no data on the clinical effects of lower doses
`of AVAPRO on diabetic nephropathy (see CLINICAL
`~IACOLOGY: Clinical Studiesl.
`Volume- and Salt-depleted Patients
`A lower initial dose of AVAPRO (75 rag) is rocemmended in
`patients with depletion ofintravascular volume or salt Long.,
`patients treated vigorously with diuretics or on hemodialy-
`sis) ~ase WARNINGS: Hypotension in Volume- or Salt-
`depleted Patients).
`
`HOW SUPPLIED
`
`saner: aventis
`Revised April 2007
`
`BENZ~,C/IN@ TOPICAL GEl.
`[ben.zA-clin]
`(ciindamycin - henzoyi peroxide gel)
`Topical Gel: Ciindamycin 11%1 As Clindamycin
`Phosphate, Benzoyl Peroxide 15%1
`For Dermatological Use Only - Not for Ophthalmic Use
`*Reconstitute Before Dispensing*
`
`I~
`
`DESCRIPTION
`BenzaClln~’ Topical Get contains clindamycin phosphate,
`(7(S)~chloro~7-deoxylincomyein~2~phasphate). Clindamycin
`phosphate is a water soluble ester of the semi-synthetin an-
`tibistic produced by a 7(S)-ch!ero-substitution of the 7(R)-
`hydroxyl group of the parent antibioxic lincemycin,
`
`OVERDOSAGE
`
`No data are available in regard to overdosage in humans,
`However, daily doses of 900 mg far 8 weeks were well-
`tolerated. The most likely manifestations of overdssage are
`
`Clindamycin phosphate has molecular weight of 504.97
`and its chemical name is Methyl 7-ehlcru-6.7.8-trideoxy-
`6-(1-methyl-trans-4-propyl-L-2-pyrrelidinecarboxamido)-l-
`thio-L-thren-alpha-D-galacts~ectopyranoside 2-(dihydrogen
`
`2hasphate)"
`BenzaClin Topical Gel also contains benzoyl peroXide, for
`~pical use.
`Chemically, benzoyl peroxide is (C14HloO0. It has the tel-
`low:an structural formula:
`
`.N ~
`--\0~
`
`Benzoyl peroxide has a molecular weight of 242,23.
`Each gram of BenzaClin Topical Get cantos, as dispensed.
`10 mg 11%~ ciindamycin as phosphate and 50 mg (5%)
`benzoyl peroxide in a base of carbomer, sodium hydroXide,
`dioetyl sodium sulfssuccinate, and purified water,
`
`CLINICAL PHARMACOLOGY
`
`.am in vitro pereutaaaons pnaetratian study comparing
`BanzaClin Topics Gel and topica! 1% clindamyein gel alone,
`demonstrated there was no statistical difference in penetra-
`lien be~’een the two drugs. Mean systemic blears:lability
`of topical clindamyein in BenzaC]in Topical Gel is suggested
`to be less than 1%.
`Bcnzoyl peroxide has been shown to be absorbed by the skin
`where it is converted to beuzoic acid. Less ~han 2% of the
`dose enters systemic circulation as benzoic acid. It is aug-
`gested that the lipophilie nature of benzoyl peroxide acts to
`coneentxats Llm compound into the lipid-rich sebaceous
`follicle
`Pharmacokinetics
`The pharmacokinetics tplasma and urinal of clindamyein
`from BenzaClin Topical Gel was studied in male and female
`patients (u=13) with aerie valgaris. BenzaClin Topical Gel
`(~2g) was applied topically to the thce and back twice daily
`tar four and a half (4.5) days. Quantifiable (>LOQ= lug/roLl
`ciindamycin plasma ccncentratio~ were obtained in six of
`thirteen subjects 146,2%) on Day 1 and twelve of thirteen
`subjects (92.3%1 on Day 5. Peak plasma asncentrations
`(C~) 0fclindamycin ranged from 1.47 ng/mL to 2.77 nghnL
`on Day 1 and 1.43 ngimL to 7.18 ng/mL on Day 5. The AUC
`(0-12hi ranged from 2.74 cg,h]mL to 12.86 ng.bJmL on Day
`1 and 1!.4 ng.l~mL to 69.7 ng.tdmL on Day 5.
`The amount of clindamycin excreted In the urine during the
`12 hour dosing interval increased from amean (SDI 0f5745
`(3130) ug 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% (0,041.
`Acemporison of the single (Day !)and multiple (Day 51 dose
`plasma and urinary concentrations efcllndamycin indicates
`that there is accumulatian af eliadamycin following multi-
`ple dosing of BenzaClin Topical Get. The degree of accumu-
`latien calculated from the plasma and urinary excretion
`data was ~2-feld.
`Microbiology
`The ctindamycin and benzoyt peroxide components indi~dd.
`uaily have been shown to have ia vitro activity against
`Prop:on:booter:urn aches an ergamsm which has been aseo-
`elated with aene ~arlgaris; however, the clinical significance
`of this activity against P. nones was not examined in eliuical
`trials with this product.
`
`CLINICAL STUDIES
`
`In ~wo adequate and well controlled clinical studies of 758
`patients, 214 used BenzaClhi, 210 used banzoyl peroxide,
`168 used clindamycin, and 166 used vehicle. BenzaCtin
`applied twice daily for 10 weeks was ~ignificantly more
`effective than vehicle in the crcatmen~ of moderate m mad-
`erately severe faucial ecne vulgaris. Patinnfs were evaluated
`and ecae lesions counted at each clinical visit; weeks 2, 4, 6,
`g and I0. The primary efficacy measures were the lea:as
`counts and the investigator’s glohal assessmeut evainatod
`at week 10. Patients were instructed to wash the face with a
`mild sasp, using only the hands. Fifteen minutes after the
`face was thoraughly 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 he
`
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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 instcucted t~ avoid sun expo-
`sure. Percent reductions in lesion cmmts after treatment for
`10 weeks in these two studies are shown below:
`
`~Ize (Net Weight)
`
`NDC 0066*
`
`Benzoyl Peroxide Gel
`
`Active Clindamycin Powder Purified Water To Be
`Added to each vial
`(In plastic vial)
`
`Study 1
`
`BenzaClin
`
`n-120
`
`Benzoy] I Clindamycin
`peroxide
`n=120
`
`n=120
`
`Vehicle
`
`N=I20
`
`Mean percent redustion in inflammatory lesion counts
`
`25 grams
`
`35 grams
`(pump)
`
`0494-25
`
`0494-35
`
`50 grams
`
`0494-50
`
`50 grams
`
`0494-55
`
`(pump) .....
`
`19.7g
`
`27.6g
`
`39.4g
`
`39Ag
`
`i t
`;%1 22% V0% ..... t+1% with2oam os
`
`Mean percent reduction in uondnflmnmatory lesion counts
`
`BanzaClin Care Kit:
`50 grams
`BenzaCliu (pump)
`
`0495-55
`
`39.4g
`
`Viscontour Serum
`Meae percent reduction in total lesion counts ......
`
`36%
`
`I
`
`28%
`
`.15%
`
`I
`I
`
`1 0.2%
`t
`
`Study 2
`
`0.3g
`
`0.4g
`
`0.6g
`
`0.6g
`
`0.6g
`
`5 mL
`
`7 mL
`
`10 mL
`
`10 mL
`
`10 mL
`
`because n pessibl ..... lative irritnnsy effest omy occur, eo- Topical Gel er ben~yl perexide to eval’aate the effect on fer-
`tility. Fertility studies in rats treated orally with up to
`peciully with the use of peeling, desquamating, or abrasive
`300 mgikg/day of elindamycin (approximately 120 times the
`agents.
`amount of elindamycin in the highest recommended adult
`The use of antihiotic agents may be associated with the
`human dose of 2.5 g BensaClin Topical GeL based on mghn2)
`overgrowth of nonsasesptible organisms including fungi. If
`revealed no effects on fertility or mating ability.
`this occurs, discontinue use of this medication and take ap-
`Pregnancy
`propriato measures.
`Teratogeniu Effects
`Avoid contact with eyes and mucous membranes,
`Pregnancy Category C
`Clindamycin and erythromycin containing products should Animal reproductive/developmentai toxicity studies have
`sot be used in combina~on. In vitro studies have shown an-
`not been conducted with BenzaClin Topical Gel or benzoyl
`
` a smbo ’esn oss n mieobl s Thso sig pero de e,olopmeoO1 toxio ty stn es p e ed rots
`
`BcuzaClin
`
`n=95
`
`Beuzoyl
`peroxide
`n=05
`
`Clindamycin
`
`Vehicle
`
`n=49
`
`I N=48
`
`Mean percent reduction in inflammatory lesion counts
`
`63%
`
`I0 I
`
`3%
`
`45%
`
`50%
`
`39%
`
`I
`
`42%
`
`I 36%
`
`Mean percent redncLion in total lesion sounm
`
`58%152%
`
`f’
`
`42%
`_
`
`] 39%
`
`The BenzaClin group shewed greater overall improvement
`than the benzoyl peroxide, clindamycin and vehicle groups
`as rated by the investigator,
`
`INDICATIONS AND USAGE
`BenzaClin Topical Gel is indicated for the topical treatment
`~f aeno vaigaris,
`CONTRAINDICATIONS
`BenzaClin Topical Gel is contraindicated in these individu-
`ale who have shown hypersensitivity te any of its compo-
`aunts or to lineomycin. It is also contraindicated in those
`having a history of regional enteritis, ulcerative colitis, or
`~ntibioLic~asseciated colitis.
`
`nificance of this in vltra antagonism is not known:
`and mice using oral doses of elindamycin up to
`[nformction far Patients
`600 mgikg!day (240 and 120 times amount cfclindamyciu in
`Mean percent reduction in nan-inflammatory lesion counts Patients using BenzaClin Topical Gel should receive the fol- the highest recommended adult human dose based on
`lowing informati ..... d instructi .... g/ms .... pectively] .... bent ....... doses of elindamycln
`1
`I
`I
`54%
`L BenzaClln Topical Gel is to be used as directed by the up to 250 mgikg/day (100 and 50 times the amount of
`[
`clindan~cin in the highest recommended adult h~an dose
`physician. It is for external use only Avoid contact with
`based on mg]ms, respeotively) revealed no evidence of tera-
`eyes, and inside the nose, mouth, and atI mucous mem-
`tegenicity.
`b ..... as this product may be irritating,
`There are no well-controlled trials in pregnant women
`2. This medication should not he used for any disorder other
`treated with BenzaClin Topical Gel. It also is not known
`than that for which iL was proscril~ed~
`whether BenzaCIin Topical Gel can cause fetal harm when
`3. Patients should not use any uther toioical ache prepara~
`administered to a pregnant woman.
`Lien unless otherwise directed by physician,
`Nursing Women
`4. Patients should mimmize or avoid exposure to naturul or
`It is not known whether BenzaClin Topical Gel is excreted in
`artificial sunlight (taamng beds or UVA!B treatment)
`human milk after topical application. However. orally and
`while using BenzaClln Topical Gel. To minimize eximsure
`parenterally administered dindamycln has been reported to
`to sunlight, a wide-brimmed hat or uther protective cloth-
`appear in breast milk. Because of the potential for sencas
`ink should be worn, and a sanscreen with SPF 15 rating
`adverse reactions in nursing inihnte, a derision should be
`made whether to discontinue nursing or to discontinue f:he
`or higher should be used.
`5. Patients who develop allergic symptoms such as Severe drug. taking into account the impedance of the drug to the
`swelling or shortness i,f breath should discontinue mother.
`BenzaClin Topical Gel and contact their physician imme- Pediatric Use
`SatbtY andeffectivenese ofthisproductinpediatricpaticuts
`dlataly.
`below the age of 12 have not been established.
`6. BensaClin Topical Gel may bleach hair or colored fabric,
`7. BenzaClio Topical Gel can be stored at room temperature ADVERSE RFACTIONS
`WARNINGS
`up to 25°C (77°F) for 3 months. De not freeze. Discard During clinical trials, the mast frequently reported adverse
`any unused product after 3 months,
`event in the BenzaClin treatment group was dry skin (12%),
`ORALLY AND PARENTERALLY ADMINISTERED
`8, Before applying BenzaCtin Topical Gel to affected areas
`CLINDAMYCIN HAS BEEN ASSOCIATED WITH SEVERE
`The Table below lists focal adverse events reported by at
`wash the skin gently, then rinse with warm water and
`COLITIS WHICH MAY RESUI~T IN PATIENT DEATH. USE 01:
`least 1% of patients iu the BenzaClin and vehicle groups.
`THE TOPICAL FORMULATION OF CLINDAMYCIN RESULTS
`pat dry.
`IN ABSORPTION OF THE ANTIBIOTIC FROM THE SKIN
`Carcinogenesis, Mutagenasis, Impairment of Fertility
`SURFACE. DIARRHEA, BLOODY DIARRHEA, AND COLITIS
`Benzoyl pere~de has been shown to he a tumor promoter
`(INCLUDING PSEUDOMEMBRANOUS COLITIS) HAVE
`and progression agent in a number of nnimRI studies, The
`BEEN REPORTED WITH THE USE OF TOPICAL AND
`clinical significance of this is IlnkDowrL
`SYSTEMIC CLINDAMYCIN. STUDIES INDICATE A TOXIN(S)
`Benzoyl peroxide in acetone at doses of 5 and 10 mg admin-
`PRODUCED BY CLOSTRIDIA IS ONE PRIMARY CAUSE OF
`istered twice per week induced skid tumors in transgenic
`ANTIBIOTIC-ASSOCIATED COLITIS. THE COLITIS fS USU.
`Tg.AC mice in a study using 20 weeks of topical treatment,
`ALLY CHARACTERIZED BY SEVERE PERSISTENT DIAR*
`In a 52 week dermal pbotocarcinogenicity study in hairless
`RHEA AND SEVERE ABDOMINAL CRAMPS AND MAY BE
`mice, themsdiant~etoonsetufskintumorformationwas
`ASSOCIATED WITH THE PASSAGE OF BLOOD AND
`d~eceasod and the number of Lumars per mouse increased
`MUCUS. ENDOSCOPIC EXAMINATION MAY REVEAL
`following chronic concurrent topical administration of
`PSEUDOMEMBRANOUS COLITIS. STOOL CULTURE FOR
`BenzaClin Topical Gel with exposure to nltravielet rsdla-
`Ctostrtdium Difficile AND STOOL ASSAY FORC. difficile
`tion (40 weeks of treatment tbllowed by t2 weeks of Peeling 9 (2%)
`TOXIN MAY SE HELPFUL DIAGNOSTICALLY. WHEN SIC-
`observation).
`NIFICANT DIARRHEA OCCURS, THE DRUG SHOULD BE
`In a 2-year dermal carcinogenicity study in rats, treatment
`DISCONTINUED, LARGE BOWEL ENDOSCOPY SHOULD SE
`with BenzaClin Topical Gel at doses ~f 100, 500 and
`CONSIDERED TO ESTABLISH A DERNITIVE DIAGNOSIS IN
`2000 mg/kg]day caused a dose-depeudent increase in the in~
`CASES OF SEVERE DIARRHEA. ANTIPERISTALTIC AGENTS
`cideure of kecateacanthoma at the trea~ skin sif~ of male
`SUCH AS OPIATES AND DIPHENOXYLATE W1TH ATROPINE
`rats. The incidence of keratcacanthema at the treated site
`MAY PROLONG AND/OR WORSEN THE CONDITION. DIAR~
`of males treated with 2000 mg/kg]day (0 times the highest
`The actual incidence of dry skin might have been greater
`RHEA, COLITIS, AND PSEUDOMEMBRANOUS COLITIS
`recornmended adnlthumandosecf2.5gBenzaClinToplcal
`wereitnotlhrtheuseofamcistu.~zcrintheses~udi~.
`HAVE BEEN OBSERVED TO BEGIN UP TO SEVERAL
`Gel, based oa mgim2) was statistically aignifitumtly higher
`Anaphylmds, as well as allergic reactions leading to hospi-
`WEEKS FOLLOWING CESSATION OF ORAL AND PAREN-
`than that in the sham- and vabiele~contrels,
`TERAL THERAPY WITH CLINDAMYCIN.
`talizatian, have been reported during post-marketing use of
`Genotoxicity sLudias were not conducted with BenzaClin clindamycinibanseyl peroxide preduets. Because these reac-
`Mild cases of pseudomembranans colitis usually respond to Topical Gel. Clindamycin phosphate was not geeatoxie in tions ure reported voluntarily from a population of uncer-
`
`Local Adverse Events - all causalities
`tn >l= I% of patients
`
`BenzaC]in
`n = 420
`
`Vehlele
`n = 168
`
`Application site reaction
`
`13 (3%)
`
`1 (<1%)
`
`Dryskin
`
`Pruritus
`
`50(12%)
`
`10(6%)
`
`8 (2%)
`
`1 (<1%)
`
`Erythema
`
`[ 6 (1%)
`
`1 (<1%)
`
`Sunburn
`
`I
`
`5 (1%)
`
`drug di~continuaLion alone. In moderato to severe cases,
`consideration should be given to management with fluids
`and electrolytes, protein supplementaLion and treatment
`with an antibacterial drug clinically effective against C. dif-
`ficile colitis~
`
`PRECAUTIONS
`General
`For dermatolegieal use only; not tbr ophthalmic use. Corn
`comitant topical acne therapy should be used with caution
`
`Salmonella typhimurium or in a rat micronucleus test.
`Clindamycin phosphate sutfexide, an oxidative degradation
`product of ctindamycin phosphate and benzoyl peroxide,
`was not cJastogenic m a mouse micronucteus test. Benzoyl sure,
`peroxide has been found to cause DNA strand breaks in a DOSAGE AND ADMINISTP~TION
`variety of mammalian ceil types, to be mutagenic in S. ty-
`BenzaCgn Topical Gel should be applied twice daily, morn-
`phimurium tests by some but not M1 investigators, and to
`ing and evening, or as directed by a physician, to affected
`cause sister chromatid exchanges in Chinese hamster ovary
`areas after the skin is gently washed, rinsed with warm wa-
`cells. Studies have not been performed with SenzaClln
`ter and patted dry.
`
`lain size, it is not always possible to reliably estimate their
`frequency or establish a causal relationship to drug expo~
`
`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 CO1VEPOUNDING INSTRUC-
`TIONS
`
`sufficient number of data points to calculate mean pharma-
`cekinetic parameters.
`
`percentage of Subjects ~fll at Le~l~t 75% Clearal~l:e
`
`lSee 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
`markJ 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 via[ to
`the gel and stir anti] homogenous in appearance (1 to 11/~
`minutes). Far the 35 and 50 gram pumps only, reassemble
`jar with pump dispenser, BenzaClin Topical Gel (as receo-
`atltuted) can be stored at room temperature up to 25~C
`(77"F) for 3 months. Place a 3 month expiraUnn 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 ofs~mofi-aventis U.S, LLC
`Bridgewater, NJ 08807
`©2010 sanofi-aventis U.S. LLC
`
`Plasma Pharmasokinetic Summary
`
`PK Parameter
`
`Carac
`n=l
`
`Efudex (Mean_+ SD}
`o=6
`
`Cm,~
`Tra~~
`
`AUG 10-241
`
`0.77 n~mL
`1.00 hr
`2.80 ng*hr/taL
`
`11.49 +- 8.24 ng]mL
`t.03 !: 0.028 hr
`22.39 :~ 7,89 ug~hr/mL
`
`I
`
`I
`
`Five of I0 patients receiving Carac and nine of 10 patients
`receiving Efudex® 5% Cream had measurable urine
`fluoruuracil levels.
`
`Urine Pharmacokinetl¢ Summary
`
`PK Parameter
`
`Carac
`(Mean ± SDI
`(Range)
`n=lg
`
`Efudm¢
`(Mean ± SDI
`(Range}
`n=10
`
`CARAC® CREAM, 0.5%
`(ca-rack}
`(fluorouracil cream)
`FOR TOPICAL DERMATOLOGICAL USE ONLY (NOT
`FOR OPHTHALMIC, ORAL, OR INTRAVAG|NAL USE)
`
`’
`
`Cure Ae*
`(min-max)
`I~ Max excretion
`rate
`(rain-max)
`
`119.8-+ 94.80 mcg
`2.74± 5.22 meg
`(0-15.02)
`(0-329.87)
`0.19 ~: 0.52 meg]hr 40.27 L47.14 mcg/hr
`
`(0-1.671
`
`(0-164.5)
`
`* CamuJative urinary excretion
`
`DESCRIPTION Bath Carae and Efudex@ 5% Cream demonstrated low men-
`surableplasmaeonceetrationsibriincceuracilwhenadmin-
`istervd m~der steady-state conditions. Cumulative urinary
`excretion of fluoreuracil was low for Carat and tbr Efude:~,
`corresponding to 0.055% and 0.24% af the applied doses, re-
`.~pectively.
`
`Cacao@ (fluorouracil cream) Cream, 0.5%, contains
`iluorouracil for topical darmatologic use. Chemically,
`tluorouracil is 5-fluoro-2,4(IH, 3H)-pyrimidinediane. Tlm
`molecular formula is CaHsFNsOs. Fluoreurncil has a melee-
`alar weight of 130.00.
`
`~u¢~
`!=~1~dy sr2~j
`
`~ w~
`
`9 wk
`
`~ w~
`
`w~E~
`
`INDICATIONS .~ND USAGE
`
`Carac is i~dicated ibr the top,cat treatment of multiple ac-
`tirdc or solar keratoses of the fi~re and anterior ecaip~
`
`CONTRAINDICATIONS
`Fluerouraeil may cease fetal harm when administered to a
`pregnant woman. Fluerourasil is contraindicated iu women
`who are or may become pregnant. If this drug is used during
`
`AN~ F
`
`HN
`
`o
`
`o
`
`H
`
`1MicTosponge is a registered trademark of Cardinal Health.
`toe. or one of ite aubsidiari~
`
`CLINICAL PHARMACOLOGY
`
`Pcrce~ag~ ,~ Subiect~ wi~h r00"~,. C’lc~r,~nct~
`
`~o~
`- ............................/-"~-~.
`eo.~ ....................
`r~---
`
`2ESldex is a registered trademark of ]~CN Pharmaceuticals,
`-
`Inc.
`Clinical Trials
`Under the experimental conditions of the topical safety
`studies Carac was net observed to cause contest sensitize-
`ties. IIowever, approximately 95% of subjects in the active
`arms ef the Phase 3 clinical stndies experienced facial in’i-
`tatioa, irritation is likely and sensitization is unlikely based
`on the results of the topical safety and Phase 3 studios,
`Two Phase 3 identically designed, multi-center, vehicle-
`ecutrolled, double-blind studies were conducted to evaluate
`Carac Cream contains 0.5% fluorouracii, with 0.35% being the clinical saihty and efficacy of Caruc, Patients with 5 or
`incorporated into a patented porous microsphero
`(Microeponge(0)~ composed af methyl methacrytate]glycal more actinic keratoses (AKs) on the face or anterior bald
`scalp were randomly allocated to active or vehicle treatment
`dimothacrylate crosspolymer and dimethicooe. The cream
`in a 2:1 ratio. Patients were randomly allocated to treat-
`fermtflatian contains the f.ollmving other inactive ingredi-
`rm=nt durations ef 1, 2, or 4 weeks in a !:1:1 ratio. They ap-
`eats: Carbomer Homapolymer ’1~¢pe C. dimethioone, glyc-
`plied the steady cream once daily to tim entire face}anterior
`erin. methyl ginceth-20, methyl methacrylate]glycol
`WARNINGS
`bald scalp. Each patient’s clinical response was evaluated 4
`dimethacrylate croospolymar, methylparnben, octyl hydroxy weeks ai?;er the patient’s last scheduled application of study The potential for a delayed hypersensitivity reaction to
`stearate, polyethylene glyca1400, polysorbate 80, prepylene cream. No additiana! post-treatment follow-up efficacy or t/uamuraci! exists. Patch testing to prove hvpereeasitivity
`glycol, prepylparaben, purified water, sorbitan monooleete.
`stearic acid. and trelamine, safety assessments were performed beyond 4 weeks aider may be inconclusive.
`the last scheduled applications. The following graphs show
`Patients should disceutinuo tberopy with Cacao if syrup-
`the percentage of patient~ in wbem 100% of treated lesions
`toms of DPD enzyme deficiency develop.
`cleared, and the percentage of patients in wham 75% or
`Rarely, unexpected, systemic toxicity (e.g. stematitis, disc-
`more of treated lesions cleared. ~f~atmant with Carat
`rhea, neutropenia, and nouretoxieity) asssciated with par-
`creem for 1, 2, or 4 weeks is compared to treatment with
`enteral administrotiee of fluc~reuracil has been attributed to
`vehicle cream. Outcomes from 1 2, and 4 weeks of treat-
`deficiency of dihydrepyrimidine dehydregenase "DPD" ac-
`There is evidence that the metabolism of fluorouracil in the ment with vehicle cream are pooled because duration of
`tivity. One case of life threatening systemic toxicity has
`anaholie pathway blocks the methylatian reaction of deox-
`treatment with vehicle had no substantive effect on clear-
`been reported with the topical use at’ 5% fluarouraci! in a
`yuridytic acid to thymidylic acid. In this manner,
`ance. Results from the two Phase 3 studies are shown sep-
`patient with a complete absence of DPD enzyme activity,
`fluarouracil interferes with the synthesis of deoxyribenu-
`stately. Although all treatment regimens of Cacao studied
`Symptoms included severe abdominal pain, bloody diar-
`cleic acid (DNA~ and ~ a lesser extent inhibits the ferma-
`demonstrated efficacy over vehicle far the treatment of an-
`rhea, vemlting, fever, and chills, Physical examination re-
`tlon of ribenueleie acid (RNA). Since DNA and RNA are es-
`tinic keratosis, continuing treatment up to4 weeks as tel-
`vealed atomatitie, erythematoue skin rash, nantropenia,
`sential for cell divieian and growtb, the effect of fluomuracil
`crated results in further lesion reduction and clemSng,
`thrombecytapenia, inflammation of the esophagus, stomach,
`may be to create a thymine deficiency that provokes tmbal-
`and small