Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Galderma Laboratories, Inc.
`IPR2015-_
`_
`Exhibit 1043
`
`

`
`Partnership for
`Prescription Assistance
`
`NATIONAL PARTNER ORGANIZATIONS
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`Action CF
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`1
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`The AIDS Institute
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`United Way of America
`}:~~~/.~~ ~~> T' ~"',; f;_::: ~ r-":
`Warnen Impacting Public Policy · "'~'-"'··''
`NationalBreast Cancer Organization
`
`Exh. 1043
`
`

`
`EDITION
`
`2007
`
`PHYSCANS'
`DESK
`REFERENCE®
`
`Executive Vice President, PDR: Kevin D. Sanborn
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`ISBN: 1-56363-568·2
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`Exh. 1043
`
`

`
`1000/CETYLITE
`
`Cetacaine-Cont.
`
`der dentures or cOtton rolls, as reterttion of the actiye ingre_-
`dients under a denture or cotton~ roll colild :POssibly cause
`an e·scharotic-effect. Routine precaution for the use of an.Y
`topical anesthetic should be observed when- using
`cetäcaine.
`Jetco® Cannula for·cetacaine Spray
`• The supplied 4" stainless steel Jetco® cannula (J-4) for
`Cetacaine Spray·is espec:ially·de~igned fpi'cicce-ssibllity
`a:rid applicatitin of CetaCffiile, :ai _the requir6d site of pail1.
`control.
`.
`.
`• The Jetco c_annula is \'}lso available -in· 6", (J-6} and:_B':_
`curved configuration, (J-8).
`.·
`. ·
`• ReplacemelltJetco. cannulas are avail.ahle.
`• The J'etcö carulUla i'S inserted firm1y into 'the protrudir~g
`plastic Stern on eaCh bottle ~?f Cefaqiine Spray.
`.
`• The J eteo eannuJa may be reinovEid and reinserted as
`many times as required for eleansin:g or steriliZation,
`and is autoclavable.
`'
`·
`PACKA~ING AVAILABLE
`CetaCaine Spray 56 g. including prO.pellant. *
`.
`·
`·
`Cetaeaine Li<iuid 56 g.
`Cetacaine Hospital Gel29 g. Tube.
`.
`*WARNING
`.
`.
`Contains CFC-1,14 and CFCc11, substances which hann
`publie health and environment by destroying ozorie i;n the
`rippei atmospher~:
`Rx On'Hy.
`CETVLITE
`ll\l!lUSTRIES, 1!\IC.
`9051 River Road
`.
`.·
`-
`Pennsauken, NJ 08110-3293'
`1-800-257-7740
`.
`.
`www.cetylite.eom
`Rev. 9/03.1
`Made in U.S.A.
`. .
`. , . · ·.·
`....
`Shown in Prod,uc_tldentification.Guide, page 309-
`
`COLD•fX. Pharrnacel.lticals {USA)
`h1c.
`5600NORTH RIVER ROAD, SUITE.801l
`CHICAGO, IL, USA, 60018
`.
`.
`
`Direct lnquiries to:
`1-877 -490·3300
`
`COLD-fXTM!t
`Strengthen~ the Immune Syst~m*
`
`.OTC
`
`Supplement Facts
`Serving Size 1 Capsule
`% Daily Va_Jue
`Amount Per Servjng
`CVT-E002 ·.is a proprietacy and patented natural extract
`containing poly-furanosyl-pyranosyl-sacchari,des deriyed
`from Panax quinqUefolius (North American Ginseng, root)
`200mg**
`** Daily ValUe not established
`Other ingredients: Gelatin
`DIRECTIONS
`Recommended for Short-Term Use
`Day 1, take 3 capsules 3 times during the day (total ~
`9 capsules)
`Day 2, take 2 capsules 3 times during the day (total ~
`6 capsules)
`,
`Day 3, take 1 capsule 3 times. during the day (total ~
`3 capsules)
`Recommended for Long· Term Use
`Take 1 capsule .2- tim es each day
`
`Recommended use for adults and chiJdren ages 12 yer;ars _and
`older.
`WARNINGS
`Inclividriills with serious health conditions or talring medi-
`cationS-, or pregnant or lactating warnen, should consult a
`health care professional before taking COLD-fX"M extract.
`As COLD-fX extract is a derivative of North American
`ginseng; 'it is not recommended for individuals with aller-
`gies to gin~eng. Do not exceed the recomrnended dail;v dose.
`OTHER INFORMATION
`Each capsule is a ChemBioPrintTM prod-qct,_-.~<3.de with a
`patented technology that is used to identi:fy'the ·active com-
`ponerits of CVT-E002, a proprietary artd patentednatural
`extract, tci-proVe'the-health benefit ofCVT-E002, and to en-
`sure that the prod1.1ct is consistelltly made from batch to
`batch.
`For inore information on COLD.fX, ·visit.www.cold-fx.com
`HOW SUPPLIED
`Available in bottles of30, 60 and.150 capsules as weil as an
`18 capsule blister pack8.ge.
`·
`*·This Statement has noil: beeul'eValuated b\t.the Food
`and Drug Administration. This prroduct is· not intended
`to diagnose, treat, eure or prevent any disease.
`
`lnformatioii''.wilrbe·-supersecieCI by sui)plements. and slibsequent editions
`
`tThe·product name·tefers to the- traditiohal co'oling energy
`öfthe source material. This.product is notintended to-trea:t,
`eure or prevent upper respiratory infections due to cOld 'or
`influenza-like viiuses.
`Distributed by: COLD-IX Pharmaceuticals !USA)Inc.
`5600 N. River Road, Suite 800, Chicago, !L, USA 60018
`1·877,490·3300 · cold·lx.com
`TM-:owned by fX Life Seiences International GmbH and
`Used under license.
`-
`US Patents #ß,432,454, #6,156,291
`REFERENCES
`1. Goel DP, et aZ: Doping-control urinalysis of a ginseng
`extract, Cold-fX, in· athletes. Int J Sport NU.tr Exerc
`Metab 2004, 14(4): 473-480.
`.
`2. McElhaney· JE, et al. Efficacy of COLD-fX in the
`prevention of respiratory symptoms '.in __ com.munity-
`dwelling adults: a randomized, double-blind, placebo-
`controlled trial. Journal of Alternative and Comple-
`mentary Medicine 2006, 12(2): 153-157.
`3. McElhaney JE; et al. A placebo-controlled tr,ail of a
`. proprietary extract of N orth American ginseng
`(CVT-E002) to prevent acute respiratory illness in in-
`stitUtionalized older adults. Journal of American Ger'-
`iatics Society 2004, 52: 13·19.
`4. McElhaney JE, et al. COLD-fX stimulates cell medi-
`ated immune i-esponse of peripheral leukocytes to
`infl.uenza virus in National Hockey League players
`2006, manuseript in'preparation.
`5. Predy GN et al. Efficacy of an extract ofNorth Ameri-
`cän · ·giriseng eontaining · poly-furanosyl-pyranosyl-
`saecharides for preventmg upper respiratory traet in-
`fectionß: a -raitdorirized controlled .trail .... Canadian
`MedicalAssociationJoumal2005, 173(9): 1043-1048. ·
`.Predy GN et al. Immune' modulating- effects öf daily
`supplementationcof COLD'fX (a·proprietaryextriwt of
`N orth Ameriean ginseng) dUring an inf:luen.Z·a seftsoil
`in healthy adults 2006, in press.
`7. Wang M et.al. A proprietary extract from NortltAmer-
`ican ginseng (Pq,nax quinquefolium).enhances IL-2 and
`IFN-y:productions in murine spleen cells induced by
`Con-A.
`International ImmunopharmacOlogy 2004;
`4:311-315.
`.
`. .
`.
`8.· Wang. -M- et" · af.-· IJilmunomodulating activity· of
`. CVT-E002,_. a proprietary extract from N orth American
`ginseng (PanaX quinquefolium). Journal of Pharmacy
`and Phannacology2001, 53:1515-1523.
`9. Ueng Y and C Chen. Effects ofCVT-E002; a proprietarj
`extract from N rirth American .ginseng_(Panax quinqite-
`folium)·: on.-··drug· metabolizing ·enzymes. Journal--of
`Chinese Medicine 2002, 13(2).: 89~96., ·
`10~ YaiJ.g JC et al. Eflects .of Arilerican_·ginseng extract
`(Panqx-quinquefolius) an formalin-inducednociception
`in miee. American Journal of Chinese Medicine 2001,
`. 29(1): 149-1.54.
`. ..
`Show_n in_Product Identification.Guide, page 309
`
`6'.
`
`CollaGenex Pharmaceuticals.,.lnc.
`41 UNIVERSITY DRIVE; SUITE 200
`NEWTOWN>,PA 18940 ·
`
`Direc~ inquiries to:
`888-339-5678
`
`ORACEATI"
`[or·RAY:sha]·
`(doxycycline, USPI
`Capsules 40 mg•
`
`*30 mg Immediate Release & 10 mg Delayed Release beads
`RxOnly
`KEEP OUT OF REACH OF CHILDREN
`The dosage of ORACEA differs from that of doxycycline
`used to treat infections. To reduce the development of.resis-
`tant bacteria as well as to maintain the effectivehess of
`other antibaeterial drugs, ORACEA should be used only as
`indicated.
`ORACEA is indicated for the treatment of only infiamma'
`tory lesions. (papules and pustules) ·of rosacea in adult pa-
`tients.
`-
`This formulation of doxycycline has· ·n'ot'-been evaluated as
`an antibacterial in the treatment of infe'ctiö:Us. ·
`DESCRIPTION
`ORACEA (doxycycline, USP) capsules 40 mg are hard
`gelatin capsule shells filled with two types of doxycycline
`beads (30 mg irirm.edi8.te release and 10 mg delayed-
`release) that tagether provide a dose of 40 mg of anhydrous
`doxycycline (C22H24N20 8).
`The struetural formula of doxycycline,"U.SP is:
`
`CH,
`
`OH
`
`CH,-...._.....ca.
`N
`
`"::C
`. " l
`,v: ~lr-
`
`~
`
`I'
`
`'
`
`OH
`
`0
`
`an
`
`0
`
`.H,O
`
`PHYSICIÄNS' DESK REFERENCE®
`
`with an empirical fornillia 'ofC22H24N20 8 •If20-<in.d_:a mo-
`lecular weight of 462.46. The chemical designation for
`doxycycline is 2-Naphthacenecarboxamide, 4-(dimethyl-
`amino)-1,4,4a,5,5a,6,11,
`. lga,octahy<Jro-3,5,J.O,i2,12a·
`pentahydroxy-6-methyl-1,11-dioxo-, [ 4S-~4aa, 4aa, 5a, 5aa,
`6a,12aa)]-, monohydra,te. : Iti· is very slightly soluble
`in·water.
`:.
`·
`: ·
`,
`Inert ingredients in th~ fonll11latlon are: hyProniel_iOse,
`iron mtide .red~ iron oxide yflllow, methacrylic- aeid- cöpoly-
`mer, polyethylene glycol, Polysorbate 80,· sugar ~pheres·,
`talc; titanium dioxide, and trlethyl citrate. Active ingredi-
`ents.:_ EaCb- capsule contaüts doxycycline, USP in 'an amount
`equivalent to 40 mg of anhydrous doxyeycline.
`CL~CALPHARMACOLOGY
`Pharmacokinetffcs ~
`to other
`ORACEA capsuleS, are not bioequivalent
`doxycyeline prod~Cts. The pharmacokineti,cS- Of doxycycline
`following or!il ci.dministration ofORACEAWas investigated
`in 2 volunteer studies involving 61 adults.: Pharmacoki~
`netic parameters for ORACEA follmying sirigle oral doses
`and at steady-state in healthy Subje.cts aie presented in Ta-
`ble 1.
`(See table 1 at top ofnext page]
`Absorption:
`In a single-dose food-effect study involving
`!;ldministration of ORACEA to healthy volunteers, coneom-
`itant administration with a 1000 calorie, high_-fat, high-
`-prot~in meal that included dairy products, resulted in a de-
`Crease in the rate arid exti:iri.t of absorptio:ri ( Cmax- and
`AUC) by about 45% and -22%, respectively, compared to
`dosing under fasted conditions. This decrease in systemic
`exposure can be clinically signifieant, and therefore if
`ORACEA is taken close to meal times, it is recommended
`that it be taken at least one hour prior to or two houl:S after
`lneals.
`Pistribution: Doxycycline is greater than 90% bO~d to
`plasma proteins.
`Metabolism: Major metabolite_s of dÜxycycline have not
`been identified. However, enzym:e ittducerS ·such as barbi-
`tllrates, carbamazepine, and phenytoin decrease the half-
`life of doxyc)rcline.
`·
`Excretion: Doxycycline is e?t-creted in the urine and feces
`as unchanged drug. It is re:Ported that between 29% and
`55.4% of an administered dose ean be accounted for in the
`urine by 72 hours. Terminal half-life averaged 21.2 hol.'lrs
`in subjects receiving a· single dose of ORACEA.
`. " .
`Special Populations
`Geriatrie: Doxycyclirte ·pharmacokinetics have not been
`evaluated in geriatriq,patients.
`Pediatric:_ ·' boxyCycline pharmacokinetics have not been
`evaluated in pediatric patients (See WARNINGS section).
`Gender: The pharmacokinetics· of ORACEA were com-
`pared in 16 male and 14 feniale subjects under fed and
`fasted conditions. While female subjects had a higher
`Crriax and, AUC than male subjects, these differences were
`thought to be due to differences in body weight!lean body
`mass.
`Race: _;Differences in doxycycline pharmacokinetics among
`racial groups have :riot been evaluated.
`Renal Insufficiency: Studies have shown .. no significant
`difference in serum half-life of doxycycline in patients with
`normal and severely impaired renal function. Heroadialy-
`sis does not altertheserum half-life of doxycycline.
`Hepatic Insufficiency: Doxyeycline pharlnacokinetics
`have not been evaluated in patients With hep.atic'insuffi-
`ciency.
`In a study in healthy volunteers
`GaStric InsliffiCiency:
`(N ~ 24) the bioavaÜability of doxycycline is reported tobe
`i"educed !lt high -pH.- This reduced· bioavailability may be
`clinic:ally significant in· patients with gastrectomy, gastric
`bypass surgery or who are otherwise deemed,achlorhydric.
`Drug Interactions: ·(See PRECAUTIONS section).
`MICROBIOLOGY
`Doxycycline is a member of the tetracycline dass of anti-
`baeteri:ll drugs. The_pla_sma concentrationS of doxycycline
`achieved with ORACEA during administration (see
`CLINICAL PHARMACOLOGY and DOSAGE AND AD-
`MINISTRATION) are less than the concentration required
`to treat bacterial diseases. In vivo microbiological studies
`utilizing a similar drug exposure for up to 18 months dem-
`onstrated no detectahle lo;ng-term e:ffects on bacterial flora
`ofthe oral cavity, skin, intestinal tract, and vagina.
`ORACEA should not be used for treating bacterial infec-
`tions, providing antibacterial prophylaxis, or reducing the
`numbers- or· eliminating microorganisms associated with
`any ba:cteria] disease.
`CLINICAL STUDIES
`The safety and efficacy ofORACEAin the treatment ofonly
`inflammatory lesions (papules.and pustules) ofrosacea was
`evaluated in two randomized, placebo-controlled,- multi-
`eentered, double-blind, 16-week Jlhase 3 studies involving
`537 patients (total of 269 patients on ORACEA from the
`two studies) with rosacea (10 to 40 papul8s and pustules
`and two orfewer nodules). Pregnant and nursing warnen,
`patients <18 years of age, and patients with ocular rosacea
`andlor blepharitis/meibomianitis who require Ophthalmo-
`logie treatment were excluded from study. Mean ·baseline
`lesion counts were -20 and 21 for ORACEA and placebo
`patient groups reSpectively.
`At·Week 16;patieints-in the ORACEA group were evaluated·
`using co~primary endpoir:i.ts of mean. reduction· in lesion
`counts and a dichotomized'static Investig8.tor's·GlobalAB·
`sessment of Clear or Ahnost Clear ( de:fi.Iie-d -as 1 to 2 small
`
`Exh. 1043
`
`

`
`PRODUCT INFORMATION
`
`Tabie 11. PharmacokinetiC Parameters [Mean ( ± S!D)l for ORA.CIEA
`Cmax*
`(ng/mL)
`
`N
`
`30
`
`31
`
`i
`
`510 ± 220.7
`
`-600 .± 194.2
`
`-
`
`--
`
`-
`
`'··-
`
`Single DÖSe
`40 mg capsules
`
`Steady-State#
`40 mg capStiles
`
`*Mean
`t Mediari
`#Day7
`
`Tab~e 2. Clinicai Results of ORACEA versus pnacebo
`
`Tmax•(hr)
`
`3.00
`(1.0-4.1)
`
`2.00
`(1.0-4.0)
`
`AUC0 .• *
`(ng-hr/mL)
`
`9227 ±
`3212.8
`7543 ±
`2443.9
`
`tl/2*
`(hr)
`
`-21.2 ± 7.6
`
`23.2 ± 6.2
`
`Study 1
`
`Study2
`
`ORACEA
`40mg
`N ~ 127
`
`-11.8
`
`Placebo
`
`-5.9
`
`ORACEA
`40mg
`N ~ 142
`
`-9.5
`
`Placebo
`
`N ~ 144
`
`-4.3
`
`39 (30.7%)
`
`24 (19.4%)
`
`21(R8%)
`
`9 (6.3%)
`
`Mean Change in ·Lesion Count
`from Baseline
`No.(%) ofSubjects Clear or Almost
`Clear in the IGA*
`* Investigator 's Global Assessment
`
`papules or pustules) when c_Ompaied to the_r~l~cebo grQup
`· ·
`in both Phase 3 sturlies
`[See table 2 above] _
`Patients treated with ORACEA did not demonstrate sig-
`nificant improvement in erythema when Conipared t~ those _
`·
`g.eated with placebo.
`lNDICATIONS AND USAGE
`ORACEA is indicated for the treatment of only ihflamma-
`tory lesions (papules and -pustules) of rosacea in adult pri-
`tients. -No meaningful effect was demonstrated. for gener-
`alized erytherila (redness) _of rosacea. ORACEA has not
`been evaluated for the-treatment ofthe erythematous, tel-
`angiectatic,- or ocular _ components ·of rosacea. Ef:ficacy of
`ORACEA beyond 16 weeks and safety beyond 9 months
`have not been established.
`This formulation of döxycyclirre,has-not been evaluated in
`the treatment or prevention of infections.- ORACEA should
`not be used for treating bacterial infections, providing an.:
`tibacterial prophylaxis, or reducing the numbers or elimi-
`nating microorganisms associated with any bacterial dis-
`ease.
`To reduce the development of drug-resistant bacteria as
`well as to maintain the effectiveness of other antibacterial
`drugs, ORACEA should be used only as indicated.
`CONTRAINDICATIONS
`This drug is contraindicated in persans who have Shown
`hypersensitivity to doxycycline or any·ofthe other tetracy-
`clines.
`WARNINGS
`Teratogenic effects
`1) Doxycyciine, lnke otlher tetracyc~ine-cia~s_ antibiotics, can
`cause fetai harm wlhen admillllistel!'ed to a preQnant woman.
`lf any te11:racycline ns IIJSedl dming ptregnancy Or if the patie1111:
`becomes pregnant Whfiie 11:aki~rng 1t:hese drugs, the patient
`should be irnformed of 1the potential tnazardl to the fiet.us and
`treatment sto'pped immediateiy.
`ORACEA should not be used during pregnancy (see PRE-
`CAUTIONS: Pregnancy).
`2) The use of drugs of the tetracycifrne class durring tooth de-
`ve!opment Oasil: half of pregnancy, nnfancy, and chi!dhood up
`to the age of 8 years) may cause permanent düscoloratioil. of
`the teeth (yei!ow-gray-lbroVIin). This adverse reaction 'is
`more comri:ton duririg long-terin use of the ·d_rug but has
`been observed following repeated short-term courses. En-
`amel hypoplasia hasalso been reported. 1'e11:racycline dn.ngs,
`therefore, sho.ulld not be-used duringtoot[h deve!opmentun-
`less other drlllgs are not. 16keny to--be effective or are contra-
`indicated.
`3) Alltetracyclines form a stable calcium. complex. in any
`bone-forming tissue. A decrease in fibula .grovvth rate has
`been observed in premature human infants giv43n oral
`tetracycline in doses of 25 mglk.g every 6 hours. This reac-
`tion was shown tobe reversible when the drug was discon-
`tinued.
`Results of animal studies indicate that tetracyclines cross
`the placenta, are found in fetal ~issues, and c3n cause re-
`tardation of skeletal development on the developing fetus.
`Evidence of embrjotoxicity has been _ ;noted in animals
`treated early in pregnancy (see PRECAUTIONS: Preg-
`nancy section).
`·
`GastJroinrtestßnai effects
`Pseudomembranous colitis has 'been rreport-ed with nearly
`all antibacteriai agrents and may range frrom mild to iife~
`threatening. Therefore, it is important to consider this d!ag~
`nosis in patientS who present wüth diarrhea subsequeil'fi to
`the administration of anil:ibacterrial agents.
`'
`.
`Treatment with antibacteria~ agents -alterS :the noriniil
`flora ofthe colon and m:iy permit oVergi:"owth of clostridia.
`Studies indicate that a toxin produced'by ClostridiUm dif~
`:ficile is a primary cause of"antibiotic-äSsoCiatedcolitis".
`
`If a diagnosis of ps€md0membranous cOlitis has been estab~
`lished, therapeutic measures should be initiated. Mild
`cases of pseudomembranous Colitis usually respond to dis-
`continuation ofthe drug alone. In moderate to severe cases,
`consideratlon should be given to management with fluids
`and electrolytes, protein supplementation, and treatment
`with an antibacterial drug clinically effective against Clos~
`tridiv.m difficile colitis.
`MetaboUne effecil:s
`The anti-ariabolic action of the tetracyclines may cause an
`increase in BUN. While this is notaproblern in-those '(Vith
`normal renal function, in patients with signi:ficantly im-
`paired function, higher serum levels of tetracycline-dass
`antibiotics may lead to azotemia, hyperphosphatemia,-and
`acidosis. If renal impairment exists, even usual oral or
`parenteral döses may·lead to excessive systemic accumu-
`lations of the drug and possible liver toxicity. Under such
`conditions, lower than usual total doses are indicated; and
`if therapy is prolonged, serum level determinations of the
`drug may be advisable.
`, Plhotoserns~tivity.
`Photosensitivity manifested by an exaggerated sunburnre-
`action has been observed in some individuals taklng
`tetracyclines. Although this was not observed during the
`duration of the clinical studies with ORACEA, patients
`should minimize or avoid exposure to natural or artificial
`suulight (tanning beds or UVA/B treatment) wbile using
`ORACEA. lf patients need to be outdoors while using
`ORACEA, they should wear loose-fitting clothes that
`protect skin from sun exposure and discuss other sun
`protection measur€)s 'with their physician.
`PRECAUTIONS
`General
`Safety of ORACEA beyond 9 months has not been estab-
`lished.
`AB with other antibiotic preparatiOns, use ofORACEAmay
`result in overgrowth of nrin-s-usceptible miCroorganisms,
`including fungi. lf superinfection occurs, ORACEA should
`be discontinued and appropriate therapy instituted. Al-
`though not observed in clinical trials with ORACEA, the
`use of tetracyclines may increase the incidence of vaginal
`candidiasis.
`ORACEA should be used with caution in patients with a
`history of or predisposition to candidiasis overgrowth.
`Bacteirial resistance to tetracyclines may develop in pa-
`tients using ORACEA. Because of the potential för drug-
`resistant-bacteria tn develop during the use Of ORACEA, it
`should be used only as indicated.
`Aurtoimmune Syndromes
`Tetracycliites have been · associated with the developmeint
`of autoimmune syndromes. Symptoms may be manifested
`by fever, rash, arthralgia, and malaise. In symptomatic pa-
`tients, liver function tests, ANA, CBC, and other appropri-
`ate tests should be performed to evaluate the patients. Use
`of all tetracycline-dass drugs should be discontinued im-
`mediatE;Jly.
`lissue Hyperpigm.entatiQn
`T~tracycline class an~ibiotics are known to cause hyperpig-
`mentation. Tetracycline therapy may induce hyperpigmen-
`tation in many organs, including nails, bon8, _skin, eyes,
`thyroid, visceral tissue, oral cavity (teeth, mucosa, alveolar
`hone), sclerae and heart valves. Skin and oral pigmentation
`has been reported to occur independently oftime or amount
`Of drug adroinistra'tion, whereas other pigmentation has
`been reported to occur upon prolonged administration.
`Skinpigmentation includes diffuse pigmentation as well as
`over sites of scars or injury.
`1Pseudlo·h.11mor cerebrli
`BUlgingfontanels in infants and benii5nintracranialhyPer-
`tensiOn-in-adults have been reported in individualS receiv-
`ing tetracyclines. These conditions disappeared ·When _ the
`drug was discontinti~d.
`
`COLLAGENEX/1001
`
`infol!'mation forr Pa1t:mernts
`See Patient Package ~1111sert that accompanies this Package
`~nsert for additional infmmation to give patients.
`1. Photosensitivity manifested by an exaggerated sun~
`burn reaction has been observed in some individuals
`taking tetracyclines, including doxycycline. Patients
`Should minimize or avoid exposure to natural or
`artificial surrlight (tanning beds or UVA!B treatment)
`while using doxyc:ycline. If patients need -to be-out-
`doors while using doxycycline,-they should wear loose-
`fitting clothes that protect .. -skin~{rom sun exPosure
`and discuss other sun protection measures with their
`physician. Treatment should be ·diScon.tinued at the
`first evidence of sunburn.
`2. Concurrent use of doxycycline tnay render oral contra-
`ceptives less effective (See Dll."Ug.lnteractions).
`3. Autoimmune syndromes,
`includ,ing- d:rug-induced
`lupus-like sy-ndrome, autoimmune hepatitis, vasculi-
`tis and serum sickness have been- observed with
`tetracycline-class antibiotics, including doxycycline.
`Symptoms may be manifested by arthralgia, fever,
`rash and malaise. Patients who experience such
`symptoms should be cautioned to stop the drug im-
`mediately and seek medical help.
`4.' Patients should be counseled about discoloration of
`skin, scars, . .teeth or gums that can arise from
`doxycycline therapy.
`5. Take ORACEA exactly as directed. Increasing doses
`beyond 40 mg every morning 'may increase the likeli-
`-hood that bacteria will develop resistance and will not
`- be treatable by other antibacterial drugs in the
`future..
`-
`6. It is recommended that ORACEA not be used by preg-
`nant or breast feeding warnen. I See Cardnogenesis9
`Mutagenesis, Impairment of Ferlil.iity, Pregnancy
`and Nursing Mothers-sections).
`7. It is recomniended·that ORACEA not be used by indi-
`viduals of either gender who are attempting to -con-
`ceive a child (See Carcinogenesis9 Mutagenesis, Im~
`pairment ofFertlHty, and· Pregnan.cy sections).
`Laiboratory Tests
`Periodic laboratory evaluations·of organ systems, including
`hematopoietic, renal and hepatic studies· should be per~
`formed. Appropriate tests for autoimmune syndromes
`should be performed as indicated.
`Drug lnrl:eractUons
`1. Because tetracyclines have been shown to depress
`plasma prothrombin activity, patients who are on anti-
`coagulant therapy may require downward adjustment
`oftheir anticoagulant dosage.
`2. Since bacteriostatic drugs may interfere with the·bacte~
`ricidal action ofpenicillin, it is advisable to avoid giving
`tetracycline-dass drugs in conjunction with penicillin.
`3. The concurrent use of tetracycline and methoxyfiurane
`has been reported to result in fatal renal toxicity.
`4. Absorption of tetracyclines is impaired by bismuth
`subsalicylate, proton pump
`inhibitors,
`antacic,ls
`cantairring aluminum, calcium or magnesium and iron-
`containing preparations.
`5. Doxycycline may interfere-with the effectiveness oflow
`dose oral contraceptives. To avoid contraceptive failure,
`females are advised to use a second form of contracep-
`tive during treatment with doxycycline.
`6. There have been reports ofpseudot-11mor cerebri (benign
`intracranial hypertension) associated with the concom-
`itant use of isotretinoin and- tetracyclines. Since .both
`oral retinoids, including isotretinoin and acitretin, and
`the tetracyclines, primarily minocycline, can cause in-
`creased intracranial pressure, the concurrent use of an
`oral retinoid and a tetracycline should be avoided.
`Drug/Laboratory Test ffrnteractions: False eievatians of
`urinary catecholamine levels may occur due to interference
`with the fluorescence test.
`Carcinogenesis, Mutagetnesis, lmpaitrment of Fertility:
`Doxycycline was assessed foi' potential to induce carcino-
`genesis in a- study in which the compound was adminis-
`tered to Sprague-Dawley rats ·by gavage ~a_t dosages of-20,
`7.5, and 200 mglkg/day for two years. An increased
`incidence of uterine polyps was observed· in female rats
`that recejved 200 mg/kg/day, a- dosage that resulted in a
`systemic exposure to doxycycline aPproximately 12.2 tim es
`that observed in female humans who use ORACEA (expo-
`sure camparisau based upon area under the curve (AUC)
`values). No impact upon tumor incidence was observed.in
`male rats at 200 mglkg/day, or in eithergender'at the other
`dosages studied. Evidence of oncogenic · activity was ob-
`tained
`in
`studies with
`related
`compounds,
`i.e~,
`oxytetracychne (adrenal and pituitary tumors) and
`minocycline (thyroid tumors).
`Doxycycline ·demonstrated no potential to cause · genetic
`toxicity in an in uitro point mutation study with mamma~
`lian cells (CHO/HGPRT forward mutation assay) or in an
`in uiuo micronucleus assay conducted in CD-1 mice. How-
`ever, data from an in vitro assay with CHO cells for poten-
`tial to cause chromosomal' aberratioiis suggest that
`doxycycline is a weak clastogen;
`Oral admirristration of doxycycline to male and female
`Sprague-Dawley rats adversely affected fertility and repro-
`ductive performancef as ·evidenced by increased tiine for
`mating to occur, reduced sperm m