v.
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1 042
`Exh. 1042
`
`

`
`JEB15-
`
`LDLK&M
`LIBRARY
`600 SOUTH AVE. WEST
`~~J 07090
`
`The Official
`
`Horne of
`
`the Physicians'
`
`Desk Reference
`
`on the Web
`
`When you need healthcare information visit the one site that
`offers the most- the PDR.net Supersite. Sponsored and
`maintained by one of the most respected names in health
`cat-e, you can access the Physicions' Desk Reference* as weil as
`thousands of professional healthcare articles from the pages
`of Medical Economics Company publications. Physicians also
`benefit from online CME, daily medical news from Reuters,
`and Stedman's Medical Dictionary. Consumers can take
`advantage ofthe PDR Fomify Guide to Prescription Drugs®, daily
`healthcare news from Reuters, as weil as PDR's Getting Weil
`Network- individual, disease-specific sites covering allergy,
`arthritis, breast cancer; depression, hypertension, osteoporosis,
`and ear infection/otitis media.
`
`From the office, your home, or the road, the healthcare
`information you can trust is always within your reach.
`
`www.pdr.net
`
`PDR .. net
`Content and
`Features:
`
`Physicians' Desl< Reference®*
`
`More than I 0,000 full text
`articles from Medical Economics
`Company publications including:
`Medica/ Economics®, Patient Care®
`and much more ...
`
`Free MEDLINE/AIDSLINE/
`CANCERLIT
`
`PDR.net for Consumers
`
`PDR's Getting Weil Networi<5M
`
`Online CME/CE
`
`*Access to the ful!, professlonal verslon of the PDR& on
`PDR,net !s free for practic!ng U.S.~based phys!clans and
`physitian asslstants. Consumers can access drug Infor-
`mation from the PDR Family Guide to Prescription DrugsB
`whlch is avai!able for free 1:hrough the PDR.net
`Supersite consumers' area.
`
`Exh. 1042
`
`

`
`EDITION
`
`2000
`
`PHYSCANS'
`DESK
`REFERENCE®
`
`Senior Vice President, Directory Services: Paul Walsh
`
`Director of Product Management: Mark A. Friedman
`Associate Product Manager: Bill Shaughnessy
`Senior Business Manager: Mark S. Ritehin
`Financial Analyst: Wayne M. Soltis
`Director of Sales: Dikran N. Barsamian
`NationalSales Manager, Pharmaceutical Sales: Anthony Sorce
`National Account Manager: Don Bruccoleri
`Senior Account Manager: Frank Karkowsky
`Account Managers:
`Marion Gray, RPh
`Lawrence C. Keary
`Jeffrey F. Pfoh I
`Suzanne E. Yarrow, RN
`Electronic Sales Account Manager: Stephen M. Silverberg
`National Sales Manager, Medical Economics Trade Sales: Bill Gaffney
`Director of Direct Marketing: Michael Bennett
`List and Production Manager: Lorraine M. Loening
`Senior Marketing Analyst: Dina A. Maeder
`
`Director, New Business Development and
`Professional Suppcnt Services: Mukesh Mehta, RPh
`Manager, Drug Information Services: Thomas Fleming, RPh
`Drug Information Specialist: Maria Deutsch, MS, RPh, CDE
`Editor, Directory Services: David W. Sifton
`Senior Associate Editor: Lori Murray
`Director of Production: Carrie Williams
`Manager of Production: Kimberly H. Vivas
`Senior Production Coordinator: Amy B. Brooks
`Production Coordinators: Gianna Caradonna, Maria Volpati
`· Data Manager: Jeffrey D. Schaefer
`Senior Format Editor: Gregory J. Westley.
`Index Editors: Johanna M. Mazur, Robert N. Woerner
`Art Associate: Joan K. Akerlind
`Senior Digital lmaging Coordil'lator: Shawn W. Cahill
`Digitallmaging Coordinator: Frank J. McEiroy, 111
`Electronlc Publishing Designer: Livio Udina
`Fulfillment Manager: Stephanie DeNardi
`
`';-. Copyright © 2000 and published by Medical Economics Company, lnc. at Montvale, NJ 07645-17 42. All rights reserved. None of th~ content of this publication may
`be reproduced, stored in a retrieval system, resold, redistributed, or Iransmitted in any form or by any means (electronic, mechanical, photocopying, recordirig, or
`otherwise) without the prior written permission of the publisher. PHYSICIANS' DESK REFERENCE•, PDR•, PDR For Ophthalmology", Pocke! PDR•, and The PDR• Family
`Guide to Prescription Drugs• are registered Irademarks used herein under license. PDR For Nonprescription Drugs and Dietary Supplements1M, PDR Campanion Guide1M,
`PDR"for Herbai MedicinesrM, PDR• Medical DictionaryrM, PDR• Nurse's Drug Handbook1M, PDR" Nurse's DictionaryrM, The PDR• Family Guide Encyclopedia of Medical
`CarerM, The PDR" Family Guide to Natural Medicines and Healing Therapies1"', The PDR• Family Guide to Common Ailments1M, The PDR• Family Guide to Over-the-
`Counter DrugsrM, and PDR• Electronic Library1M are Irademarks used herein under license.
`
`•"
`
`Officers of Medical Economics Company: President and Chief Executive Officer: Curtis B. Allen; Vice President, New Media: L. Suzanne BeDell; Vice President, Gorparate Human
`Resources: Pamela M. Bilash; Vice President and Chief Information Officer: Steven M. Bressler; Chief Rnancial Officer: Christopher Caridi; Vice President and Controller: Barry
`Gray; Vice President, New Business Planning: Linda G. Hope; Vice President, Business Integration: David A. Pitler; Vice President, Finance: Donna Santarpia; Senior Vice President,
`Directory 5ervices: Paul Walsh; Senior Vice President, Operations: John R. Ware; Senior Vice President, Internet Strateg/es: Raymond Zoeller
`
`ISBN: 1·56363-330-2
`
`® Printed on recycled paper
`
`Exh. 1042
`
`

`
`944/CHIRON
`
`RabAvert-Cont.
`
`years and, if the titer is less than complete neutralization at
`a 1:5 serum dilution by RFFIT, should have a booster dose of
`vaccine. Alternatively, a booster can be administered in the
`absence of a titer determination.
`Veterinarians and animal·control and wildlife officers work-
`ing in areas of low rabies enzooticity (infrequent-exposure
`group) do not require routine pre-exposure booster doses of
`RabAvert after completion of a full primary pre-exposure
`immunization scheme (Table 1).
`B. Post-exposure Dosage
`lmmunization should begin as soon as possible after expo·
`sure. A complete course of immunization consists of a total
`of 5 injections of 1 mL each: one injection on each of·days 0,
`3, 7, 14 and 28 in conjunction with the administration of
`HRIG on day 0. For children, see Pediatric Use section,
`above.·
`Begin with the admiuistration ofHRIG. Give 20 IU/kg body
`weight.
`This formula is applicable to all age groups, including chil-
`dren. The recommended dosage of HRIG should not exceed
`20 IU/kg body weight because it may otherwise interfere
`with acti~e antibody production. Since vaccine-induced
`antibody appears within 1 week, HRIG is not indicated
`more than 7 days after initiating post-exposure immuniza-
`tion with RabAvert. If possible, up to one-half the dose of
`HRIG should be thoroughly irlfiltrated in the area around
`the wound and the rest should be administered IM, in a dif-
`ferent site from the rabiesvaccine, preferably in the gluteal
`area.
`Because the antibody response following the recommended
`immunization regimen with RabAvert has beeJ:l satisfactory,
`routine post·i1fimunization serologic testing is not recom-
`mended. Serologie testing is in\licated in unusual circuni-
`stances, as when the patient is known to be- i,mmunosup-
`presßed. , Contact state health deparlment or CDC for rec-
`ommendations.
`.
`-
`C. Post-exposure Therapy of Previou;ly I;"munized Persans
`When rabies exposure occurs in an immunized person who
`was vaccinated according to the recommended regimen with
`RabAvert or other tissue culture vaccines or ~ho had previ,
`ously demonstrated r~bies antibody, that person should re-
`ceive two IM doses (1.0 mL each) of RabAvert: one immedi-
`ately and one 3 days later. HRIG should not be given in
`these cases. Persons _should be considered to have been im-
`munized previously if they received pre- or post-exposure
`prophylaxis with RabAvert or other tissue culture vaccines
`or have been documented to have had an adequate antibody
`response to duck embryo rabies vaccine. I{the immune sta-
`tus of a previously vaccinated person is not known, full pri-
`mary post-exposure imtirabies treatment (HRIG plus 5
`doses of vaccine) may be necessary. In such cases, if anti-
`hodies can ]:,e demonstrated in a seriim sample collected be-
`fore vaccine is given, treatment can be discontinued after at
`least two doses of vaccine.
`HOW SUPPLIED
`Package with:
`1 vial of freeze"dried vaccine containing a single dose
`1 disposäble syringe-
`1longer needle for reconstitution, 21 gauge X 1.5"
`1 vial of sterile Water For Injection, USP (1 mL)
`1 sma:ller needle for injection, 25 gauge X 1"
`N.D.C.# 53905-501-01 CAUTION: Federallaw prohibits
`dispensing without a prescri ption
`Storage
`RabAvert should be stored protected from light at 2°C to 8°C
`(36°F to 46°F). After reconstitution the vaccine is to be used
`immediately. The vaccine may not be used after the expira-
`tion date given on package and container.
`HEFERENCES
`1. Smith JS, Yager, PA & Baer, GM. A rapid reproducible
`test for determining rabies neutralisation antibody. Bull
`WHO. 1973;-48: 535-541.
`2. Eighth Report of the WHO Expert Committee on Ra-
`bies. WHO Technical Report Series, no. 824; 1992.
`3. Dreesen DW, et al. Two-year comparative trial on the
`immunogenicity and adverse effects of purified chick
`embryo cell rabies vaccine for pre-exposure immuniza-
`tion. Vaccine. 1989; 7: 397--400.
`4. Dreesen DW. Investigation of antib_ody response to pu-
`rified chick embryo cell tissue culture vaccine (PC~CV)
`or human diploid cell culture vaccine (HDCV) in health
`volunteers. Study synopsis 7USA401RA, Septem~er
`1996-December 1996 (unpublished)
`5. Nieholsan KG, et al. Pre-exposure studies withJ>urified
`chick embryo cell culture rabies vaccine and human dip-
`loid cell vaccine: serological and .clinical responses in
`man. Vaccine. 1987; 5: 208-210.
`6. Vodopija I, et al. An evaluation of second generation tis'
`sue culture rabies vaccine for use in man: a four~Vaccine
`comparative immunogenicity study using a pre-expo-
`sure vaccination schedule and an abbreviated 2-1-1
`post-exposure schedule. Vaccine. 1986; 4: 245:C248
`7. Wasi C, et al. Purified chick embryo cell rabies vaccine
`(Ietter). Lancet. 1986; 1: 40.
`8. Wasi C. Rabies prophylaxis with purified chick embryo
`(PCEC) rabies vaccine. Protocol 8T -201RA, 1983-1984
`(unpublished).
`9. Wasi C. Personal communication to Bebringwerke AG,
`1990.
`Information will.be superseded by supplements and subsequerlt editions
`
`10. Bijok U, et al. Cliuical trials in healthy volunteers with
`the new purified chick embryo cell rabies vaccine for
`man. J Commun Dis. 1984; 16: 61-69.
`11. Vodopija I. Post-exposure rabies prophylaxis with puri-
`fied chick embryo cell (PCEC) rabies vaccine. Protocol
`7YU-201RA, 1983-1985 (unpublished).
`12. John J. Evaluation of purified chick embryo cell culture
`(PCEC) rabies vaccine, 1987 (unpublished).
`13. Tanphaichitra D, Siristonpun Y. Study ofthe efficacy of
`a purified chick embryo cell vaccine in patients bitten by
`rabid animals. Intern Med. 1987; 3: 158-160.
`14. Thongcharoen P, et al. Effectiveness of new economical
`schedule of rabies postexposure prophylaxis using puri-
`fied chick embryo cell tissue culture rabies vaccine. Pro-
`tocol 7T-301lP, 1993 (unpublished).
`15. Ljubicic M, .et al. Efficacy of PCEC vaccines in post-
`exposure rabies prophylaxis. In: Vodopija, Nicholson,
`Smerdel & Bijok (eds.): Improvements in rabies post-
`exposure treatment (Proceedings of a meeting in Du-
`brovnik, Yugoslavia). Zagreh Institute of Public Health
`1985.
`16. Madhusudana SN, Tripathi KK: Post exposure studies
`with human diploid eell rabies vaccine and purified
`chick embryo cell.vaccine: Comparative Serological Re-
`sponses in Man. Int. Med Microbiol. 1989; 271: 345-350.
`17. Sehgal S, et al. Ten year longitudinal study of efficacy
`and safety of purified chick embryo cell vacci0e for pre-
`and post-exposure prophylaxis of rabies in Indian popu-
`lation. J Commun Dis. 1995; 27: 36--43.
`18. Sehgal S, et al. Cinical evaluation of purified chick em-
`-bryo cell antirabies vaccine for-post-exposuretreatment.
`J Commun Dis. 1988; 20: 293-300.
`19. Suntharasamai P, et al.: Purified chick embryo cell ra-
`. bies vaccine: economical multisite intradermal regimen
`for post-exposure prophylaxis. Epidemiol Infect. 1987;
`99; (3): 755-765.
`20. Meesomboon V, et al. Antibody response to PCEC:rabies
`vaccine. J. Commun.Dis. 1987; 13: 130-136.
`21. Sehgal S. Report of the trials ofPCEC (Purified Chlck
`Embryo Cell) rabies vaccine in India. In: Vodopija,
`Nicholson, Smerdel & Bijok (eds.): lmprovements in ra-
`bies post-exposure treatment (Proceedings of a nieeting
`in Dubrovnik, Yugoslavia). Zagreh Institute of Public
`Heath 1985 pp. 71-75.
`22. Lesic L, Petrovic M. Study Repmi: Findings. of Cliriica!
`Trials .on Rabipur PCEC, Rabies Vaccine .. National Ref-
`erence Laboratory for Rabies, Nov'i Sad, Yugosiavia,
`1988 (unpublished)._
`.
`23. Centers for Disease Control. Rabies Prevention- United
`States, 1991. Recom:rnendations of the Immiinization
`Practices Advisory Conimittee (ACIP). MMWR, 1991; 40
`(RR-3): 1-19.
`24. Dreesen D. et al.: A comp'lfative study of cell culture ra-
`bies: vaccine: Immunogenicity and safety. Protocol
`8USA301RA, 1985-1986 (unpublished).
`25. Centers for Disease Control. Systemic allergic reactions
`following inimunization witli HDC · rabies vaccine.
`MMWR. 1984; 33: 185-187.
`26. Centers for Disease _ Control. Rabies Prevention · United
`States. MMWR. 1984;·33: 393--402.
`27. Dreesen DW, et al. Immune co:rnplex-like disease in 23
`persons follovring a booster dose of rabies HDC vaccine.
`.
`Vaccine. 1986; 4: 45.--49.
`28. Anderson, MC, et al. The role of specific IgE and beta-
`propiolactone in reactions resultirtg from booster dose of
`human diploid rabies cell vaccine. J Allergy Clin. Immu-
`nol. 1987; 80: 861-868.
`29. Swanson MC, et al. IgE and IgG antibodies to beta-
`propiolactone and human seriim albumin associated
`with urticarial reactions to rabies vaccine. J Infect Dis.
`1987; 155: 909-913.
`.
`.
`30.'Marwick C.'Changes recominended in u_se ofhuman dip-
`loid cell rabies vaccine (news). JAMA. 1985; 245: 14-15.
`31. Lumbiganon P, Wasi C. Survival after rabies immunisa-
`tion in newborn infant of affected mother . .Lancet. 1990;
`. 336: 319-332.
`32. Lumbiganon P, et al. Pre-exposure vaccination with pu-
`rified chick embryo cell rabies · vaccines in children.
`Asian Pacific J Allergy Immunol, 1989; 7: 99-101.
`33. Ganzales de Ciso. Öomparative evaluation of PCEC and
`Fluenzalida vaccines. Protocol 8Mex201RA, 1983-1984
`(unpublished).
`· ·
`·
`Manufactured by:
`Chiron Bebring GmbH & Co,
`D,35006 Marburg, Germany
`Distributed by:
`Chiron Corporation .
`Emei-yville, CA 94608, USA
`
`Rev. 10/97
`Shown in Product Identification Guide, page 310
`
`For EMERGENCY telephone numbers,
`consult the Manufacturers' Index.
`
`PHYSICIANS' DESK REFERENCE®
`
`CibaGeneva Pharmaceuticals
`Ciba-Geigy Corporation
`
`Geneva Pharmaceuticals; lnc.
`
`PLEASE NOTE:
`Due to the merger of CibaGeneva Pharmaceuticals and
`Sandoz Pharmace'"'ticals Corporation, please refer to
`Novartis Pharmaceuticals Corporation for branded product
`information and Geneva Pharmaceuticals, lnc. for branded
`generic product information.
`
`Colgate Oral Pharmaceuticals,
`lnc.
`a subsidiary of Colgate-Palmolive Company
`ONE COLGATE WAY
`CANTON, MA 02021 U.S.A.
`
`Direct lnquiries to:
`Professional Services Department
`(800) 226-5428
`For Medical Information Contact:
`ln Emergencies:
`Pittsburgh Poiso11 Control
`(412) 692-5596
`
`LURIDE® DROPS ..
`brand of sodium fluoride
`oral solution
`1.69 fl oz (50 mL) bottles, calibrated dropper
`
`LURIDE® LOZI-TABS®
`brand· of sodium fluoride
`120 tablet bottles 0.25 mg F vauilla
`120 tablet bottles 0.5 mg F grape
`120 tablet bottles 1 mg F cherry
`
`PERIOGARD®
`(chlorhexidine gluconate
`oral rinse, 0.12%)
`16 fl oz bottles
`
`PREVIDENT 5000 PLUS®
`brand of 1.1 o/o Sodium Fluoride
`prescription dental cream
`1.8 oz. (51g) net wt. tubes Spearmint or FruitasticTM
`Twin Pack (two 1.8 oz (51g) net wt. tubes) Spearmint
`
`CollaGenex Pharmaceuticals,
`lnc.
`41 UNIVERSITY DRIVE
`NEWTOWN, PA 18940
`
`Direct in-quiries to:
`888-339-5678
`
`PERIOST AT®
`[perio-stat]
`(doxycycline hyclate capsules)
`
`DESCRIPTION
`Periostat® is available as a 20 mg capsule formulation of
`doxycycline hyclate for oral administration.
`Doxycycline is synthetically derived from oxytetracycline.
`The structura] formula of doxycycline hyclate is:
`
`yH3 ?H
`' H
`' H
`
`N(CH3h
`'
`OH
`
`. j
`
`•HCI
`CONH 2
`·
`
`r
`
`OHO OHO
`
`2
`of
`formula
`empirical
`an
`.
`with
`(C22H24N20 8·HCl)2·C2H60·H20 and a molecular weiglit of
`1025.89. The chemical desigoation for doxycycline is 4-(dim-
`ethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-
`
`Exh. 1042
`
`

`
`PRODUCT INFORMATION
`
`pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxa-
`mide monohydrochloride,~compound with ethyl alcohol (2:1);
`monohydrate.
`.
`'
`~·
`Doxycycline hyclate is a light-yellow crystalline powder
`which is soluble in water.
`Inert ingrerlients in the formulation are: hard gelatin cap-
`sules; magnesium stearate; an<l microcrystalline cellulose.
`Each capsule conta.ins doxycycline hyclate equivalent to 20
`mg of doxycycline.
`~ ·
`· ·
`~
`CLTIUCALPHARMACOLOGY
`After oral administration, doxycycline hyclate is rapidly and
`nearly completely absorbed from the gastrointestinal tract.
`Doxycycline is eliminated with a half-life of approximafely
`18 hours by .renal and fecal excretion of unchanged dr:ug.
`Mechanism .of Action: Doxycycline ~Iias been shown to in-
`hibit collagenase activity in vitro.1 Additional sturlies have
`shown that doxycycline reduces the elevated collagenase ac-
`tivity in the gingival crevicular fluid of patients with adult
`periodontitis?·3 The clinical significance of these~ findings is
`not known.
`Mlcrobiology: Doxycycline is a member of the tetracycline
`class of antibiotics. The dosage of doxycycline ~ achieved with
`this product during administration is well below the concen-
`tration required to inhibit microorgauisms commonly asso-
`ciated with adult periodontitis. Cliuical sturlies witli this
`product demonstrated no effect on total anaerobic and fac-
`ultative bacteria in plaque samples from patients admims-
`tered this dose regimen for 9 to 18 months. This · product
`should not be used for redudng the nill:nbers of or eliminatc
`ing those microorganisms associated with periodontitis.
`Pharmacokinetics
`'
`The pha;.macokinetics of doxycycline following oral admin-
`istration of Periostat® were investigated in 3 yolunteer
`sturlies involving 87 adults. Additionally, doxycycline pharc
`m:lcokinetics have been characterized in numeroüs scien-
`tific publications 4 Pharmacokinetic parameters for Peri-
`ostat® following single oral doses and at steady-state in
`healthy subjects are presented as follows:
`[See first table above]
`Absorption: Doxycycline is virtually completely absorbed
`after oral administration. Following 2.0 mg doxycycline,
`twice· a day, in healthy volunteers, the mean peak concen-
`tration in plasma was 790 ng/mL and the average steady"
`state concentration was 482 ng/mL. The effect of food on the
`absorption of doxycycline from Periostat® Iias not been
`studied.
`Distribution: 'Doxycycline is greater t)lan 90% bound to
`plasma proteins. Its apparent volume of distribution is var-
`iously reported as between 52.6 and 134 L.4•6
`Metabolism:. Major metabolites of doxycycline have not
`been identified: However, enzyme inducers such as barbitu-
`rates, ~carbamazepine, and phenytoin decrease the half-life
`of doxycycline:
`.
`. .
`·
`Excretion: Doxycycline is excreted in the urine and feces
`as unchanged drug. It is variously reported that between
`29% and 55.4% of an administered dose can be accounted for
`in the urine by 72 hours. 5•6 Half-life averaged 18 hours in
`subjects receiving a single 20 mg doxycycline dose.
`Special Populations
`Geriatrie: Doxycycline pharmacokinetics have not been
`evaluated in geriatric patients.
`Pediatric: Doxycycline pharinacokinetics have not been
`evaluated in perliatric patients. (See WARNINGS.)
`Gender: A study was conducted in 42 subjects where doxy-
`cycline pharmacokinetics were compared in men and
`woni.en. It was observed that Cmax was approximately 1. 7-
`fold higher in warnen than in men. There were no apparent
`rlifferences in other phatmacokinetic parameters.
`Ra.ce: Diff<irences in doxycycline pharmacokinetics among
`racial groups have not been evaluated.
`Renflllnsumciency: Sturlies have shown no significant dif-
`ference in senim half-life of doxycycline in patients with
`normal and severely impaired renal function. Hemorlialysis
`does not alter the half-life of doxycycline.
`Hepatic lnsufficiency: Dmcycycline pharmacokinetics have
`not been evaluated in patients With hepatiC insufliciency.
`Drug lnteracti(!ns: See "Prec~u~ons"
`Clinical Study
`In a randomized, multi-centered, double-blind, 9-month
`Phase 3 study involving 190 adult patients with periodontal
`disease [at least two prohing sites per quadrant of between
`5 and 9 mm packet depth (PD) and attachment level (ALv)],
`the effects of oral administration of 20 mg twice a day of
`doxycycline hyclate plus scaling and root planing (SRP)
`were compared to placebo control plus SRP. Both treatment
`groups were administered a course of scaling and niot plan-
`ing in 2 quadrants at Baseline. Measurements of ALv; PD
`and bleeding-on-probing (BOP) were obtained at Baseline,
`3, 6, and 9 months from each site about each tooth in the
`two quadrants that received SRP using the UNC-15 manual
`probe. Each tooth site was categorized into one of three
`strata based on Baselirre PD: 0-3 mm (no disease), 4-6 mm
`(mild/moderate disease), "'= 7 mm (severe disease). For each
`stratum and treatment group, the following were calculated
`at month 3, 6, and 9: mean change in ALv from baseline,
`mean change in PD from baseline, mean percentage oftooth
`sites per patient exhibiting attachment loss of "'= 2 mm from
`baS'eline, and percentage of tooth sites with bleeding on
`probing. The results are summarized in the following table.
`[See second table above]
`INDICATIONS AND USAGE
`Periostat® is indicated for use as an adjunct to scaling and
`root planing to promote attacliment level gain and to reduce
`pocket depth in patients with adult periodontitis.
`
`COLLAGENEX/945
`
`Pharmacokinetic Parameters for Periostat®
`
`n
`
`42
`
`30
`
`Cmax
`(ng/ml)
`
`400 ± 142
`
`790 ± 285
`
`Tmax
`(hr)
`
`1.5
`(0.5-4.0)
`
`2
`(0.98-12.0)
`
`CI/F
`(l/hr)
`
`t,,2
`(hr)
`
`3.80 ± 0.85
`
`18.4 ± 5.38
`
`3.76 ± 1.06
`
`Not
`Determined ~
`
`Clinical Results at Nine Months as an Adjunct to SRP
`Baseline Packet Depth
`4-Smm
`90
`
`Q-3 mm~
`90
`
`1.03 mm*
`0.86mm
`
`0.95 mm**
`0.69mm
`
`1.3%
`2.4%
`
`64%*
`70%
`
`C.:7mm
`79
`
`1.55 mm*
`1.17 mm
`
`1.68 mm**
`1.20 mm
`
`0.3%*
`3.6%
`
`75%
`80%
`
`Single dose 20 mg
`
`Steady-State
`20 mgBID
`
`Parameter
`
`Number of Patients
`
`Mean Gain in ALv
`Periostat® 20 mg EID
`Placebo
`
`Mean Decrease in PD
`Periostat® 20 mg EID
`Placebo
`
`% of Sites with lass of ALv
`"'=2mm
`Periostat® 20 mg EID
`~Placebo
`
`0.25mm
`0.20mm
`
`0.16 mm**
`0.05mm
`
`1.9%
`2.2%
`
`39%**
`46%
`
`% of Sites with BOP
`Periostat® 20 mg EID
`Placebo
`*p<0.050 vs. the placebo cmitrol group.
`**·p<O.OlO vs. the placebo control group.
`
`CONTRAINDICATIONS
`This drug is contrainrlicated in persans who have shown hy-
`persensitivity to any of the tetracyclines.
`WARNINGS
`THE USE OF DRUGS OF THE TETRACYCLINE CLASS
`DURING TOOTH DEYELOPMENT ~(LAST HALF OF
`PREGNANCY, INFANCY AND CHILDHODD TO THE
`AGE OF 8 YEARS) MAY CAUSE PERMANENT DISCOL-
`ORATION OF THE TEE:TH (YELLOW-GRAY-BROWN).
`This adverse reaction is more common during long-term use
`ofthe drugs but Iias been observed following repeated short-
`term Courses. Enamel hypoplasia Iias also been reported.
`TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT
`BE USED IN THIS AGE GROUP ANDIN PREGNANT OR
`NURSING MOTHERS UNLESS THE POTENTIAL BEN-
`EFITS MAY BE ACCEPTABLE DESPITE THE POTEN-
`TIAL RISKS.
`~
`All tetracyclines form a stable calcium complex in any hone
`forming tissue. A decrease in fibula growth rate Iias been
`observed in premature infants given oral tetracyclines in
`doses of 25 mg/kg every 6 hours. This reaction was shown to
`be reversible when the drug was discontinued.
`Doxycycline can cause fetal harm when administered to a
`pregnant woman. Results of aniii)al sturlies indicate that
`tetracyclines cross the placenta, ai'e found in fetal tissues,
`and can have toxic effects on the developing fetus ( often re-
`lated to retardation of skeletal development) .. Evidence of
`embryotoxicity Iias also been noted in animals treated early
`in pregnancy. If any tetracyclines are used. during preg'
`nancy, or if the patient becomes pregnant while taking this
`drug, the patient should be apprised of the potential hazard
`to the fetus.
`The catabolic action of the tetracyclines may cause an in-
`crease in BUN. Sturlies to date inrlicate· that this does not
`occur with the use of doxycycline in patients with impaired
`renal function.
`Photosensitivity mauifested by an exaggerated sunburn re-
`action Iias been observed in some individuals taking tetra-
`eyclines. Patients apt to be exposed to rlirect sunlight or ul-
`traviolet light should be advised that this reaction can occur
`with tetracycline drugs, and treatment should be rliscontin-
`ued at the first evidence of skin erythema.
`PRECAUTIONS
`While no overgrowth by opportunistic microorgauisms such
`as yeast were noted duringc clinicar sturlies, as with other
`antimicrobials, Periostat® therapy may result in· over-
`growth of nonsusceptible microorganisms inclurling fungi.
`The use of tetracyclines may increase the incidence t>f vag-
`inal canrlidiasis.
`Periostat® should be used with caution in patients with a
`history or predisposition to oral candirliasis. The safety and
`effectiveness of Periöstat® Iias not been established for the
`treahn(mt of periodontitis in patients with coexistant oral
`candirliasis.
`If superinfection is suspected, appropriate measures should
`be taken.
`Labaratory Tests: In long term .therapy, periorlic labora-
`tory evaluations of organ systems, including hematopoietic,
`renal, and hepatic sturlies should be performed.
`Drug lnteractions: Because tetracyclines have been shown
`to depress plasma prothrombin activity, patients who are on
`anticoagulant therapy may require downward adjustment
`of their anticoagulant dosage.
`Since bacteriostatic antibiotics, such as the tetracycline
`class of antibiotics, may interfere with the bactericidal ac-
`
`tion ofmembers ofthe b-lactam (e.g. penicillin) class ofan-
`tibiotics, it is not advisable to administer these antibiotics
`concomitantly.
`Absorption oftetracyclines is impaired by antacids contain-
`ing aluminum, ßalcium, or magnesium, and by iron-contain-
`ing preparations. Absorption is also impaired by bismuth
`subsalicylate. ~
`Barbiturates, carbamazepine, and phenytoin decrease the
`half-life of doxycycline.
`The concurrent use oftetracycline an~ Penthrane (methoxy-
`f!uorane) Iias been reported to result in fatal renal toxicity.
`Concurrent use oftetracycline may render oral contracep-
`tives less e:ffective.
`Drug/Laboratory Test lnteractions: False elevations.ofuri-
`nary catecholamine Ievels may occur due to interference
`with the f!uorescence test.
`Carcinogettesis, Mutagenesis, lmpairment of Fertility:
`Döxycyclln:e hyclate Iias not been evaluated for carcinogenic
`potential in long-term auimal studies. Evidence of oncogenic
`activity was obtained in sturlies with related compounds,
`i.e., oxytetracycline (adrenal and pituitary tumors), and mi-
`nocycline (thyroid tuil1ors).
`Doxycycline hyclate demonstrated no potential to cause ge-
`netic toX:icity in an in vitro point mutation study with mam-
`malian cells (CHO/HGPRT forward mutation assay) or in
`an in vivo micronucleus assay conducted in CD-1 mice.
`However, data from an in vitro assay with CHO cells for po-
`ten.tial to cause chromosomal aberrations suggest that doxy-
`cycline hyclate is a weak clastogen.
`Oral administration of doxycycline hyclate to male and fe,
`niale Sprague-Dawley rats adversely affected fertility and
`reproductive performance; as evidenced by increased time
`for mating to occur, reduced sperm motility, velocity, and
`concentration, abnormal sperm morphology, and increased
`pre- and post-implantation lasses. Doxycycline hyclate in-
`duced reproductive toxicity at all·dosages that were exam-
`ined in this study, as even the lowest dosage tested (50 mg/
`kg/day) induced a statistically significant reduction in
`sperm velocity. Note that 50 mg/kg/day is approximately 10
`times the amount of doxycycline hyclate contained in the
`recommended daily dose of Periostat® for a 60 kg human
`when compared on the basis of body surface area estimates
`(mg/m2). Although doxycycline impairs the fertility of rats
`when administered at suf!icient dösage, the effect of Peri-
`ostat® on human ferlility is unknown.
`Pregnancy: Teratogenic Effects: Pregnancy Category D.
`(See WARNINGS.) Results from auimal sturlies indicate
`that doxycycline crosses the placenta al1d is found in fetal
`tissues.
`(See WARNINGS.)
`Nonteratogenic effects:
`Labor and Delivery: The effect of tetracyclines on labor
`and delivery is unknown.
`Nursing Mothers: Tetracyclines are excreted in human
`milk. Because of the potential for serious adverse reactions
`in nursing infants from doxycycline, the use ofPeriostat® in
`nursing mothers is contraindicated. (See WARNINGS.)
`Pediatric Use: The use ofPeriostat® ii) infancy and child-
`hood is contrainrlicated. (See WARNINGS.)
`ADVERSE REACTIONS
`In clin-
`Adverse Reactions in Clinica/ Trials of Periostat®:
`ical trials of adult patients with periodontal disease 213 pa-
`tients received Periostat® 20 mg EID over a 9-12 month
`period. The most frequent adverse reactions occurring in
`sturlies involving treatment with Periostat® or placebo are
`listed below:
`
`Continued on next page
`Consult 2 0 0 0 PDR® supplements and future editions for revisions
`
`Exh. 1042
`
`

`
`946/COLLAGENEX
`
`Periostat-Cont.
`
`lncidence (%) of Adverse Reactions in
`Periostat Clinical Trials
`Adverse Reaction
`Periostat 20 mg
`BIO (n=213)
`
`Placebo
`(n=215)
`
`Headache
`
`Common Cold
`
`Flu Symptoms
`
`ToothAche
`
`Periodontal
`Abscess
`
`Tooth Disorder
`
`Nausea
`
`Sinusitis
`
`Injury
`
`Dyspepsia
`
`Sore Tbroat
`
`Joint Pain
`
`Diarrhea
`
`Sinus
`Gongestion
`
`Coughing
`
`Sinus Headache
`
`Rash
`
`Back Pain
`
`BackAche
`
`Menstrual
`Cramp
`
`Acid Indigestion
`
`Pain
`
`Infection
`
`GumPain
`
`Bronchitis
`
`Museie Pain
`
`55 (26%)
`
`47 (22%)
`
`24 (11%)
`
`14 (7%)
`
`8(4%)
`
`13 (6%)
`
`17 (8%)
`
`7 (3%)
`
`11 (5%)
`
`13 (6%)
`
`11 (5%)
`
`12 (6%)
`
`12 (6%)
`
`11 (5%)
`
`9 (4%)
`
`8 (4%)
`
`8(4%)
`
`7(3%)
`
`4(2%)
`
`56 (26%)
`
`46 (21%)
`
`. 40 (19%)
`
`28 (13%)
`
`21 (10%)
`
`19 (9%)
`
`12 (6%)
`
`18 (8%)
`
`18 (8%)
`
`5 (2%)
`
`13 (6%)
`
`8 (4%)
`
`8 (4%)
`
`11 (5%)
`
`11 (5%)
`
`8 (4%)
`
`6 (3%)
`
`8(4%)
`
`9 (4%)
`
`9(4%).
`
`. 5 (2%)
`
`8 (4%)
`
`8(4%)
`
`4(2%)
`
`1 (%)
`
`7 (3%)
`
`2 (1%)
`
`7 (3%)
`
`5(2%)
`
`6 (3%)
`
`6 (3%)
`
`5 (2%)
`
`6 (3%)
`
`Note: Percentages are based on total number of study
`participants in each treatment group.
`
`Periostat® should be administered at least one hour prior to
`morning and evening meals.
`Administration of adequate amounts of fluid along with the
`capsules is recommended to wash down the drug and reduce
`the risk of esophageal irritation and ulceration. (SEE An-
`VERSE REACTIONS.)
`HOW SUPPLIED
`Periostat® (white capsule imprinted with "PeriostatTM")
`cantairring doxycycline hyclate equivalent to 20 mg doxycy-
`cline. Bottle of 100 (NDC 27280-007-01).
`Storage: All products are to be stored at controlled room
`temperatures of 59 °F-86 OF (15 °C-30 °C) and dispensed in
`tight, light-resistant containers (USP).
`Rx Only
`PERIOST AT® is a trademark of CollaGenex Pharmaceuti-
`cals, Inc., Newtown, PA 18940.
`Manufactured by
`Applied Analytical Inc.
`Wilmington, NC 28403
`Marketed by
`CollaGenex Pharmaceuticals, Inc.
`Newtown, PA 18940
`U.S. Patents 4,666,897
`and RE 34,656
`REFERENCES
`1. Golub L.M., Sorsa T., Lee H-M, Ciancio S., Sorbi D., Ra-
`mamurthy N.S., Gruber B., Salo T., Konttinen y.T.:
`Doxycycline Inhibits Neutrophil (PMN)-type Matrix
`Metalloproteinases in Human Adult Periodontitis Gin-
`giva. J. Clin. Periodontol 1995; 22: 100-109.
`2. Golub L.M., Ciancio S., Ramamurthy N.S., Leung M.,
`McNamara T.F.: Low-dose Doxycycline Therapy: Effect
`on Gingival and Crevicular Fluid Collagenase Activity
`in Humans. J. Periodout Res 1990; 25: 321-330.
`3. Golub L.M., Lee H.M., Greenwald RA., Ryan M.E., Salo
`· T.; Giannobile W.V.: A Matrix Metalloproteinase Inhibi-
`tor Reduces Bone-type Collagen Degradation Frag-
`ments and Specific Collagenases in Gingival Crevicular
`Fluid During Adult Periodontitis. Infla:mmation Re-
`search 1997; 46: 310-319.
`4. Saivain S., Houin G.: Clinical Pharmacokinetics of
`Doxycycline and Minocycline. Clin. P