CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION:NDA 50-744
`
`CONTENTS
`
`Included
`
`A22roval Letter
`Tenative A22roval Letter
`A22rovable Letter
`Final Printed Labeling
`Medical Review(s)
`Chemistry Review~s~
`EAIFONSI
`Pharmacoloay Review(s)
`Statistical Review(s)
`Microbiolo2Y Review(s)
`Clinical Pharmacology
`Bio2harmaceutics Review(s)
`Bioeguivalence Review(s)
`Administrative Document(s)
`Corres2ondence
`
`X
`
`X
`X
`X
`X
`X
`X
`
`X
`
`X
`X
`
`Pending
`Com2letion
`
`Not
`Pre2ared
`
`Not
`Reguired
`
`X
`
`X
`
`X
`
`X
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1053
`
`Exh. 1053, Page 1 of 22
`
`

`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approyal Package for:
`
`Application Number: NDA 50-744
`
`Trade Name: PERlOSTAT CAPSULES, 20 MG
`
`Generic Name:(doxycycline byclate USP)
`
`Sponsor:CollaGenex Pharmaceuticals, Inc.
`
`Approval Date: September 30, 1998
`
`INDICATION: Provides for the use of Periostat
`( doxycycline hyclate USP) Capsules, 20 mg as an adjunct to
`subgingival scaling and root planing to promote attachment
`Ievel gain and to reduce pocket depth in patients with adult
`periodontitis.
`
`Exh. 1053, Page 2 of 22
`
`

`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Application Number: NSA 50-744
`
`APPROVAL LETTER
`
`Exh. 1053, Page 3 of 22
`
`

`
`,.......
`
`".r ( k • .!>EPARTMENT OF HEALTH & HUMAN SERVICES
`.. ---,~
`
`.(.-.,.,,.a~
`
`NDAS0-744
`
`CollaGenex Phannaceuticals, Inc.
`Attention: Christopher Powala
`Director, Drug Development and Regulatory Affairs
`301 South State Street
`Newtown, PA 18940
`
`Dear Mr. Powala:
`
`...
`
`Public Health Service
`
`Food and Drug Administration
`Rockvilla MD 20857
`
`SEP 3 0 1998
`
`Piease refer to your new drug application (NDA) dated August 30, 1996, received August 30,
`1996, submitted under section SOS(b) ofthe Federal Food, Drug, and Cosmetic Act for
`Periostat™ (dox:ycycline hyclate USP) Capsules, 20 mg. We note that this application is subject
`to the exemption provisions contained in section 125(d)(2} ofTitle I ofthe FDA Modernization
`Act of1997.
`
`We acknowledge receipt ofyour submissions dated August 28, October 1, November 13,
`December 8, 1997; January 6, 14,-and 19, February 10, March 2, 18, and 31, April23 and 28,
`July 9 and 29, and September 3, 14, 16, 22, 24 (2), and 25, 1998. Your submission ofMarch 31,
`1998 constituted a full response to our August 27, 1997, action Ietter. The user fee goal date·for
`this application is October 1, 1998.
`
`)
`
`This new drug application provides for the use ofPeriostat™ (dox:ycycline hyclate USP)
`Capsules, 20 mg as an adjunct to subgingival scaling and root planing to promote attachment Ievel
`gain and to reduce pocket depth in patients with adult periodontitis.
`
`We have completed the review of this application, as amended, and have concluded that adequate
`information has been presented to demoostrate that the drug product is safe and effective for use
`as recommended in the enclosed labeling text. Accordingly, the application is approved effective
`on the date of this Ietter.
`
`The final printed labeling (FPL} must be identical to the enclosed labeling (text for the package
`insert, immediate container and carton Iabels). Marketing the product with FPL that is not -
`identical to the approved labeling text may render the product misbranded and an unapproved
`new drug. We acknowledge your commitment made in the teleconference with this Divisionon
`September 16, 1998, to revise the carton and container labeling so that the prominence of the
`established name and tradename is commensurate andin accordance with 21 CFR 201.10(g)(2).
`I
`Piease submit 20 copies ofthe FPL as soon as it is available, in no case more than 30 days after it
`is printed. Piease individually mount ten of the copies on heavy-weight paper or similar material
`For administrative purposes, this submission should be desi5nated "FPL for approved NDA
`50-744". Approval oftbis submission by FDA is not required before the labeling is used.
`
`)
`
`Exh. 1053, Page 4 of 22
`
`

`
`...
`
`)
`
`NDAS0-744
`Page2
`
`We remind you ofyourPhase 4 commitments agreed to in your~submissions dated August 3,
`1998, and September 14, 1998. These commitments, respectively, are listed below:
`
`Protocols, data, and final reports should be submitted to your IND for this product and a copy of
`the cover Ietter sent to this NDA If an IND is not required to meet your Phase 4 commitments,
`please submit protocols, data and final reports to this NDA as correspondence. In addition, under
`21 CFR 3l4.82(b}(2)(vii}, we request that you include a status summary of each commitment in
`your annual report to this NDA. The status summary should include the nurober of patients
`entered in each clinical study, expected completion and submission dates, and any changes in
`plans since the last annual report. For administrative purposes, all subrnissions, including labeling
`Supplements, relating to these Phase 4 commitments must be clearly designated "Phase 4
`,..
`Commitments".
`
`_)
`
`In addition, please submit three copies of the introductory promotional materials that you propose
`to use for this product. All proposed materials should be submitted in draft or mock-up fomi, not
`final print. Piease submit one copy to this Division and two copies ofboth the promotional
`materials and the package insert directly to:
`
`Division ofDrug Marketing, Advertising, and Communications, HFD-40
`F ood and Drug Adminis!ration
`5600 Fishers Lane
`Rockville, Mary~and 20857
`
`Piease submit one market package of the drug product when it is available.
`
`We remind you that you must comply with the requirements for an approved NDA set forth under
`21 CFR 314.80 and 314.81.
`
`_)
`
`Exh. 1053, Page 5 of 22
`
`

`
`)
`
`NDAS0-744
`Page3
`
`Ifyou have any questions, contact Roy Blay, Ph.D., Project Manager, at (301) 827-2020.
`
`...
`
`Sincerely,
`
`J~l
`Jon~than K. Wdkm, M.U.
`Dirtctor
`Division ofDennatologic and Dental Drug Products
`Office ofDrug Evaluation V
`Center for Drug Evaluation and Research
`
`Enclosure
`
`_)
`
`)
`
`Exh. 1053, Page 6 of 22
`
`

`
`Exh. 1053, Page 7 of 22
`
`

`
`6
`
`----
`
`...... ""·"7-••
`
`.-
`
`Exh. 1053, Page 8 of 22
`
`

`
`NDA50-744
`
`SEP 3 0 1998
`
`CollaGenex Pharmaceuticals, Inc.
`Attention: Christopher Powala
`Director, Drug Development and Regulatory Affairs
`301 South State Street
`. Newtown, PA 18940
`
`Dear Mr. Powala:
`
`Piease refer to your new drug application (NDA) dated August 30, 1996, received August 30,
`1996, submitted under section 505(b) ofthe Federal Food, Drug, and Cosmetic Act for
`Periostat™ (doxycycline hyclate USP) Capsules, 20 mg. We note that this application is subject
`to the exemption provisions contained in section 125(d)(2} ofTitle t ofthe FDA Modernization
`Act of 1997.
`
`We acknowledge receipt ofyour submissions dated August 28, October 1, November 13,
`December 8, 1997; January 6, 14, and 19, February 10, March 2, 18, and 31, April 23 and 28,
`July 9 and 29, and September 3, 14, 16, 22, 24 (2), and 25, 1998. Your submission ofMarch 31,
`1998 constituted a full response to our Augtist 27, 1997, action Ietter. The user fee goal date for
`this application is October 1, 1998.
`
`This new drug application provides for the use ofPeriostat™ (doxycycline hyclate USP)
`Capsules, 20 mg as an adjunct to subgingival scaling and root planing to promote attachment Ievel
`gain and to reduce pocket depth in patients with adult periodontitis.
`
`Wehave completed the reviewoftbis application, as amended, and have concluded that adequate
`information has been presented to demoostrate that the drug product is safe and effective for use
`as recommended in the enclosed labeling text. Accordingly, the application is approved effective
`on the date of this Ietter.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package
`insert, immediate container and carton Iabels). Marketing the product with FPL that is not
`identical to the approved labefing text may render the product misbranded and an unapproved
`new drug. ·we aeknowledge your commitment made in the teleconference with this Division on
`September 16,..1998, to revise the carton and container labeling so that the promi..,ence ofthe
`established name and tradename is commensurate and in accordance with 21 CFR 20 L 1 O(g)(2).
`
`Piease submit 20 copies ofthe FPL as soon as it is available, in no case more than 30 days after it
`is printed. Piease individually mount ten of the copies on heavy-weight paper or similar material.
`For administrative purposes, this submission should be designated "FPL for·approved NDA
`50-7 44". Approval of this submission by FD A is not required before the labefing is used.
`
`•
`
`Exh. 1053, Page 9 of 22
`
`

`
`NDA 50-744
`Page2
`
`We rerründ you ofyour Phase 4 commitments agreed to in your submissions da;ed August 3,
`1998, and September 14, 1998. These cornmitments, respectively, are listed below:
`
`In addition, please submit three copies of the introductory promotional materials that you propose
`to use for this product. All proposed materials should be submitted in draft or mock-up form, not
`final print. Piease submit one copy to this Division and two copies ofboth the promotional
`materials and the package insert directly to:
`
`Division ofDrug Marketing, Advertising, and Communications, HFD-40
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, Maryland 20857
`
`Piease submit one market package of the drug product when it is available.
`
`We remind you that you must comply with the requirements for an approved NDA set forth under
`21 CFR 314.80 and 314.81.
`
`•
`
`__ -...-
`
`Exh. 1053, Page 10 of 22
`
`

`
`NDAS0-744
`Page3
`
`Ifyou have any questions, contact Roy Blay, Ph.D., Project Manager, at (301),827-2020.
`
`Sincerely,
`
`lj (/'So/9'6
`
`Jonat an K. Wdkin, M.D.
`Dire
`r
`Division ofDermatologic and Dental Drug Products
`Office ofDrug Evaluation V
`Center for Drug Evaluation and Research
`
`Endesure
`
`Exh. 1053, Page 11 of 22
`
`

`
`PERIOSTA 'fTM
`(doxycycline hyclate capsules)
`
`DESCRIP'riON
`
`SEP 3 0 1998
`
`PeriostatTM is available as a 20 mg capsule formulation of doxycycline hyclate for oral administration.
`
`Doxycycline is synthetically derived from oxytetracycline. The structural formula of doxycycline hyclate is:
`
`CH3
`H
`
`OH
`: H
`
`N(CH3)2
`
`OH
`
`0
`
`2
`
`with an empirical fonnula of (C22H24N 20 8•HClkC2H60•H:zÜ and a molecular weight of 1025.89. Tbe chemical
`designation for doxycycline is 4-(dimethylamino)-1,4,4a,5,5a,6.1 1,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-
`methyl-l,ll-dioxo-2-naphthacenecarboxamide monohydrochJoride, compound with ethyl alcohol (2: 1), monohydrate.
`
`Doxycycline hyclate is a light-yellow crystailine powder which is soluble in water.
`
`Inert ingredients in the formulation are: hard gelatin capsules; magnesiwn stearate; and rnicrocrystalline cellulose.
`Each capsule contains doxycycline hyclate equivalent to 20 mg of doxycycline.
`
`CLINICAL PHARMACOLOGY
`
`After oral administration, doxycycline hyclate is rapidly and nearly completely absorbed from the gastrointestinal
`tract. Doxycycline is eliminated with a half-life of approximately 18 hours by renal and fecal excretion ofuncbanged
`drug.
`
`Mechanism of Action: Dox:ycycline has been shown to inhibit collagenase activity in vitro.1 Additional studies bave
`sbown tbat doxycycline reduces the elevated collagenase activity in the gingival crevicular fluid of patients witb adult
`periodontitis. 1.3 The clinical significance of these findings is not known.
`
`Microbiology: Doxycycline is a member of the tetracycline dass of antibiotics. The dosage of doxycycline acbieved
`with this product during administration is weU below the concentration required to inhibit microorganisms commonly
`associated witb adult periodontitis. Clinical studies with this product demonstrated no effect on total anaerobic and
`facultative bacteria in plaque samples from patients administered this dose regimen for 9 to 18 montbs. This pwduct
`should not be used for reducmg the numbers of or eliminating those microorganisms associated with periodontitis.
`
`Exh. 1053, Page 12 of 22
`
`

`
`Phannacokinetics
`The pharmacokinetics of doxycycline following oral administ::r-a:tion ofPeriostatTN were investigated in 3 volunteer
`studies involving 87 adults. Additionally, doxycycline pharmacokinetics have beeil characterized in numemus
`scientific publications:' Pharmacokinetic parameters for PeriostatTM following singleoral doses and at steady-state
`in healthy subjects are presented as follows:
`
`2
`
`Single dose 20 mg
`
`Pharmacokinetic Parameters for Periostat-rn
`c .. x
`(n!!/mL)
`400± 142
`
`n
`
`42
`
`T .. ,.
`(hrl
`1.5
`(0.5- 4.0)
`
`OfF
`(l/hr)
`
`tlll
`(hr)
`
`3.80±0.85
`
`18.4 ± 5.38
`
`Steady-State 20 mg BID
`
`30
`
`790± 285
`
`2
`(0.98 - 12.0)
`
`3.76± 1.06
`
`Not Determined
`
`Absorption: Doxycycline is virtually completely absorbed afteroral administration. Following 20 mg doxycycline,
`twice a day, in healthy volunteers, the mean peak concentration in plasmawas 790 ng/mL and the average steady-state
`concentration was 482 ng/mL. The effect of food on the absorption of doxycycline from Periostat™ has not been
`studied.
`
`Distribution: Doxycycline is greater than 90% bolllld to plasma proteins. Its apparent volume of distribution is
`variously reported as between 52.6 and 134 L.4
`•6
`
`Metabolism: Major metabolites of doxycycline have not been identified. However, enzyme inducers such as
`barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.
`
`Excretion: Doxycycline is excreted in the urine and feces as llllchanged 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 pbarmacokinetics bave not been evaluated in geriatric patients.
`
`Pediatric: Doxycycline pharmacokinetics bave not been evaluated in pediatric patients (See W ARNINGS).
`
`Gender: A study was conducted in 42 subjects where doxycycline pbarmacokinetics were compared in men and
`warnen. It was observed that C,_ was approxirnately 1.7-fold higher in warnen than in men. There were no apparent
`differences in other pharmacokinetic-parameters.
`
`Race: Differences in doxycycline pharmacokinetics among racial groups have not been evaluated.
`
`•
`
`Renal Insuffidency: Studies have shown no significant difference in serum balf-life of doxycycline in patients with
`normal and severely impaired renal function. Heroadialysis does not alter the half-life of doxycycline.
`
`Hepatic Insuffidency: Doxycycline pharmacokinetics have not been evaluated in patients with hepatic insufficiency.
`
`Exh. 1053, Page 13 of 22
`
`

`
`3
`
`Drug I nteractions: See "Precautions"
`
`Oinical Study
`
`In a randomized, multi-<:entered, 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 nun pocket depth (PD) and attachment Ievel
`(ALv)], the effects of oral acf.minjstration of 20 mg twice a day of doxycycline hyclate plus scaling and root planing
`(SRP) were compared to placebo control plus SRP. Both treatrnent groups were administered a course of scaling and
`root planing in 2 quadrants at Baseline. Measurements of ALv, PD and bleeding on prohing (BOP} were obtained
`at Baseline, 3, 6, and 9 rnontbs from each site about each tooth in the two quadrants that received SRP using the
`UNC- L5 manual probe. Each tooth site was categorized into one of three strata based on Baseline PD: 0-3 mm (no
`d.isease), 4-6 mm (mild/moderate disease), ~ 7 mm (severe disease). Foreachstratum and treatment group. the
`following were calculated at month 3, 6, and 9: mean change in ALv frorn baseline, mean change in PD from baseline,
`mean percentage of tooth sites per patient exhibiting attachment loss of ~ 2 nun from baseline, and percentage of
`tooth sites with bleeding on probing. The results are summarized in the following table.
`
`Oinical Results at Nine Months as an Adjunct to SRP
`
`Parameter
`
`NumberofPatients
`
`Mean Gain in ALv
`Periostat™ 20 mg BID
`Placebo
`
`Mean Decrease in PD
`Periostat™ 20 mg BID
`Placebo
`
`% ofSites with loss of ALv?.: 2 mm
`Periostat™ 20 mg BID
`Placebo
`
`% ofSites with BOP
`Periostat™ 20 mg BID
`Placebo
`
`Basefine Pocket Depth
`
`0-3mm
`
`4-6mm
`
`90
`
`90
`
`~7mm
`
`79
`
`0.25 mm
`0.20mm
`
`1.03 mm*
`0.86mm
`
`1.55mm*
`l.l7mm
`
`0.16 mm**
`0.05 mm
`
`0.95mm**
`0.69mm
`
`L68mm**
`L20nun
`
`1.9.%
`2.2%
`
`39%**
`46%
`
`1.3%
`2.4%
`
`64%*
`70%
`
`0.3%*
`3.6%
`
`75%
`80%
`
`* p<0.050 vs. the placebo control group. ** p<O.O 10 vs. the placebo control group.
`
`INDICATIONS AND USAGE
`
`•
`
`Periosta(TM is indicated for use as an adjunct to scaling and root planing to promote attacbment Ievei gain and t6
`reduce pocket depth in patients with adult periodontitis.
`
`Exh. 1053, Page 14 of 22
`
`

`
`4
`
`CONfRAINDICATIONS
`
`This drug is contraindicated in persans who have shown hypersensitivity to any of ilie tetracyclines_
`
`WARNINGS
`
`THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH DEVELOPMENT (LAST HALF
`OF PREGNANCY, INF ANCY AND CIDLDHOOD TO THE AGE OF 8 YEARS) MA Y CAUSE PERMANENT
`DISCOLORATION OF TIIE TEETII (YELLOW-GRA Y-BROWN). This adverse reaction is more common during
`Iang-term use ofthe drugs but has been observed foUowing repeated short-term courses. Enamel hypoplasia has also
`been reported. TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE USED IN THIS AGE GROUP AND
`IN PREGNANT OR NURSING MOTHERS UNLESS THE POTENTIAL BENEFITS MA Y BE ACCEPT ABLE
`DESPITE THE POTENTIAL RISKS.
`
`All tetracyclines form a stable caicium complex. in any bone forming tissue. A decrease i.it fibuJa growth rate bas been
`observed in premature infants given oral tetracyclines in doses of 25 mglkg every 6 hours. This reaction was shown
`to be reversible when the drug was discontinued.
`
`Doxycycline can cause fetal bann when administered to a pregnant woman. Results of animal studies indicate that
`tetracydines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus ( often
`related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated
`early in pregnancy. lf any tetracyclines are used during pregnancy, or ifthe patient becomes pregnant wbile taking
`this drug, the patient should be apprised ofthe potential hazard to the fetus.
`
`The catabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not
`occur with the use of doxycycline in patients with impaired renal function.
`
`Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking
`tetracyclines. Patients apt tobe exposed to direct sunlight or ultraviolet light should be advised that this reaction can
`occur with tetracycline drugs, and treatment should be discootinued at the ftrst evidence of skin erythema
`
`PRECAUTIONS
`
`While no overgrowth by opportlmistic miaoorganisms such as yeast were noted during clinical studies, as with other
`antimicrobials, PeriostatTM therapy may result in overgrowth ofnonsusceptible microorganisms including fungi.
`
`The use of tetracyclines may increase the incidence of vaginal candidiasis.
`
`PeriostatTM should be used with caution in patients witb a history or predisposition to oral candidiasis. The safety
`and ef:fectiveness of PeriostatTM has not been established for the treatment of periodontitis in patients with coexistent
`oral candidiasis.
`-
`-
`
`If superinfection is suspected, appropriate measures should be taken.
`
`•
`Laboratory Tests: In lang tenn therapy. periodic Iabaratory evaluations of organ systems, including hematopoietic.
`renal, and hepatic studies should be performed.
`~;r=·-
`·
`·
`
`-
`
`Exh. 1053, Page 15 of 22
`
`

`
`5
`
`Drug Interactions: Because tetracyclines have been shown todepress plasma prothrombin activity, patieots who
`are on anticoagulant therapy may require downward adjustment oftheir anticoagulant dosage.
`
`Since bacteriostatic antibiotics, such as the tetracycline dass of antibiotics, may interfere with the bactericidal actioo
`of members of the ß-Iactarn (e.g. penicillin) dass of antibiotics, it is not advisable to administer these antibiotics
`concomi tantly.
`
`Absorption of tetracyclines is impaired by antacids containing alwninwn. calcium, or magnesium and by iroo-
`containing preparations. Absorption is also impaired by bismuth subsalicylate.
`
`Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.
`
`The concurreot use oftetracycline and Penthrane (methoxy-fluorane} has been reported to result in fatal renal toxicity.
`
`Concurrent use of tetracycline may render oral contraceptives less effective.
`
`Drug!Laboratory Test Interactions: False eievatians of urinary catecbolamine Ievels may occuc due to interference
`with the fluorescence test..
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility: Doxycycline hyclate has not been evaluated for
`carcinogenic potential in long-term animal studies. Evidence of oncogenic activity was obtained in studies with
`related compmmds, i.e., oxytetracycline (adrenal and pituitary turnors) and minocycline (thyroid tumors).
`
`Doxycycline hyclate demonstrated no potential to cause genetic toxicity in an in vitro point mutation study with
`mammalian ceUs (CHO/HGPRT forward mutation assay) or in an in vivo micronucleus assay conducted in CD-I
`mice. However, data from an in vitro assay with CHO cells for potential to cause chromosomal aberrations suggest
`that doxycycline hyclate is a weak clastogen.
`
`Oral administration of doxycycline hyclate to male and female Sprague-Dawley rats adversely affected fertility and
`reproductive performance, as evidenced by increased time for mating to occur, reduced sperm motility, velocity, and
`coocentration, abnormal sperm morphology, and i.ncreased pre- and post·implantation Iosses. Doxycycline hyclate
`induced reproductive toxicity at all dosages that were examined in this study, as even the lowest dosage tested (50
`mg/kg/day) induced a statistically significant reduction in sperm velocity. Note that 50 mglkg/day is approximately
`I 0 times the amount of doxycycline hyclate contained in the recommended daily dose of PeriostatTM for a 60 kg
`human when compared on the basis of body surface area estimates (mgfml). Although doxycycline impairs tbe
`fertility of rats when administered at sufficient dosage, the effect ofPeriostatTM on human fertility is unknown.
`
`Pregnancy: Teratogenic Effeds: Pregnancy Category D. (See WARNINGS.) Results from animal studies indicate
`that doxycycline crosses the placenta and is found in fetal tissues.
`
`Nonteratogenic effeds: (See W ARNINGS).
`
`Labor and Delivery: The effect oftetracyclines on Iabor and delivery is unknown.
`
`Nursing Mothers: Tetracyclinesare excreted in human milk. Because ofthe potential for serious adverse reactions
`in nursing infants from doxycydine, the-u5e ofPeriostat.,.,. in nursing mothers is contraindicated. (See W ARNINGS)
`
`Exh. 1053, Page 16 of 22
`
`

`
`Pediatric Use: The use of Periostatn.r in infancy and childhood is coatraindicated. (See W ARN1NGS)
`
`ADVERSE REACfiONS
`
`Adverse Reactions in Cli.nical Trials of PeriostaJfM: In clinical tri als of adult patieuts with periodootal disease 213
`patients received Periostat'N 20 mg BID over ~9- 12 month per:iod. ihe mostfrequent advecse reactioos occurring
`in studies involving treatmeot with Periostat or placebo are listed below:
`
`6
`
`Exh. 1053, Page 17 of 22
`
`

`
`lncidence (%) of Adverse Reactions in PeriostatTM Oinical Trials
`Adverse Reaction
`
`Periostat 20 mg BID (n=213)
`55 (26%)
`47 (22%}
`
`Placebo (n=215)
`. 56 (26%)
`
`46(21%)
`
`40 (19%)
`
`28 (13%)
`
`21 (lO%)
`
`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%)
`
`5 (2%)
`
`7(3%)
`5 (2%).
`
`6(3%)
`
`6 (3%)
`
`5 (2%)
`
`6(3%)
`-·
`
`Headache
`
`CommonCold
`
`Flu Symptoms
`
`Tooth Ache
`
`Periodental Abcess
`
`T ooth Disorder
`
`Nausea
`
`Sinusitis
`
`Injury
`
`Dyspepsia
`
`Sore Throat
`
`Joint Pain
`
`Diarrhea
`
`Sinus Congestion
`
`Coughing
`
`Sinus Headache
`
`Rash
`
`Back Pain
`
`BackAche
`
`Menstrual Cramp
`
`Acid Indigestion
`
`Pain
`
`Infection
`
`GumPain
`
`Bronchitis
`
`Museie Pain
`
`24 (ll%)
`
`14 (7%)
`
`8 (4%)
`
`13 (6%)
`
`17 (8%)
`
`7 (3%)
`
`ll (5%)
`
`13 (6%)
`
`11 (5%)
`
`12 (6%)
`
`12 (6%)
`
`I I (5%)
`
`9{4%)
`
`8 (4%)
`
`8 (4%)
`
`7 (3%)
`
`4(2%)
`
`9(4%)
`
`8 (4%)
`
`8 (4%)
`
`4 .(2%)
`
`1 (I%)
`
`7 (3%)
`
`2(1%)
`
`Note: Percentages are based on total nwnber of study participants in each treatment group.
`
`7
`
`I
`
`Exh. 1053, Page 18 of 22
`
`

`
`8
`
`Adverse Reactions for Tetracyclines: The following adverse reactions have been observed in patients receiv.ing
`tetracyclines:
`
`Gastrointestinal: anorexia, nausea, vomiting. diarrhea, glossitis, dysphagia, enterocolitis, and inflanunatory lesions
`(with vaginal candidiasis) in the anogenital region. Hepatotöxicity has been repo~ rarely. Rare instances of
`esophagitis and esophageal ulcerations have been reported in patients receiving the capsule forms ofthe drugs in the
`tetracycline dass. Most ofthese patients took medications immediately before going to bed (SEE DOSAGE AND
`ADMINISTRATION.)
`
`Skin: maculopapular and erythematous rashes. Ex.foliative dennatitis has been reported but is uncommon.
`Photosensitivity is discussed above. (See W ARNINGS.}
`
`Renal toxicity: Rise in BUN has been reported and is apparently dose related. (See WARNlNGS.)
`
`Hypersensitivity reactions: urticaria. angioneurotic edema. anaphylaxis, anaphylactoid purpura. serum sickness.
`pericarditis, and exacerbation of systemic Iupus erythematosus.
`
`Blood: Hemolytic anernia. thrombocytopenia. neutropenia, and eosinophilia have been reported.
`
`OVERDOSAGE
`
`In case of overdosage, d.iscontinue medication, treat symptomatically and institute supportive measures. Dialysis does
`not alter serum half-life and thus would not be ofbenefit in treating cases of overdose.
`
`DOSAGE AND ADMINISTRATION
`
`THE DOSAGE OF PERlOSTAT™ DIFFERS FROM THAT OF DOXYCYCLINE USED TO TREAT
`INFECTIONS. EXCEEDING THE RECOMMENDED DOSAGE MA Y RESUL T IN AN INCREASED
`INCIDENCE OF SIDE EFFECTS INCLUDING THE DEVELOPMENT OF RESISTANT MICROORGANISMS.
`
`Periostat™ 20 mg twice daily as an adjunct following scaling and root planing may be administered for up to 9
`months. Safety beyond 12 months and efficacy beyond 9 months have not been established.
`
`PeriostatTM should be administered at least one hour prior to moming 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 ADVERSE REACTIONS.)
`
`HOW SUPPLIED
`
`Periostat""(white capsule imprinted with "Periostat "} containing doxycycline byclate equivalent to 20 mg
`doxycycline. Bottle of 100 (NDC XXXX-XXXX-XX).
`Storage: All products are to bestored atcontrolled room temperatures of 59°F- 86 °F (15 oc- 30 °C) and dispensed
`in tight. light-resistant containers (USP).
`•
`
`Rx Only
`
`PERIOSTATnc is ~ trademark ofCollaGenex Pharmaceuticals, Inc., Newtown, PA, 18940
`
`-- ....~-..... --
`
`Manufactured by
`Applied Analytical Inc.
`Wilmington, NC. 28403
`
`Exh. 1053, Page 19 of 22
`
`

`
`9
`
`Marketed by
`CollaGenex Pharmaceutica1s,1nc.
`Newtown, PA, 18940
`
`RE FE RENCES
`
`L Golub L.M., Sorsa T., Lee H-M., Ciancio S .• Sorbi D., Ramamurthy N.S., Grober B., Salo T., Konttinen Y.T.:
`Doxycydine Inhibits Neutrophil (PMN)-type Matrix Metalloproteinases in Human Adult Periodontitis Gingiva. 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 Hmnans. J. Periodout Res 1990; 25:321-330
`
`3. Golub L.M., Lee H.M., Greenwald R.A.. Ryan M.E .• Salo T .• Giannobile W.V.: A Matrix Metalloproteinase
`Inhibitor Reduces Bone-type Collagen Degradation Fragments and Specific Collegenases in Gingival Crevicular Fluid
`During Adult Periodontitis. Inßanunation Research 1997; 46: 310-319.
`
`4. Saivain S., Houin G.: Clinical Pharmacokinetics ofDox:ycycline and Minocycline. Clin. Pharmacokinetics 1988;
`15; 355-366.
`
`5. Schach von Wittenau M., Twomey T.: The Disposition ofDox:ycycline by Man and Dog. Chemotherapy 1971; 16:
`217-228.
`
`6. Campistron G .• Coulais Y., Caillard C., Mosser J., Pontagnier H., Houin G.: Pharmacokinetics and Bioavailability
`ofDoxycycline in Humans. Arzneimittel Forschung 1986; 36: 1705-1707.
`
`-_,.,_ ·-
`
`Exh. 1053, Page 20 of 22
`
`

`
`INERT INGREDIENTS:
`Microcrystalline Cellulose, NF
`Magnest um Stearate, NF
`
`See package insert for dosage
`infonnation.
`
`6. 75"
`
`NDC XXXXX-XXX-XX
`
`Periostat
`Doxycycline Hyclate
`· Capsules USP
`1 2o mg
`1
`100 Bottles X lOOs
`
`CAUTION: Federal (U.S.A.) law prohibits
`dis~nsing wi!hout n prcscription.
`
`Manufactured for:
`CollaGenex, Inc.
`Newtown, PA 18940
`
`Manufactured by:
`AAl, Inc.
`Wilmington, NC 28403
`
`Exp:
`Lot
`(Control No.)
`
`4"
`
`~
`I
`0
`0
`N
`l-...)
`
`..
`
`(ACTUAL SIZE)
`
`Exh. 1053, Page 21 of 22
`
`

`
`AAI, Inc.
`Manufactured by:
`Newtown, PA 18940
`CollaGenex, Inc.
`Manufactured for:
`
`()1
`•
`()1
`
`-
`
`~ ~~~
`::c: oo
`i.l
`].cffl ~ (1> 0
`
`ct
`sr.
`F' i:
`~g_.~ '
`g•"<!l
`~ EI
`"". :E
`Cor.l'< ~
`c
`§~
`~ >
`'
`.
`.. V..
`[c: Q 0 e. s-~· .
`J~ -~~~ ~ ~
`~. [ 8t--.:> cn <:'J
`n
`v~@
`
`n~ (t>
`
`"ii 0
`~3
`~
`
`'l
`
`15°·30°C (59°-86°F)
`Store at controlled room temperature
`infonnation.
`See package insert for dosage
`Magnesium Stearate, NF
`Microcrystalline Cellulose, NF
`INERT INGREDIENTS:
`
`•
`
`I
`
`I
`
`z 0
`::J Wilmington, NC 28403
`'§
`
`§ -Exp:
`
`Lot:
`
`L__
`.:..."
`
`m
`~N
`0-
`~Cf)
`~m
`~()
`::0-
`Q :E
`"-1
`,.,-...
`
`-
`
`0
`0 t....)
`0
`I
`A
`
`I'
`
`Exh. 1053, Page 22 of 22