Dr. Reddy's Laboratories, Ltd ., et al.
`v.
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1073
`
`Exh. 1073
`
`

`
`JEB11>2lW
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`
`Exh. 1073
`
`

`
`s
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`ED LT I 0 N _
`
`),
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`- ·-
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`PDR®
`54
`2000
`-p-H--_ y·---s--- c· ·.•· ·IA· .. ··•···.··· ... N·········s~
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`Exh. 1073
`
`

`
`Doxycycline is also indicated for tbe tr"atm•en1; oLin&""-~
`caused by the following gram-negative mill:l'C)<>rg>!DU"'>B:·~
`· Chancroid caused by Hrumophilus ducreyi.
`Plagce due to Yersinia pestis (funnerly Pasteurell
`. Tularemia due to Francisella tularensis (formerly
`rella tularensis ).
`Cholera caused by Vibrio cholerae
`Campylobecter fetus infections caused by
`tus (formerly Vibrio fetus).
`Brucellosis due to Brucella species (in, coDjunction
`streptomycin).
`Bartonallosis due to Bartonella bacilliformis.
`Granuloma inguinale caused by Cai,Y,.;"""IobG<et.Jriur.ngran::
`ulomatis.
`Because many strains of the follOwing groups of
`ganiams have been shown to be resistant to doxycyc!ine, cul-
`ture and susceptibility testing are recommsnded. .
`'
`Doxycycline is indicated for treatment ofinfecticms
`by the following gram-negative ~~~~=~=:b~~.~
`teriologic testing indicates appropriate
`drug:
`Escherichia coli
`Ent.robocter aerogenes {formerly Aerobacter aerogenes)
`Shigella species
`~
`Acinetobac;l£< spscies {formerly Mirna speciss and Here!ka
`tipecies)
`.
`.
`.
`:
`Respiratory tract infections caused by Haemophilus in-
`fluenzae.
`llaspiratory tract and urinary tract infections caused by:
`Klebsiella species.
`· .
`Doxycycline is indicated for ~atment of infections caused '
`by tbe follOwing gram-positive microorganisms when bacia'
`riologic testing indicates appropriate susceptibility to the
`drug:
`Upper respiratory infections caused by Streptococcus prwu-
`moniae (formerly Diplococcus pneum.oniae ).
`·
`Skio and skin structure infections caused by StophylococcUB ~
`au.reWI. Doxycycline is not the drug of choice in the treat.
`ment of any type of stapbylococcel infections.
`.
`When penicillin is contraindicated, doxycycline is an alter-
`native drug in the treatment of the following infections:
`Uncomplicated gonorrhea caused by Neiseeria
`Syphilis caused by 'freponema pallidum.
`Yaws caused by Treponema pertenue. ·.
`Listeriosis due to Listeria monocytogenee.
`Aotbrax due to Bacillus anthracis.
`vm.ent's infection caused by Fusobacterium fusifo1711<.
`Actinomycosis caused by Actinomyces israelii.
`Infections caused by Clostridium species.
`In acute intestiual amebiasis, doxycycline may be a
`- ..
`adjunct to amebicides.
`In eevere acoe, doxyeycline may be useful adjunctive tllsi-
`apy.
`CONTRAINDICATIONS
`This drug is contraindicated in persons who have shown hy-
`persensitivity to any of the tetracyclines.
`WARNINGS
`THE USE OF DRUGS OF THE TETRACYCLINE
`DURING· TOOTH DEVELOPMENT (LAST
`PREGNANCY, .. INFANCY, AND CHILDHOOD
`AGE OF 8 YEARS) MAY CAUSE_~~~~~.p~~Olr.
`ORATION OF THE TEETH \>.lloU..IJW·-\.t.ti.IU-DlUJYU"·
`
`• Streptococr:u.s pyogems
`• Streptococcus pneumoniae
`• EntErococcus group (Streptococcus faecalis and Streptococ-
`cus faecium}
`· ·
`• Alpha-hemolytic streptococci (virioons group)
`OTHER MICROORGANISMS:
`• Chlamydia psittaci
`• Chlamydia trtu:homatis
`• Ureaplasma urealyticum
`• Borrelia recurrep.tis
`• 2reponema pallidum
`• 1)-eponema pertenue.
`• Clostridium sPecies
`• Fusobacterium {usiforme
`• Actinomyces species
`• Bacillus anthraiis
`• Prop~nibacterium acnes
`• "Entamoeba species
`• Balantidium coli
`SusceptJ'bi6ty tasts: Diffusion Techniques: Quantitative
`methode that.require measurement of zone diameters give
`the most precise estimate of tbe eusceptibility ofhacteris to
`antimicrobial agents.
`·
`One such. standard pro~ure1. which hAs been recom-
`mended fur use with disks to tesi susc:epb.'bility of organisms
`to doxycycline uses the 30-mcg tetracycline-class disk or the
`30-mcg doxycycline disk. Interpretation involves tbe cor.re-
`lation of the dialneter obtained in tbe disk tesi with the
`minimum inhibitory concentration (MIC) fur tetracycline or·
`doxyeycline, respectively.
`Reports from the laboratory giving results of tbe standard
`single-disk susceptibility test with a 30-mcg tetraeycline-
`class disk or tbe 30-mcg doxyeycline disk should be inter-
`preted acconling to the .fullowing criteria ..
`
`Zone Diameter (mm)
`tetraCycline
`doxyeycline
`. 0':19
`"'16
`15-18
`13--15
`:<14
`:<12
`
`Interpretation
`
`Susceptible
`Intermediate
`):lesistant
`
`A report of "susceptible" indicates that the pathogen is
`likely to be inhibited by ganerally achievable blood levels. A
`report. of "intermediate" suggesis that tbe'orgauism woulcl:
`be sliscepb.'ble if a high il.e>Sage.is used or if the infection is
`coiifined to tissues and lluide in which high antimicrobial
`Jevels are attained. A report of "resistant" indicates that
`achievable conCentrations are unlikely to be inhibitory, aud
`other therapy should be selected.
`Standardized procedures require the use of laboratory con-
`trol organisms. The 30-mcgtetrecycline-class disk or tbe 30-
`incg doxYcycline disk sh01Jld give tbe following zone diam-
`eters:
`
`Organism
`
`E. coli ATCC 25922
`S. aureus ATCC 25923
`
`Zone Diameter
`tetracycline
`doxycycline
`13--25
`13--24
`19-28
`23--29
`
`Dilution Techniques:
`tree a standardized dilution method' (broth, agar, microdi-
`lutionl or equivalent witb tetracycline powcjer_ The MlC val-
`. ues obtained should be interpreted according to tbe follow-
`ing criteria:
`MIC (mcg/ml)
`s4
`8
`~16
`
`. Interpretation
`Suscepb.'ble
`Intermediate
`Resistant
`As with standard di!fusion ~clmiques, dilution methode re-
`quire the use oflaboratory control organisms. Standard tot.
`racycline powder should provide tbe following MlC values:
`MIC (mcg/ml)
`0.25-1
`!h'l2
`1-4
`!h'l2
`
`Organism
`S. aureus ATCC 29213
`E. faecelis ATCC 29212 ·
`E. coli ATCC 25922
`P. aeruginosa ATCC 27853
`
`2082/0ClASSEN
`
`MONODOX®
`1.
`DOXYCYCLINE MONOHYDRATE CAPSULES
`[mon 'o-dox I
`
`~
`
`DESCRIPTION
`Doxycycline is a broad-spectrum antibiotic S)>'nthetically de-
`rived from oxytei.racycline. Monodox® 100 mg and 50 mg
`capsulea contani doxycycline monohydrate equivalent to
`100 mg or 50 mg of doxycycline for oral administration. The
`chemical designation of the light-yellow crystalline powder
`is alpha-6-deoxy-5-oxytetracycline.
`Structural formula:
`
`C2,HuN20 8·IfoO
`M.W.=Ml2.46
`Doxycycline has a high degree of lipid solubility and a low
`affinity for calcium binding. It is highly stsble in normal hu-
`man serum. Doxycycline will not degrade into an epianby-
`droform.
`·
`Inert Ingredients: colloidal silicon dioxide; 'hard gelatin
`capsule; magnesium stearate; microcrystalline cellulose;
`snd sodium starch glycolate.
`·
`· CLlNICAL PHARMACOLOGY
`'Ietracyclines are readily absorbed and ere bouud to plasma
`pioteins in varying degreas. ~y are conceni;rated by tbe
`'liver in tbe bile aud excreted in the urine and feces at high
`concentrations in a biologically active 'form. Doxycyc)in.e is
`W:tually ·completely absorbed attar oral administretiOIL
`Following a 200 mg dose of doxycycline monohydrate, 24
`normal adult volunteers averaged the·following serum con-
`centration values:
`[Sea table below} ·
`Average Observed Values ..
`Maximum Concentration
`3.61 mcglmL (:!: 0.9 sd)
`2.60 hr (:!: 1.10 sd)
`Time of Maximum
`Concentration ·
`0.049 per In' (± 0.030 sd)
`· Elimination Bate Constant
`16.33 hr (:!: 4-53 sd)
`Half-Life
`
`Excretion of doxycycline by tbe kidney is about 40%172 .
`hours in individuals' with normal fuliction (creatinine clear-
`ance about 75 mL!tirin). This percentage excretion may fall
`as low as 1-5%172 hours in individuals with severe renal in-
`sufliciency (craetinine clearance below 10 mllmin). Studies
`have shown no significant di:ff'erence in serum. half-life of
`doxycycline (range 18-22 hours) in individuals with normal
`and severely impaired reual function;
`Hemodialysis does not alter serum half-life.
`Microbiolo9Y: The tetracyclines. are piimari!y bacterio-
`static and are thought to axert their·antiniicrobial e1!'eot by.
`the inhibition of protein synthesis. The tetraeyclines, in-
`cluding doxycycline, have a similar antimicrobial speotrum·
`of activity against a wide range Of gram-positive and gram-
`negative oi-gemsme. Cross-resistance oftbeae.organislns to
`tetraeyclines is common::
`·
`While in vitro studias have·demonstreted tbe sueceptibility:
`of most etrafus of the following microorganisms, clinical ef-
`ficacy fur infections otber tbau tbose.included in tbe INDI-
`CATIONS:AND USAGE section has not been documented.
`GRAM-NEGATIVE BACTERIA:
`• Neisseria gonorrhoeae
`• Haemophilus duc,..Yi
`• Hoerrwphilus in[luenzoe
`• Yersin.ia pestis (formerly Pasteurella pestis)
`• Fra.ncisella tularensis (formerly Pasteurella tulare718is)
`• Vibrio cholerae (formerly Vwrio comma)
`• Bartonella bacilliformis
`• -Brucella species
`.
`Because. many strains oftbe following groups of gram-neg-
`ative microorganisms have been shOwn to be resistant to
`tetracyclines, culture and suseepb.'bility testing are recom-
`mended:'
`• Escherichia coli
`• Klebsiella species
`• En.terPbacter aerogene&
`• Shigella species
`• Acinetobacter species (formerly Mirna species andHerellea
`-species)
`• Bacteroides species
`GRAM-POSITIVE BACTERIA:
`Because many strsins of the following groups of gram-posi-
`tive microorganisms have been ehown to be resietant to tot.
`raeyclines, culture and eusceptibility testing are recom-
`mended. Up to 44 percent of strains of Streptococcus pyog-
`enes and 74 percent of Streptococcus faecolis have been
`found ·to be resistant to tetracycline drugs. Therefore, tetra-
`cyclines should not be uSed to treat streptococcal infections
`unlese the organism has been demonstrated to be suscepti-
`ble.
`·
`
`INDICATIONS AND USAGE
`Doxycycline is indicated for the treatment of the following
`infections:
`. .
`·
`Rocky mountain spotted fever, typhus fever and tbe typhus
`group, Q fever, rickettsislpox, and tick fevers caused by Ric-
`kettsiae..
`,
`Respiratory treot infections. caused by Mycoplasma
`moniae.
`Lymphogranuloma venereum caused by Chlamydia tracho- ·
`matis.
`Psitt.acosis (omithosis) caused by Chlamydia psittoci.
`'Irachoma caueed by Chlamydia trachomatis, although tbe
`infectioue agent is not always elimineted as juclgecl bY im-
`munofluOrescence.
`'
`.
`· Inclusion conjunctivitis caused by· Chlamydia troehomatis.
`Uncomplicated urethral, endocervical or rectal infections in
`adults caused by Chlamydia trtu:komatis.
`Nongonococcal urethriti& caused by Ureaplasma ·urea-
`lyticum.
`.
`Relapsing fever due to Borrelia. recurrentis.
`
`General:
`As with other antibiotic preparations, use of this
`result in overgrowth of non-susceptible
`ing fungi If superinfection oceurs, the
`discontinued and appropriate thcoraJ?Y inst
`Bulging fontanels in infants
`tension in adults have been
`ing tetracyclines. These
`drug was discontinued.
`
`Time (hr):
`Cone.
`(mcglmL)
`
`0.5
`
`1.02
`
`1.0
`
`2.26
`
`1.5
`
`2.67
`
`2.0
`
`3.01
`
`3.0
`
`3.16
`
`4.0
`
`3.03
`
`8.0
`
`2.03
`
`12.0
`
`1.62
`
`24.0
`
`0.95
`
`. 46.0
`
`0.37.
`
`72.0
`
`0.15
`
`Information wiD be superseded by supplements and subseque.rt..editians
`
`Exh. 1073
`
`

`
`1\NS' DESK REFERENCE®
`
`DUCT INFORMATION
`
`:ed for the treatment of infectious
`·am~negative microorganisms:
`nophilus ducreyi.
`stis (formerly Pasteurella. pestis).
`ella tularensis (formerly Pasteu. -. ·
`
`:holerae (formerly Vibrio comma),
`t:ions caused by Campylobacter fe.
`
`Ua species (in conjunction with
`
`mlla bacilliformi3.
`ed by Calymmatobacterium gran-
`
`the following groups of microol-
`to be resistant to doxycycline, cul-
`ting are recommended ..
`lr .treatment of infections caused
`ative microorganisms, when hac.
`appropriate susceptibility to the
`
`rmerly Aerobacter aerogenes)
`
`nerly Mima species and Hf!rellea
`
`Jns caused by Haemophilus in-
`
`:nary tract infections caused by
`
`>r treatment of infections caused
`tive microorganisms when bacte-
`appropriate susceptibility to the
`
`ns caused by Streptococcus pn.eu-
`t!US prummoniae ).
`:'ections caused by Staphylococcus
`; the drug of choice in the treat-
`rlococcal infections.
`(ldicated; doxycycline is an alter-
`mt of the following infections:
`caused by Neisseria gonorrhoeae.
`~rna pallidum.
`:tperUmue.
`monocytogenes.
`tthracis.
`by Fusobacterium fusiforme.
`,ctinomyces israelii.
`-idium species.
`LSis, doxycycline may be a useful
`
`e may be useful adjunctive ther-
`
`din persons who have shown hY·
`! tetracyclines.
`
`' TilE TETRACYCIJNE CLASS
`:LOPMENT (LAST HALF OF
`; AND CHILDHOOD TO THE
`cAUSE PERMANENT .DISCOL-
`H (YELLOW-GRAY-BROWN).
`>re common during long;term use
`bserved following repeated short-,-
`Jplasia has also been. reported.
`, TIIEREFORE, SHOULD NOT
`fE GROUP UNLESS OTHER
`II TO BE EFFECTIVE OR ARE
`
`ble calcium complex in any bone-
`: in the fibula growth rate has
`ures given oral tetracycline- in
`: hours. This reaction was shown:
`lrug was discontinued.
`indicate that tetracyclines cross
`fetal tissues, and can have toxic
`ltus (often related to retardation,
`~vidence of embryo toxicity has
`;ed early in pregnancy. If any te_t~
`~gnancy odfthe patient becomes
`,se drugs, the patient should be
`azard to the fetus.
`the tetracyclines may cause
`o- date indicate that this· does
`:ycline in patients with impair~d
`
`1ncision and drainage or other surgical procedures should
`be performed in conjunction with antibiotic therapy when
`indicated.
`(.aboratory tests: In venereal disease when coexistent
`syphilis is suspected, a dark-field examination should be
`done before treatment is started and the blood serology re-
`peated monthly for at least four months.
`In long-term therapy, periodic laboratory. evaluations of or-
`gan systems, including hematopoietic, renal, and hepatic
`studies should be performed.
`orug interactions: 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 drugs may interfere with the bacterici-
`dal actioD. of penicillin, it is advisable to avoid giving tetra-
`cyclines in conjunction with penicillin.
`Absorption _of tetracyclines is .impaired by antacids contain-:
`mg aluminum, calcium, or magnesium, and iron-containing
`preparations.
`Barbiturates, carbamazepine, and phenytoin decrease the
`half'life of doxycycline.
`The concurrent use of tetracycline and methoxyflurane has
`been reported to result in fatal renal toxicity.
`Concurrent rise of tetracycline may ren·der oral contracep-
`tives less effective.
`Drug{laboratory test interactions: -False elevations of uri-
`-nary catecholamine levels may occur due to interference
`with the fluorescence test.
`Carcinogenesis, mutagenesis, impairment of fertility: Long-
`term studies in animals to evaluate the carcinogenic poten-
`tial of doxycycline have not been conducted. However, there
`- has been evidence of oncogenic activity in rats in studies
`with related antibiotics, oxytetracycline (adrenal and pittri-
`tary tumors) and minocycline (thyroid tumors). Likewise,
`although mutagenicity studies of doxycycline have not been
`conducted, positive results ·in in vitro mammalian cell as-
`says have been reported for related antibiotics (tetracycline,
`oxytetracycline). Doxycycline administered orally at dosage
`levels as high as 250 mg/kg/day had no ~pparent effect on
`the fertility of female rats. Effect on male fertility has not
`been studied.
`Pregnancy: Pregnancy Category D. (See WARNINGS).
`Labor and Delivery: The effect of tetracyclines on labor
`and delivery is unknown.
`Nursing mothers: Tetracyclines -are present in the milk of
`lactating women who are taking a drug in this class. Be-
`cause of the potential for serious adverse ·reactions in nurs·
`ing infants from the tetracyclines, a decision should be
`made whether to discontinue nursing or discontinue the
`drug, taking into account the importance of the drug tO the
`mother. (See WARNINGS).
`Pediatric Use: See WARNINGS and DOSAGE AND AD-
`1\UNISTRATION sect~ons.
`
`oral doxycycline's virtually complete absorption, side
`to the lower bowel, particularly diarrhea, have been
`infrequent. The following adverse reactions have been ob-
`served in patients receiving tetracyclines.
`Gastrointestinal: Anorexia, nausea, vomiting, diarrhea,
`glossitis, dysphagia, enterocolitis, and inflammatory lesions
`(With monilial overgrowth) in the anogenital re!Qon. These
`reactions have been caused by both the oral and parenteral
`" aLdmini,Ltration of tetracyclines. Rare instances of esophagi-
`tis and esophageal ulcerations have been reported in pa-
`tients receiving capsule and tabletforms of drugs in the tet-
`racycline class. Most of these patients took medications im-
`mediately before going to bed. (See DOSAGE AND
`ADMlNISTRATION).
`Maculopapular and erythematous rashes. Exfolia-
`dermS:titis has been reported but is uncommon. Photo-
`sensitivity is discussed above. (See WARNINGS.)
`toxicity: Rise in BUN has been reported and is ap-
`parently dose related. (See WARNINGS.)
`.~ypersensitivity reactions: Urticaria, angioneurotic ede-
`anaphylactoid purpura, pe:P,carditis, and
`· lupus erythematosus.
`anemia, thrombocytopenia, neutropenia,
`have been reported with tetracyclines.
`fontanels in infants and intracranial hy-
`(See PRECAur:IONS-Gerieral)
`en 1~ve'n over prolonged Periods, tetracyclines have been
`to produce browil.-black microscopic discoloration
`thyroid gland. No abnormalities of thyroid function
`to occur.
`·
`·
`~
`
`DOSAGE AND FREQUENCY OF ADMINIS-
`DOXYCYCLINE DIFFERS FROM THAT OF
`Tillm 1~TIRAC:YCLINES.EXCEEDINGTIIE REO-
`DOSAGE MAY RESULT IN AN m:
`INCIDENCE OF SIDE EFFECTS.
`The·usual dose of oral doxycycline is 200 mg on the
`of treatment (administered 100 mg every 12 hours
`mg every 6 hoUrs) followed by a maintenance do.se of
`
`100 mg!day. The maintenance dose may be administered as
`a single dose or as 50 mg every 12 hours. In the manage-
`ment of more severe infections (particularly chronic infec·
`tions of the urinary tract), 100 mg every 12 hours is recom-
`mended.
`For pediatric Patients abov.e eight years of age: The rec-
`ommended dosage schedule for pediatric patients Weighing
`100 pounds or less is 2 mg/lb of body weight divided into twO
`doses on the first day of treatment, followed by 1 mg/lb -of
`body weight given as a single daily dose or divided into two
`doses, Oil: subsequent days. For more severe llifections, up to ·
`2 mg/lb of body weight may be used. For pediatric patients
`over 100 lbs the usual adult dose should be used.
`Uncomplicated gonococcal infections in adults (except
`anorectal infections in men): 100 mg by mouth, twice a
`day for 7 days. As an alternate single visit dose; administer
`300 mg stat followed in one hour by a second 300 mg dOse.
`Acute epididymo:..o~chitis Caused by N: gonorrhoeae : 100
`mg, by mouth, twice a day for at leaSt 10 days.
`Primary and secondary syphilis: 300 mg a day in divided
`doseS for at least iO days.
`Uncomplicated urethral, endocervical, or rectal infection in
`adults caused by Chlamydia trachomatis: 100 mg, by
`mouth, twice a day for at least 7 days.
`Nongonococcal urethritis caused by C. trachomatis and U.
`urealyticum: 100 mg, by mouth, twice a day for at least 7
`days.
`Acute epididymo-orchitis caused by C. trachomatis: 100
`·
`mg, by mouth, ,twice a day for at lea.!'t "10 days.
`When used in streptococcal infections, therapy should be
`continued for 10 days.
`Administration of adequa~e amounts of fluid aiong with_cap-
`sule and tablet forms of drugs in the tetracycline class is
`recommended to wash down the drugs and.reduce the risk
`of esophageal irritation and. ulceration. (See ADVERSE
`REACTiONS). If g8.Stric irritation occUrs, doxycycline may
`be given with food. Ingestion of a. high fat meal has been
`shown to delay the time to peak plasma concentrations by
`an average of one hour and 20 minutes. However, in the
`same study, food enhanced the average peak concentration
`by 7.5% and the area under the curve by 5.7%.
`HOW SUPPLIED
`MONODOX® 50 mg Capsules have a white opaque body
`with a yellow opaque cap. The capsule bears the inscription
`"MONODOX 50'' in brown and "M 260" in brown. Each cap-
`sule contains doxycycline monohydrate equivalent to 50 mg
`doxycycline.
`MONODOX® 50 mg iS available in: Bottles of 100 capsules,
`NDC 55515-260,06. MONODOX® :1,00 mg Capsules have a
`yellow opaque body with a brown opaque cap. The capsule
`bears the inscription ~MONODOX 100" in white and "M
`259" in brown. Each capsule contains doxycycline monohy-
`drate equivalent to 100 mg of doxycycline. MONODOX®
`100 :ing is available in: Bottles of 50 capsules, NDC 55515:.
`259-04 and in bottles of250 capsules, NDC 55515-259-07.
`STORE AT CONTROLLED ROOM TEMPERATURE 15"-30"C
`{59"-86"FJ. PROTECT FROM LIGHT.
`ANIMAL PHARMACOLOGY AND. ANIMAL TOXICOL-
`OGY
`.
`Hyperpigmentation of the thyroid has been produced by
`members of the tetracycline class in the following species: iD:
`ratS by oxytetracycline, doxycycline, tetracycline P04, and
`methacycline; in minipigs by doxycycline, minocycline, tet-
`racycline P04, and methacycline; in dogs by doxycycline and
`'minocycline; in monkeys by minocycline.
`"Minocycline, tetracycline PO 4, methacycline, doxycycline,
`tetracycline base, oxytetracyclii::te HCl and tetracycline HCl
`were goitrogenic in rats fed a loW iodine diet. This goitro-
`genic effect was accompanied by high radioactive iodiJ;I.e up-
`take. Administration of nrinocycline also produced a large
`goiter with high radioiodine uptake in rats fed a· relatively
`high iodine diet.
`.
`.
`·
`Ti-eatment of various animal species With this class of drugs
`has also resulted in the induction of thyroid hyperplasia in
`the following: in ratS and dogs (minocycline), in chickens
`(chlortetracyclfue) B.nd in rats and _mice (oxytetracycline).
`Adreilal gland hyperplasia.has been observed in goats and
`rats treated with oxytetracycline:
`REFERENCES:
`1. National Committee for Clinical Laboratory Standards,
`Perfa,rmance .Standards .for Antimicrobial Disk Suscepti·
`bility Tests, Fourth Edition. Approved Standard NCCLS
`Dpcument M2-A4, VoL 10, No. 7 NCCLS, Villanova, PA,
`Aprill990.
`2. National Committee for Clinical Laboratory Standards,
`Methods for Dilution Antimicrobial. Susceptibility Tests
`for Bacteria That Grow Aerobically, Second Edition. Ap-
`proved Standard NCCLS Document M7-A2, VoL 10, No. 8
`NCCLS, Villanova, PA, April1990.
`Rx Only
`·
`Manufactured for
`OCLASSEN
`PHARMACEUTICALS
`A Division of Watson Labs. Inc., Corona, CA 91720
`by Vmtage Pharmaceuticals; Inc., Charlotte, N.C.
`RevisedApril28, 1998
`02-183911R7
`Shown in Product Identification Guide, page 327
`
`ORGANON/2083
`
`OHMEDA
`Pharmaceutical Products Division Inc.
`(see BAXTER PHARMACEUTICAL PRODUCTS
`INC.)
`
`Organon Inc.
`375 MT. PLEASANT AVE.
`WEST ORANGE, NJ 07052.
`
`Direct Inquiries to:
`(973) 325-4500
`
`Currently available products are listed below. For complete
`product line information and price lists, direct inquiries to
`Organon Inc. Customer Service. For specific product infor-
`mation~ contact Organon Inc. Medical Services Department.
`
`ARDUAN®
`(pipecuronium bromide) for injection
`
`HOW SUPPLIED
`10 mL vials/10 mg-hoxes of 6 vials-NDC-0052-0446-36
`
`TICE® BCG, BCG Live
`BCG.VACCINE USP
`(for Intravesical u.se)
`
`Distributed by Organon Inc.
`(See page 2111 complete product information.)
`
`CALDEROL®
`[kal-dah 'roll
`(calcifedio"! capsules, USP)
`
`HOW SUPPLIED
`20 pg (white, soft elastic capsules) bottle of 60
`50 )lg (orange, soft elastic capsules) bottle of 60
`Shown in Product Identification Guide; page 327
`
`CORTROSYN®
`[cOr-trO-sin]
`(cosyntropin} for injection
`FOR DIAGNOSTIC USE ONLY
`
`DESCRIPTION
`Cortrosyn® (cosyntropin) for injection is a sterile lyophi-
`lized powder in vials containing 0.25mg of Cortrosyn® and
`lOmg of mannitol to be reconstituted with 1m.L sodium chlo-
`ride for injection, USP as solvent. Administration is by in-
`travenous Or intramuscWax injection. Cosyntropin is ct 1-24
`co:rtlcotropin, a synthetic subunit of ACTH. It is an open
`chain polypeptide containing, from the N terminus, the first
`24 of the 39 amino acids of natural ACTH. The sequence of
`amino acids in the 1-24 compound is as follows:
`--~-~~~~~-~-~-~-~---~
`
`1.
`
`2
`
`3
`
`4 .
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`~-W---~-~-~-~-~-~-~-~
`u ~ M
`u m m m m a
`H
`g
`
`Tyr-Pro
`23
`24
`CLINICAL PHARMACOLOGY
`Corlrosyn® (cosyntropin) for injection exhibits the full cor-
`ticosteroidogenic activity of natural ACTH. Various studies
`have shoWn.that the biologic activity ofACTH resides in the
`N-terminal portion of the molecule and that -$e 1-20 amino
`acid residue is_ the minimal sequence retaining full activity.
`Paitial or complete loss of activity is noted with progressive
`shortening of the chain beyond 20 amino acid residue. For
`example, the decrement fro~ 20 to 19 results in a 70% loss
`of potency.
`The phatn;1acologic profile of Cortrosyn® is similar to that of
`purified naturalACTH. It has been established that 0.25 mg
`of Cortrosyn® Will stimulate the adr~nal cortex maximally
`and to the same extent. as 25 units of natural ACTH. This
`dose of Cortrosyn® will produce ."maximal s8cretion of
`17-0H corticosteroids, 17-ketosteroids and/or 17-k~togenic
`ster.oids.
`The extra-adrenal effects which natural ACTH and Cor-
`trosyn® have in common include increased melanotropic ac-
`tivity, increased growth hormone secretion and an adipok:i ..
`netic effect. These are considered to- be withou~ physiological
`or clipical significance.
`Animal, human and synthetic ACTH (1-39) which all con-
`tain 39 amino acids exhibit similar -immunologi.c activity.
`Continued on next page
`Consult 20 00 PDR• supplements and future editions for revisions
`
`Exh. 1073
`
`

`
`2384/PFIZER INC
`
`Viagra-Cont. ·
`
`.
`
`ritonavir's .marked ell'ects on a broad .range of P450 sub-
`strates. VIAGR.Ahad no ell'ect on ritonavir phm-macoldnet-
`.
`ies'·'(see DOSAGE AND ADMINISTRATION).
`Although the interaction between other protease inhibitors
`and' sildenafll has not bean studied, their concomitant use is
`expected to increase· sildena1illevels.
`It can be expected that concomitant admimstration of
`CYPSA4 inducers, such as rifampin, will decrease plasma
`levels of sildenaiil.·:
`·
`Single d~ses of antacid (magnesium hydroxide/aluminum
`hydroxide) did not all'ect the bioavailability ofVIAGRA.
`Pharmacokinetic data from patients in clinical trials
`Showed no .effect on sildenafll pharmacokinetics of CYP2C9
`inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibi-
`tors (such as selective serotonin.reuptake inhibitors, tricyc
`clic antidepressants), thiazide and related diuretics, ACE
`nihlbitors and calcium channel bloCkers. The AUC of the
`active meiabolite;, N~esmethyl sildenafil, waS increased
`62%. by loop and potassium-sparing diuretics and 102% by
`nonspecific beta-bloCkers. These effects on the metabolite
`are not expected to be of clinical consequence •.
`.
`Effects of VJAGRA on Qther Drugs
`.
`In vitro studies: Sildanaiil is a weak inhibitor of the cyto-
`chrome P450 iaoforms 1A2, 2C9, 2C19, 2D6, 2E1 aod 3A4
`ciC50 :>150 pM). Given sildenaJil peak plasma concen!"~­
`tions of approximately 1 pM aft~ recommended doses, 1t 1s
`unirkel.y that VIAGRA. will alter the clearaoce of Sl!bstrates
`·
`·
`of these isoenzymes..
`In vivo Studies: ·When VIAGRA.lOO mg oral was coadmin-
`istered with amlodipine, 5 mg or 10 mgoral, to hypertensive
`pati,en~, the mean adttitionaJ rediJ.ctiOIL on. ~upin~ tilood
`pressure was 8 mmKg systolic aod 7 mmH!f <fiaetolic.
`.
`No ·significan,t interact;i.oiis :W~ shown with tolbutaJI?~e
`(250 mg) or warfarin (40 mg), both of which are metabolized
`byCYP2C9:
`. ·
`· .
`VIAGRA (50 mg) di4 not potentiate thE> increase iii bleeding
`time caused· by aspirin (150 mg).
`·
`.
`VIAGRA (50 mg) .did not poten:tiate the hypotensive effect of
`alcohol in hOaltby volunteers ,With mean maximum bloodal-
`; · _-
`·
`cohollevels of 0.08%... .
`In a study of healthy male volunt.ers,. sildananl (100 mg)
`did not affect the steady state phermacokinetii:s of th~ HIV
`protease inhibitors, saqnin