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`Page 1 Dr. Reddy's Exh. 1049
`
`

`

`PRODUCT INFORMATION
`
`It is not known whether
`this drug is se-
`Nursing Mothers:
`creted in hun&an m&lk and because of the potential
`for seri-
`fram folodipine m the infant, a deci-
`ous adverse reactions
`sion should be made whether
`to discontinue
`nursing or to
`the importance of
`discontinue
`taking mto account
`the drug,
`the d&srg to the mother.
`Pediatric Use: Safety and eflectiveness m pediatiuc pa-
`tients have not been estabhshed
`
`Based on patient weight of 50 kg
`
`ADVERSE REACTIONS
`
`In controlled studies in the United States and overseas, ap-
`proximately 3000 patients were treated with felodipine
`as
`either the extended-release
`or the immediate-release
`formu-
`lation.
`The most common
`clinical adverse
`events
`reported with
`PLENDIL administered
`at the recom-
`as monotherapy
`mended dosage range of 2.5 mg to 10 mg once a day were
`peripheral
`edema and headache. Peripheral
`edema was
`generally niild, but it was age and dose related and resulted
`of therapy in about 3% of the enrolled
`in discongnuation
`pat&ents. D&scontinuation of Iherapy due to any clin&cal ad-
`verse event occurred in about 6%o of the patients
`receiving
`PLENDIL, princ&pally
`edema, headache, or
`for pempheral
`flushing
`events that occurred with an me&dence of I 5% or
`Adverse
`greater at any of the recommended
`doses of 2.6 mg to 10 mg
`once a day (PLENDIL, N = S61; Placebo, N = 334), without
`regard to causality, are compared to placebo and are listed
`by dose m the table below These events are reported from
`controlled clm&cal tisals w&th patient., who &vere randomized
`to a fixed dose of PLENDIL or titrated from an initial dose
`of 2 5 nig or 6 n&g once a day A dose of 20 mg once a day has
`been evaluated
`the anti-
`in some clmical si.udice Although
`hyper tens&ve eflect of PLENDIL is increased at, 20 mg once
`a day, I,here &s a dispropor
`tionate mcroase in adverse events,
`those assoc&ated with vaso&1&latory eflects (see
`uspec&ally
`DOSAGE and ADMINISTRATION).
`[See table at boLtom of previous page]
`events that occurred u& 0 5 up to 1.5% of patients
`Adverse
`trials at the
`who rece&ved PLEiNDIL m all controlled climcal
`dosage range of 2 5 mg to 10 mg once a day,
`recommended
`and seisous adverse events that occurred at a lower rate, or
`events
`(those lower
`reporLed durmg marketu&g
`expeinence
`rate events are in ii.alice) are hated below These events are
`listed in order of decreasmg severity within each category,
`of these events
`and the relationship
`of
`to administration
`PLENDIL is uncertain Body as a Who/e: Chest pain, famal
`flu-like &llness; Cardiovascular: Myocardrul &uforc-
`edema,
`angina pectoris, arrhythmia,
`tiorr, hypotension,
`syncope,
`tachycardia,
`premature
`beats; Digestive: Abdommal
`pain,
`diarrhea,
`diy mouth,
`acid regurghta-
`flatulence,
`vomitmg,
`t&on; Endocrine: Gynecomastia; Hematologic: Anemia, Met-
`sho/icr ALT (SGPT) increased;
`Arthralgia,
`lttuscu/oske/eta/:
`back pain,
`leg pain, foot pam, muscle cramps, myalgha,
`arm
`pain, knee pa&n, hip pain, Nervous/Psychiatric:
`Insomnia,
`depression,
`anxiety d&sorders,
`irritability,
`nervousness,
`decreased libido; Respiratory: Dyspnea, phar-
`somnolence,
`yng&tts, bronchitis,
`respira-
`epistaxis,
`influenza,
`s&nusitis,
`tory infection; Skin: Contusion,
`erythema, urticaria; Special
`Senses: Visual disturbances; Urogenital:
`uri-
`Impotence,
`nary frequency, urinary uigency, dysu&sa, polyuria.
`I/yperplusia —Gingival hyperplas&a,
`usually mild,
`G&r&grual
`accursed in (0.5% of patients
`studies. This
`in controlled
`cond&tron may be avoided or may regress with improved
`for Pa-
`(See PRECAUTIONS,
`dontal hygiene,
`Information
`tients.)
`Serum Electro/y&es —No
`Clinical Laboratory Test Findings:
`significant
`effects on se&s&m electrolytes were obseived dur-
`mg short- and long-term therapy (see CLINICAL PIIARMA-
`COLOGY, Renal/Endocnne
`Effects)
`Serum Glucose —No significan effects on fastmg serum glu-
`treated with PLENDIL in
`cose were obseived in patients
`the U.S. controlled study
`I.ruer Enzymes —I of 2 episodes of elevated serum trans-
`anunases decreased once drug hvas discontinued
`in clinical
`studies; no follow-up was available for the other patient.
`
`OVEIIDOSAGE
`
`Oral doses of 240 mg/kg and 264 nig/kg in male and female
`and 2390 mg/kg and 2250 mg/kg in male
`mice, respectively,
`and female rats, respectively,
`caused significant
`lethality
`In a suicide attempt, one patient
`took 150 mg felodipine to-
`gether with 15 tablets each of atenolol and spironolactone
`and 20 tablets of nitrazepsm. The patient's
`blood pressure
`and heart
`rate were normal
`to hospital; he
`on admission
`significant
`subsequently
`recovered without
`sequelae.
`Over&losage unght be expected to cause excessive peripheral
`vasodrlation with n&arkod hypotension
`and possibly brady.
`car&I&a
`If severe hypotension
`ti eatment
`occurs, symptomatic
`should
`be mstii.uted The patient
`should be placed supine with the
`of intravenous Auids may
`logs elevated, The administration
`to treat hypotens&on
`ivith cal-
`be useful
`due to overdosage
`at-
`In case of accompanymg
`cium antagonists
`bradycardia,
`iopine (0.5—I mg) should be admmistered
`intravenously.
`d& ugs may also be given &f the phys&cian
`Syn&pathonuniet&c
`feels they are warranted.
`It has not been established whether
`felodipme
`rnoved from the ciiculation by hemodialysis.
`about, Lhe treatment
`of
`To obtain up-to-date mformation
`consult your Regional Poison-Cont.rol Centei.
`overdose,
`
`can be re-
`
`numbers of certified poison-control
`Telephone
`centers are
`hated in fe Physicians'Desk Reference (PDR) In managing
`the possibilities of multiple-drug
`consider
`overdose,
`over-
`interactions,
`doses, drug-drug
`and unusual
`dkshg kinetics in
`your patient.
`
`DOSAGE AND ADMINISTRATION
`
`starting dose is 5 mg once a day. Depend-
`The recommended
`iesponse,
`the dosage can be decreased to
`ing on the pat&ent's
`2 5 mg or increased to 10 mg once a day. These adjustments
`should occur generally at intervals of not less than 2 weeks.
`dosage range is 2.5—10 mg once daily. In
`The recommended
`trials, doses above 10 iug dady showed an increased
`clinical
`blood pressure response but a large increase in the rate of
`edema and other vasodilatoiy
`pe»pheral
`events
`adverse
`(see ADVERSE REACTIONS). Modification of Ihe recom-
`mended dosage is usually not required &n patients with re-
`nal
`impairment.
`PLENDIL should regularly be taken e&ther without
`food or
`with a light meal (see CLINICAL PHARMACOLOGY, Phar-
`macokinetics
`and Metabolism). PLENDIL should be swal-
`lowed whole and not crushed or chewed.
`Use &x the Elderly or Pu/&eats wit/& I&ups&red Liucr Punc-
`tron —Patients over 65 years of age, or patients with im-
`paired liver function, may develop higher plasma concentra-
`I.ions of felodipme;
`a starting dose of 2 5 mg once
`therefore,
`a day is iecommended. Dosage may be adjusted as descinbed
`above. (See PRECAUTIONS )
`
`HOW SUPPLIED
`No 3584—Tablets PLENDH., 2 5 nig, aie sage groen,
`round
`convex tablets, with code 450 on one side and PLENDIL on
`the other They are supplied as follows:
`NDC 0186-0450-28 unit dose packages of 100
`NDC 0186-0450-58 umt of use bottles of 100
`NDC 0186-0450-31 umt of use bottles of 30
`No. 3585—Tablets PLENDIL, 6 mg, are hght,
`red-brown,
`convex tablets, with
`code 451 on one side and
`round
`PLENDIL on the other, They are supplied as follows;
`NDC 0186-0451-28 unit dose packages of 100
`NDC 018G-0451-58 unit of use bottles of 100
`iNDC 0186-0451-31 un&t of use bottles of 30
`No 3586—Tablets PLENDIL, 10 mg, are red-brown,
`round
`convex tablets, with code 452 on one side and PLENDIL on
`the other They are supplied as follows:
`NDC 0186-0452-28 unit dose packages of 100
`&VDC 0186-0452-58 unit of use bottles of 100
`NDC 0186-0452-31 unit of use bottles of 30
`Storage
`Store below 30'C (86'F). Keep contmner
`tect from hght
`Manufactured
`by.
`Merck & Co., Inc, West Point, PA 19486
`Distributed by.
`Astra Pharmaceuticals, L P, Wayne, PA 19087
`63000211
`Issued December 1998
`Ider&trficatror& Guide, page 305
`Shown ru. Product
`
`tightly closed Pro-
`
`POLOCAINE&6&
`Ipo Llo-caine oj
`(Mepivacaine Hydrochloride
`POLOCAINE-IIAPF
`Injection, USP)
`(Mepivacaine Hydrochloride
`THESE SOLUTIONS ARE NOT INTENDED FOR SPINAL
`ANESTHESIA OR DENTAL USE
`
`Injection, USP)
`
`(For details of indications, dosage and adnunistration,
`pre-
`see cucular
`and adverse reactions,
`cautions,
`in package.)
`HOW SUPPLIED
`POLOCAINE-MPF (Mepivacaine HCI In)ection, USP) with-
`out preseivatives
`&s available as follows:
`1% Single-dose vials of 30 mL (NDC 0186-0412-01)
`1.5% Single-dose vials of 30 mL (NDC 018G-0418-01)
`2% Single-dose vials of 20 mL (NDC 0186-0422-01)
`POLOCAINE (Mepivacaine HCI Injection, USP) with pre-
`seivatives
`is available as follows
`vials of 50 mL (NDC 0186-0410-01)
`1/o Multiple-dose
`vials of 50 mL (NDC 0186-0420-01)
`2o/o Multiple-dose
`Unused portions of solutions not containing
`preservatives
`should be discarded.
`Store at controlled room temperatur
`021GGSROO
`
`e 15'-30'C (59' 86'F),
`Iss I/92
`
`PRILOSEC¹I&
`(omeprazole)
`DELAYED-RELEASE CAPSULES
`
`DESCRIPTION
`in PRILOSEC'omcpi azoic) Delayed-
`The active ingredient
`Release Capsules
`6-meth-
`is a substituted
`benznnidazole,
`oxy-2-[[(4-methoxy-3,
`sulfi-
`5-dimethyl-2-pyr&clinyi)
`methyl)
`a compound
`that mhibits gastric
`nyl]-1H-benzmudazole,
`acid secretion. Its empn ical foi nnila is C&sH»N&Orq, with a
`formula is:
`molecular weight of 345,42. The structural
`structure at top of next columnl
`[See chemical
`is a white to oA'-white crystalline powder which
`Omeprazole
`at about 155 C It is a weak base,
`melts with decomposition
`freely soluble in ethanol and n&ethanol, and slightly soluble
`
`ASTRAZE NECA LP/617
`
`ocr&o
`and veiy slightly soluble in wa-
`m acetone and isopropanol
`ter. The stabihty of omeprazole &s a function of pH; it is rap-
`idly degraded in acid media, but has acceptable
`tabrlity un-
`der alkahne
`conditions.
`PRILOSEC is supplied as delayed-release
`for oral
`capsules
`ei-
`capsule contains
`Each delayed-release
`adn&inistration.
`ther 10 mg, 20 mg or 40 mg of omeprazole
`&n the form of
`enter&c-coated granules with the following inactive ingred&-
`ents: cellulose, disodium hydrogen
`hydroxypro-
`phosphate,
`lactose, man-
`pyl cellulose, hydroxypropyl methylcellulose,
`sulfate and other ingredients. The caps
`mtol, sodium lauryl
`sule shells have the following inactive ingredients:
`gelatin-
`NF, FD&C Blue ¹1, FD&C Red ¹40, D&C Red ¹28,
`titanium
`butyl alco-
`dioxide, synthetic black iron oxide,
`isopropanol,
`in ad-
`hol, FD&C Blue ¹2, D&C Red ¹7 Calcium Lake, and,
`the 10 mg and 40 mg capsule shells also contain
`dition,
`D&C Yellow ¹10
`
`"Registered trademark of Astra AB
`Astra Pharmaceuticals, L.P., 1998
`All rights reseived
`CLINICAL PHARMACOLOGY
`Pharmacokinetics
`and Metabotismi Omeprazole
`PRILOSEC Delayed-Release Capsules
`contain an enferic-
`of omeprazole
`coated granule formulation
`(because omepra-
`so that absorption of omeprazole begins
`zole is acid-labile),
`only after the granules
`leave the stomach. Absorption
`is
`levels of omeprazole
`rapid, w&th peak plasma
`occurmng
`w&tlun 0.5 to 3.5 hours, Peak plasn&a concentrat&ons of ome-
`prazole and AUC are approramately
`to doses
`propo&tional
`up Lo 40 mg, but because of a saturable
`first-pass offect, a
`than linear
`response &n peak plasma concentration
`gheater
`than 40 mg. Absolute
`and AUC occurs hvith doses greater
`administration)
`(compared to intravenous
`is
`bioavailabihty
`about 30-40%o at doses of 20-40 mg, due in large part
`to
`presystem&c metabolisn& In healthy
`subjects
`the plasma
`half-life is 0 5 to I hour, and the total bocly clearance is 500-
`600 n&1/min. Protein binding is approximately
`95%.
`The bioavailability of omeprazole
`increases shghtly upon re-
`of PRILOSEC Delayed-Release Cap-
`peated administration
`sules
`of a buffered so-
`Following smgle dose oral administration
`little if any unchanged
`drug was ex-
`lution of omeprazole,
`creted in uisne, The n&ajor&ty of the dose (about 77%) was
`in u&sne as at least six metabolites. Two were
`eliminated
`car-
`identified as hydroxyomeprazole
`and the corresponding
`boxyhc acid The remainder of the dose was recoverable
`in
`feces This implies a significant b&liary excretion of the me-
`tabohtes of omeprazole Three n&etabolites have been iden-
`tified in plasma —the sulfide and sulfone derivatives of ome-
`These metabolites
`have
`prazole, and hydroxyomeprazole.
`very little or no antisecretory
`activity.
`In patients with chron&c hepatic disease,
`the bioavailability
`100% compared to an I.V, dose,
`increased to approximately
`effect, and the plasma half-
`reflecting decreased first-pass
`life of the drug increased to nearly 3 hours compared to the
`half-life in normals of 0 5-1 hour. Plasma clearance aver-
`aged 70 mLhnin, compared to a value of 500-600 mL/min
`in
`subjects.
`normal
`impan'ment, whose creati-
`In patients with chronic renal
`nine clearance ranged between 10 and 62 mL/min/1 73 mz,
`to that
`the disposition of omeprazole was very simflar
`in
`although there was a slight
`increase in
`healthy volunteers,
`bioavailability, Because ur&nary excretion is a pnmary route
`of excretion of omeprazole metabolites,
`their ehnnnation
`slowed in proportion to the decreased creatinme
`clearance
`de-
`rate of omeprazole was
`The ehmination
`somewhat
`and bioavailability was increased
`creased in the elderly,
`Omeprazole was 76'/o bioavailable when a single 40 mg oral
`dose of omeprazole
`(buifered solution) hvas administered
`to
`versus 58/o in young volunteers
`healthy elderly volunteers,
`given the same dose Nearly 70% of the dose ives recovered
`of omeprazole
`in urine as metabolites
`and no unchanged
`drug was detected. The plasma clearance of omeprazole was
`(about half that of young volunteers)
`250 mI/min
`and its
`twice Lhat of
`plasma half-life
`averaged one hour, about
`young healLhy volunteers
`studies of single 20 mg omep&azoic
`In phamnacokmetic
`doses, an mcrease in AUC of approximately
`four-fold was
`noted in Asian subjects compared to Caucasians.
`of heal-
`particularly where maintenance
`Dose ad)ustment,
`is indicated,
`for the hepatically
`mg of erosive esophag&tis
`nnpaned and Asian subjects should be considered.
`Pharmacokinetics: Combination Therapy with Antimicrobi-
`ale
`40 mg daily was given in combination with
`Omeprazole
`claritlu omycin 500 mg every 8 hours to healthy adult male
`sub)ects The steady state plasma concentrations of omepra-
`zole were increased (C„,„„,AUCo z„,and Tu increases of
`30'/&, 89%o and S4/o respect&vely) by the concomitant
`admm-
`istration of claisthromycin. The obseived increases in ome-
`prazole plasma concentration were associated hvith the fol-
`eAects The mean 24-hour gast&ac
`lowing pharmacolog&ca[
`pH value hvas 5 2 hvhen omeprazole was adm&metered
`alone
`and 5.7 when co-admimsLered with clar&thromyc&n.
`Tho plasma
`levels of clamthromycm
`and
`14-hydroxy-
`clarithromycin were increased by the concomitant
`admm&s-
`the mean C„,„,
`For cia»thromyc&n,
`tration of on&eprazole
`the mean Cuoo was 27% g&eater, mid the
`was 10'/o greaLer,
`
`Continued oo next page
`
`Page 2 Dr. Reddy's Exh. 1049
`
`

`

`Study 126
`
`Study 127
`
`Study M96-446
`
`"77 [G4, 86]
`(n = G4)
`*78 [67, 88]
`(n = 65)
`90 [80, 96]
`(n = 69)
`
`37 [27, 48)
`(n = 84)
`36 l26, 47]
`(n = 83)
`32 [23, 42]
`(n = 99)
`
`43 [31, 56]
`«G9 [57 79]
`(n = 80)
`(n = 67)
`"73 [61, 82]
`41 [29 54]
`(n = 68)
`(n = 77)
`"83 [74, 91]
`33 [24, 44]
`(n = 93)
`(» = 84)
`if they had confirmed duodenal ulcer d&sease (active ulcer, studies 126 and 127;
`l'Patients were included in the analysis
`infection at baseline defined as at least two of tlu ee positive
`history of ulcer w&thin 5 years, study M96446) and H. py/o&i
`if they completed the
`endoscopic tests from CLOtes&&ii&, histology,
`culture Patients were included
`in the analysis
`and/or
`if patients dropped out of the study due to an adverse
`related to the study drug,
`they were
`event
`study. Additionally,
`included m the analysis as failures of therapy. The impact of eradication on ulcer recurrence has not been assessed in
`patients with a past history of ulcer.
`3Patients were included m the analysis if they had documented H. /&y(ori
`ulcer disease. All dropouts v,ere included as fadures of therapy
`(p&0.05) versus
`clat&thro&nyc&n plus amoxicillin.
`
`!
`
`!
`
`618/ASTRAZE NECA LP
`
`Prilosec —Cont.
`
`mean AUCo „was15% greater when clarithromyci
`ministered with omeprazole
`than when clarithrom
`results were seen for 14-hy-
`alone Similar
`admin&stered
`the mean C,„was45% greater,
`the
`droxy-clawthromycin,
`mean C,«co was 57% greater, and the mean AUCo s was 45%
`greater. Clarithromycin
`concentrations
`in the gastr&c tissue
`and mucus were also increased by concomitant
`adm&nistra-
`tion of omeprazole.
`
`Clarithromycin
`
`T&ssue Concentrations
`
`2 hours after Dose
`+
`Clarithromycin
`Omeprazole
`
`10.48 «2.01 (n = 5)
`20.81 ". 7.64 (n = 5)
`4.15 2 7.74 (n = 4)
`
`19 96 2 4.71 (n = 5)
`24 25 2 6.37 (n = 5)
`3929 2 32 79 (n = 4)
`
`T&ssue
`
`Antrum
`Fund us
`Mucus
`
`'Mean 2 SD (Pg/g)
`
`clarithromycin,
`and
`studied ivhen all three
`
`For information
`on claiathromycm phaianacokinetics
`and
`the clamthromycin
`microbiology,
`package msert.,
`consi&lt
`CLINICAL PHARMACOLOGY section
`The pharmacokinetics
`of omeprazole,
`amoxicilhn have not been adequately
`drugs are adm&n&stered
`concom&tantly.
`For information
`and micro-
`on amoxic&lhn phaianacolnnetics
`. ee the amoxicill&n
`insert, ACTIONS,
`package
`l»ology,
`PHARV»ACOLOGY and MICROBIOLOGY sections.
`Pharmacodynamics
`«Macho»is&n of Action
`to a new class of antisecretory
`com-
`belongs
`Omeprazole
`that do not exhibit
`the substituted
`pounds,
`benzim&dazoles,
`or Hz histamme
`antagonistic
`antichohnerg&c
`prope&t&es, but
`that suppress gastr&c acid sonation by spemfic mhibition of
`the H "/K'TPase enzyme system at the secretory surfiace of
`the gastiic parietal cell Because this enzyme
`system is re-
`garded as the acid (proton) pump wit)un the gastric mucosa,
`as a gastric acid-pump
`omeprazole has been characterized
`it blocks the fina step of acid produchon,
`in that
`&nhil»tor,
`This efiect is dose-ielated
`aud loads to inl»bition
`of both
`acid secret&on irrespective of the stim-
`basal and stmiulated
`that afier rapid disappear-
`indicate
`studies
`ulus. An&mal
`ance from plasma, omeprazole
`can be found within the gas-
`tr&c mucosa for a day or more.
`Ant&secretory Activity
`the onset of the antisecretory ef-
`After oral administration,
`fect of omeprazole
`occurs witlun one hour, with the maxi-
`nium eifect occumng within two hours.
`Inhibit&on of secre-
`at 24 houis and the duration
`tion &s about 50% of maximuiu
`of inhibition
`last,s up to 72 hours The antisecretory
`effect
`thus lasts far longer
`than would be expected from the very
`short (less than one hour) plasina half life, appa&wetly due
`to prolonged bind&ng to the par&eta[ H'/K'TPaae
`enzyme.
`When the d&ug is discontinued,
`secretmy activity returns
`over 3 to 5 days. The inh&bite&y efi'ect of omepra-
`gradually,
`zole on amd secretion increases w&th repeated once-daily
`reaching a plateau after four days
`dosing,
`studies of the antisecretory effect of
`Results from numerous
`multiple doses of 20 mg and 40 mg of omeprazole
`in normal
`and patients are shown below. The "max" value
`volunteers
`at a time of maximum effect
`represents
`determinat&ons
`(2—6 hours after dosing), while "m&n" values are those 24
`hours after the last dose of omeprazole.
`
`Range of Mean Values ibom Multiple Studies
`of the Mean Antisecretoiy E(Facts of Omeprazole
`««« ~M« & «D &~D.«
`Omeprazole
`~20 m
`Max
`78*
`
`Omeprazole
`40 &njf
`Max
`M&n
`94*
`80-93
`
`M&n
`58-80
`
`Parameter
`% Decrease in
`Basal Acid Output
`
`% Decrease in
`Peak Acid Output
`
`'/c Decrease m
`24-hr. Intragastric
`Acid&ty
`
`'Single Studies
`
`79"
`
`50-59
`
`88'2-68
`
`80-97
`
`92-94
`
`rang&ng from a dose of
`Single dady oral doses of omeprazole
`10 mg to 40 mg have produced 100% inlubition of 24-hour
`acidity in some patients
`intragastr&c
`(ECL) Cell E/fects
`Entcrochromoffin-/&he
`In 24-month carcinogenicity
`in rats, a dose-related
`studies
`increase m gast&ac carcino&d tumors and ECL cell
`significant
`hyperplasia was observed in both male and female animals
`(see PRECAUTIONS, Carcinogenes&s, Mutagenesis,
`Im-
`pairment of Feil,ility) Carcinoid tumors have also been ob-
`served in rats sub)ected to fundectomy
`or long-term treat-
`ment with other proton pump inhibitors or high doses of H&-
`receptor antagomsts.
`Human gastric biopsy specimens have been obtamed from
`more than 3000 patients
`treated with oineprazole
`in long-
`tnals The incidmice of ECL ceil hyperplasia
`term chnical
`in
`these studies
`increased with time, however, no case of ECL
`cell carcino&ds, dysplasia,
`or. »copies&a has been found in
`these patients.
`(See also CLINICAL PHARMACOLOGY,
`Pathological Hypersocreto&y Conditions
`)
`Serum Gastr&n Effects
`In studies involving more &,han 200 patients,
`s&rum gastwn
`levels inc&eased duriug the hrst 1 to 2 weeks of once-da&ly
`
`PHYSiCIANS'ESK REFERENCE
`
`Per-Protocol and Intent-to-Treat H, pylori Eradication Bates
`% of Patients Cured [95% Confidence
`Intorvall
`
`PRILOSEC +clar&thromycm +amoxicillin
`
`Clat&tbromyc&n
`
`+amo&uc&11&n
`
`Per-Protoco[7
`
`Intent-to-Treatt
`
`Per-Protoco[1
`
`Intent-to-Treatt
`
`infection at baseline and had confirmed duodenal
`
`H pylori Eradication I(ates (Per-Protocol Analysis at 4 to 6 weeks)
`% of Patients Cured [95% Confidence
`Ini,erval]
`
`PRILOSEC +
`Clarithromycin
`
`74 [GO 85] j»
`{n = 53)
`64 [51, 76] ti.
`(n = 61)
`
`83 [71, 92]t
`(n = 60)
`74 [64, 83][.
`(n = 86)
`
`PRILOSEC
`
`Cl antlu ofiiycin
`
`0 [0, 7]
`(n = 54)
`0 [0, 6]
`(n =- 59)
`
`1 [0,7]
`(n = 74)
`1 [0,6]
`(n = 90)
`
`31 [18, 47]
`(n = 42)
`39 M&4, 55]
`(n = 44)
`
`N/A
`
`N/A
`
`U.S. Studies
`Study M93-067
`
`Study M93-100
`
`Non U.S. Studies
`Si.udy &M92-812b
`
`Study M93-058
`
`t Statistically s&gmficantly higher
`;.Statistically significantly
`higher
`
`(p & 0 05)
`than clawthromycin monotherapy
`than omepi azoic monothei spy (p & 0.05)
`
`of therapeucc doses of omeprazole
`in paral-
`admmistrat&on
`lel with inhibition of ac&d secrecon.
`increase in
`iVo further
`serum gastwn occurred with continued treatment
`In com-
`paiison w&th histamine H&-receptor
`the me-
`antagon&ste,
`dian increases produced by 20 mg doses of omeprazole were
`(1 3 to 3 6 fold vs 1.1 to 1 8 fold increase). Gastrin
`l»gher
`returned to pretreatment
`values
`levels, usually withm 1 to
`of therapy.
`2 weeks a(ter discontmuation
`Ot/&er Effects
`Systemic efFects of omepiazole
`in the CNS, cachovascular
`and resp&ratory systems have not been found to date. Ome-
`prazole, given &n oral doses of 30 or 40 mg for 2 to 4 weeks,
`had no effect an thyroid function, carbohydrate metabolism,
`or circulating levels of parathyi oid hormone, cortisol, estra-
`diol, testosterone,
`or secretin.
`cholecystokinin
`prolactin,
`No effect on gastric emptyu&g of the solid and hquid compo-
`nents of a test meal was demonstrated
`afier a smgle dose of
`a rungle I V. dose of
`omeprazole 90 mg In healthy'hub)acts,
`(0 35 mg/kg) had no effect on intrinsic factor se-
`omeprazole
`cretion No systemic dose-dependent
`eiiect has been ob-
`served on basal or stimulated
`pepsin'output
`in humans.
`at 4.0 or
`pH is maintained
`However, when intragastnc
`is low, and pepsin activ&ty is de-
`above, basal pepsin output
`creased.
`As do other agents that elevate intragastric
`pH, omepi'azoic
`for 14 days in healthy sub)ects produced a sig-
`administered
`increase in the intragastric
`concentrations
`nificant
`of viable
`bacteria The pattern
`of the bacter&al
`species was un-
`changed from that commonly
`found m saliva. All changes
`resolved witlun three days of stopping treatment.
`Clinical Studies
`Duodenal Vice& Diseuse
`Act&ue Duodenal Ulcer—In a multicenter,
`double-blind,
`pla-
`study of 147 patients with endoscopically
`cebo-controlled
`documented
`of patients
`du»denal
`the percentage
`ulcer,
`healed (per protocol) at 2 aml 4 weeks was sibmificantly
`1»gher with PRILOSEC 20 mg once a day than with placebo
`{p s 0.01).
`
`Treatment of Active Duodenal
`% of Patients Healed
`PRILOSEC
`20 mg a.m
`(n = 99)
`'41
`'75
`
`Ulcer
`
`Placebo
`a.m.
`(n = 48)
`13
`27
`
`Week 2
`Week 4
`
`I**/p &0,01)
`
`pmn relief occurred signif-
`Con&piete daytime and nighttnne
`icantly faster (p =- 0.01)m patients treated with PRILOSEC
`treated with pla&ebo At the ond of
`20 mg than iu patients
`the study,
`significantly more pat&ants who had race&ved
`PRILOSEC had complote rehef of daytime pain (p w 0 05)
`(p - 0,01).
`and nighttime
`paui
`study of 293 patients
`In a multicenter,
`clouble-blind
`iv&th en-
`the percentage of
`doscop&cally documented
`duodenal
`ulcer,
`potie»ts healed {pe& protocol) at 4 weeks was s&gnificantly
`lugher &vith PRILOSEC 20 mg once a day than &vith &snit&-
`d&ne 150 n&g b i d (p & 0 01)
`
`Treatment of Ac&,ive Duodenal
`% of Patients
`
`Healed'RILOSEC
`
`20 mg a.m.
`(n = 145)
`42
`«82
`
`Ulcer
`
`Ranitidine
`150 mg b i d
`(n = 148)
`34
`63
`
`Week 2
`Week 4
`*(p&0 01)
`
`treated
`faster &n pat&ents
`Idea]ing occurred significantly
`&vith PRILOSEC than in those treated with raniti«hne
`150 mg b.i.d, (p & 0.01).
`In a foreign multinational
`double-blind.
`study
`randonnzed,
`of 105 patients with endoscopically
`duodenal
`documented
`ulcer, 20 mg and 40 mg of PRILOSEC were compared
`to
`at 2, 4 and 8 weeks. At 2 and
`150 mg b.i.d. of ranitidine
`4 weeks both doses of PRILOSEC were statistically super&or
`to
`but 40 mg was not superior
`to ranitidme,
`(per protocol)
`20 mg of PRILOSEC, and at 8 weeks there was no &ngnifi-
`cant ddference i&etween any of the active d»&gs&
`Ulcer
`
`Treatment of Active Duodenal
`% of Patients Healed
`PRILOSEC
`20 mg
`40 mg
`(n = 36)
`(n = 34)
`'83
`"83
`"100
`"97
`100
`100
`
`Ranit&dine
`150 mg b.i d
`(n = 35)
`53
`82
`94
`
`Week 2
`Week 4
`IVeek 8
`"(p&s0.01)
`
`&n Patients
`
`oath Duodenal Ulcer
`
`H py/o&i Eradication
`Diseuse
`Tr&pie Therapy (PRILOSEC/cianthromyc&n/amozic&ilia}—
`Tluee U.S„randomized, double-blind
`chnical studies in pa-
`infection and duo&le»el ulcer disease
`tients with H. Py/o&'i
`(n = 558) compared PRILOSEC plus clarithromycin
`plus
`amoxicill&n to c[a&sthromyc&n plus amoximllui. Two studies
`&126 and 127) were conducted &n patients with an act&ve du-
`odenal ulcer, and the other study (M96-446) was conducted
`ulcer &n the past
`in pat&ents with a history of a duodenal
`5 years but &vithout an ulcer present at the tune of enroll-
`&n the studies was PBILOSEC
`ment. The dose regnnen
`20 mg b & d. plus c[ar&th&omycin 500 mg b.i.d plus amoxic&l-
`lin 1 g b.i.d for 10 days, or clarithromyc&n 500 mg b.&.d plus
`In studies 126 and 127,
`an&ox&c&))ln 1 g b.&.d. for 10 days.
`regrimen also received an
`patients who took the omeprazole
`18 days of PRILOSEC 20 mg q.d Endpoints
`additional
`studied were e&ad&cation of H pylon and duodenal
`ulcer
`healing (stud&es 126 and 127 only) H. pylor& status was de-
`three
`by CLO&est«3&, histology and culture
`termined
`in all
`stud&es. For a gwen patient, H. pylori was considered erad-
`&cated &f at least
`two of these teste were negative,
`and none
`ives positive.
`of on&eprazole
`plus clawthromycm plus
`The conibination
`amoxicillin was efiect&ve in eradicating H pylon
`[See first table at top of page]
`Dual T/&eropy (PRILOSEC/c/u»th&omymn/ —Four random-
`studies {M93—067, M93-
`ized, douMc-bhod, mul»-center
`100, ib192-8126, and M93-058) evaluated PRH.OSEC 40 mg
`q d phis &:laiiibromycin 500 mg t,i d. for 14 days,
`followed
`
`Page 3 Dr. Reddy's Exh. 1049
`
`

`

`PRODUCT INFORMATION
`
`by PRILOSEC 20 mg q d, (M93-067, M93-100, M93-058) or
`by PRILOSEC 40 mg q.d. (M92-812b) for an additional
`14 days in patients with active duodenal
`ulcer associated
`with H pylon Studies M93—067 and M93-100 were con-
`ducted in the U.S and Canada
`and enrolled
`242 and
`256 patients,
`respectively. H. pylori
`infection and duodenal
`ulcer were confirmed in 219'patients in Study M93-067 and
`in Study M93-100. These studies
`228 patients
`compared
`the combination regimen to PRILOSEC and clanthromycin
`Studies M92—812b and M93—058 were con-
`monotherapies.
`ducted in Europe and em'oiled 154 and 215 patients,
`respec-
`tively. H. py/oi
`i infection and duodenal ulcer were confirmed
`m 148 patients
`in study M92-812b and 208 patients
`in
`Study M93-058. These studies
`compared the combination
`regimen to omeprazole monotherapy. The results for the ef-
`for these studies are described below. H, py-
`ficacy analyses
`/on eradication was defined as no positive test (culture or
`histology) at 4 weeks following the end of treatment,
`and
`tests were required
`i.wo negative
`to be considered
`eradi-
`cated of H pylon. In the per-protocol analysis,
`the following
`patients were excluded. dropouts, patients with missing H.
`tests post-treatment,
`that were riot as-
`and patients
`pylori
`sessed for H. Pylori eradication because they were found to
`have an ulcer at the end of treatment
`of omeprazole
`The combination
`and claritluomycin
`effective m eradicating H. pylori'.
`(See second table at top of previous page]
`Ulcer healing was not significantly different when clarithro-
`mycin was added to omeprazole
`therapy compared to ome-
`pi'arole tllol'apy a)01m,
`The combmation of omeprazole
`and clarithromycin was ef-
`fective in eradicating H. pylon and reduced duodenal
`ulcer
`recurrence.
`
`was
`
`Duodenal Ulcer Recurrence Rates by H. Pylori Eradication
`Status, % of Patients with Ulcer Recurrence
`
`H. py(on
`eradicated¹
`
`H pylon
`not eradicated¹
`
`U.S. Studiest
`6 mon~ths
`ost-treatment
`Study M93-067
`
`Study M93-100
`
`Non U S. Studies3
`6 months post-treatment
`Study M92-812b
`
`Study M93-058
`
`12 months post-treatment
`Study M92-812b
`
`'35
`(n = 49)
`'8
`(n = 53)
`
`(n = 43)
`6
`(n = 53)
`
`»5
`(n = 39)
`
`60
`(n = 88)
`GO
`(n = 106)
`
`46
`(n = 78)
`43
`(n = 107)
`
`68
`(n = 71)
`
`¹H. pylon eradication status assessed at same timepoint as
`ulcer recurrence
`results
`for PRILOSEC + clairthroniycin,
`-I Combined
`PRILOSEC, and clarithromycin
`tieatment
`arms
`results
`for PRILOSEC + clarithromyc