NDA 20-406/S-038
`Prevacid (lansoprazole) Delayed-Release Capsules Package Insert Text
`Page 3 of 28
`
` (Nos. 1541, 3046)
`XX-XXXX-RXX-Rev. Month, 200x
`
`PREVACID®
`(lansoprazole)
`Delayed-Release Capsules
`DESCRIPTION
`The active ingredient in PREVACID (lansoprazole) Delayed-Release Capsules is a substituted
`benzimidazole, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methyl] sulfinyl] benzimidazole, a
`compound that inhibits gastric acid secretion. Its empirical formula is C16H14F3N3O2S with a molecular
`weight of 369.37. The structural formula is:
`
`Lansoprazole is a white to brownish-white odorless crystalline powder which melts with
`decomposition at approximately 166°C. Lansoprazole is freely soluble in dimethylformamide; soluble in
`methanol; sparingly soluble in ethanol; slightly soluble in ethyl acetate, dichloromethane and acetonitrile;
`very slightly soluble in ether; and practically insoluble in hexane and water.
`Lansoprazole is stable when exposed to light for up to two months. The compound degrades in aqueous
`solution, the rate of degradation increasing with decreasing pH. At 25°C the t1/2 is approximately 0.5 hour
`at pH 5.0 and approximately 18 hours at pH 7.0.
`PREVACID is supplied in delayed-release capsules for oral administration. The delayed-release
`capsules contain the active ingredient, lansoprazole, in the form of enteric-coated granules and are
`available in two dosage strengths: 15 mg and 30 mg of lansoprazole per capsule. Each delayed-release
`capsule contains enteric-coated granules consisting of lansoprazole, hydroxypropyl cellulose, low
`substituted hydroxypropyl cellulose, colloidal silicon dioxide, magnesium carbonate, methacrylic acid
`copolymer, starch, talc, sugar sphere, sucrose, polyethylene glycol, polysorbate 80, and titanium dioxide.
`Components of the gelatin capsule include gelatin, titanium dioxide, D&C Red No. 28, FD&C Blue No. 1,
`FD&C Green No. 3*, and FD&C Red No. 40.
`* PREVACID 15-mg capsules only.
`
`CLINICAL PHARMACOLOGY
`Pharmacokinetics and Metabolism
`PREVACID Delayed-Release Capsules contain an enteric-coated granule formulation of lansoprazole.
`Absorption of lansoprazole begins only after the granules leave the stomach. Absorption is rapid, with
`mean peak plasma levels of lansoprazole occurring after approximately 1.7 hours. Peak plasma
`concentrations of lansoprazole (Cmax) and the area under the plasma concentration curve (AUC) of
`lansoprazole are approximately proportional in doses from 15 mg to 60 mg after single-oral administration.
`Lansoprazole does not accumulate and its pharmacokinetics are unaltered by multiple dosing.
`
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`NDA 20-406/S-038
`Prevacid (lansoprazole) Delayed-Release Capsules Package Insert Text
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`
`Absorption
`The absorption of lansoprazole is rapid, with mean Cmax occurring approximately 1.7 hours after oral
`dosing, and relatively complete with absolute bioavailability over 80%. In healthy subjects, the mean
`(±SD) plasma half-life was 1.5 (± 1.0) hours. Both Cmax and AUC are diminished by about 50% if the drug
`is given 30 minutes after food as opposed to the fasting condition. There is no significant food effect if the
`drug is given before meals.
`
`Distribution
`Lansoprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration
`range of 0.05 to 5.0 µg/mL.
`
`Metabolism
`Lansoprazole is extensively metabolized in the liver. Two metabolites have been identified in measurable
`quantities in plasma (the hydroxylated sulfinyl and sulfone derivatives of lansoprazole). These metabolites
`have very little or no antisecretory activity. Lansoprazole is thought to be transformed into two active
`species which inhibit acid secretion by (H+,K+)-ATPase within the parietal cell canaliculus, but are not
`present in the systemic circulation. The plasma elimination half-life of lansoprazole does not reflect its
`duration of suppression of gastric acid secretion. Thus, the plasma elimination half-life is less than two
`hours, while the acid inhibitory effect lasts more than 24 hours.
`
`Elimination
`Following single-dose oral administration of lansoprazole, virtually no unchanged lansoprazole was
`excreted in the urine. In one study, after a single oral dose of 14C-lansoprazole, approximately one-third
`of the administered radiation was excreted in the urine and two-thirds was recovered in the feces. This
`implies a significant biliary excretion of the metabolites of lansoprazole.
`
`Special Populations
`Geriatric
`The clearance of lansoprazole is decreased in the elderly, with elimination half-life increased
`approximately 50% to 100%. Because the mean half-life in the elderly remains between 1.9 to 2.9 hours,
`repeated once daily dosing does not result in accumulation of lansoprazole. Peak plasma levels were not
`increased in the elderly.
`Pediatric
`The pharmacokinetics of lansoprazole has not been investigated in patients <18 years of age.
`Gender
`In a study comparing 12 male and 6 female human subjects, no gender differences were found in
`pharmacokinetics and intragastric pH results. (Also see Use in Women.)
`Renal Insufficiency
`In patients with severe renal insufficiency, plasma protein binding decreased by 1.0%-1.5% after
`administration of 60 mg of lansoprazole. Patients with renal insufficiency had a shortened elimination
`half-life and decreased total AUC (free and bound). AUC for free lansoprazole in plasma, however, was
`not related to the degree of renal impairment, and Cmax and Tmax were not different from subjects with
`healthy kidneys.
`Hepatic Insufficiency
`In patients with various degrees of chronic hepatic disease, the mean plasma half-life of the drug was
`prolonged from 1.5 hours to 3.2-7.2 hours. An increase in mean AUC of up to 500% was observed at
`
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`steady state in hepatically-impaired patients compared to healthy subjects. Dose reduction in patients with
`severe hepatic disease should be considered.
`Race
`The pooled mean pharmacokinetic parameters of lansoprazole from twelve U.S. Phase 1 studies (N=513)
`were compared to the mean pharmacokinetic parameters from two Asian studies (N=20). The mean AUCs
`of lansoprazole in Asian subjects were approximately twice those seen in pooled U.S. data; however, the
`inter-individual variability was high. The Cmax values were comparable.
`
`Pharmacodynamics
`Mechanism of Action
`Lansoprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that do not
`exhibit anticholinergic or histamine H2-receptor antagonist properties, but that suppress gastric acid
`secretion by specific inhibition of the (H+,K+)-ATPase enzyme system at the secretory surface of the
`gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the parietal
`cell, lansoprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step
`of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated gastric
`acid secretion irrespective of the stimulus.
`
`Antisecretory Activity
`After oral administration, lansoprazole was shown to significantly decrease the basal acid output and
`significantly increase the mean gastric pH and percent of time the gastric pH was >3 and >4. Lansoprazole
`also significantly reduced meal-stimulated gastric acid output and secretion volume, as well as
`pentagastrin-stimulated acid output. In patients with hypersecretion of acid, lansoprazole significantly
`reduced basal and pentagastrin-stimulated gastric acid secretion. Lansoprazole inhibited the normal
`increases in secretion volume, acidity and acid output induced by insulin.
`In a crossover study that included lansoprazole 15 and 30 mg for five days, the following effects
`on intragastric pH were noted:
`
`Mean Antisecretory Effects After Single and Multiple Daily Dosing
`PREVACID
`
`30 mg
`15 mg
`Baseline
`Day 1
`Day 5
`Day 1
`Day 5
`Value
`Parameter
`3.6*
`4.9*
`2.7+
`4.0+
`2.1
`Mean 24-Hour pH
`3.8*
`3.0+
`2.6
`2.4
`1.9
`Mean Nighttime pH
`51*
`72*
`33+
`59+
`18
`% Time Gastric pH>3
`41*
`66*
`22+
`49+
`12
`% Time Gastric pH>4
`NOTE: An intragastric pH of >4 reflects a reduction in gastric acid by 99%.
`*(p<0.05) versus baseline and lansoprazole 15 mg.
`+(p<0.05) versus baseline only.
`
`After the initial dose in this study, increased gastric pH was seen within 1-2 hours with lansoprazole 30 mg
`and 2-3 hours with lansoprazole 15 mg. After multiple daily dosing, increased gastric pH was seen within
`the first hour postdosing with lansoprazole 30 mg and within 1-2 hours postdosing with lansoprazole
`15 mg.
`
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`Acid suppression may enhance the effect of antimicrobials in eradicating Helicobacter pylori
`(H. pylori). The percentage of time gastric pH was elevated above 5 and 6 was evaluated in a crossover
`study of PREVACID given q.d., b.i.d. and t.i.d.
`
`30 mg t.i.d.
`77*
`45*
`
`Mean Antisecretory Effects After 5 Days of b.i.d. and t.i.d. Dosing
`PREVACID
`15 mg b.i.d.
`30 mg b.i.d.
` 59+
`47
`23
`28
`
`30 mg q.d.
`Parameter
`43
`% Time Gastric pH>5
`20
`% Time Gastric pH>6
`+(p<0.05) versus PREVACID 30 mg q.d.
`*(p<0.05) versus PREVACID 30 mg q.d., 15 mg b.i.d. and 30 mg b.i.d.
`The inhibition of gastric acid secretion as measured by intragastric pH returns gradually to normal over two
`to four days after multiple doses. There is no indication of rebound gastric acidity.
`Enterochromaffin-like (ECL) Cell Effects
`During lifetime exposure of rats with up to 150 mg/kg/day of lansoprazole dosed seven days per week,
`marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid
`tumors, especially in female rats. (See PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of
`Fertility.)
`Gastric biopsy specimens from the body of the stomach from approximately 150 patients treated
`continuously with lansoprazole for at least one year did not show evidence of ECL cell effects similar to
`those seen in rat studies. Longer term data are needed to rule out the possibility of an increased risk of the
`development of gastric tumors in patients receiving long-term therapy with lansoprazole.
`
`Other Gastric Effects in Humans
`Lansoprazole did not significantly affect mucosal blood flow in the fundus of the stomach. Due to the
`normal physiologic effect caused by the inhibition of gastric acid secretion, a decrease of about 17% in
`blood flow in the antrum, pylorus, and duodenal bulb was seen. Lansoprazole significantly slowed the
`gastric emptying of digestible solids. Lansoprazole increased serum pepsinogen levels and decreased
`pepsin activity under basal conditions and in response to meal stimulation or insulin injection. As with
`other agents that elevate intragastric pH, increases in gastric pH were associated with increases in nitrate-
`reducing bacteria and elevation of nitrite concentration in gastric juice in patients with gastric ulcer. No
`significant increase in nitrosamine concentrations was observed.
`
`Serum Gastrin Effects
`In over 2100 patients, median fasting serum gastrin levels increased 50% to 100% from baseline but
`remained within normal range after treatment with lansoprazole given orally in doses of 15 mg to 60 mg.
`These elevations reached a plateau within two months of therapy and returned to pretreatment levels within
`four weeks after discontinuation of therapy.
`
`Endrocrine Effects
`Human studies for up to one year have not detected any clinically significant effects on the endocrine
`system. Hormones studied include testosterone, luteinizing hormone (LH), follicle stimulating hormone
`(FSH), sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEA-S), prolactin,
`cortisol, estradiol, insulin, aldosterone, parathormone, glucagon, thyroid stimulating hormone (TSH),
`triiodothyronine (T3), thyroxine (T4), and somatotropic hormone (STH). Lansoprazole in oral doses of 15
`
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`to 60 mg for up to one year had no clinically significant effect on sexual function. In addition, lansoprazole
`in oral doses of 15 to 60 mg for two to eight weeks had no clinically significant effect on thyroid function.
`In 24-month carcinogenicity studies in Sprague-Dawley rats with daily dosages up to 150 mg/kg,
`proliferative changes in the Leydig cells of the testes, including benign neoplasm, were increased compared
`to control rates.
`
`Other Effects
`No systemic effects of lansoprazole on the central nervous system, lymphoid, hematopoietic, renal, hepatic,
`cardiovascular or respiratory systems have been found in humans. No visual toxicity was observed among
`56 patients who had extensive baseline eye evaluations, were treated with up to 180 mg/day of lansoprazole
`and were observed for up to 58 months. Other rat-specific findings after lifetime exposure included focal
`pancreatic atrophy, diffuse lymphoid hyperplasia in the thymus, and spontaneous retinal atrophy.
`
`Microbiology
`Lansoprazole, clarithromycin and/or amoxicillin have been shown to be active against most strains of
`Helicobacter pylori in vitro and in clinical infections as described in the INDICATIONS AND USAGE
`section.
`
`Heliobacter
`Helicobacter pylori
`Pretreatment Resistance
`Clarithromycin pretreatment resistance (≥ 2.0 µg/mL) was 9.5% (91/960) by E-test and 11.3% (12/106)
`by agar dilution in the dual and triple therapy clinical trials (M93-125, M93-130, M93-131, M95-392, and
`M95-399).
`Amoxicillin pretreatment susceptible isolates (≤ 0.25 µg/mL) occurred in 97.8% (936/957) and 98.0%
`(98/100) of the patients in the dual and triple therapy clinical trials by E-test and agar dilution, respectively.
`Twenty-one of 957 patients (2.2%) by E-test and 2 of 100 patients (2.0%) by agar dilution had amoxicillin
`pretreatment MICs of >0.25 µg/mL. One patient on the 14-day triple therapy regimen had an unconfirmed
`pretreatment amoxicillin minimum inhibitory concentration (MIC) of >256 µg/mL by E-test and the patient
`was eradicated of H. pylori.
`
`Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomesa
`Clarithromycin Pretreatment
`Clarithromycin Post-treatment
`Results
`Results
`H. pylori positive –
`not eradicated
`Post-treatment susceptibility results
`Ib
`Rb
`Sb
`No MIC
`Triple Therapy 14-Day (lansoprazole 30 mg b.i.d./amoxicillin 1 gm b.i.d./clarithromycin 500 mg b.i.d.)
`(M95-399, M93-131, M95-392)
`Susceptibleb
`112
`Intermediateb
`3
`Resistantb
`17
`
`H. pylori negative –
`eradicated
`
`105
`3
`6
`
`7
`
`4
`
`7
`
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`Triple Therapy 10-Day (lansoprazole 30 mg b.i.d./amoxicillin 1 gm b.i.d./clarithromycin 500 mg b.i.d.)
`(M95-399)
`Susceptibleb
`Intermediateb
`Resistantb
`1
`4
`aIncludes only patients with pretreatment clarithromycin susceptibility test results
`bSusceptible (S) MIC ≤0.25 µg/mL, Intermediate (I) MIC 0.5 - 1.0 µg/mL, Resistant (R) MIC ≥2 µg/mL
`
`42
`
`40
`
`1
`
`1
`
`3
`
`Patients not eradicated of H. pylori following lansoprazole/amoxicillin/clarithromycin triple therapy will
`likely have clarithromycin resistant H. pylori. Therefore, for those patients who fail therapy, clarithromycin
`susceptibility testing should be done when possible. Patients with clarithromycin resistant H. pylori should
`not be treated with lansoprazole/amoxicillin/ clarithromycin triple therapy or with regimens which include
`clarithromycin as the sole antimicrobial agent.
`
`Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes
`In the dual and triple therapy clinical trials, 82.6% (195/236) of the patients that had pretreatment
`amoxicillin susceptible MICs (≤ 0.25 µg/mL) were eradicated of H. pylori. Of those with pretreatment
`amoxicillin MICs of >0.25 µg/mL, three of six had the H. pylori eradicated. A total of 30% (21/70) of the
`patients failed lansoprazole 30 mg t.i.d./amoxicillin 1 gm t.i.d. dual therapy and a total of 12.8% (22/172)
`of the patients failed the 10- and 14-day triple therapy regimens. Post-treatment susceptibility results were
`not obtained on 11 of the patients who failed therapy. Nine of the 11 patients with amoxicillin post-
`treatment MICs that failed the triple therapy regimen also had clarithromycin resistant H. pylori isolates.
`
`Susceptibility Test for Helicobacter pylori
`The reference methodology for susceptibility testing of H. pylori is agar dilution MICs.1 One to three
`microliters of an inoculum equivalent to a No. 2 McFarland standard (1 x 107 – 1 x 108 CFU/mL for
`H. pylori) are inoculated directly onto freshly prepared antimicrobial-containing Mueller-Hinton agar plates
`with 5% aged defibrinated sheep blood (≥ 2 weeks old). The agar dilution plates are incubated at 35°C in
`a microaerobic environment produced by a gas generating system suitable for campylobacters. After 3 days
`of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required to inhibit
`growth of the organism. The clarithromycin and amoxicillin MIC values should be interpreted according
`to the following criteria:
`
`Interpretation
`Susceptible (S)
`Intermediate (I)
`Resistant (R)
`
`Clarithromycin MIC (µg/mL)a
`≤0.25
`0.5-1.0
`≥2.0
`Amoxicillin MIC (µg/mL)b
`Interpretation
`≤0.25
`Susceptible (S)
`a These are tentative breakpoints for the agar dilution methodology and they should not be used to interpret results
`obtained using alternative methods.
`b There were not enough organisms with MICs >0.25 µg/mL to determine a resistance breakpoint.
`
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`Standardized susceptibility test procedures require the use of laboratory control microorganisms to control
`the technical aspects of the laboratory procedures. Standard clarithromycin and amoxicillin powders should
`provide the following MIC values:
`MIC (µg/mL)a
`Antimicrobial Agent
`Microorganism
`0.015-0.12 µg/mL
`H. pylori ATCC 43504
`Clarithromycin
`0.015-0.12 µg/mL
`H. pylori ATCC 43504
`Amoxicillin
`a These are quality control ranges for the agar dilution methodology and they should not be used to control test results
`obtained using alternative methods.
`Reference
`1. National Committee for Clinical Laboratory Standards. Summary Minutes, Subcommittee on
`Antimicrobial Susceptibility Testing, Tampa, FL, January 11-13, 1998.
`CLINICAL STUDIES
`Duodenal Ulcer
`In a U.S. multicenter, double-blind, placebo-controlled, dose-response (15, 30, and 60 mg of PREVACID
`once daily) study of 284 patients with endoscopically documented duodenal ulcer, the percentage of
`patients healed after two and four weeks was significantly higher with all doses of PREVACID than with
`placebo. There was no evidence of a greater or earlier response with the two higher doses compared with
`PREVACID 15 mg. Based on this study and the second study described below, the recommended dose of
`PREVACID in duodenal ulcer is 15 mg per day.
`
`15 mg q.d.
`(N=68)
`Week
`42.4%*
`2
`89.4%*
`4
`* (p≤0.001) versus placebo.
`
`Duodenal Ulcer Healing Rates
`PREVACID
`30 mg q.d.
`(N=74)
`35.6%*
`91.7%*
`
`60 mg q.d.
`(N=70)
`39.1%*
`89.9%*
`
`Placebo
`
`(N=72)
`11.3%
`46.1%
`
`PREVACID 15 mg was significantly more effective than placebo in relieving day and nighttime abdominal
`pain and in decreasing the amount of antacid taken per day.
`In a second U.S. multicenter study, also double-blind, placebo-controlled, dose-comparison (15 and
`30 mg of PREVACID once daily), and including a comparison with ranitidine, in 280 patients with
`endoscopically documented duodenal ulcer, the percentage of patients healed after four weeks was
`significantly higher with both doses of PREVACID than with placebo. There was no evidence of a greater
`or earlier response with the higher dose of PREVACID. Although the 15 mg dose of PREVACID was
`superior to ranitidine at 4 weeks, the lack of significant difference at 2 weeks and the absence of a
`difference between 30 mg of PREVACID and ranitidine leaves the comparative effectiveness of the two
`agents undetermined.
`
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`Duodenal Ulcer Healing Rates
`PREVACID
`Ranitidine
`300 mg h.s.
`(N=82)
`30.5%
`70.5%*
`
`30 mg q.d.
`(N=77)
`44.2%
`80.3%*
`
`Dual therapy:
`
`Placebo
`
`(N=41)
`34.2%
`47.5%
`
`15 mg q.d.
`(N=80)
` Week
`35.0%
`2
`92.3%**
`4
`* (p≤0.05) versus placebo.
`** (p≤0.05) versus placebo and ranitidine.
`H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
`Randomized, double-blind clinical studies performed in the U.S. in patients with H. pylori and duodenal
`ulcer disease (defined as an active ulcer or history of an ulcer within one year) evaluated the efficacy of
`PREVACID in combination with amoxicillin capsules and clarithromycin tablets as triple 14-day therapy
`or in combination with amoxicillin capsules as dual 14-day therapy for the eradication of H. pylori. Based
`on the results of these studies, the safety and efficacy of two different eradication regimens were
`established:
`Triple therapy:
`
`PREVACID 30 mg b.i.d./
`amoxicillin 1 gm b.i.d./
`clarithromycin 500 mg b.i.d.
`PREVACID 30 mg t.i.d./
`amoxicillin 1 gm t.i.d.
`All treatments were for 14 days. H. pylori eradication was defined as two negative tests (culture and
`histology) at 4-6 weeks following the end of treatment.
`Triple therapy was shown to be more effective than all possible dual therapy combinations. Dual
`therapy was shown to be more effective than both monotherapies. Eradication of H. pylori has been shown
`to reduce the risk of duodenal ulcer recurrence.
`A randomized, double-blind clinical study performed in the U.S. in patients with H. pylori and
`duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) compared the
`efficacy of PREVACID triple therapy for 10 and 14 days. This study established that the 10-day triple
`therapy was equivalent to the 14-day triple therapy in eradicating H. pylori.
`
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`H pylori Eradication Rates – Triple Therapy
`(PREVACID/amoxicillin/clarithromycin)
`Percent of Patients Cured
`[95% Confidence Interval]
`(Number of patients)
`
`Study
`M93-131
`
`Duration
`14 days
`
`Triple Therapy
`Triple Therapy
`Intent-to-Treat Analysis#
`Evaluable Analysis*
`86†
`92†
`[73.3-93.5]
`[80.0-97.7]
`(N=55)
`(N=48)
`83‡
`86‡
`[72.0-90.8]
`[75.7-93.6]
`(N=70)
`(N=66)
`82
`85
`[73.9-88.1]
`[77.0-91.0]
`(N=126)
`(N=113)
`81
`84
`[73.9-87.6]
`[76.0-89.8]
`(N=135)
`(N=123)
`* Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pylori infection at
`baseline defined as at least two of three positive endoscopic tests from CLOtest®, histology and/or culture. Patients
`were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due
`to an adverse event related to the study drug, they were included in the evaluable analysis as failures of therapy.
`# Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and
`had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures of therapy.
`† (p<0.05) versus PREVACID/amoxicillin and PREVACID/clarithromycin dual therapy
`‡ (p<0.05) versus clarithromycin/amoxicillin dual therapy
`+ The 95% confidence interval for the difference in eradication rates, 10-day minus 14-day is (-10.5, 8.1) in the
`evaluable analysis and (-9.7, 9.1) in the intent-to-treat analysis.
`
`M95-392
`
`14 days
`
`M95-399+
`
`14 days
`
`10 days
`
`H. pylori Eradication Rates – 14-Day Dual Therapy
`(PREVACID/amoxicillin)
`Percent of Patients Cured
`[95% Confidence Interval]
`(Number of patients)
`Dual Therapy
`Evaluable Analysis*
`
`Dual Therapy
`Intent-to-Treat Analysis#
`
`77†
`[62.5-87.2]
`(N=51)
`66‡
`[51.9-77.5]
`(N=58)
`
`70†
`[56.8-81.2]
`(N=60)
`61‡
`[48.5-72.9]
`(N=67)
`
`Study
`
`M93-131
`
`M93-125
`
`
`Page 9 of 25
`
`Patent Owner Ex. 2005
`CFAD v. Pozen
`IPR2015-01718
`
`

`
`NDA 20-406/S-038
`Prevacid (lansoprazole) Delayed-Release Capsules Package Insert Text
`Page 12 of 28
`
`* Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pylori infection at
`baseline defined as at least two of three positive endoscopic tests from CLOtest®, histology and/or culture. Patients
`were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to
`an adverse event related to the study drug, they were included in the analysis as failures of therapy.
`# Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and
`had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures of therapy.
`† (p<0.05) versus PREVACID alone.
`‡ (p<0.05) versus PREVACID alone or amoxicillin alone.
`
`Long-Term Maintenance Treatment of Duodenal Ulcers
`PREVACID has been shown to prevent the recurrence of duodenal ulcers. Two independent, double-blind,
`multicenter, controlled trials were conducted in patients with endoscopically confirmed healed duodenal
`ulcers. Patients remained healed significantly longer and the number of recurrences of duodenal ulcers was
`significantly less in patients treated with PREVACID than in patients treated with placebo over a 12-month
`period.
`
`#2
`
`Endoscopic Remission Rates
`Percent in Endoscopic Remission
`0-3 mo.
`0-6 mo.
`0-12 mo.
`90%*
`87%*
`84%*
`49%
`41%
`39%
`94%*
`94%*
`85%*
`87%*
`79%*
`70%*
`33%
`0%
`0%
`
`No. of Pts.
`86
`83
`18
`15
`15
`
`Trial Drug
`PREVACID 15 mg q.d.
`#1
`Placebo
`PREVACID 30 mg q.d.
`PREVACID 15 mg q.d.
`Placebo
`%=Life Table Estimate
`* (p≤0.001) versus placebo.
`In trial #2, no significant difference was noted between PREVACID 15 mg and 30 mg in maintaining
`remission.
`Gastric Ulcer
`In a U.S. multicenter, double-blind, placebo-controlled study of 253 patients with endoscopically
`documented gastric ulcer, the percentage of patients healed at four and eight weeks was significantly higher
`with PREVACID 15 mg and 30 mg once a day than with placebo.
`
`Gastric Ulcer Healing Rates
`PREVACID
`30 mg q.d.
`(N=63)
`58.1%*
`96.8%*
`
`60 mg q.d.
`(N=61)
`53.3%*
`93.2%*
`
`15 mg q.d.
`(N=65)
`Week
`64.6%*
`4
`92.2%*
`8
`* (p≤0.05) versus placebo.
`Patients treated with any PREVACID dose reported significantly less day and night abdominal pain along
`with fewer days of antacid use and fewer antacid tablets used per day than the placebo group.
`
`Placebo
`
`(N=64)
`37.5%
`76.7%
`
`
`Page 10 of 25
`
`Patent Owner Ex. 2005
`CFAD v. Pozen
`IPR2015-01718
`
`

`
`NDA 20-406/S-038
`Prevacid (lansoprazole) Delayed-Release Capsules Package Insert Text
`Page 13 of 28
`
`Independent substantiation of the effectiveness of PREVACID 30 mg was provided by a meta-analysis
`of published and unpublished data.
`
`Healing of NSAID-Associated Gastric Ulcer
`In two U.S. and Canadian multicenter, double-blind, active-controlled studies in patients with
`endoscopically confirmed NSAID-associated gastric ulcer who continued their NSAID use, the percentage
`of patients healed after 8 weeks was statistically significantly higher with 30 mg of PREVACID than with
`the active control. A total of 711 patients were enrolled in the study, and 701 patients were treated.
`Patients ranged in age from 18 to 88 years (median age 59 years), with 67% of female patients and 33%
`male patients. Race was distributed as follows: 87% Caucasian, 8% Black, 5% other. There was no
`statistically significant difference between PREVACID 30 mg q.d. and the active control on symptom relief
`(i.e., abdominal pain).
`
`Week 4
`Week 8
`
`Active Control2
`
`28% (23/83)
`55% (41/74)
`
`NSAID-Associated Gastric Ulcer Healing Rates 1
`Study #1
`PREVACID
`30 mg q.d
`60% (53/88) 3
`79% (62/79) 3
`Study #2
`PREVACID
`30 mg q.d.
`53% (40/75)
`Week 4
`77% (47/61) 3
`Week 8
`1Actual observed ulcer(s) healed at time points + 2 days
`2 Dose for healing of gastric ulcer.
`3(p≤0.05) versus active control
`
`Active Control2
`
`38% (31/82)
`50% (33/66)
`
`Risk Reduction of NSAID-Associated Gastric Ulcer
`In one large U.S., multicenter, double-blind, placebo- and misoprostol-controlled (misoprostol blinded only
`to the endoscopist) study in patients who required chronic use of an NSAID and who had a history of an
`endoscopically documented gastric ulcer, the proportion of patients remaining free from gastric ulcer at
`4, 8, and 12 weeks was significantly higher with 15 or 30 mg of PREVACID than placebo. A total of 537
`patients were enrolled in the study, and 535 patients were treated. Patients ranged in age from 23 to 89
`years (median age 60 years), with 65% female patients and 35% male patients. Race was distributed as
`follows: 90% Caucasian, 6 % Black, 4% other. The 30 mg dose of PREVACID demonstrated no
`additional benefit in risk reduction of the NSAID-associated gastric ulcer than the 15 mg dose.
`
`
`Page 11 of 25
`
`Patent Owner Ex. 2005
`CFAD v. Pozen
`IPR2015-01718
`
`

`
`NDA 20-406/S-038
`Prevacid (lansoprazole) Delayed-Release Capsules Package Insert Text
`Page 14 of 28
`
`Placebo
`
`NSAID-Associated Gastric Ulcer Risk Reduction Rates
`% of Patients Remaining Gastric Ulcer-Free1
`PREVACID PREVACID Misoprostol
`200 µg q.i.d.
`15 mg q.d.
`30 mg q.d.
`(N=121)
`(N=116)
`(N=106)
`Week
`90%
`92%
`96%
`4
`86%
`88%
`95%
`8
`80%
`82%
`93%
`12
`1 % = Life Table Estimate
`(p<0.001) PREVACID 15 mg q.d. versus placebo; PREVACID 30 mg q.d. versus placebo; and
`misoprostol 200 µg q.i.d. versus placebo.
`(p<0.05) Misoprostol 200 µg q.i.d. versus PREVACID 15 mg q.d; and Misoprostol 200 µg q.i.d. versus
`PREVACID 30 mg q.d.
`
`(N=112)
`66%
`60%
`51%
`
`Gastroesophageal Reflux Disease (GERD)
`Symptomatic GERD
`In a U.S. multicenter, double-blind, placebo-controlled study of 214 patients with frequent GERD
`symptoms, but no esophageal erosions by endoscopy, significantly greater relief of heartburn associated
`with GERD was observed with the administration of lansoprazole 15 mg once daily up to 8 weeks than
`with placebo. No significant additional benefit from lansoprazole 30 mg once daily was observed.
`The intent-to-treat analyses demonstrated significant reduction in frequency and severity of day and
`night heartburn. Data for frequency and severity for the 8-week treatment period were as follows:
`
`Variable
`
`% of Days without Heartburn
`Week 1
`Week 4
`Week 8
`% of Nights without Heartburn
`Week 1
`Week 4
`Week 8
`* (p<0.01) versus placebo.
`
`Frequency of Heartburn
`Placebo
`PREVACID 15 mg
`(n=43)
`(n=80)
`Median
`
`PREVACID 30 mg
`(n=86)
`
`0%
`11%
`13%
`
`17%
`25%
`36%
`
`71%*
`81%*
`84%*
`
`86%*
`89%*
`92%*
`
`46%*
`76%*
`82%*
`
`57%*
`73%*
`80%*
`
`
`Page 12 of 25
`
`Patent Owner Ex. 2005
`CFAD v. Pozen
`IPR2015-01718
`
`

`
`NDA 20-406/S-038
`Prevacid (lansoprazole) Delayed-Release Capsules Package Insert Text
`Page 15 of 28
`
`In two U.S., multi-center double-blind, ranitidine-controlled studies of 925 total patients with frequent
`GERD symptoms, but no esophageal erosions by endoscopy, lansoprazole 15 mg was superior to ranitidine
`150 mg (b.i.d.) in decreasing the frequency and severity of day and night heartburn associated with GERD
`for the 8-week treatment period. No significant additional benefit from lansoprazole 30 mg once daily was
`observed.
`
`Erosive Esophagitis
`In a U.S. multicenter, double-blind, placebo-controlled study of 269 patients entering with an endoscopic
`diagnosis of esophagitis with mucosal grading of 2 or more and grades 3 and 4 signifying erosive disease,
`the percentages of patients with healing were as follows:
`
`
`Page 13 of 25
`
`Patent Owner Ex. 2005
`CFAD v. Pozen
`IPR2015-01718
`
`

`
`NDA 20-406/S-038
`Prevacid (lansoprazole) Delayed-Release Capsules Package Insert Text
`Page 16 of 28
`
`Erosive Esophagitis Healing Rates
`PREVACID
`30 mg q.d.
`(N=65)
`81.3%**
`95.4%*
`95.4%*
`
`60 mg q.d.
`(N=72)
`80.6%**
`94.3%*
`94.4%*
`
`15 mg q.d.
`(N=69)
`Week
`67.6%*
`4
`87.7%*
`6
`90.9%*
`8
` * (p≤0.001) versus placebo.
`** (p≤0.05) versus PREVACID 15 mg and placebo.
`
`Placebo
`
`(N=63)
`32.8%
`52.5%
`52.5%
`
`In this study, all PREVACID groups reported significantly greater relief of heartburn and less day and night
`abdominal pain along with fewer days of antacid use and fewer antacid tablets taken per day than the
`placebo group.
`Although all doses were effective, the earlier healing in the higher two doses suggests 30 mg q.d. as
`the recommended dose.
`PREVACID was also compared in a U.S. multicenter, double-blind study