NDA 19810/S-074
`Page 4
`
`
`
`
`FDA Revised July 12, 2002
`
`91941XX
`640004-XX
`
`PRILOSEC®
`(OMEPRAZOLE)
`DELAYED-RELEASE CAPSULES
`
`
`DESCRIPTION
`The active ingredient in PRILOSEC (omeprazole) Delayed-Release Capsules is a substituted
`benzimidazole, 5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H-
`benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is
`C17H19N3O3S, with a molecular weight of 345.42. The structural formula is:
`
`
`
`
`
`Omeprazole is a white to off-white crystalline powder which melts with decomposition at
`about 155°C. It is a weak base, freely soluble in ethanol and methanol, and slightly soluble in
`acetone and isopropanol and very slightly soluble in water. The stability of omeprazole is a
`function of pH; it is rapidly degraded in acid media, but has acceptable stability under alkaline
`conditions.
`
`PRILOSEC is supplied as delayed-release capsules for oral administration. Each delayed-
`release capsule contains either 10 mg, 20 mg or 40 mg of omeprazole in the form of enteric-
`coated granules with the following inactive ingredients: cellulose, disodium hydrogen
`phosphate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, mannitol,
`sodium lauryl sulfate and other ingredients. The capsule shells have the following inactive
`ingredients: gelatin-NF, FD&C Blue #1, FD&C Red #40, D&C Red #28, titanium dioxide,
`synthetic black iron oxide, isopropanol, butyl alcohol, FD&C Blue #2, D&C Red #7 Calcium
`Lake, and, in addition, the 10 mg and 40 mg capsule shells also contain D&C Yellow #10.
`
`
`CLINICAL PHARMACOLOGY
`Pharmacokinetics and Metabolism: Omeprazole
`PRILOSEC Delayed-Release Capsules contain an enteric-coated granule formulation of
`omeprazole (because omeprazole is acid-labile), so that absorption of omeprazole begins only
`after the granules leave the stomach. Absorption is rapid, with peak plasma levels of
`omeprazole occurring within 0.5 to 3.5 hours. Peak plasma concentrations of omeprazole and
`AUC are approximately proportional to doses up to 40 mg, but because of a saturable first-
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`NDA 19810/S-074
`Page 5
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`pass effect, a greater than linear response in peak plasma concentration and AUC occurs with
`doses greater than 40 mg. Absolute bioavailability (compared to intravenous administration)
`is about 30-40% at doses of 20-40 mg, due in large part to presystemic metabolism. In healthy
`subjects the plasma half-life is 0.5 to 1 hour, and the total body clearance is 500-600 mL/min.
`Protein binding is approximately 95%.
`
`The bioavailability of omeprazole increases slightly upon repeated administration of
`PRILOSEC Delayed-Release Capsules.
`
`Following single dose oral administration of a buffered solution of omeprazole, little if any
`unchanged drug was excreted in urine. The majority of the dose (about 77%) was eliminated
`in urine as at least six metabolites. Two were identified as hydroxyomeprazole and the
`corresponding carboxylic acid. The remainder of the dose was recoverable in feces. This
`implies a significant biliary excretion of the metabolites of omeprazole. Three metabolites
`have been identified in plasma — the sulfide and sulfone derivatives of omeprazole, and
`hydroxyomeprazole. These metabolites have very little or no antisecretory activity.
`
`In patients with chronic hepatic disease, the bioavailability increased to approximately 100%
`compared to an I.V. dose, reflecting decreased first-pass effect, and the plasma half-life of the
`drug increased to nearly 3 hours compared to the half-life in normals of 0.5-1 hour. Plasma
`clearance averaged 70 mL/min, compared to a value of 500-600 mL/min in normal subjects.
`
`In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and
`62 mL/min/1.73 m2, the disposition of omeprazole was very similar to that in healthy
`volunteers, although there was a slight increase in bioavailability. Because urinary excretion
`is a primary route of excretion of omeprazole metabolites, their elimination slowed in
`proportion to the decreased creatinine clearance.
`The elimination rate of omeprazole was somewhat decreased in the elderly, and
`bioavailability was increased. Omeprazole was 76% bioavailable when a single 40 mg oral
`dose of omeprazole (buffered solution) was administered to healthy elderly volunteers, versus
`58% in young volunteers given the same dose. Nearly 70% of the dose was recovered in urine
`as metabolites of omeprazole and no unchanged drug was detected. The plasma clearance of
`omeprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life
`averaged one hour, about twice that of young healthy volunteers.
`
`In pharmacokinetic studies of single 20 mg omeprazole doses, an increase in AUC of
`approximately four-fold was noted in Asian subjects compared to Caucasians.
`
`Dose adjustment, particularly where maintenance of healing of erosive esophagitis is
`indicated, for the hepatically impaired and Asian subjects should be considered.
`
`PRILOSEC Delayed-Release Capsule 40 mg was bioequivalent when administered with and
`without applesauce. However, PRILOSEC Delayed-Release Capsule 20 mg was not
`bioequivalent when administered with and without applesauce. When administered with
`applesauce, a mean 25% reduction in Cmax was observed without a significant change in AUC
`for PRILOSEC Delayed-Release Capsule 20 mg. The clinical relevance of this finding is
`
`MYLAN PHARMS. INC. EXHIBIT 1044 PAGE 2
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`

`

`Cmax*
`(ng/mL)
`AUC*
`(ng h/mL)
`
`511 (n=7)
`
`1140 (n=32)
`
`1220
`
`668
`
`Repeated Dosing
`539 (n=4)
`851 (n=32)
`
`1179 (n=2)
`
`2276 (n=23)
`
`1458
`
`3352
`
`NDA 19810/S-074
`Page 6
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`unknown.
`
`The pharmacokinetics of omeprazole have been investigated in pediatric patients of different
`ages.
`
`
`Pharmacokinetic Parameters of Omeprazole Following Single and Repeated Oral Administration in
`Pediatric Populations Compared to Adults
`Children†
`Adults‡
`Children†
`Single or
`Repeated
` < 20 kg
`> 20 kg
`(mean 76 kg)
`Oral Dosing
`2-5 years
`6-16 years
`23-29 years
`/Parameter
`10 mg
`20 mg
`(n=12)
`Single Dosing
`288 (n=10)
`495 (n=49)
`
`Cmax*
`(ng/mL)
`AUC*
`(ng h/mL)
`Note: * = plasma concentration adjusted to an oral dose of 1 mg/kg.
`†Data from single and repeated dose studies
`
`
`‡Data from a single and repeated dose study
` Doses of 10, 20 and 40 mg Omeprazole as Enteric-Coated Granules
`
`
`Following comparable mg/kg doses of omeprazole, younger children (2-5 years) have lower AUCs
`than children 6 – 16 years or adults; AUCs of the latter two groups did not differ. (See DOSAGE AND
`ADMINISTRATION – Pediatric Patients.)
`
`Pharmacokinetics: Combination Therapy with Antimicrobials
`Omeprazole 40 mg daily was given in combination with clarithromycin 500 mg every 8 hours to
`healthy adult male subjects. The steady state plasma concentrations of omeprazole were increased
`(Cmax, AUC0-24, and T1/2 increases of 30%, 89% and 34% respectively) by the concomitant
`administration of clarithromycin. The observed increases in omeprazole plasma concentration were
`associated with the following pharmacological effects. The mean 24-hour gastric pH value was 5.2
`when omeprazole was administered alone and 5.7 when co-administered with clarithromycin.
`
`The plasma levels of clarithromycin and 14-hydroxy-clarithromycin were increased by the concomitant
`administration of omeprazole. For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was
`27% greater, and the mean AUC0-8 was 15% greater when clarithromycin was administered with
`omeprazole than when clarithromycin was administered alone. Similar results were seen for 14-
`hydroxy-clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean
`AUC0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also
`increased by concomitant administration of omeprazole.
`
`Clarithromycin Tissue Concentrations
`2 hours after Dose1
`Clarithromycin +
`Omeprazole
`19.96 ± 4.71 (n = 5)
`24.25 ± 6.37 (n = 5)
`39.29 ± 32.79 (n = 4)
`
`
`Tissue
`Antrum
`Fundus
`Mucus
`1 Mean ± SD (µg/g)
`
`
`
`
`Clarithromycin
`10.48 ± 2.01 (n = 5)
`20.81 ± 7.64 (n = 5)
` 4.15 ± 7.74 (n = 4)
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`NDA 19810/S-074
`Page 7
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`
`For information on clarithromycin pharmacokinetics and microbiology, consult the clarithromycin
`package insert, CLINICAL PHARMACOLOGY section.
`
`The pharmacokinetics of omeprazole, clarithromycin, and amoxicillin have not been adequately
`studied when all three drugs are administered concomitantly.
`
`For information on amoxicillin pharmacokinetics and microbiology, see the amoxicillin package insert,
`ACTIONS, PHARMACOLOGY and MICROBIOLOGY sections.
`
`Pharmacodynamics
`Mechanism of Action
`Omeprazole belongs to a new class of antisecretory compounds, the substituted benzimidazoles, that do
`not exhibit anticholinergic or H2 histamine antagonistic 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
`gastric mucosa, omeprazole 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 acid secretion irrespective of the stimulus. Animal studies indicate that after rapid
`disappearance from plasma, omeprazole can be found within the gastric mucosa for a day or more.
`
`Antisecretory Activity
`After oral administration, the onset of the antisecretory effect of omeprazole occurs within one hour,
`with the maximum effect occurring within two hours. Inhibition of secretion is about 50% of maximum
`at 24 hours and the duration of inhibition lasts up to 72 hours. The antisecretory effect thus lasts far
`longer than would be expected from the very short (less than one hour) plasma half-life, apparently due
`to prolonged binding to the parietal H+/K+ ATPase enzyme. When the drug is discontinued, secretory
`activity returns gradually, over 3 to 5 days. The inhibitory effect of omeprazole on acid secretion
`increases with repeated once-daily dosing, reaching a plateau after four days.
`
`Results from numerous studies of the antisecretory effect of multiple doses of 20 mg and 40 mg of
`omeprazole in normal volunteers and patients are shown below. The “max” value represents
`determinations at a time of maximum effect (2-6 hours after dosing), while “min” values are those 24
`hours after the last dose of omeprazole.
`
`
`Range of Mean Values from Multiple Studies
`of the Mean Antisecretory Effects of Omeprazole
`After Multiple Daily Dosing
`Omeprazole
`20 mg
`Max
`78*
`
`79*
`
`
`Max
`94*
`
`88*
`
`
`Omeprazole
`40 mg
`
`Min
`80-93
`
`62-68
`
`92-94
`
`
`Parameter
`% Decrease in
`Basal Acid Output
`% Decrease in
`Peak Acid Output
`% Decrease in
`24-hr. Intragastric
`Acidity
`* Single Studies
`
`Min
`58-80
`
`50-59
`
`80-97
`
`
`
`
`Single daily oral doses of omeprazole ranging from a dose of 10 mg to 40 mg have produced 100%
`inhibition of 24-hour intragastric acidity in some patients.
`
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`MYLAN PHARMS. INC. EXHIBIT 1044 PAGE 4
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`NDA 19810/S-074
`Page 8
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`Enterochromaffin-like (ECL) Cell Effects
`In 24-month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid
`tumors and ECL cell hyperplasia was observed in both male and female animals (see PRECAUTIONS,
`Carcinogenesis, Mutagenesis, Impairment of Fertility). Carcinoid tumors have also been observed in
`rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of
`H2-receptor antagonists.
`
`Human gastric biopsy specimens have been obtained from more than 3000 patients treated with
`omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies
`increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in
`these patients. (See also CLINICAL PHARMACOLOGY, Pathological Hypersecretory Conditions.)
`However, these studies are of insufficient duration and size to rule out the possible influence of long-
`term administration of omeprazole on the development of any premalignant or malignant conditions.
`
`Serum Gastrin Effects
`In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2 weeks
`of once-daily administration of therapeutic doses of omeprazole in parallel with inhibition of acid
`secretion. No further increase in serum gastrin occurred with continued treatment. In comparison with
`histamine H2-receptor antagonists, the median increases produced by 20 mg doses of omeprazole were
`higher (1.3 to 3.6 fold vs. 1.1 to 1.8 fold increase). Gastrin values returned to pretreatment levels,
`usually within 1 to 2 weeks after discontinuation of therapy.
`
`Other Effects
`Systemic effects of omeprazole in the CNS, cardiovascular and respiratory systems have not been
`found to date. Omeprazole, given in oral doses of 30 or 40 mg for 2 to 4 weeks, had no effect on
`thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol,
`estradiol, testosterone, prolactin, cholecystokinin or secretin.
`
`No effect on gastric emptying of the solid and liquid components of a test meal was demonstrated after
`a single dose of omeprazole 90 mg. In healthy subjects, a single I.V. dose of omeprazole (0.35 mg/kg)
`had no effect on intrinsic factor secretion. No systematic dose-dependent effect has been observed on
`basal or stimulated pepsin output in humans.
`
`However, when intragastric pH is maintained at 4.0 or above, basal pepsin output is low, and pepsin
`activity is decreased.
`
`As do other agents that elevate intragastric pH, omeprazole administered for 14 days in healthy
`subjects produced a significant increase in the intragastric concentrations of viable bacteria. The pattern
`of the bacterial species was unchanged from that commonly found in saliva. All changes resolved
`within three days of stopping treatment.
`
`The course of Barrett’s esophagus in 106 patients was evaluated in a U.S. double-blind controlled
`study of PRILOSEC 40 mg b.i.d. for 12 months followed by 20 mg b.i.d. for 12 months or ranitidine
`300 mg b.i.d. for 24 months. No clinically significant impact on Barrett’s mucosa by antisecretory
`therapy was observed. Although neosquamous epithelium developed during antisecretory therapy,
`complete elimination of Barrett’s mucosa was not achieved. No significant difference was observed
`between treatment groups in development of dysplasia in Barrett’s mucosa and no patient developed
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`NDA 19810/S-074
`Page 9
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`
`
`esophageal carcinoma during treatment. No significant differences between treatment groups were
`observed in development of ECL cell hyperplasia, corpus atrophic gastritis, corpus intestinal
`metaplasia, or colon polyps exceeding 3 mm in diameter (see also CLINICAL PHARMACOLOGY,
`Enterochromaffin-like (ECL) Cell Effects).
`
`Clinical Studies
`Duodenal Ulcer Disease
`Active Duodenal Ulcer— In a multicenter, double-blind, placebo-controlled study of 147 patients
`with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol) at 2
`and 4 weeks was significantly higher with PRILOSEC 20 mg once a day than with placebo (p ≤ 0.01).
`
`
`
`Treatment of Active Duodenal Ulcer
`% of Patients Healed
`
`PRILOSEC
`20 mg a.m.
`(n = 99)
`*41
`*75
`
`Placebo
`a.m.
`(n = 48)
`13
`27
`
`
`
`
`
`Week 2
`Week 4
`* (p ≤ 0.01)
`
`
`Complete daytime and nighttime pain relief occurred significantly faster (p ≤ 0.01) in patients treated
`with PRILOSEC 20 mg than in patients treated with placebo. At the end of the study, significantly
`more patients who had received PRILOSEC had complete relief of daytime pain (p ≤ 0.05) and
`nighttime pain (p ≤ 0.01).
`
`In a multicenter, double-blind study of 293 patients with endoscopically documented duodenal ulcer,
`the percentage of patients healed (per protocol) at 4 weeks was significantly higher with PRILOSEC 20
`mg once a day than with ranitidine
`150 mg b.i.d. (p < 0.01).
`
`
`
`Treatment of Active Duodenal Ulcer
`% of Patients Healed
`
`PRILOSEC
`20 mg a.m.
`(n = 145)
` 42
`*82
`
`Ranitidine
`150 mg b.i.d.
`(n = 148)
`34
`63
`
`
`
`
`
`Week 2
`Week 4
`* (p < 0.01)
`
`
`Healing occurred significantly faster in patients treated with PRILOSEC than in those treated with
`ranitidine 150 mg b.i.d. (p < 0.01).
`
`In a foreign multinational randomized, double-blind study of 105 patients with endoscopically
`documented duodenal ulcer, 20 mg and 40 mg of PRILOSEC were compared to 150 mg b.i.d. of
`ranitidine at 2, 4 and 8 weeks. At 2 and 4 weeks both doses of PRILOSEC were statistically superior
`(per protocol) to ranitidine, but 40 mg was not superior to 20 mg of PRILOSEC, and at 8 weeks there
`was no significant difference between any of the active drugs.
`
`
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1044 PAGE 6
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`NDA 19810/S-074
`Page 10
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`
`Treatment of Active Duodenal Ulcer
`% of Patients Healed
`
`PRILOSEC
`
`20 mg
`(n = 34)
`* 83
`* 97
`100
`
`40 mg
`(n = 36)
`* 83
`*100
`100
`
`Ranitidine
`150 mg b.i.d.
`(n = 35)
`53
`82
`94
`
`
`
`
`Week 2
`Week 4
`Week 8
`* (p ≤ 0.01)
`
`
`
`H. pylori Eradication in Patients with Duodenal Ulcer Disease
`Triple Therapy(PRILOSEC/clarithromycin/amoxicillin)— Three U.S., randomized, double-blind
`clinical studies in patients with H. pylori infection and duodenal ulcer disease (n = 558) compared
`PRILOSEC plus clarithromycin plus amoxicillin to clarithromycin plus amoxicillin. Two studies (126
`and 127) were conducted in patients with an active duodenal ulcer, and the other study (M96-446) was
`conducted in patients with a history of a duodenal ulcer in the past 5 years but without an ulcer present
`at the time of enrollment. The dose regimen in the studies was PRILOSEC 20 mg b.i.d. plus
`clarithromycin 500 mg b.i.d. plus amoxicillin 1 g b.i.d. for 10 days; or clarithromycin 500 mg b.i.d.
`plus amoxicillin 1 g b.i.d. for 10 days. In studies 126 and 127, patients who took the omeprazole
`regimen also received an additional 18 days of PRILOSEC 20 mg q.d. Endpoints studied were
`eradication of H. pylori and duodenal ulcer healing (studies 126 and 127 only). H. pylori status was
`determined by CLOtest®, histology and culture in all three studies. For a given patient, H. pylori was
`considered eradicated if at least two of these tests were negative, and none was positive.
`
`The combination of omeprazole plus clarithromycin plus amoxicillin was effective in eradicating H.
`pylori.
`
`
`
`Per-Protocol and Intent-to-Treat H. pylori Eradication Rates
`% of Patients Cured [95% Confidence Interval]
`PRILOSEC +clarithromycin
`Clarithromycin +amoxicillin
`+amoxicillin
`Per-Protocol †
`Intent-to-
`Treat ‡
`37 [27, 48]
`43 [31, 56]
`*69 [57, 79]
`*77 [64, 86]
`(n = 84)
`(n = 67)
`(n = 80)
`(n = 64)
`
`
`
`
`36 [26, 47]
`41 [29, 54]
`*73 [61, 82]
`*78 [67, 88]
`(n = 83)
`(n = 68)
`(n = 77)
`(n = 65)
`
`
`
`
`32 [23, 42]
`33 [24, 44]
`*83 [74, 91]
`*90 [80, 96]
`(n = 99)
`(n = 93)
`(n = 84)
`(n = 69)
`† Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer, studies 126 and 127; history of ulcer within 5
`years, study M96-446) 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. The impact of eradication on ulcer recurrence has not been
`assessed in patients with a past history of ulcer.
`‡ Patients were included in the analysis if they had documented H. pylori infection at baseline and had confirmed duodenal ulcer disease. All dropouts were
`included as failures of therapy.
`* (p < 0.05) versus clarithromycin plus amoxicillin.
`
`
`Study M96-446
`
`Per-Protocol †
`
`Intent-to-Treat ‡
`
`Study 126
`
`
`Study 127
`
`
`
`
`
`
`
`
`Dual Therapy (PRILOSEC/clarithromycin)— Four randomized, double-blind, multicenter studies
`(M93-067, M93-100, M92-812b, and M93-058) evaluated PRILOSEC 40 mg q.d. plus clarithromycin
`500 mg t.i.d. for 14 days, followed 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. pylori. Studies M93-067 and M93-100 were conducted 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 228 patients in Study M93-100. These studies compared the
`combination regimen to PRILOSEC and clarithromycin monotherapies. Studies M92-812b and M93-
`058 were conducted in Europe and enrolled 154 and 215 patients, respectively. H. pylori infection and
`
`MYLAN PHARMS. INC. EXHIBIT 1044 PAGE 7
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`

`

`
`duodenal ulcer were confirmed in 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
`efficacy analyses for these studies are described below. H. pylori eradication was defined as no positive
`test (culture or histology) at 4 weeks following the end of treatment, and two negative tests were
`required to be considered eradicated of H. pylori. In the per-protocol analysis, the following patients
`were excluded: dropouts, patients with missing H. pylori tests post-treatment, and patients that were
`not assessed for H. pylori eradication because they were found to have an ulcer at the end of treatment.
`
`The combination of omeprazole and clarithromycin was effective in eradicating H. pylori.
`
`H. pylori Eradication Rates (Per-Protocol Analysis at 4 to 6 Weeks)
`% of Patients Cured [95% Confidence Interval]
`PRILOSEC +
`
`Clarithromycin
`PRILOSEC
`
`
`NDA 19810/S-074
`Page 11
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`
`
`U.S. Studies
` Study M93-067
`
`
`
` Study M93-100
`
`Non U.S. Studies
` Study M92-812b
`
`
`
` Study M93-058
`
`
`
`0 [0, 7]
`(n = 54)
`0 [0, 6]
`(n = 59)
`
`
`Clarithromycin
`
`
`31 [18, 47]
`(n = 42)
`39 [24, 55]
`(n = 44)
`
`
`
`N/A
`
`N/A
`
`74 [60, 85] †‡
`(n = 53)
`64 [51, 76] †‡
`(n = 61)
`83 [71, 92] ‡
`1 [0, 7]
`(n = 74)
`(n = 60)
`74 [64, 83] ‡
`1 [0, 6]
`(n = 90)
`(n = 86)
`† Statistically significantly higher than clarithromycin monotherapy (p < 0.05)
`‡ Statistically significantly higher than omeprazole monotherapy (p < 0.05)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Ulcer healing was not significantly different when clarithromycin was added to omeprazole therapy
`compared to omeprazole therapy alone.
`
`The combination of omeprazole and clarithromycin was effective in eradicating H. pylori and reduced
`duodenal ulcer recurrence.
`
`
`Duodenal Ulcer Recurrence Rates by
`H. pylori Eradication Status
`% of Patients with Ulcer Recurrence
`H. pylori
`
`eradicated#
`
`
`H. pylori not
`eradicated#
`
`
`60
`(n = 88)
`60
`(n = 106)
`
`
`*35
`(n = 49)
`*8
`(n = 53)
`
`
`U.S. Studies †
`6 months post-treatment
` Study M93-067
`
` Study M93-100
`
`Non U.S. Studies ‡
`6 months post-treatment
` Study M92-812b
`
` Study M93-058
`
`12 months post-treatment
` Study M92-812b
`
`46
`*5
`(n = 78)
`(n = 43)
`43
`*6
`(n = 107)
`(n = 53)
`
`
`68
`*5
`(n = 71)
`(n = 39)
`# H. pylori eradication status assessed at same timepoint as ulcer recurrence
`† Combined results for PRILOSEC + clarithromycin, PRILOSEC, and clarithromycin treatment arms
`‡ Combined results for PRILOSEC + clarithromycin and PRILOSEC treatment arms
`* (p ≤ 0.01) versus proportion with duodenal ulcer recurrence who were not H. pylori eradicated
`
`
`Gastric Ulcer
`In a U.S. multicenter, double-blind, study of omeprazole 40 mg once a day, 20 mg once a day, and
`placebo in 520 patients with endoscopically diagnosed gastric ulcer, the following results were
`obtained.
`
`
`MYLAN PHARMS. INC. EXHIBIT 1044 PAGE 8
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`

`

`NDA 19810/S-074
`Page 12
`
`
`
`
`
`
`
`
`
`
`
`Placebo
`(n = 104)
`30.8
`48.1
`
`
`
`
`
`Treatment of Gastric Ulcer
`% of Patients Healed
`(All Patients Treated)
`
`PRILOSEC
`PRILOSEC
`40 mg q.d.
`20 mg q.d.
`(n = 214)
`(n = 202)
`47.5**
`Week 4
`55.6**
`Week 8
`74.8**
` 82.7**,+
` ** (p < 0.01) PRILOSEC 40 mg or 20 mg versus placebo
` +(p < 0.05) PRILOSEC 40 mg versus 20 mg
`
`For the stratified groups of patients with ulcer size less than or equal to 1 cm, no difference in healing
`rates between 40 mg and 20 mg was detected at either 4 or 8 weeks. For patients with ulcer size greater
`than 1 cm, 40 mg was significantly more effective than 20 mg at 8 weeks.
`
`In a foreign, multinational, double-blind study of 602 patients with endoscopically diagnosed gastric
`ulcer, omeprazole 40 mg once a day, 20 mg once a day, and ranitidine 150 mg twice a day were
`evaluated.
`
`
`
`
`
`
`
`Treatment of Gastric Ulcer
`% of Patients Healed
`(All Patients Treated)
`
`PRILOSEC
`PRILOSEC
`40 mg q.d.
`20 mg q.d.
`(n = 187)
`(n = 200)
`78.1**,++
`63.5
`Week 4
`81.5
`Week 8
`91.4**,++
`** (p < 0.01) PRILOSEC 40 mg versus ranitidine
`++ (p < 0.01) PRILOSEC 40 mg versus 20 mg
`
`
`
`
`
`
`
`
`
`
`
`Ranitidine
`150 mg b.i.d.
`(n = 199)
`56.3
`78.4
`
`
`Gastroesophageal Reflux Disease (GERD)
`Symptomatic GERD
`A placebo controlled study was conducted in Scandinavia to compare the efficacy of omeprazole 20
`mg or 10 mg once daily for up to 4 weeks in the treatment of heartburn and other symptoms in GERD
`patients without erosive esophagitis. Results are shown below.
`
`
`
`
`PRILOSEC
`20 mg a.m.
`All patients
`46*,†
`
`(n = 205)
`Patients with
`56*,†
`confirmed GERD
`(n = 115)
`aDefined as complete resolution of heartburn
`*(p < 0.005) versus 10 mg
`†(p < 0.005) versus placebo
`
`Erosive Esophagitis
`In a U.S. multicenter double-blind placebo controlled study of 20 mg or 40 mg of PRILOSEC Delayed-
`Release Capsules in patients with symptoms of GERD and endoscopically diagnosed erosive
`esophagitis of grade 2 or above, the percentage healing rates (per protocol) were as follows:
`
`
`
` 20 mg PRILOSEC
`(n = 83)
`Week
`4
`39**
`8
`74**
`** (p < 0.01) PRILOSEC versus placebo.
`
`In this study, the 40 mg dose was not superior to the 20 mg dose of PRILOSEC in the percentage
`
`% Successful Symptomatic Outcomea
`
`
`
`
`
`
`PRILOSEC
`10 mg a.m.
`31†
`(n = 199)
`36†
`(n = 109)
`
`
`
`
`
`Placebo
`a.m.
`13
`(n = 105)
`14
`(n = 59)
`
`
`
` 40 mg PRILOSEC
`(n = 87)
`45**
`75**
`
`
`
`
`
`
`
`Placebo
`(n = 43)
` 7
`14
`
`MYLAN PHARMS. INC. EXHIBIT 1044 PAGE 9
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`

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`NDA 19810/S-074
`Page 13
`
`
`
`healing rate. Other controlled clinical trials have also shown that PRILOSEC is effective in severe
`GERD. In comparisons with histamine H2-receptor antagonists in patients with erosive esophagitis,
`grade 2 or above, PRILOSEC in a dose of 20 mg was significantly more effective than the active
`controls. Complete daytime and nighttime heartburn relief occurred significantly faster (p < 0.01) in
`patients treated with PRILOSEC than in those taking placebo or histamine H2- receptor antagonists.
`
`In this and five other controlled GERD studies, significantly more patients taking 20 mg omeprazole
`(84%) reported complete relief of GERD symptoms than patients receiving placebo (12%).
`
`Long Term Maintenance Treatment of Erosive Esophagitis
`In a U.S. double-blind, randomized, multicenter, placebo controlled study, two dose regimens of
`PRILOSEC were studied in patients with endoscopically confirmed healed esophagitis. Results to
`determine maintenance of healing of erosive esophagitis are shown below.
`
`
`Life Table Analysis
`
`
`
`
`
`
`
`
`
`PRILOSEC
`
`
`20 mg 3 days
`PRILOSEC
`Placebo
`per week
`20 mg q.d.
`(n = 131)
`(n = 137)
`(n = 138)
`
`Percent in
`
`
`endoscopic
`
`
`
`remission at
`
`
`
`6 months
`11
`34
`*70
`∗(p < 0.01) PRILOSEC 20 mg q.d. versus PRILOSEC 20 mg 3 consecutive days per week or placebo.
`
`In an international multicenter double-blind study, PRILOSEC 20 mg daily and 10 mg daily were
`compared to ranitidine 150 mg twice daily in patients with endoscopically confirmed healed
`esophagitis. The table below provides the results of this study for maintenance of healing of erosive
`esophagitis.
`
`
`
`
`
`
`
`
`
`
`Life Table Analysis
`
`
`
`
`
`
`
`
`
`
`Ranitidine
`PRILOSEC
`PRILOSEC
`150 mg b.i.d.
`10 mg q.d.
`20 mg q.d.
`(n = 128)
`(n = 133)
`(n = 131)
`
`Percent in
`
`
`endoscopic
`
`
`
`remission at
`
`
`
`12 months
`46
`‡58
`*77
`* (p = 0.01) PRILOSEC 20 mg q.d. versus PRILOSEC 10 mg q.d. or Ranitidine.
` ‡ (p = 0.03) PRILOSEC 10 mg q.d. versus Ranitidine.
`
`In patients who initially had grades 3 or 4 erosive esophagitis, for maintenance after healing 20 mg
`daily of PRILOSEC was effective, while 10 mg did not demonstrate effectiveness.
`
`Pathological Hypersecretory Conditions
`In open studies of 136 patients with pathological hypersecretory conditions, such as Zollinger-Ellison
`(ZE) syndrome with or without multiple endocrine adenomas, PRILOSEC Delayed-Release Capsules
`significantly inhibited gastric acid secretion and controlled associated symptoms of diarrhea, anorexia,
`and pain. Doses ranging from 20 mg every other day to 360 mg per day maintained basal acid secretion
`below 10 mEq/hr in patients without prior gastric surgery, and below 5 mEq/hr in patients with prior
`gastric surgery.
`
`Initial doses were titrated to the individual patient need, and adjustments were necessary with time in
`some patients (see DOSAGE AND ADMINISTRATION). PRILOSEC was well tolerated at these high
`
`MYLAN PHARMS. INC. EXHIBIT 1044 PAGE 10
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`

`

`NDA 19810/S-074
`Page 14
`
`
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`dose levels for prolonged periods (> 5 years in some patients). In most ZE patients, serum gastrin levels
`were not modified by PRILOSEC. However, in some patients serum gastrin increased to levels greater
`than those present prior to initiation of omeprazole therapy. At least 11 patients with ZE syndrome on
`long-term treatment with PRILOSEC developed gastric carcinoids. These findings are believed to be a
`manifestation of the underlying condition, which is known to be associated with such tumors, rather
`than the result of the administration of PRILOSEC. (See ADVERSE REACTIONS.)
`
`Microbiology
`Omeprazole and clarithromycin dual therapy and omeprazole, clarithromycin and amoxicillin triple
`therapy 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.
`
`Helicobacter
`Helicobacter pylori
`Pretreatment Resistance
`Clarithromycin pretreatment resistance rates were 3.5% (4/113) in the omeprazole/clarithromycin dual
`therapy studies (M93-067, M93-100) and 9.3% (41/439) in omeprazole/clarithromycin/amoxicillin
`triple therapy studies (126, 127, M96-446).
`
`Amoxicillin pretreatment susceptible isolates (≤ 0.25 µg/mL) were found in 99.3% (436/439) of the
`patients in the omeprazole/clarithromycin/amoxicillin triple therapy studies (126, 127, M96-446).
`Amoxicillin pretreatment minimum inhibitory concentrations (MICs) > 0.25 µg/mL occurred in 0.7%
`(3/439) of the patients, all of whom were in the clarithromycin and amoxicillin study arm. One patient
`had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of > 256
`µg/mL by Etest®.
`
`Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes
`
`
`
`Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes a
`Clarithromycin
`Clarithromycin Post-treatment Results
`Pretreatment Results
`
`
`
`H. pylori positive - not eradicated
`
`H. pylori negative -
`eradicated
`Post-treatment susceptibility results
`
`
`
`S b
`I b
`R b
`No MIC
`
`
`
`Dual Therapy - (omeprazole 40 mg q.d./clarithromycin 500 mg t.i.d. for 14 days followed by
`omeprazole 20 mg q.d. for another 14 days) (Studies M93-067, M93-100)
`9
`26
`Susceptible b
`108
`72
`1
`
`
`1
`Intermediate b
`1
`
`
`
`
`4
`Resistant b
`4
`
`
`
`Triple Therapy - (omeprazole 20 mg b.i.d./clarithromycin 500 mg b.i.d./amoxicillin 1 g b.i.d. for
`10 days - Studies 126, 127, M96-446; followed by omeprazole 20 mg q.d. for another 18 days -
`Studies 126, 127)
`3
`
`7
`153
`171
`Susceptible b
`8
`
`
`
`
`
`Intermediate b
`
`6
`
`1
`4
`14
`Resistant b
`3
`aIncludes only patients with pretreatment clarithromycin susceptibility test results
` bSusceptible (S) MIC ≤ 0.25 µg/mL, Intermediate (I) MIC