SANTARUS, INC.
`CONFIDENTIAL
`Zegerid® Capsules
`August 9, 2007
`
`
`ZEGERID®
`(omeprazole/sodium bicarbonate)
`
`
`
`DESCRIPTION
`
`NDA 21-849
`Prior Approval Supplement
`1.14.1.3 Draft Labeling Text
`Page 1
`
`
`Rx only
`Capsules
`Powder for Oral Suspension
`
`ZEGERID® (omeprazole/sodium bicarbonate) is a combination of omeprazole, a proton-pump
`inhibitor, and sodium bicarbonate, an antacid. Omeprazole is a substituted benzimidazole,
`5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, a racemic
`mixture of two enantiomers 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.
`
`
`
`ZEGERID is supplied as immediate-release capsules and unit-dose packets as powder for oral
`suspension. Each capsule contains either 40 mg or 20 mg of omeprazole and 1100 mg of sodium
`bicarbonate with the following excipients: croscarmellose sodium and sodium stearyl fumarate.
`Packets of powder for oral suspension contain either 40 mg or 20 mg of omeprazole and 1680 mg
`of sodium bicarbonate with the following excipients: xylitol, sucrose, sucralose, xanthan gum, and
`flavorings.
`
`CLINICAL PHARMACOLOGY
`
`Omeprazole is acid labile and thus rapidly degraded by gastric acid. ZEGERID Capsules and
`Powder for Oral Suspension are immediate-release formulations that contain sodium bicarbonate
`which raises the gastric pH and thus protects omeprazole from acid degradation.
`
`Pharmacokinetics:
`
`Absorption
`In separate in vivo bioavailability studies, when ZEGERID Oral Suspension and Capsules are
`administered on an empty stomach 1 hour prior to a meal, the absorption of omeprazole is rapid,
`with mean peak plasma levels (% CV) of omeprazole being 1954 ng/mL (33%) and 1526 ng/mL
`(49%), respectively, and time to peak of approximately 30 minutes (range 10-90 min) after a
`single-dose or repeated-dose administration. Absolute bioavailability of ZEGERID Powder for Oral
`Suspension (compared to I.V. administration) is about 30-40% at doses of 20 – 40 mg, due in large
`part to presystemic metabolism.
`
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`

`

`SANTARUS, INC.
`CONFIDENTIAL
`Zegerid® Capsules
`August 9, 2007
`
`
`When ZEGERID Oral Suspension 40 mg/1680 mg was administered in a two-dose loading
`regimen, the omeprazole AUC(0-inf) (ng∗hr/mL) was 1665 after Dose 1 and 3356 after Dose 2,
`while Tmax was approximately 30 minutes for both Dose 1 and Dose 2.
`
`NDA 21-849
`Prior Approval Supplement
`1.14.1.3 Draft Labeling Text
`Page 2
`
`
`Following single or repeated once daily dosing, peak plasma concentrations of omeprazole from
`ZEGERID are approximately proportional from 20 to 40 mg doses, but a greater than linear mean
`AUC (three-fold increase) is observed when doubling the dose to 40 mg. The bioavailability of
`omeprazole from ZEGERID increases upon repeated administration.
`
`When ZEGERID is administered 1 hour after a meal, the omeprazole AUC is reduced by
`approximately 24% relative to administration 1 hour prior to a meal.
`
`Distribution
`Omeprazole is bound to plasma proteins. Protein binding is approximately 95%.
`
`Metabolism
`Following single-dose oral administration of omeprazole, the majority of the dose (about 77%) is
`eliminated in urine as at least six metabolites. Two metabolites have been 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.
`
`Excretion
`Following single-dose oral administration of omeprazole, little if any, unchanged drug is excreted in
`urine. The mean plasma omeprazole half-life in healthy subjects is approximately 1 hour (range 0.4
`to 3.2 hours) and the total body clearance is 500-600 mL/min.
`
`Special Populations
`
`Geriatric
`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 subjects, versus 58% in young subjects
`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 subjects) and its plasma half-life averaged one hour, similar to that of
`young healthy subjects.
`
`Pediatric
`The pharmacokinetics of ZEGERID have not been studied in patients < 18 years of age.
`
`Gender
`There are no known differences in the absorption or excretion of omeprazole between males and
`females.
`
`Page 2
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`

`

`SANTARUS, INC.
`CONFIDENTIAL
`Zegerid® Capsules
`August 9, 2007
`
`
`Hepatic Insufficiency
`In patients with chronic hepatic disease, the bioavailability of omeprazole from a buffered solution
`increased to approximately 100% compared to an I.V. dose, reflecting decreased first-pass effect,
`and the mean plasma half-life of the drug increased to nearly 3 hours compared to the mean
`half-life of 1 hour in normal subjects. Plasma clearance averaged 70 mL/min, compared to a value
`of 500-600 mL/min in normal subjects.
`
`NDA 21-849
`Prior Approval Supplement
`1.14.1.3 Draft Labeling Text
`Page 3
`
`
`Renal Insufficiency
`In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and
`62 mL/min/1.73 m2, the disposition of omeprazole from a buffered solution was very similar to that
`in healthy subjects, 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.
`
`Asians
`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.
`
`Drug-Drug Interactions
`When omeprazole 40 mg was given once daily in combination with clarithromycin 500 mg every
`8 hours to healthy adult male subjects, the steady-state plasma concentrations of omeprazole were
`increased by the concomitant administration of clarithromycin [Cmax, AUC(0-24) and T½ increased
`30%, 89%, and 34%, respectively].
`
`Pharmacodynamics:
`
`Mechanism of Action
`Omeprazole belongs to a 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
`Results from a PK/PD study of the antisecretory effect of repeated once-daily dosing of 40 mg and
`20 mg of ZEGERID Oral Suspension in healthy subjects are shown in Table 1 below.
`
`Page 3
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`Dr. Reddy's Exh. 1039
`
`

`

`SANTARUS, INC.
`CONFIDENTIAL
`Zegerid® Capsules
`August 9, 2007
`
`
`
`
`
`NDA 21-849
`Prior Approval Supplement
`1.14.1.3 Draft Labeling Text
`Page 4
`
`
`Table 1: Effect of ZEGERID Oral Suspension on Intragastric pH on Day 7
`Omeprazole/Sodium Bicarbonate
`40 mg/1680 mg
`20 mg/1680 mg
`(n = 24)
`(n = 28)
`84%
`82%
`
`Parameter
`% Decrease from Baseline for
`Integrated Gastric Acidity (mmol∗hr/L)
`24%
`20%
` Coefficient of variation
`51%
`77%
`% Time Gastric pH > 4*
`(12.2 h)
`(18.6 h)
`(Hours)*
`43%
`27%
` Coefficient of variation
`4.2
`5.2
`Median pH
`37%
`17%
` Coefficient of variation
`Note: Values represent medians. All parameters were measured over a 24-hour period.
`* p < 0.05 20 mg vs. 40 mg
`
`Results from a separate PK/PD study of antisecretory effect on repeated once-daily dosing of
`40 mg/1100 mg and 20 mg/1100 mg of ZEGERID Capsules in healthy subjects show similar effects
`in general on the above three PD parameters as those for ZEGERID 40 mg/1680 mg and
`20 mg/1680 mg Oral Suspension, respectively.
`
`The antisecretory effect thus lasts far longer than would be expected from the very short (1 hour)
`plasma half-life, apparently due to irreversible binding to the parietal H+/K+ ATPase enzyme.
`
`Repeated single daily oral doses of ZEGERID 40 mg and 20 mg have produced nearly 100%
`inhibition of 24-hour integrated gastric acidity in some subjects.
`
`In 178 critically ill patients treated with ZEGERID Powder for Oral Suspension 40 mg/1680 mg via
`nasogastric or orogastric tube, the median daily gastric pH was above 4 in ≥ 95% of patients over
`the course of the 14-day trial. The gastric pH was above 4 for almost all patients beginning with the
`first dose (99% of patients 1-2.5 hours postdose and 92% of patients 6 hours postdose).
`
`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. 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
`
`Page 4
`
`Dr. Reddy's Exh. 1039
`
`

`

`SANTARUS, INC.
`CONFIDENTIAL
`Zegerid® Capsules
`August 9, 2007
`
`
`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.
`
`NDA 21-849
`Prior Approval Supplement
`1.14.1.3 Draft Labeling Text
`Page 5
`
`
`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 omeprazole 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 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 omeprazole 20 mg once a day than with placebo
`(p ≤ 0.01). (See Table 2.)
`
`Table 2: Treatment of Active Duodenal Ulcer
`% of Patients Healed
`Omeprazole
`20 mg a.m.
`(n = 99)
`41*
`75*
`
`Placebo
`a.m.
`(n = 48)
`13
`27
`
`
`
`Week 2
`Week 4
`* (p ≤ 0.01)
`
`
`
`Page 5
`
`Dr. Reddy's Exh. 1039
`
`

`

`SANTARUS, INC.
`CONFIDENTIAL
`Zegerid® Capsules
`August 9, 2007
`
`
`Complete daytime and nighttime pain relief occurred significantly faster (p ≤ 0.01) in patients treated
`with omeprazole 20 mg than in patients treated with placebo. At the end of the study, significantly
`more patients who had received omeprazole had complete relief of daytime pain (p ≤ 0.05) and
`nighttime pain (p ≤ 0.01).
`
`NDA 21-849
`Prior Approval Supplement
`1.14.1.3 Draft Labeling Text
`Page 6
`
`
`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
`omeprazole 20 mg once a day than with ranitidine 150 mg b.i.d. (p < 0.01). (See Table 3.)
`
`
`
`Table 3: Treatment of Active Duodenal Ulcer
`% of Patients Healed
`Omeprazole
`Ranitidine
`20 mg a.m.
`150 mg b.i.d.
`(n = 145)
`(n = 148)
`42
`34
`82*
`63
`
`Week 2
`Week 4
`* (p < 0.01)
`
`
`Healing occurred significantly faster in patients treated with omeprazole 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, 40 mg and 20 mg of omeprazole were compared to 150 mg b.i.d. of
`ranitidine at 2, 4 and 8 weeks. At 2 and 4 weeks both doses of omeprazole were statistically
`superior (per protocol) to ranitidine, but 40 mg was not superior to 20 mg of omeprazole, and at 8
`weeks there was no significant difference between any of the active drugs. (See Table 4.)
`
`Table 4: Treatment of Active Duodenal Ulcer
`% of Patients Healed
`Omeprazole
`40 mg
`20 mg
`(n = 36)
`(n = 34)
`83*
`83*
`100*
`97*
`100
`100
`
`Ranitidine
`150 mg b.i.d.
`(n = 35)
`53
`82
`94
`
`
`
`Week 2
`Week 4
`Week 8
`*(p ≤ 0.01)
`
`
`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. (See Table 5.)
`
`Page 6
`
`Dr. Reddy's Exh. 1039
`
`

`

`SANTARUS, INC.
`CONFIDENTIAL
`Zegerid® Capsules
`August 9, 2007
`
`
`
`NDA 21-849
`Prior Approval Supplement
`1.14.1.3 Draft Labeling Text
`Page 7
`
`
`
`
`Table 5: Treatment of Gastric Ulcer
`% of Patients Healed (All Patients Treated)
`Omeprazole
`Omeprazole
`Placebo
`40 mg q.d.
`20 mg q.d.
`(n = 104)
`(n = 214)
`(n = 202)
`30.8
`55.6**
`47.5**
`Week 4
` 82.7**,+
`48.1
`74.8**
`Week 8
`** (p < 0.01) Omeprazole 40 mg or 20 mg versus placebo
`+ (p < 0.05) Omeprazole 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. (See Table 6.)
`
`
`
`Table 6: Treatment of Gastric Ulcer
`% of Patients Healed (All Patients Treated)
`Omeprazole
`Omeprazole
`Ranitidine
`40 mg q.d.
`20 mg q.d.
`150 mg b.i.d.
`(n = 187)
`(n = 200)
`(n = 199)
`78.1**,++
`63.5
`56.3
`Week 4
`91.4**,++
`81.5
`78.4
`Week 8
`**(p < 0.01) Omeprazole 40 mg versus ranitidine
`++(p < 0.01) Omeprazole 40 mg versus 20 mg
`
`
`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 in Table 7.
`
`Table 7: % Successful Symptomatic Outcomea
`
`Omeprazole
`Omeprazole
`Placebo
`20 mg a.m.
`10 mg a.m.
`a.m.
`46*,†
`31†
`13
`All patients
`(n = 205)
`(n = 199)
`(n = 105)
`56*,†
`36†
`14
`Patients with
`(n = 115)
`confirmed GERD
`(n = 109)
`(n = 59)
`a Defined 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 40 mg or 20 mg of omeprazole in
`patients with symptoms of GERD and endoscopically diagnosed erosive esophagitis of grade 2 or
`above, the percentage healing rates (per protocol) were as shown in Table 8.
`
`Page 7
`
`Dr. Reddy's Exh. 1039
`
`

`

`SANTARUS, INC.
`CONFIDENTIAL
`Zegerid® Capsules
`August 9, 2007
`
`
`
`NDA 21-849
`Prior Approval Supplement
`1.14.1.3 Draft Labeling Text
`Page 8
`
`
`Placebo
`(n = 43)
`7
`14
`
`
`
`Table 8: % Patients Healed
`Omeprazole
`Omeprazole
`40 mg
`20 mg
`(n = 87)
`(n = 83)
`45*
`39*
`Week 4
`75*
`74*
`Week 8
`* (p < 0.01) Omeprazole versus placebo.
`
`
`In this study, the 40-mg dose was not superior to the 20-mg dose of omeprazole in the percentage
`healing rate. Other controlled clinical trials have also shown that omeprazole is effective in severe
`GERD. In comparisons with histamine H2-receptor antagonists in patients with erosive esophagitis,
`grade 2 or above, omeprazole 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 omeprazole 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
`omeprazole were studied in patients with endoscopically confirmed healed esophagitis. Results to
`determine maintenance of healing of erosive esophagitis are shown in Table 9.
`
`
`
`Placebo
`(n = 131)
`
`Table 9: Life Table Analysis
`Omeprazole
`Omeprazole
`20 mg q.d.
`20 mg 3 days per week
`(n = 138)
`(n = 137)
`Percent in endoscopic
`11
`70*
`34
`remission at 6 months
`* (p < 0.01) Omeprazole 20 mg q.d. versus Omeprazole 20 mg 3 consecutive days
`per week or placebo.
`
`
`In an international multicenter double-blind study, omeprazole 20 mg daily and 10 mg daily were
`compared to ranitidine 150 mg twice daily in patients with endoscopically confirmed healed
`esophagitis. Table 10 provides the results of this study for maintenance of healing of erosive
`esophagitis.
`
`
`
`Table 10: Life Table Analysis
`Omeprazole
`Omeprazole
`Ranitidine
`20 mg q.d.
`10 mg q.d.
`150 mg b.i.d.
`(n = 131)
`(n = 133)
`(n = 128)
`Percent in endoscopic
`58‡
`46
`77*
`remission at 12 months
`* (p = 0.01) Omeprazole 20 mg q.d. versus Omeprazole 10 mg q.d. or Ranitidine.
`‡ (p = 0.03) Omeprazole 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 omeprazole was effective, while 10 mg did not demonstrate effectiveness.
`
`Page 8
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`Dr. Reddy's Exh. 1039
`
`

`

`NDA 21-849
`Prior Approval Supplement
`1.14.1.3 Draft Labeling Text
`Page 9
`
`
`SANTARUS, INC.
`CONFIDENTIAL
`Zegerid® Capsules
`August 9, 2007
`
`
`Reduction of Risk of Upper Gastrointestinal Bleeding in Critically Ill Patients
`A double-blind, multicenter, randomized, non-inferiority clinical trial was conducted to compare
`ZEGERID Oral Suspension 40 mg/1680 mg and I.V. cimetidine for the reduction of risk of upper
`gastrointestinal (GI) bleeding in critically ill patients (mean APACHE II score = 23.7). The primary
`endpoint was significant upper GI bleeding defined as bright red blood which did not clear after
`adjustment of the nasogastric tube and a 5 to 10 minute lavage, or persistent Gastroccult® positive
`coffee grounds for 8 consecutive hours which did not clear with 100 cc lavage. ZEGERID Oral
`Suspension 40 mg/1680 mg (two doses administered 6 to 8 hours apart on the first day via
`orogastric or nasogastric tube, followed by 40 mg q.d. thereafter) was compared to continuous I.V.
`cimetidine (300 mg bolus, and 50 to 100 mg/hr continuously thereafter) for up to 14 days
`(mean = 6.8 days). A total of 359 patients were studied, age range 16 to 91 (mean = 56 yrs), 58.5%
`were males, and 64% were Caucasians. The results of the study showed that ZEGERID was
`non-inferior to I.V. cimetidine, 10/181(5.5%) patients in the cimetidine group vs. 7/178 (3.9%)
`patients in the ZEGERID group experienced clinically significant upper GI bleeding.
`
`INDICATIONS AND USAGE
`
`Duodenal Ulcer
`ZEGERID is indicated for short-term treatment of active duodenal ulcer. Most patients heal within
`four weeks. Some patients may require an additional four weeks of therapy.
`
`Gastric Ulcer
`ZEGERID is indicated for short-term treatment (4-8 weeks) of active benign gastric ulcer. (See
`CLINICAL PHARMACOLOGY, Clinical Studies, Gastric Ulcer.)
`
`Treatment of Gastroesophageal Reflux Disease (GERD)
`Symptomatic GERD
`ZEGERID is indicated for the treatment of heartburn and other symptoms associated with GERD.
`
`Erosive Esophagitis
`ZEGERID is indicated for the short-term treatment (4-8 weeks) of erosive esophagitis which has
`been diagnosed by endoscopy. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
`
`The efficacy of ZEGERID used for longer than 8 weeks in these patients has not been established.
`In the rare instance of a patient not responding to 8 weeks of treatment, it may be helpful to give up
`to an additional 4 weeks of treatment. If there is recurrence of erosive esophagitis or GERD
`symptoms (eg, heartburn), additional 4-8 week courses of omeprazole may be considered.
`
`Maintenance of Healing of Erosive Esophagitis
`ZEGERID is indicated to maintain healing of erosive esophagitis. Controlled studies do not extend
`beyond 12 months.
`
`Reduction of Risk of Upper Gastrointestinal Bleeding in Critically Ill Patients
`ZEGERID Powder for Oral Suspension 40 mg/1680 mg is indicated for the reduction of risk of
`upper GI bleeding in critically ill patients.
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`SANTARUS, INC.
`CONFIDENTIAL
`Zegerid® Capsules
`August 9, 2007
`
`
`CONTRAINDICATIONS
`
`NDA 21-849
`Prior Approval Supplement
`1.14.1.3 Draft Labeling Text
`Page 10
`
`
`ZEGERID is contraindicated in patients with known hypersensitivity to any components of the
`formulation.
`
`PRECAUTIONS
`
`General
`Symptomatic response to therapy with omeprazole does not preclude the presence of gastric
`malignancy.
`
`Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated
`long-term with omeprazole.
`
`Each ZEGERID Capsule contains 1100 mg (13 mEq) of sodium bicarbonate. The total content of
`sodium in each capsule is 303 mg.
`
`Each packet of ZEGERID Powder for Oral Suspension contains 1680 mg (20 mEq) of sodium
`bicarbonate (equivalent to 460 mg of Na+).
`
`The sodium content of ZEGERID products should be taken into consideration when administering
`to patients on a sodium restricted diet.
`
`Sodium bicarbonate is contraindicated in patients with metabolic alkalosis and hypocalcemia.
`Sodium bicarbonate should be used with caution in patients with Bartter’s syndrome, hypokalemia,
`respiratory alkalosis, and problems with acid-base balance. Long-term administration of bicarbonate
`with calcium or milk can cause milk-alkali syndrome.
`
`Information for Patients
`ZEGERID should be taken on an empty stomach at least one hour prior to a meal. ZEGERID is
`available either as 40 mg or 20 mg capsules with 1100 mg sodium bicarbonate. ZEGERID is also
`available either as 40 mg or 20 mg single-dose packets of powder for oral suspension with 1680 mg
`sodium bicarbonate.
`
`Directions for Use:
`Capsules: Swallow intact capsule with water. DO NOT USE OTHER LIQUIDS. DO NOT OPEN
`CAPSULE AND SPRINKLE CONTENTS INTO FOOD.
`
`Powder for Oral Suspension: Empty packet contents into a small cup containing 1-2 tablespoons of
`water. DO NOT USE OTHER LIQUIDS OR FOODS. Stir well and drink immediately. Refill cup with
`water and drink.
`
`Drug Interactions
`Omeprazole can prolong the elimination of diazepam, warfarin and phenytoin, drugs that are
`metabolized by oxidation in the liver. There have been reports of increased INR and prothrombin
`time in patients receiving proton pump inhibitors, including omeprazole, and warfarin concomitantly.
`Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients
`treated with proton pump inhibitors and warfarin may need to be monitored for increases in INR and
`prothrombin time. Although in normal subjects no interaction with theophylline or propranolol was
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`SANTARUS, INC.
`CONFIDENTIAL
`Zegerid® Capsules
`August 9, 2007
`
`
`found, there have been clinical reports of interaction with other drugs metabolized via the
`cytochrome P-450 system (eg, cyclosporine, disulfiram, benzodiazepines). Patients should be
`monitored to determine if it is necessary to adjust the dosage of these drugs when taken
`concomitantly with ZEGERID.
`
`NDA 21-849
`Prior Approval Supplement
`1.14.1.3 Draft Labeling Text
`Page 11
`
`
`Because of its profound and long-lasting inhibition of gastric acid secretion, it is theoretically
`possible that omeprazole may interfere with absorption of drugs where gastric pH is an important
`determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). In the clinical
`efficacy trials, antacids were used concomitantly with the administration of omeprazole.
`
`Concomitant administration of omeprazole and atazanavir has been reported to reduce the plasma
`levels of atazanavir.
`
`Concomitant administration of omeprazole and tacrolimus may increase the serum levels of
`tacrolimus.
`
`Co-administration of omeprazole and clarithromycin have resulted in increases of plasma levels of
`omeprazole, clarithromycin, and 14-hydroxy-clarithromycin (see also CLINICAL PHARMACOLOGY,
`Pharmacokinetics).
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0
`and 140.8 mg/kg/day (approximately 0.5 to 28.5 times the human dose of 40 mg/day, based on
`body surface area) produced gastric ECL cell carcinoids in a dose-related manner in both male and
`female rats; the incidence of this effect was markedly higher in female rats, which had higher blood
`levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell
`hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats
`were treated with 13.8 mg omeprazole/kg/day (approximately 2.8 times the human dose of
`40 mg/day, based on body surface area) for one year, then followed for an additional year without
`the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL
`cell hyperplasia was observed at the end of one year (94% treated vs 10% controls). By the second
`year the difference between treated and control rats was much smaller (46% vs 26%) but still
`showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%).
`No similar tumor was seen in male or female rats treated for two years. For this strain of rat no
`similar tumor has been noted historically, but a finding involving only one tumor is difficult to
`interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in a
`small number of males that received omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about
`0.1 to 3.3 times the human dose of 40 mg/day, based on body surface area). No astrocytomas were
`observed in female rats in this study. In a 2-year carcinogenicity study in Sprague-Dawley rats, no
`astrocytomas were found in males and females at the high dose of 140.8 mg/kg/day (about
`28.5 times the human dose of 40 mg/day, based on body surface area). A 78-week mouse
`carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was
`not conclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity study was not positive.
`Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal
`aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow
`cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames Test, an in vitro
`mouse lymphoma cell forward mutation assay and an in vivo rat liver DNA damage assay.
`
`Omeprazole at oral doses up to 138 mg/kg/day (about 28 times the human dose of 40 mg/day,
`based on body surface area) was found to have no effect on the fertility and general reproductive
`performance in rats.
`
`Page 11
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`Dr. Reddy's Exh. 1039
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`

`

`NDA 21-849
`Prior Approval Supplement
`1.14.1.3 Draft Labeling Text
`Page 12
`
`
`SANTARUS, INC.
`CONFIDENTIAL
`Zegerid® Capsules
`August 9, 2007
`
`
`Pregnancy
`Pregnancy Category C
`There are no adequate and well-controlled studies on the use of omeprazole in pregnant women.
`The vast majority of reported experience with omeprazole during human pregnancy is first trimester
`exposure and the duration of use is rarely specified, eg, intermittent vs. chronic. An expert review of
`published data on experiences with omeprazole use during pregnancy by TERIS – the Teratogen
`Information System – concluded that therapeutic doses during pregnancy are unlikely to pose a
`substantial teratogenic risk (the quantity and quality of data were assessed as fair).1
`
`Three epidemiological studies compared the frequency of congenital abnormalities among infants
`born to women who used omeprazole during pregnancy to the frequency of abnormalities among
`infants of women exposed to H2-receptor antagonists or other controls. A population-based
`prospective cohort epidemiological study from the Swedish Medical Birth Registry, covering
`approximately 99% of pregnancies, reported on 955 infants (824 exposed during the first trimester
`with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose
`mothers used omeprazole during pregnancy.2 In utero exposure to omeprazole was not associated
`with increased risk of any malformation (odds ratio 0.82, 95% CI 0.50-1.34), low birth weight or low
`Apgar score. The number of infants born with ventric