`
`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`
`
`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
`
`
`
`NDA 21-636
`
`
`Santarus, Inc.
`Attention: Christine Simmons, Pharm.D.
`10590 West Ocean Air Drive, Suite 200
`San Diego, CA 92130
`
`
`Dear Dr. Simmons:
`
`Please refer to your new drug application (NDA) dated August 14, 2003, received August 15, 2003,
`submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Zegerid
`(omeprazole) Powder for Oral Suspension, 20 mg.
`
`We acknowledge receipt of your submissions dated December 9, 2003; January 7 and 15, February 9,
`13, 19, and 26, March 2, 11, 16, 22, and 30, April 5 9, 15, 19, 20, and 26, May 11, 13, 18, 19, and 28,
`June 2, 8, and June 14, 2004.
`
`This new drug application provides for the use of omeprazole powder for suspension 20 for short-term
`treatment (4-8 wks) of active duodenal ulcer; treatment of heartburn and other symptoms associated
`with gastroesophageal reflux disease (GERD); short-term treatment (4-8 wks) of erosive esophagitis
`which has been diagnosed by endoscopy; and maintenance of healing of erosive esophagitis.
`
`We completed our review of this application, as amended. It is approved, effective on the date of this
`letter, for use of Zegerid (omeprazole) Powder for Oral Suspension, 20 mg, as recommended in the
`agreed-upon labeling text.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package insert)
`and submitted labeling (immediate container and carton labels submitted June 14, 2004). Marketing
`the product(s) with FPL that is not identical to the approved labeling text may render the products
`misbranded and an unapproved new drug.
`
`The electronic labeling rule published December 11, 2003 (68 FR 69009) requires submission of
`labeling content in electronic format effective June 8, 2004. For additional information, consult the
`following guidances for industry regarding electronic submissions: Providing Regulatory Submissions
`in Electronic Format – NDAs (January 1999) and Providing Regulatory Submissions in Electronic
`Format – Content of Labeling (February 2004). The guidances specify that labeling to be submitted in
`pdf format. To assist in our review, we request that labeling also be submitted in MS Word format. If
`formatted copies of all labeling pieces (i.e. package insert, patient package insert, container labels, and
`carton labels) are submitted electronically, labeling does not need to be submitted in paper. Approval
`of this submission by FDA is not required before the labeling is used.
`
`All applications for new active ingredients, new dosage forms, new indications, new routes of
`administration, and new dosing regimens are required to contain an assessment of the safety and
`
`MYLAN PHARMS. INC. EXHIBIT 1010 PAGE 1
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`

`

`NDA 21-636
`Page 2
`
`effectiveness of the product in pediatric patients unless this requirement is waived or deferred. We are
`deferring submission of your pediatric studies for ages 2 to 16 years until July 15, 2007.
`
`Your deferred pediatric studies for GERD (symptomatic GERD and Erosive Esophagitis) required
`under section 2 of the Pediatric Research Equity Act (PREA) are considered required postmarketing
`study commitments. The statuses of these postmarketing studies shall be reported annually according
`to 21 CFR 314.81. These commitments are listed below.
`
`
`1) Single and multiple-dose pharmacokinetics (PK), pharmacodynamics (PD) and safety study in
`pediatric patients aged 2 to 11 years.
`
`Protocol submission by: December 15, 2004 (6 mos. post-approval)
`Study start:
`
` July 15, 2005 (1 year post-approval)
`Final report submission: July 15, 2007 (3 years post approval)
`
`
`2) Single and multiple-dose pharmacokinetics (PK), pharmacodynamics (PD) and safety study in
`pediatric patients aged 12 to 16 years.
`
`Protocol submission by: December 15, 2004 (6 mos. post-approval)
`Study start:
`
` July 15, 2005 (1 year post-approval)
`Final report submission: July 15, 2007 (3 years post approval)
`
`
`Submit final study reports to this NDA. For administrative purposes, all submissions related to
`this/these pediatric postmarketing study commitment(s) must be clearly designated “Required
`Pediatric Study Commitments”.
`
`Please submit one market package of the drug product when it is available.
`
`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
`If you have any questions, call Susan Daugherty, Regulatory Project Manager, at (301) 827-7456.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Robert L. Justice, M.D., M.S.
`Director
`Division of Gastrointestinal and
` Coagulation Drug Products
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`
`
`
`Enclosure: Labeling
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1010 PAGE 2
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Joyce Korvick
`6/15/04 01:47:29 PM
`for Dr. Robert Justice
`
`MYLAN PHARMS. INC. EXHIBIT 1010 PAGE 3
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`

`

`NDA 21-636
`Page 3
`
`
`Zegerid (omeprazole)
`Powder for Oral Suspension
`
`
`
`DESCRIPTION
`
`The active ingredient in Zegerid (omeprazole) powder for oral suspension, 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 Powder for Oral Suspension is supplied in unit dose packets as an immediate release formulation to be
`constituted with water for oral administration. Each packet contains 20 mg of omeprazole and the following
`excipients: sodium bicarbonate, sucrose, sucralose, xanthan gum, xylitol, and flavorings.
`
`CLINICAL PHARMACOLOGY
`
`Omeprazole is acid labile and thus rapidly degraded by gastric acid. Zegerid Powder for Oral Suspension is an
`immediate-release formulation that contains sodium bicarbonate to protect omeprazole from acid degradation.
`
`Pharmacokinetics:
`Absorption
`
`When Zegerid is administered on an empty stomach 1 hour prior to a meal, absorption of omeprazole is rapid,
`with mean peak plasma levels of omeprazole occurring at around 30 minutes (range 10 to 90 minutes) after a
`single dose or repeated once-daily administration (see figures below).
`
`
`Mean Plasma Omeprazole Concentrations (Days 1 and 7)
`(Day 1)
`(Day 7)
`
`
`The AUC(0-inf)(ng*hr/mL) was 1446 after 7 days of 20 mg daily doses and the Tmax was approximately 30
`minutes.
`
`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
`
`
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1010 PAGE 4
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`

`

`NDA 21-636
`Page 4
`
`observed when doubling the dose to 40 mg. The bioavailability of omeprazole from Zegerid Powder for Oral
`Suspension increases upon repeated administration of Zegerid.
`
`
`Pharmacokinetic Parameters of Zegerid Following
`Oral 20 mg Once-Daily Dosing for 1 and 7 Days
`
`
`Parameter
`AUC(0-inf) (ng*hr/mL)
`Coefficient of variation
`Cmax (ng/mL)
`Coefficient of variation
`Tmax (min)
`T½ (hr)
`
`Day 1
`825
`72%
`672
`44%
`29.8
`0.86
`Values represent arithmetic means.
`
`
`Parameter
`AUC(0-inf) (ng*hr/mL)
`Coefficient of variation
`Cmax (ng/mL)
`Coefficient of variation
`Tmax (min)
`T½ (hr)
`
`Day 7
`1446
`61%
`902
`40%
`28.3
`1.08
`Values represent arithmetic means.
`
`When Zegerid is administered 1 hour after a meal, Cmax and AUC are reduced by 63% and 24%, respectively,
`relative to administration prior to a meal.
`
`Distribution
`Omeprazole is bound to plasma proteins. Protein binding is approximately 95%.
`
`Metabolism
`Absolute bioavailability (compared to intravenous administration) is about 30-40% at doses of 20-40 mg, due in
`large part to pre-systemic metabolism.
`
`Excretion
`In healthy subjects, the mean plasma half-life is 1 hour (range 0.4 to 3.2 hours), and the total body clearance is
`500-600 mL/min.
`
`Following single dose oral administration of omeprazole, little if any unchanged drug is excreted in urine. 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.
`
`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.
`
`
`MYLAN PHARMS. INC. EXHIBIT 1010 PAGE 5
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`

`

`NDA 21-636
`Page 5
`
`Gender
`There are no known differences in the absorption or excretion of omeprazole between males and females.
`
`Hepatic insufficiency
`In patients with chronic hepatic disease, the bioavailability of omeprazole increased to approximately 100%
`compared to an l.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 healthy subjects. Plasma clearance
`averaged 70 mL/min, compared to a value of 500-600 mL/min in normal subjects.
`
`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 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.
`
`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 once 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 by the
`concomitant administration of clarithromycin (Cmax, AUC 0-24 and T1/2 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 study of the antisecretory effect of repeated once-daily dosing of 20 mg of Zegerid in healthy
`subjects (n = 28) is shown below.
`
`
`Effect of Zegerid 20 mg on Intragastric pH on Day 7
`
`(19)
`
`Parameter
`% Decrease from Baseline for Integrated Intragastric
`Acidity (mmol*hr/L)
`51% (12.2 h) /(43%)*
`% Time Gastric pH > 4 (hours)
`4.2/(37%)*
`Median pH
` Values represent medians. All parameters were measured over a 24-hour period.
` * Coefficient of variation
`
`
`82%/(24%)*
`
`MYLAN PHARMS. INC. EXHIBIT 1010 PAGE 6
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`

`

`NDA 21-636
`Page 6
`
`
`The antisecretory effect thus lasts far longer than would be expected from the very short plasma half-life
`(1 hour) apparently due to irreversible binding to the parietal H+/K+ ATPase enzyme. Repeated single daily oral
`doses of Zegerid20 mg have produced nearly 100% inhibition of 24-hour integrated intragastric acidity in some
`subjects.
`
`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 l.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).
`
`
`MYLAN PHARMS. INC. EXHIBIT 1010 PAGE 7
`
`

`

`NDA 21-636
`Page 7
`
`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).
`
`
`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)
`
`
`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).
`
`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).
`
`
`Treatment of Active Duodenal Ulcer
`% of Patients Healed
`Omeprazole
`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 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, 20 mg and 40 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.
`
`
`Treatment of Active Duodenal Ulcer
`% of Patients Healed
`Omeprazole
`
`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)
`
`
`Gastroesophageal Reflux Disease (GERD)
`
`Symptomatic GERD
`
`
`MYLAN PHARMS. INC. EXHIBIT 1010 PAGE 8
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`

`

`NDA 21-636
`Page 8
`
` 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.
`
`
`
`
`All patients
`
`Patients with
`confirmed GERD
`
`% Successful Symptomatic Outcomea
`Omeprazole
`Omeprazole
`20 mg a.m.
`10 mg a.m.
`46*,†
`31†
`(n = 205)
`(n = 199)
`56*,†
`36†
`(n = 115
`(n = 109
`aDefined as complete resolution of heartburn
`*(p < 0.005) versus 10 mg
`†(p < 0.005) versus placebo
`
`Placebo
`a.m.
`13
`(n = 105)
`14
`(n = 59)
`
`
`Erosive Esophagitis
`
`In a US multicenter double-blind placebo controlled study of 20 mg or 40 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 follows:
`
`
`20 mg Omeprazole
`
`(n = 83)
`Week
`39*
`4
`74*
`8
`*(p < 0.01) Omeprazole versus placebo.
`
`40 mg Omeprazole
`(n = 87)
`45*
`75*
`
`Placebo
`(n = 43)
`7
`14
`
`
`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 below.
`
`
`
`
`
`
`
`
`Life Table Analysis
`
`Omeprazole
`
`
`20 mg 3 days
`Omeprazole
`Placebo
`per week
`20 mg q.d.
`(n = 131)
`(n = 137)
`(n = 138)
`Percent in
`
`
`
`endoscopic
`
`
`
`remission at 6
`*70
`11
`34
`months
`*(p < 0.01) Omeprazole 20 mg q.d. versus Omeprazole 20 mg 3 consecutive days per
`week or placebo.
`
`MYLAN PHARMS. INC. EXHIBIT 1010 PAGE 9
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`

`

`NDA 21-636
`Page 9
`
`
`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. The table below
`provides the results of this study for maintenance of healing of erosive esophagitis.
`
`
`
`
`Life Table Analysis
`
`
`
`Omeprazole
`Ranitidine
`Omeprazole
`20 mg q.d.
`150 mg b.i.d.
`10 mg q.d.
`(n = 131)
`(n = 128)
` (n = 133)
`
`
`
`Percent in
`endoscopic
`
`
`
`remission at 12
`‡58
`*77
`46
`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.
`
`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.
`
`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 (e.g. heartburn), additional
`4-8 week courses of omeprazole may be considered.
`
`Maintenance of Healing of Erosive Esophagitis
`
`Zegerid Powder for Oral Suspension is indicated to maintain healing of erosive esophagitis.
`
`Controlled studies do not extend beyond 12 months.
`
`CONTRAINDICATIONS
`
`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.
`
`MYLAN PHARMS. INC. EXHIBIT 1010 PAGE 10
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`

`

`NDA 21-636
`Page 10
`
`
`Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with
`omeprazole.
`
`Zegerid contains 460 mg sodium per dose in the form of sodium bicarbonate. This should be taken into
`consideration for patients on a sodium-restricted diet.
`
`Zegerid contains 1680 mg (20 mEq) of sodium bicarbonate. 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, and respiratory alkalosis. Long-term administration of bicarbonate with
`calcium or milk can cause milk-alkali syndrome.
`
`Information for Patients
`Zegerid is supplied as a powder for oral suspension. It should be taken on an empty stomach at least 1 hour
`prior to a meal.
`
`Zegerid is available as 20 mg single-dose packets. Directions for use: Empty packet contents into a small cup
`containing 2 tablespoons of water. DO NOT USE OTHER LIQUIDS OR FOODS. Stir well and drink
`immediately. Refill cup with water and drink.
`
`Drug Interactions
`Other
`
`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 healthy subjects no
`interaction with theophylline or propranolol was found, there have been clinical reports of interaction with other
`drugs metabolized via the cytochrome P-450 system (e.g., 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.
`
`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 (e.g., ketoconazole, ampicillin esters, and iron salts). In the clinical trials, antacids were used
`concomitantly with the administration of omeprazole.
`
`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 (about 0.7 to 57 times the human dose of 20 mg per 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 (about 5.7 times the human
`dose of 20 mg per 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 0.2 to 6.5 times the human dose of 20 mg/day, based on body surface area). No
`
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`NDA 21-636
`Page 11
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`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 57 times the
`human dose of 20 mg per 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 Salmonella typhimurium assay, an in vitro
`mouse lymphoma cell forward mutation assay and an in vivo rat liver DNA damage assay.
`
`Omeprazole at oral doses up to 138.0 mg/kg/day (about 56 times the human dose of 20 mg per day, based on
`body surface area) was found to have no effect on fertility and reproductive performance.
`
`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, e.g., 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).
`
`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. 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 ventricular septal defects and the number of stillborn infants
`was slightly higher in the omeprazole exposed infants than the expected number in the normal population. The
`author concluded that both effects may be random.
`
` A
`
` A
`
` retrospective cohort study reported on 689 pregnant women exposed to either H2-blockers or omeprazole in
`the first trimester (134 exposed to omeprazole). The overall malformation rate was 4.4% (95% CI 3.6-5.3) and
`the malformation rate for first trimester exposure to omeprazole was 3.6% (95% CI 1.5-8.1). The relative risk of
`malformations associated with first trimester exposure to omeprazole compared with nonexposed women was
`0.9 (95% CI 0.3-2.2). The study could effectively rule out a relative risk greater than 2.5 for all malformations.
`Rates of preterm delivery or growth retardation did not differ between the groups.
`
` controlled prospective observat