PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 53041-664-77

Omeprazole and Sodium Bicarbonate Capsules
20 mg/1100 mg

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

Rx only
30 capsules
Guardian

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in labeling:

• Acute Tubulointerstitial Nephritis [ see Warnings and Precautions (5.2) ]
• Clostridium difficile-Associated Diarrhea [ see Warnings and Precautions (5.4) ]
• Bone Fracture [see Warnings and Precautions (5.5) ]
• Severe Cutaneous Adverse Reactions[seeWarnings and Precautions (5.6)]
• Cutaneous and Systemic Lupus Erythematosus [ see Warnings and Precautions (5.7) ]
• Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.9) ]
• Hypomagnesemia and Mineral Metabolism [ seeWarnings and Precautions (5.10)]
• Fundic Gland Polyps [ see Warnings and Precautions (5.14) ]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Omeprazole and Sodium Bicarbonate capsules has been established, in part, based on oral studies of an oral delayed-release omeprazole product.

Clinical Trials with Omeprazole

In the U.S. clinical trial population of 465 adult patients, the adverse reactions summarized inTable 3were reported to occur in 1% or more of patients on therapy with omeprazole. Numbers in parentheses indicate percentages of the adverse reactions considered by investigators as possibly, probably or definitely related to the drug.

Table 3: Adverse Reactions Occurring in 1% or More of Adult Patients in US Clinical Trials of Omeprazole Therapy

	** Omeprazole** ** %** (n = 465)	Placebo ** %** (n = 64)	Ranitidine ** %** (n = 195)
Headache	7	6	8
Diarrhea	3	3	2
Abdominal Pain	2	3	3
Nausea	2	3	4
Upper Respiratory Infection URI	2	2	3
Dizziness	2	0	3
Vomiting	2	5	2
Rash	2	0	0
Constipation	1	0	0
Cough	1	0	2
Asthenia	1	2	2
Back Pain	1	0	1

Table 4summarizes the adverse reactions that occurred in 1% or more of omeprazole-treated patients from international double-blind and open-label clinical trials in which 2,631 patients and subjects received omeprazole.

Table 4: Adverse Reactions Occurring in 1% or More of Adult Patients in International Clinical Trials of Omeprazole Therapy

	Omeprazole % (N = 2631)	Placebo % (N = 120)
Abdominal Pain	5.2	3.3
Nausea	4.0	6.7
Diarrhea	3.7	2.5
Vomiting	3.2	10.0
Headache	2.9	2.5
Flatulence	2.7	5.8
Acid Regurgitation	1.9	3.3
Constipation	1.5	0.8
Asthenia	1.3	0.8

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of omeprazole and sodium bicarbonate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Omeprazole

Body as a Whole: Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema,bronchospasm, urticaria (see also Skin below), fever, pain, fatigue, malaise, and systemic lupus erythematosus.

Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitation, elevated blood pressure, and peripheral edema.

Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, flatulence, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, dry mouth, stomatitis, abdominal swelling and fundic gland polyps. Gastroduodenal carcinoids have been reported in patients with Zollinger- Ellison syndrome on long-term treatment with omeprazole. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors.

Hepatic: Mild and, rarely, marked elevations of liver function tests [ALT (SGPT), AST (SGOT), γ- glutamyl transpeptidase, alkaline phosphatase, and bilirubin (jaundice)]. In rare instances, overt liver disease has occurred, including hepatocellular, cholestatic, or mixed hepatitis, liver necrosis (some fatal), hepatic failure (some fatal), and hepatic encephalopathy.

Infections and Infestations: Clostridium difficile-associated diarrhea.

Metabolism and Nutritional Disorders: Hypomagnesemia, hypocalcemia, hypokalemia [see Warnings and Precautions (5.10)], hyponatremia,

hypoglycemia, and weight gain.

Musculoskeletal: Muscle cramps, myalgia, muscle weakness, joint pain, bone fracture, and leg pain.

Nervous System/Psychiatric: Psychic disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, tremors, apathy, somnolence, anxiety, dream abnormalities; vertigo; paresthesia; and hemifacial dysesthesia.

Respiratory: Epistaxis, pharyngeal pain.

Skin: Severe generalized skin reactions including TEN (some fatal), SJS, DRESS, AGEP, cutaneous lupus erythematosus and erythema multiforme (some severe); purpura and/or petechiae (some with rechallenge); skin inflammation, urticaria, angioedema, pruritus, photosensitivity, alopecia, dry skin, and hyperhidrosis.

Special Senses: Tinnitus, taste perversion.

Ocular: Blurred vision, ocular irritation, dry eye syndrome, optic atrophy, anterior ischemic optic neuropathy, optic neuritis, and double vision.

Urogenital: Tubulointerstitial nephritis, urinary tract infection, microscopic pyuria, urinary frequency, elevated serum creatinine, proteinuria, hematuria, glycosuria, testicular pain, and gynecomastia.
Hematologic: Rare instances of pancytopenia, agranulocytosis (some fatal), thrombocytopenia, neutropenia, leukopenia, anemia, leukocytosis, and hemolytic anemia have been reported.

The incidence of clinical adverse experiences in patients greater than 65 years of age was similar to that in patients 65 years of age or less.

Additional adverse reactions that could be caused by sodium bicarbonate include metabolic alkalosis, seizures, and tetany.

Sodium Bicarbonate

Metabolic alkalosis, seizures, and tetany.

7 DRUG INTERACTIONS

Tables 6and7 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with omeprazole and instructions for preventing or managing them.

Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs.

Table 6: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics

Antiretrovirals

Clinical Impact:

The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)] . Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)] . There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.

Intervention:	Rilpivirine-containing products: Concomitant use with Omeprazole and Sodium Bicarbonate capsules are contraindicated**[see Contraindications (4)].** Atazanavir: Avoid concomitant use with Omeprazole and Sodium Bicarbonate capsules. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with Omeprazole and Sodium Bicarbonate capsules. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir- related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.

Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted.[see Warnings and Precautions (5.12)].
Intervention:	A temporary withdrawal of Omeprazole and Sodium Bicarbonate capsules may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel

Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with Omeprazole and Sodium Bicarbonate capsules. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.7)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation**[seeClinical Pharmacology (12.3)] .**
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol)[see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam**[see Clinical Pharmacology (12.3)] .**
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin**[ see Clinical Pharmacology (12.3)].**
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving Omeprazole and Sodium Bicarbonate capsules and MMF. Use Omeprazole and Sodium Bicarbonate capsules with caution in transplant patients receiving MMF**[seeClinical Pharmacology (12.3)] .** See the prescribing information for other drugs dependent on gastric pH for absorption.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [**see Warnings and Precautions(5.11) ,**Clinical Pharmacology (12.2) ].

Intervention:	Temporarily stop PRILOSEC treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop Omeprazole and Sodium Bicarbonate capsules treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology ( 12.2 ) ].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receivingPPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with Omeprazole and Sodium Bicarbonate capsules.

Table 7: Clinically Relevant Interactions Affecting Omeprazole When Co- Administered with Other Drugs

CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12.3 )].
Intervention:	St. John’s wort, rifampin: Avoid concomitant use with Omeprazole and Sodium Bicarbonate capsules [see Warnings and Precautions ( 5.10 )]. Ritonavir-containing products: See prescribing information for specificdrugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology ( 12.3 ].
Intervention:	Voriconazole: Dosage adjustment of Omeprazole and Sodium Bicarbonate capsules is not required.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies with Omeprazole and Sodium Bicarbonate capsules in pregnant women. Omeprazole and Sodium Bicarbonate capsules contains omeprazole and sodium bicarbonate.

Omeprazole

There are no adequate and well-controlled studies with omeprazole in pregnant women. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use. Reproduction studies in rats and rabbits resulted in dose-dependent embryo-lethality at omeprazole doses that were approximately 3.4 to 34 times an oral human dose of 40 mg (based on a body surface area for a 60 kg person). Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole (an enantiomer of omeprazole) magnesium in rats and rabbits during organogenesis with doses about 68 times and 42 times, respectively, an oral human dose of 40 mg esomeprazole or 40 mg omeprazole (based on bodysurface area for a 60 kg person). Changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age (see Data).

Sodium Bicarbonate

Available data with sodium bicarbonate use in pregnant women are insufficient to identify a drug associated risk of major birth defects or miscarriage. Published animal studies report that sodium bicarbonate administered to rats, mice or rabbits during pregnancy did not cause adverse developmental effects in offspring.
The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data
Human Data

There are no adequate and well-controlled studies with Omeprazole and Sodium Bicarbonate capsules in pregnant women. Four published epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H2-receptor antagonists or other controls.

A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Register, covering approximately 99% of pregnancies, from 1995-99, 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. The number of infants exposed in utero

to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population. 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 this population.

A population-based retrospective cohort study covering all live births in Denmark from 1996-2009 reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837,317 live births whose mothers did not use any PPI. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any PPI during the first trimester.

A retrospective cohort study reported on 689 pregnant women exposed to either H2-blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H2-blocker, or were unexposed was 3.6%, 5.5%, and 4.1%, respectively.

A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease-paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups.

Several studies have reported no apparent adverse short-term effects on the infant when single-dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia

Animal Data
Omeprazole

Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at doses up to 69.1 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) during organogenesis did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis) administered during organogenesis produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis), administered prior to mating through the lactationperiod.

Esomeprazole

The data described below was generated from studies using esomeprazole, an enantiomer of omeprazole. The animal to human dose multiples are based on the assumption of equal systemic exposure to esomeprazole in humans following oral administration of either 40 mg esomeprazole or 40 mg omeprazole.

No effects on embryo-fetal development were observed in reproduction studies with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg of esomeprazole or 40 mg omeprazole on a body surface area basis) administered during organogenesis.

A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development were performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg of esomeprazole or 40 mg omeprazole on a body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal toor greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg/kg/day (about 17 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses of esomeprazole magnesium equal to or greater than 14 mg/kg/day (about 3.4 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis).

Effects on maternal bone were observed in pregnant and lactating rats in a pre- and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). When rats were dosed from gestational Day 7 through weaning on postnatal Day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses of esomeprazole magnesium equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis).

A pre- and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above.

A follow-up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day 2 to adulthood was performed with esomeprazole magnesium at oral doses of 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) where esomeprazole administration was from either gestational Day 7 or gestational Day 16 until parturition. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age.

8.2 Lactation

Risk Summary

Available data from the published literature suggest both components of Omeprazole and Sodium Bicarbonate capsules, omeprazole and sodium bicarbonate, are present in human milk. There are no clinical data on the effects of omeprazole or sodium bicarbonate on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Omeprazole and Sodium Bicarbonate capsules and any potential adverse effects on the breastfed infant from Omeprazole and Sodium Bicarbonate capsules or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of Omeprazole and Sodium Bicarbonate capsules have not been established in pediatric patients.

Juvenile Animal Data

Esomeprazole, an enantiomer of omeprazole, was shown to decrease body weight, body weight gain, femur weight, femur length, and overall growth at oral doses about 34 to 68 times a daily human dose of 40 mg esomeprazole or 40 mg omeprazolebased on body surface area in a juvenile rat toxicity study. The animal to human dose multiples are based on the assumption of equal systemic exposure to esomeprazole in humans following oral administration of either 40 mg esomeprazole or 40 mg omeprazole.

A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg/kg/day (about 17 to 68 times a daily oral human dose of 40 mg esomeprazole or 40 mg omeprazoleon a body surface area basis). An increase in the number of deaths at the high dose of 280 mg/kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole.

8.5 Geriatric Use

Omeprazole was administered to over 2,000 elderly individuals (≥65 years of age) in clinical trials in the U.S. and Europe. There were no differences in safety and effectiveness between the elderly and younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Pharmacokinetic studies with buffered omeprazole have shown the elimination rate was somewhat decreased in the elderly and bioavailability was increased. The plasma clearance of omeprazole was 250 mL/min (about half that of young subjects). The plasma half-life averaged one hour, about twice that in nonelderly, healthy subjects taking Omeprazole and Sodium Bicarbonate capsules. However, no dosage adjustment is necessary in the elderly.

[see Clinical Pharmacology (12.3)]

8.6 Hepatic Impairment

In patients with hepatic impairment (Child-Pugh Class A, B, or C) exposure to omeprazole substantially increased compared to healthy subjects. Avoid use of Omeprazole and Sodium Bicarbonate capsules in patients with hepatic impairment for maintenance of healing of erosive esophagitis [see Clinical Pharmacology (12.3) ].

8.7 Asian Population

In studies of healthy subjects, Asians had approximately a four-fold higher exposure than Caucasians. Avoid use of Omeprazole and Sodium Bicarbonate capsules in Asian patients for maintenance of healing of erosive esophagitis.[ see Clinical Pharmacology (12.5) ].

14 CLINICAL STUDIES

The effectiveness of Omeprazole and Sodium Bicarbonate capsules has been established, in part, based on studies of an oral delayed- release omeprazole product for the treatment of active duodenal ulcer, active benign gastric ulcer, symptomatic GERD, EE due to acid-mediated GERD, and maintenance of healing of EE due to acid- mediated GERD [seeClinical Studies ( 14.1 ,14.2, 14.3, 14.4 , 14.5 )]

14.1 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 delayed-release capsules 20 mg once a day than with placebo (p ≤ 0.01). (See Table 11)

Table 11: Treatment of Active Duodenal Ulcer

** % of Patient Healed**
	Omeprazole 20 mg a.m. (n = 99)	Placebo a.m. (n = 48)
Week 2	411	13
Week 4	751	27

1.(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 twice daily (p < 0.01). (SeeTable 12)

Table 12: Treatment of Active Ulcer % of Patients Healed

	Omeprazole 20 mg a.m. (n = 145)	Ranitidine 150 mg twice daily (n = 148)
Week 2	42	34
Week 4	821	63

1.(p < 0.01)

Healing occurred significantly faster in patients treated with omeprazole than in those treated with ranitidine 150 mg twice daily (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 twice daily 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 13)

** Table 13: Treatment of Active Duodenal Ulcer % of Patients Healed**

	Omeprazole	Ranitidine 150 mg twice daily (n = 35)
	** 40 mg** (n = 36)	20 mg (n = 34)
Week 2	831	831	53
Week 4	1001	971	82
Week 8	100	100	94

1.(p < 0.01)

14.2 Active Benign 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. (SeeTable 14.)

Table 14: Treatment of Gastric Ulcer % of Patients Healed (All Patients Treated)

	** Omeprazole** 40 mg once daily (n = 214)	Omeprazole 20 mg once daily (n = 202)	Placebo (n = 104)
Week 4	55.61	47.51	30.8
Week 8	82.71,2	74.81	48.1

1.(p < 0.01) Omeprazole 40 mg or 20 mg versus placebo
2.(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. (SeeTable 15)

Table 15: Treatment of Gastric Ulcer % of Patients Healed (All Patients Treated)

	** Omeprazole** 40 mg once daily (n = 187)	Omeprazole 20 mg once daily (n = 200)	Ranitidine ** 150 mg twice daily** (n = 199)
Week 4	78.11,2	63.5	56.3
Week 8	91.41,2	81.5	78.4

1.(p < 0.01) Omeprazole 40 mg versus ranitidine
2.(p < 0.01) Omeprazole 40 mg versus 20 mg

14.3 Symptomatic 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 inTable 16.

---

Table 16: % Successful Symptomatic Outcome****1

	** Omeprazole** 20 mg a.m.	Omeprazole 10 mg a.m.	Placebo a.m.
All Patients	462,3 (n = 205)	313 (n = 199)	13 (n = 105)
Patients with Confirmed GERD	562,3 (n = 115)	363 (n = 109)	14 (n = 59)

1. Defined as complete resolution of heartburn
2. (p < 0.005) versus 10 mg
3. (p < 0.005) versus placebo

14.4 EE Due to Acid-Mediated GERD

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 inTable 17.

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** Table 17: % Patients Healed**

	** Omeprazole** 40 mg (n = 87)	Omeprazole 20 mg (n = 83)	Placebo (n = 43)
Week 4	451	391	7
Week 8	751	741	14

1. (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%).

14.5 Maintenance of Healing of EE Due to Acid-Mediated GERD

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 inTable 18.

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****Table 18: Life Table Analysis

	** Omeprazole** 20 mg once daily (n = 138)	Omeprazole 20 mg 3 days per week (n = 137)	Placebo (n = 131)
Percent in Endoscopic Remission at 6 Months	701	34	11

1. (p < 0.01) omeprazole 20 mg once daily 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 19 provides the results of this study for maintenance of healing of EE.

Table 19: Life Table Analysis

	** Omeprazole** 20 mg once daily (n = 131)	Omeprazole 10 mg once daily (n = 133)	Ranitidine 150 mg twice daily (n = 128)
Percent in Endoscopic Remission at 12 Months	771	582	46

1. (p = 0.01) omeprazole 20 mg once daily versus omeprazole 10 mg once daily or Ranitidine.

2.(p = 0.03) omeprazole 10 mg once daily 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