OMEPRAZOLE - omeprazole capsule, delayed release

United States - English - NLM (National Library of Medicine)

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Active ingredient:
OMEPRAZOLE (UNII: KG60484QX9) (OMEPRAZOLE - UNII:KG60484QX9)
Available from:
STAT Rx USA LLC
INN (International Name):
OMEPRAZOLE
Composition:
OMEPRAZOLE 40 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Omeprazole delayed-release capsules are indicated for short-term treatment of active duodenal ulcer in adults. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy. Omeprazole delayed-release capsules in combination with clarithromycin and amoxicillin, is indicated for treatment of patients with H. pylori infection and duodenal ulcer disease (active or up to 1-year history) to eradicate H. pylori in adults. Omeprazole delayed-release capsules, in combination with clarithromycin is indicated for treatment of patients with H. pylori infection and duodenal ulcer disease to eradicate H. pylori in adults. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence [see Clinical Studies (14.1) and Dosage and Administration (2) ]. Among patients who fail therapy, Omeprazole delayed-release capsules with clarithromycin is more likely to be associated with the development of clarithromycin resistance as compared with triple therapy. In pa
Product summary:
Omeprazole delayed-release capsules, USP 40 mg are off-white to pale yellow, elliptical to spherical pellets filled in size ‘Oel’ hard gelatin capsules with opaque yellow colored cap and opaque lavender colored body, imprinted on cap ‘OMEPRAZOLE’  40 mg and body ‘R159’ with black ink. The capsules are supplied in bottles of 30, 60 and 90.                                                                                       Bottles of 30                                                                  NDC 42549-658-30 Bottles of 60                                                                  NDC 42549-658-60 Bottles of 90                                                                  NDC 42549-658-90 Storage         Store  delayed-release capsules in a tight container protected from light and moisture. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Relabeling and Repackaging by: STAT Rx USA LLC Gainesville, GA.  30501
Authorization status:
Abbreviated New Drug Application
Authorization number:
42549-658-30, 42549-658-60, 42549-658-90

OMEPRAZOLE - omeprazole capsule, delayed release

STAT Rx USA LLC

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HIGHLIGHTS OF PRESCRIBING INFORMATION

Omeprazole Delayed-Release Capsules

These highlights do not include all the information needed to use.

See full prescribing information for.

Initial U.S. Approval:

RECENT MAJOR CHANGES

Indications and Usage, Treatment of Gastroesophageal Reflux Disease (1.3) 03/2008

Dosage and Administration, Pediatric Patients (2.7) 03/2008

INDICATIONS AND USAGE

Omeprazole is a proton pump inhibitor indicated for: (1)

Treatment of duodenal ulcer in adults (1.1) (1)

Treatment of gastric ulcer in adults (1.2) (1)

Treatment of gastroesophageal reflux disease (GERD) in pediatric patients and adults (1.3) (1)

Maintenance of healing of erosive esophagitis in pediatric patients and adults (1.4) (1)

Treatment of pathological hypersecretory conditions in adults (1.5) (1)

The safety and effectiveness of omeprazole in pediatric patients < 1 year of age have not been established. (8.4) (1)

DOSAGE AND ADMINISTRATION

Indication (2)

Omeprazole Dose (2)

Frequency (2)

Short-Term Treatment of Active

Duodenal Ulcer (2.1) (2)

20 mg (2)

Once daily for 4 weeks. Some patients may require

an additional 4 weeks (2)

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence (2.2) (2)

Triple Therapy: (2)

Omeprazole (2)

20 mg (2)

Each drug twice daily for 10 days (2)

Amoxicillin (2)

1000 mg (2)

Clarithromycin (2)

500 mg (2)

Dual Therapy: (2)

Omeprazole (2)

40 mg (2)

Once daily for 14 days (2)

Clarithromycin (2)

500 mg (2)

Three times daily for 14 days (2)

Gastric Ulcer (2.3) (2)

40 mg (2)

Once daily for 4 to 8 weeks (2)

GERD (2.4) (2)

20 mg (2)

Once daily for 4 to 8 weeks (2)

Maintenance of Healing of Erosive

Esophagitis (2.5) (2)

20 mg (2)

Once daily (2)

Pathological Hypersecretory

Conditions (2.6) (2)

60 mg (varies with

individual patient) (2)

Once daily (2)

Pediatric Patients (2 to 16 years of

age) (2.7) (2)

GERD (2)

Weight (2)

10 < 20 kg (2)

> 20 kg (2)

Dose (2)

10 mg (2)

20 mg (2)

Once daily (2)

And Maintenance of Healing of

Erosive Esophagitis (2)

CONTRAINDICATIONS

Known hypersensitivity to any component of the formulation (4) (4)

WARNINGS AND PRECAUTIONS

Concomitant Gastric Malignancy: Symptomatic response to therapy with omeprazole does not preclude the presence

of gastric malignancy (5.1) (5)

Atrophic Gastritis: Has been observed in gastric corpus biopsies from patients treated long-term with omeprazole (5.2)

Combination Use with Clarithromycin and/or Amoxicillin: Refer to full prescribing information for individual drugs when

used in combination (5.3, 5.4) (5)

ADVERSE REACTIONS

Adults: Most common adverse reactions (incidence >2%) are: (6)

headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence. (6) (6)

Pediatric patients (2 - 16 years of age): (6)

Safety profile similar to that in adults, except that respiratory system events and fever were the most frequently reported

reactions in pediatric studies. (8.4) (6)

To report suspected adverse reactions (6)

1-800-FDA-1088 (6)

DRUG INTERACTIONS

Drugs for which gastric pH can affect bioavailability (e.g., ketoconazole, ampicillin esters, iron salts): omeprazole may

interfere with absorption due to inhibition of gastric acid secretion (7) (7)

Drugs metabolized by cytochrome P450 (e.g., diazepam, warfarin, phenytoin, cyclosporine, disulfiram,

benzodiazepines): omeprazole can prolong their elimination. Monitor to determine need for possible dose adjustments

when taken with omeprazole (7) (7)

Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR

and prothrombin time (7) (7)

Voriconazole: May increase plasma levels of omeprazole (7) (7)

Atazanavir: Omeprazole may reduce plasma levels of atazanavir (7) (7)

Nelfinavir: Omeprazole may reduce plasma levels of nelfinavir (7)

Tacrolimus: Omeprazole may increase serum levels of tacrolimus (7) (7)

Saquinavir: Omeprazole may increase plasma levels of saquinavir (7)

USE IN SPECIFIC POPULATIONS

Hepatic Impairment: (8)

Consider dose reduction, particularly for maintenance of healing of erosive esophagitis (12.3) (8)

Asian Patients: (8)

Consider dose reduction, particularly for maintenance of healing of erosive esophagitis (12.3) (8)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 2/2012

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Duodenal Ulcer (adults)

1.2 Gastric Ulcer (adults)

1.3 Treatment of Gastroesophageal Reflux Disease (GERD) (adults and pediatric patients)

1.4 Maintenance of Healing of Erosive Esophagitis (adults and pediatric patients)

1.5 Pathological Hypersecretory Conditions (adults)

2 DOSAGE AND ADMINISTRATION

2.1 Short-Term Treatment of Active Duodenal Ulcer

2.2 H. pylori Eradication for the Reduction of the Risk of Duodenal Ulcer Recurrence

2.3 Gastric Ulcer

2.4 Gastroesophageal Reflux Disease (GERD)

2.5 Maintenance of Healing of Erosive Esophagitis

2.6 Pathological Hypersecretory Conditions

2.7 Pediatric Patients

2.8 Alternative Administration Options

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5. WARNINGS AND PRECAUTIONS

5.1 Concomitant Gastric Malignancy

5.2 Atrophic Gastritis

5.3 Combiniation Use of Omeprazole with Amoxicillin

5.4 Combination Use of Omeprazole with Clarithromycin

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience with Omeprazole Monotherapy

6.2 Clinical Trials Experience with Omeprazole in Combination Therapy for H. pylori Eradication

6.3 Post-marketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

8.8 Asian Population

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Microbiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2. Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Duodenal Ulcer Disease

14.2 Gastric Ulcer

14.3 Gastroesophageal Reflux Disease (GERD)

14.4 Erosive Esophagitis

14.5 Pathological Hypersecretory Conditions

14.6 Pediatric GERD

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

1.1 Duodenal Ulcer (adults)

Omeprazole delayed-release capsules are indicated for short-term treatment of active duodenal ulcer in

adults. Most patients heal within four weeks. Some patients may require an additional four weeks of

therapy.

Omeprazole delayed-release capsules in combination with clarithromycin and amoxicillin, is indicated

for treatment of patients with H. pylori infection and duodenal ulcer disease (active or up to 1-year

history) to eradicate H. pylori in adults.

Omeprazole delayed-release capsules, in combination with clarithromycin is indicated for treatment of

patients with H. pylori infection and duodenal ulcer disease to eradicate H. pylori in adults.

Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence [see Clinical

Studies (14.1) and Dosage and Administration (2) ].

Among patients who fail therapy, Omeprazole delayed-release capsules with clarithromycin is more

likely to be associated with the development of clarithromycin resistance as compared with triple

therapy. In patients who fail therapy, susceptibility testing should be done. If resistance to

clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy

should be instituted. [See Microbiology section (12.4)], and the clarithromycin package insert,

Microbiology section.)

1.2 Gastric Ulcer (adults)

Omeprazole delayed-release capsules are indicated for short-term treatment (4-8 weeks) of active

benign gastric ulcer in adults. [See Clinical Studies (14.2) ]

1.3 Treatment of Gastroesophageal Reflux Disease (GERD) (adults and pediatric patients)

Symptomatic GERD

Omeprazole delayed-release capsules are indicated for the treatment of heartburn and other symptoms

associated with GERD in pediatric patients and adults.

Erosive Esophagitis

Omeprazole delayed-release capsules are indicated for the short-term treatment (4-8 weeks) of erosive

esophagitis that has been diagnosed by endoscopy in pediatric patients and adults. [See Clinical Studies

(14.4) ]

The efficacy of Omeprazole delayed-release capsules used for longer than 8 weeks in these patients

has not been established. If a patient does not respond to 8 weeks of treatment, an additional 4 weeks of

treatment may be given. If there is recurrence of erosive esophagitis or GERD symptoms (e.g.,

heartburn), additional 4-8 week courses of omeprazole may be considered.

1.4 Maintenance of Healing of Erosive Esophagitis (adults and pediatric patients)

Omeprazole delayed-release capsules are indicated to maintain healing of erosive esophagitis in

pediatric patients and adults.

Controlled studies do not extend beyond 12 months. [See Clinical Studies (14.4) ]

1.5 Pathological Hypersecretory Conditions (adults)

Omeprazole delayed-release capsules are indicated for the long-term treatment of pathological

hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine adenomas and systemic

mastocytosis) in adults.

2 DOSAGE AND ADMINISTRATION

Omeprazole delayed-release capsules should be taken before eating. In the clinical trials, antacids were

used concomitantly with omeprazole.

Patients should be informed that the omeprazole delayed-release capsule should be swallowed whole.

For patients unable to swallow an intact capsule, alternative administration options are available. [See

Dosage and Administration (2.8)]

2.1 Short-Term Treatment of Active Duodenal Ulcer

The recommended adult oral dose of Omeprazole delayed-release capsules is 20 mg once daily. Most

patients heal within four weeks. Some patients may require an additional four weeks of therapy.

2.2 H. pylori Eradication for the Reduction of the Risk of Duodenal Ulcer Recurrence

Triple Therapy (omeprazole/clarithromycin/amoxicillin) — The recommended adult oral regimen is

omeprazole delayed-release capsules 20 mg plus clarithromycin 500 mg plus amoxicillin 1000 mg

each given twice daily for 10 days. In patients with an ulcer present at the time of initiation of therapy,

an additional 18 days of omeprazole delayed-release capsules 20 mg once daily is recommended for

ulcer healing and symptom relief.

Dual Therapy (omeprazole/clarithromycin) — The recommended adult oral regimen is omeprazole

delayed-release capsuels 40 mg once daily plus clarithromycin 500 mg three times daily for 14 days. In

patients with an ulcer present at the time of initiation of therapy, an additional 14 days ofomeprazole

delayed-release capsules 20 mg once daily is recommended for ulcer healing and symptom relief.

2.3 Gastric Ulcer

The recommended adult oral dose is 40 mg once daily for 4-8 weeks.

2.4 Gastroesophageal Reflux Disease (GERD)

The recommended adult oral dose for the treatment of patients with symptomatic GERD and no

esophageal lesions is 20 mg daily for up to 4 weeks. The recommended adult oral dose for the

treatment of patients with erosive esophagitis and accompanying symptoms due to GERD is 20 mg daily

for 4 to 8 weeks.

2.5 Maintenance of Healing of Erosive Esophagitis

The recommended adult oral dose is 20 mg daily. [See Clinical Studies (14.4) ]

2.6 Pathological Hypersecretory Conditions

The dosage of omeprazole delayed-release capsules in patients with pathological hypersecretory

conditions varies with the individual patient. The recommended adult oral starting dose is 60 mg once

daily. Doses should be adjusted to individual patient needs and should continue for as long as clinically

indicated. Doses up to 120 mg three times daily have been administered. Daily dosages of greater than

80 mg should be administered in divided doses. Some patients with Zollinger-Ellison syndrome have

been treated continuously with omeprazole delayed-release capsules for more than 5 years.

2.7 Pediatric Patients

For the treatment of GERD and maintenance of healing of erosive esophagitis, the recommended daily

dose for pediatric patients 2 to 16 years of age is as follows:

Patient WeightOmeprazole Daily Dose

10 < 20 kg

10 mg

≥ 20 kg

20 mg

On a per kg basis, the doses of omeprazole required to heal erosive esophagitis in pediatric patients are

greater than those for adults.

Alternative administrative options can be used for pediatric patients unable to swallow an intact capsule

[See Dosage and Administration (2.8) ].

2.8 Alternative Administration Options

Omeprazole is available as a delayed-release capsule.

For patients who have difficulty swallowing capsules, the contents of an omeprazole delayed-release

capsules can be added to applesauce. One tablespoon of applesauce should be added to an empty bowl

and the capsule should be opened. All of the pellets inside the capsule should be carefully emptied on

the applesauce. The pellets should be mixed with the applesauce and then swallowed immediately with

a glass of cool water to ensure complete swallowing of the pellets. The applesauce used should not be

hot and should be soft enough to be swallowed without chewing. The pellets should not be chewed or

crushed. The pellets/applesauce mixture should not be stored for future use.

3 DOSAGE FORMS AND STRENGTHS

Omeprazole delayed-release capsules, USP 10 mg are off-white to pale yellow, elliptical to spherical

pellets filled in size '3' hard gelatin capsules with opaque lavender colored cap and opaque yellow

colored body, imprinted on cap 'OMEPRAZOLE' 10 mg and on body 'R157' with black ink.

Omeprazole delayed-release capsules, USP 20 mg are off-white to pale yellow, elliptical to spherical

pellets filled in size '2' hard gelatin capsules with opaque lavender colored cap and opaque iron grey

colored body, imprinted on cap 'OMEPRAZOLE' 20 mg and on body 'R158' with black ink.

Omeprazole delayed-release capsules, USP 40 mg are off-white to pale yellow, elliptical to spherical

pellets filled in size 'Oel' hard gelatin capsules with opaque yellow colored cap and opaque lavender

colored body, imprinted on cap 'OMEPRAZOLE' 40 mg and on body 'R159' with black ink.

4 CONTRAINDICATIONS

Omeprazole delayed-release capsules are contraindicated in patients with known hypersensitivity to any

component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock,

angioedema, bronchospasm, interstitial nephritis, and urticaria [see Adverse Reactions (6)].

5. WARNINGS AND PRECAUTIONS

5.1 Concomitant Gastric Malignancy

Symptomatic response to therapy with omeprazole does not preclude the presence of gastric

malignancy.

5.2 Atrophic Gastritis

Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-

term with omeprazole.

5.3 Combiniation Use of Omeprazole with Amoxicillin

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients

on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin

hypersensitivity and/or a history of sensitivity to multiple allergens. Before initiating therapy with

amoxicillin, careful inquiry should be made concerning previous hypersensitivity reactions to

penicillins, cephalosporins or other allergens. If an allergic reaction occurs, amoxicillin should be

discontinued and appropriate therapy instituted. Serious anaphylactic reactions require immediate

emergency treatment with epinephrine. Oxygen, intravenous steroids and airway management, including

intubation, should also be administered as indicated.

Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range in

severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients

who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of

clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-

associated colitis.”

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be

initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone.

In moderate to severe cases, consideration should be given to management with fluids and electrolytes,

protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium

difficile colitis.

5.4 Combination Use of Omeprazole with Clarithromycin

Clarithromycin should not be used in pregnant women except in clinical circumstances where no

alternative therapy is appropriate. If pregnancy occurs while taking clarithromycin, the patient should be

apprised of the potential hazard to the fetus. (See Warnings in prescribing information for

clarithromycin.)

Co-administration of omeprazole and clarithromycin has resulted in increases in plasma levels of

omeprazole, clarithromycin, and 14-hydroxy-clarithromycin. [See Clinical Pharmacology (12) ]

Concomitant administration of clarithromycin with cisapride or pimozide, is contraindicated.

6 ADVERSE REACTIONS

To report suspected adverse reactions

1-800-FDA-1088

6.1 Clinical Trials Experience with Omeprazole Monotherapy

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 data described below reflects exposure to omeprazole delayed-release capsules in 3096

patients from worldwide clinical trials (465 patients from US studies and 2,631 patients from

international studies). Indications clinically studied in US trials included duodenal ulcer, resistant ulcer,

and Zollinger-Ellison syndrome. The international clinical trials were double blind and open-label in

design. The most common adverse reactions reported (i.e., with an incidence rate ≥ 2%) from

omeprazole delayed-release capsules-treated patients enrolled in these studies included headache

(6.9%), abdominal pain (5.2%), nausea (4.0%), diarrhea (3.7%), vomiting (3.2%), and flatulence (2.7%).

Additional adverse reactions that were reported with an incidence ≥1% included acid regurgitation

(1.9%), upper respiratory infection (1.9%), constipation (1.5%), dizziness (1.5%), rash (1.5%), asthenia

(1.3%), back pain (1.1%), and cough (1.1%).

The clinical trial safety profile in patients greater than 65 years of age was similar to that in patients 65

years of age or less.

The clinical trial safety profile in pediatric patients who received omeprazole delayed-release capsules

was similar to that in adult patients. Unique to the pediatric population, however, adverse reactions of

the respiratory system were most frequently reported in the 2 to 16 year age group (18.5%). Similarly,

accidental injuries were reported frequently in the 2 to 16 year age group (3.8%).[See Use in Specific

Populations (8.4)]

6.2 Clinical Trials Experience with Omeprazole in Combination Therapy for H. pylori Eradication

In clinical trials using either dual therapy with omeprazole and clarithromycin, or triple therapy with

omeprazole, clarithromycin, and amoxicillin, no adverse reactions unique to these drug combinations

were observed. Adverse reactions observed were limited to those previously reported with

omeprazole, clarithromycin, or amoxicillin alone.

Dual Therapy (omeprazole/clarithromycin)

Adverse reactions observed in controlled clinical trials using combination therapy with omeprazole and

clarithromycin (n = 346) that differed from those previously described for omeprazole alone were taste

perversion (15%), tongue discoloration (2%), rhinitis (2%), pharyngitis (1%) and flu-syndrome (1%).

(For more information on clarithromycin, refer to the clarithromycin prescribing information, Adverse

Reactions section).

Triple Therapy (omeprazole/clarithromycin/amoxicillin)

The most frequent adverse reactions observed in clinical trials using combination therapy with

omeprazole, clarithromycin, and amoxicillin (n = 274) were diarrhea (14%), taste perversion (10%), and

headache (7%). None of these occurred at a higher frequency than that reported by patients taking

antimicrobial agents alone. (For more information on clarithromycin or amoxicillin, refer to the

respective prescribing information, Adverse Reactions sections).

6.3 Post-marketing Experience

The following adverse reactions have been identified during post-approval use of omeprazole delayed-

release capsules. Because these reactions are voluntarily reported from a population of uncertain size,

it is not always possible to reliably estimate their actual frequency or establish a causal relationship to

drug exposure.

Body As a Whole: Hypersensitivity reactions including anaphylaxis, anaphylactic shock, angioedema,

bronchospasm, interstitial nephritis, urticaria, (see also Skin below); fever; pain; fatigue; malaise;

Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitations, elevated blood pressure,

peripheral edema

Endocrine: Gynecomastia

Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, fecal discoloration, esophageal

candidiasis, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth. During treatment

with omeprazole, gastric fundic gland polyps have been noted rarely. These polyps are benign and

appear to be reversible when treatment is discontinued. Gastroduodenal carcinoids have been reported

in patients with ZE 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: Liver disease including hepatic failure (some fatal), liver necrosis (some fatal), hepatic

encephalopathy hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice, and elevations of

liver function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin]

Metabolic/Nutritional: Hypoglycemia, hyponatremia, weight gain

Musculoskeletal: Muscle weakness, myalgia, muscle cramps, joint pain, leg pain

Nervous System/Psychiatric: Psychiatric and sleep disturbances including depression, agitation,

aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, and dream

abnormalities; tremors, paresthesia; vertigo

Respiratory: Epistaxis, pharyngeal pain

Skin: Severe generalized skin reactions including toxic epidermal necrolysis (some fatal), Stevens-

Johnson syndrome, and erythema multiforme; photosensitivity; urticaria; rash; skin inflammation;

pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis

Special Senses: Tinnitus, taste perversion

Ocular: Optic atrophy, anterior ischemic optic neuropathy, optic neuritis, dry eye syndrome, ocular

irritation, blurred vision, double vision

Urogenital: Interstitial nephritis, hematuria, proteinuria, elevated serum creatinine, microscopic pyuria,

urinary tract infection, glycosuria, urinary frequency, testicular pain

Hematologic: Agranulocytosis (some fatal), hemolytic anemia, pancytopenia, neutropenia, anemia,

thrombocytopenia, leukopenia, leucocytosis

7 DRUG INTERACTIONS

Drugs for which gastric pH can affect bioavailability

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.

Drugs metabolized by cytochrome P450 (CYP)

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 found, there have been

clinical reports of interaction with other drugs metabolized via the cytochrome P450 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 omeprazole.

Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and

CYP3A4) resulted in more than doubling of the omeprazole exposure. Dose adjustment of omeprazole

is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require

higher doses up to 240 mg/day, dose adjustment may be considered. When voriconazole (400 mg Q12h

x 1 day, then 200 mg x 6 days) was given with omeprazole (40 mg once daily x 7 days) to healthy

subjects, it significantly increased the steady-state C

and AUC

of omeprazole, an average of 2

times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4) respectively as compared to when omeprazole

was given without voriconazole.

Antiretroviral Agents

Concomitant use of atazanavir and proton pump inhibitors is not recommended. Co-administration of

atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma

concentrations and thereby reduce its therapeutic effect.

Omeprazole has been reported to interact with some antiretroviral drugs. The clinical importance and

the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole

treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms

0-24

are via CYP2C19. For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum

levels have been reported when given together with omeprazole. Following multiple doses of

nelfinavir (1250 mg, bid) and omeprazole (40 mg, qd), AUC was decreased by 36% and 92%, C

37% and 89% and C

by 39% and 75% respectively for nelfinavir and M8. Following multiple doses

of atazanavir (400 mg, qd) and omeprazole (40 mg, qd, 2 hr before atazanavir), AUC was decreased by

94%, C

by 96%, and C

by 95%. Concomitant administration with omeprazole and drugs such as

atazanavir and nelfinavir is therefore not recommended. For other antiretroviral drugs, such as

saquinavir, elevated serum levels have been reported with an increase in AUC by 82%, in C

by 75%

and in C

by 106% following multiple dosing of saquinavir/ritonavir (1000/100 mg) bid for 15 days

with omeprazole 40 mg qd co-administered days 11 to 15. Dose reduction of saquinavir should be

considered from the safety perspective for individual patients. There are also some antiretroviral drugs

of which unchanged serum levels have been reported when given with omeprazole .

Tacrolimus

Concomitant administration of omeprazole and tacrolimus may increase the serum levels of tacrolimus.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

Reproductive studies in rats and rabbits with omeprazole and multiple cohort studies in pregnant women

with omeprazole use during the first trimester do not show an increased risk of congenital anomalies or

adverse pregnancy outcomes. There are no adequate and well controlled studies on the use of

omeprazole in pregnant women. Because animal reproduction studies are not always predictive of

human response, this drug should be used during pregnancy only if clearly needed. 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 with the frequency of abnormalities among infants of

women exposed to H –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 retrospective cohort study reported on 689 pregnant women exposed to either H –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 non-exposed 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.

A controlled prospective observational study followed 113 women exposed to omeprazole during

pregnancy (89% first trimester exposures). The reported rates of major congenital malformations was

4% for the omeprazole group, 2% for controls exposed to non-teratogens, and 2.8% in disease-paired

controls (background incidence of major malformations 1–5%). Rates of spontaneous and elective

abortions, preterm deliveries, gestational age at delivery, and mean birth weight did not differ between

the groups. The sample size in this study has 80% power to detect a 5–fold increase in the rate of major

malformation.

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.

Reproductive studies conducted with omeprazole on rats at oral doses up to 56 times the human dose

and in rabbits at doses up to 56 times the human dose did not show any evidence of teratogenicity. In

pregnant rabbits, omeprazole at doses about 5.5 to 56 times the human dose produced dose-related

increases in embryo-lethality, fetal resorptions, and pregnancy loss. In rats treated with omeprazole at

doses about 5.6 to 56 times the human dose, dose-related embryo/fetal toxicity and postnatal

developmental toxicity occurred in offspring. [See Animal Toxicology and/or Pharmacology (13.2)].

8.3 Nursing Mothers

Omeprazole concentrations have been measured in breast milk of a woman following oral administration

of 20 mg. The peak concentration of omeprazole in breast milk was less than 7% of the peak serum

concentration. This concentration would correspond to 0.004 mg of omeprazole in 200 mL of milk.

Because omeprazole is excreted in human milk, because of the potential for serious adverse reactions

in nursing infants from omeprazole, and because of the potential for tumorigenicity shown for

omeprazole in rat carcinogenicity studies, a decision should be made whether to discontinue nursing or

to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Use of omeprazole in pediatric and adolescent patients 2 to 16 years of age for the treatment of GERD

is supported by a) extrapolation of results, already included in the currently approved labeling, from

adequate and well-controlled studies that supported the approval of omeprazole for adults, and b) safety

and pharmacokinetic studies performed in pediatric and adolescent patients. [See Clinical Pharmacology,

Pharmacokinetics, Pediatricfor pharmacokinetic information (12.3) and Dosage and Administration (2) .

Adverse Reactions (6.1) and Clinical Studies, (14.6)]. The safety and effectiveness of omeprazole for the

treatment of GERD in patients < 1 year of age have not been established. The safety and effectiveness

of omeprazole for other pediatric uses have not been established.

8.5 Geriatric Use

Omeprazole was administered to over 2000 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 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 volunteers) and its plasma half-life averaged one hour, about twice that of young healthy

volunteers. However, no dosage adjustment is necessary in the elderly. [See Clinical Pharmacology

(12.3)]

8.6 Hepatic Impairment

Consider dose reduction, particularly for maintenance of healing of erosive esophagitis. [See Clinical

Pharmacology (12.3)]

8.7 Renal Impairment

No dosage reduction is necessary. [See Clinical Pharmacology (12.3) ]

8.8 Asian Population

Consider dose reduction, particularly for maintenance of healing of erosive esophagitis. [See Clinical

Pharmacology (12.3) ]

10 OVERDOSAGE

Reports have been received of overdosage with omeprazole in humans. Doses ranged up to 2400 mg

(120 times the usual recommended clinical dose). Manifestations were variable, but included confusion,

drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, dry mouth,

and other adverse reactions similar to those seen in normal clinical experience. [See Adverse Reactions

(6)] Symptoms were transient, and no serious clinical outcome has been reported when omeprazole was

taken alone. No specific antidote for omeprazole overdosage is known. Omeprazole is extensively

protein bound and is, therefore, not readily dialyzable. In the event of overdosage, treatment should be

symptomatic and supportive.

As with the management of any overdose, the possibility of multiple drug ingestion should be

considered. For current information on treatment of any drug overdose, contact your local Poison

Control Center.

Single oral doses of omeprazole at 1350, 1339, and 1200 mg/kg were lethal to mice, rats, and dogs,

respectively. Animals given these doses showed sedation, ptosis, tremors, convulsions, and decreased

activity, body temperature, and respiratory rate and increased depth of respiration.

11 DESCRIPTION

The active ingredient in omeprazole delayed-release capsules is a substituted benzimidazole, 5-

methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H-benzimidazole, a compound

that inhibits gastric acid secretion. Its empirical formula is C

H N O S, with a molecular weight of

345.42. The structural formula is:

Omeprazole Chemical Structure

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.

Omeprazole delayed-release capsules meets USP Drug release test 2.

Omeprazole is supplied as delayed-release capsules for oral administration. Each delayed-release

capsule contains either 10 mg, 20 mg or 40 mg of omeprazole in the form of enteric-coated

granules with the following inactive ingredients: crospovidone, hypromellose, magnesium stearate,

mannitol, meglumine, methacrylic acid copolymer, poloxamer, povidone and triethyl citrate.

The capsule shells contains: D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow

No. 6, yellow iron oxide, gelatin, silicon dioxide, sodium lauryl sulphate and titanium dioxide.

Imprinting ink contains: D&C Yellow No. 10 aluminum lake, FD&C Blue No. 1 aluminum lake, FD&C

Blue No. 2 aluminum lake, FD&C Red No. 40 aluminum lake, n-butyl alcohol, pharmaceutical glaze,

propylene glycol, SDA-3A alcoho and synthetic black iron oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, 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.

12.2 Pharmacodynamics

Antisecretory Activity

After oral administration, the onset of the antisecretory effect of omeprazole occurs within one hour,

with the maximum effect occurring within two hours. Inhibition of secretion is about 50% of maximum

at 24 hours and the duration of inhibition lasts up to 72 hours. The antisecretory effect thus lasts far

longer than would be expected from the very short (less than one hour) plasma half-life, apparently due

to prolonged binding to the parietal H /K ATPase enzyme. When the drug is discontinued, secretory

activity returns gradually, over 3 to 5 days. The inhibitory effect of omeprazole on acid secretion

increases with repeated once-daily dosing, reaching a plateau after four days.

Results from numerous studies of the antisecretory effect of multiple doses of 20 mg and 40 mg of

omeprazole in normal volunteers and patients are shown below. The “max” value represents

determinations at a time of maximum effect (2-6 hours after dosing), while “min” values are those 24

hours after the last dose of omeprazole.

Table 1

Range of Mean Values from Multiple Studies of the Mean Antisecretory

Effects of Omeprazole After Multiple Daily Dosing

Omeprazole 20 mg Omeprazole 40 mg

Parameter

Max

Min

Max

Min

% Decrease in Basal Acid Output

58–80

80–93

% Decrease in Peak Acid Output

50–59

62–68

% Decrease in 24–hr Intragastric Acidity

80–97

92–94

Single daily oral doses of omeprazole ranging from a dose of 10 mg to 40 mg have produced 100%

inhibition of 24-hour intragastric acidity in some patients.

Serum Gastric Effects

Single Studies

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 H -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.

Enterochromaffin-like (ECL) Cell Effects

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 Clinical Pharmacology (12 ] 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.

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 twice daily for 12 months followed by 20 mg twice daily for 12 months or

ranitidine 300 mg twice daily 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 Clinical Pharmacology (12)].

12.3 Pharmacokinetics

Absorption

Omeprazole delayed-release capsules contain an enteric-coated granule formulation of omeprazole

(because omeprazole is acid-labile), so that absorption of omeprazole begins only after the granules

leave the stomach. Absorption is rapid, with peak plasma levels of omeprazole occurring within 0.5 to

3.5 hours. Peak plasma concentrations of omeprazole and AUC are approximately proportional to doses

up to 40 mg, but because of a saturable first-pass effect, a greater than linear response in peak plasma

concentration and AUC occurs with doses greater than 40 mg. Absolute bioavailability (compared with

intravenous administration) is about 30-40% at doses of 20-40 mg, due in large part to presystemic

metabolism. In healthy subjects the plasma half-life is 0.5 to 1 hour, and the total body clearance is 500-

600 mL/min.

600 mL/min.

The bioavailability of omeprazole increases slightly upon repeated administration of omeprazole

delayed-release capsules.

Omeprazole delayed-release capsules 40 mg was bioequivalent when administered with and without

applesauce. However, Omeprazole delayed-release capsules 20 mg was not bioequivalent when

administered with and without applesauce. When administered with applesauce, a mean 25% reduction in

was observed without a significant change in AUC for Omeprazole delayed-release capsules 20

mg. The clinical relevance of this finding is unknown.

Distribution

Protein binding is approximately 95%.

Metabolism

Omeprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme system.

Excretion

Following single dose oral administration of a buffered solution of omeprazole, little if any unchanged

drug was excreted in urine. The majority of the dose (about 77%) was eliminated in urine as at least six

metabolites. Two were identified as hydroxyomeprazole and the corresponding carboxylic acid. The

remainder of the dose was recoverable in feces. This implies a significant biliary excretion of the

metabolites of omeprazole. Three metabolites have been identified in plasma — the sulfide and sulfone

derivatives of omeprazole, and hydroxyomeprazole. These metabolites have very little or no

antisecretory activity.

Combination Therapy with Antimicrobials

Omeprazole 40 mg daily was given in combination with clarithromycin 500 mg every 8 hours to healthy

adult male subjects. The steady state plasma concentrations of omeprazole were increased (C

, and T

increases of 30%, 89% and 34% respectively) by the concomitant administration of

clarithromycin. The observed increases in omeprazole plasma concentration were associated with the

following pharmacological effects. The mean 24-hour gastric pH value was 5.2 when omeprazole was

administered alone and 5.7 when co-administered with clarithromycin.

The plasma levels of clarithromycin and 14-hydroxy-clarithromycin were increased by the concomitant

administration of omeprazole. For clarithromycin, the mean C

was 10% greater, the mean C

27% greater, and the mean AUC

was 15% greater when clarithromycin was administered with

omeprazole than when clarithromycin was administered alone. Similar results were seen for 14-

hydroxy-clarithromycin, the mean C

was 45% greater, the mean C

was 57% greater, and the mean

was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also

increased by concomitant administration of omeprazole.

Table 2

Clarithromycin Tissue Concentrations 2 hours after

Dos e

Tis s ue

Clarithromycin

Clarithromycin + Omeprazole

Antrum

10.48 ± 2.01 (n = 5)

19.96 ± 4.71 (n=5)

Fundus

20.81 ± 7.64 (n = 5)

24.25 ± 6.37 (n= 5)

Mucus

4.15 ± 7.74 (n = 4)

39.29 ± 32.79 (n=4)

mean ± SD (mcg/g)

0-24

1

Special Populations

Geriatric Population

The elimination rate of omeprazole was somewhat decreased in the elderly, and bioavailability was

increased. Omeprazole was 76% bioavailable when a single 40 mg oral dose of omeprazole (buffered

solution) was administered to healthy elderly volunteers, versus 58% in young volunteers given the

same dose. Nearly 70% of the dose was recovered in urine as metabolites of omeprazole and no

unchanged drug was detected. The plasma clearance of omeprazole was 250 mL/min (about half that of

young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy

volunteers.

Pediatric Use

The pharmacokinetics of omeprazole have been investigated in pediatric patients 2 to 16 years of age:

Table 3

Pharmacokinetic Parameters of Omeprazole Following Single and Repeated Oral Administration

in Pediatric Populations Compared with Adults

Single or Repeated Oral

Dosing /Parameter

Children ≤ 20 kg

2-5 years

Children > 20 kg

6-16 years

Adults

(mean 76 kg) 23-29

years (n=12)

10 mg

20 mg

Single Dosing

*(ng/mL)

288 (n=10)

495 (n=49)

AUC*(ng h/mL)

511 (n=7)

1140 (n=32)

1220

Repeated Dosing

* (ng/mL)

539 (n=4)

851 (n=32)

1458

AUC *(ng h/mL)

1179 (n=2)

2276 (n=23)

3352

Note: * = plasma concentration adjusted to an oral dose of 1 mg/kg.

Data from single and repeated dose studies

Data from a single and repeated dose study

Doses of 10, 20 and 40 mg omeprazole as enteric-coated granules

Following comparable mg/kg doses of omeprazole, younger children (2 to 5 years of age) have lower

AUCs than children 6 to16 years of age or adults; AUCs of the latter two groups did not differ. [See

Dosage and Administration (2) ]

Hepatic Impairment

In patients with chronic hepatic disease, the bioavailability increased to approximately 100% compared

with an I.V. dose, reflecting decreased first-pass effect, and the plasma half-life of the drug increased

to nearly 3 hours compared with the half-life in normals of 0.5-1 hour. Plasma clearance averaged 70

mL/min, compared with a value of 500-600 mL/min in normal subjects. Dose reduction, particularly

where maintenance of healing of erosive esophagitis is indicated, for the hepatically impaired should

be considered.

Renal Impairment

In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and 62

mL/min/1.73 m , 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.

No dose reduction is necessary in patients with renal impairment.

Asian Population

In pharmacokinetic studies of single 20 mg omeprazole doses, an increase in AUC of approximately

four-fold was noted in Asian subjects compared with Caucasians. Dose reduction, particularly where

maintenance of healing of erosive esophagitis is indicated, for Asian subjects should be considered.

12.4 Microbiology

Omeprazole and clarithromycin dual therapy and omeprazole, clarithromycin and amoxicillin triple

therapy have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical

infections as described in the Indications and Usage section (1.1).

Helicobacter

Helicobacter pylori- Pretreatment Resistance

Clarithromycin pretreatment resistance rates were 3.5% (4/113) in the omeprazole/clarithromycin dual

therapy studies (4 and 5) and 9.3% (41/439) in omeprazole/clarithromycin/amoxicillin triple therapy

studies (1, 2, and 3).

Amoxicillin pretreatment susceptible isolates (≤ 0.25 mcg/mL) were found in 99.3% (436/439) of the

patients in the omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2, and 3). Amoxicillin

pretreatment minimum inhibitory concentrations (MICs) > 0.25 mcg/mL occurred in 0.7% (3/439) of the

patients, all of whom were in the clarithromycin and amoxicillin study arm. One patient had an

unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of > 256 mcg/mL by

Etest

Table 4

Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes

Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes

Clarithromycin Pretreatment Results

Clarithromycin Post-treatment Results

H. pylori negative – eradicated

H. pylori positive – not eradicated

Post-treatment susceptibility results

No MIC

Dual Therapy – (omeprazole 40 mg once daily/clarithromycin 500 three times daily for 14 days

followed by omeprazole 20 mg once daily for another 14 days) (Studies 4,5)

Susceptible

Intermediate

Resistant

Triple Therapy – (omeprazole 20 mg twice daily/clarithromycin 500 mg twice daily/amoxicillin 1 g

a

b

b

b

b

b

b

twice daily for 10 days – Studies 1, 2,3; followed by omeprazole 20 mg once daily for another 18 days

– Studies 1,2)

Susceptible

Intermediate

Resistant

Includes only patients with pretreatment clarithromycin susceptibility test results

Susceptible (S) MIC ≤ 0.25 mcg/mL, Intermediate (I) MIC 0.5 – 1.0 mcg/mL, Resistant (R) MIC ≥ 2

mcg/mL

Patients not eradicated of H. pylori following omeprazole/clarithromycin/amoxicillin triple therapy or

omeprazole/clarithromycin dual therapy will likely have clarithromycin resistant H. pylori isolates.

Therefore, clarithromycin susceptibility testing should be done, if possible. Patients with

clarithromycin resistant H. pylori should not be treated with any of the following:

omeprazole/clarithromycin dual therapy, omeprazole/clarithromycin/amoxicillin triple therapy, or other

regimens which include clarithromycin as the sole antimicrobial agent.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes

In the triple therapy clinical trials, 84.9% (157/185) of the patients in the

omeprazole/clarithromycin/amoxicillin treatment group who had pretreatment amoxicillin susceptible

MICs (≤ 0.25 mcg/mL) were eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28

patients who failed triple therapy, 11 had no post-treatment susceptibility test results and 17 had post-

treatment H. pylori isolates with amoxicillin susceptible MICs. Eleven of the patients who failed triple

therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs.

Susceptibility Test for Helicobacter pylori

The reference methodology for susceptibility testing of H. pylori is agar dilution MICs . One to three

microliters of an inoculum equivalent to a No. 2 McFarland standard (1 x 10 - 1 x 10 CFU/mL for H.

pylori) are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates

with 5% aged defibrinated sheep blood (≥ 2 weeks old). The agar dilution plates are incubated at 35°C

in a microaerobic environment produced by a gas generating system suitable for campylobacters. After

3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required

to inhibit growth of the organism. The clarithromycin and amoxicillin MIC values should be interpreted

according to the following criteria:

Table 5

Clarithromycin MIC (mcg/mL)

Interpretation

≤ 0.25

Susceptible (S)

Intermediate (I)

> 1.0

Resistant (R)

Amoxicillin MIC (mcg/mL)

Interpretation

b

b

b

a

b

a

a,b

≤ 0.25

Susceptible (S)

These are tentative breakpoints for the agar dilution methodology and they should not be used to

interpret results obtained using alternative methods.

There were not enough organisms with MICs > 0.25 mcg/mL to determine a resistance breakpoint.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to

control the technical aspects of the laboratory procedures. Standard clarithromycin and amoxicillin

powders should provide the following MIC values:

Microorganism

Antimicrobial Agent

MIC (mcg/mL) .

H. pylori ATCC 43504

Clarithromycin

0.016- 0.12 (mcg/mL)

H. pylori ATCC 43504

Amoxicillin

0.016- 0.12 (mcg/mL)

These are quality control ranges for the agar dilution methodology, and they should not be used to

control test results obtained using alternative methods

Effects on Gastrointestinal Microbial Ecology

Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts

of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead

to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter.

13 NONCLINICAL TOXICOLOGY

13.1 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 a human dose of 20 mg/day, as expressed on a body surface area

basis) 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 6 times a human dose of 20 mg/day, based on body surface area) for one

year, and 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 on a body surface area basis). 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 or females at the high dose of 140.8 mg/kg/day (about 57 times the

human dose on a body surface area basis). 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

a

b

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 in rats (about 56 times the human dose on a body surface

area basis) was found to have no effect on fertility and reproductive performance.

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 Warnings and

Precautions (5) ] Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term

treatment with other proton pump inhibitors or high doses of H -receptor antagonists.

13.2. Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 56

times the human dose on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 56

times the human dose on a body surface area basis) 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 5.5 to 56

times the human dose on a body surface area basis) 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 138.0 mg/kg/day (about 5.6 to 56 times the human doses on a body surface area

basis).

14 CLINICAL STUDIES

14.1 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 daily than with placebo (p ≤ 0.01).

Treatment of Active Duodenal Ulcer % of

Patients Healed

Omeprazole 20 mg a.m. Placebo a.m.

(n=99)

(n=48)

Week 2

Week 4

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 daily than with ranitidine 150 mg b.i.d. (p < 0.01).

Treatment of Active Duodenal Ulcer

% of Patients Healed

(p ≤ 0.01)

Omeprazole

Ranitidine

20 mg a.m.

150 mg twice daily

(n = 145)

(n = 148)

Week 2

Week 4

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 with 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

Ranitidine

20 mg (n=34) 40 mg (n=36) 150 mg twice daily (n=35)

Week 2

Week 4

Week 8

H. pylori Eradication in Patients with Duodenal Ulcer Disease

Triple Therapy(omeprazole/clarithromycin/amoxicillin)— Three U.S., randomized, double-blind clinical

studies in patients with H. pylori infection and duodenal ulcer disease (n=558) compared omeprazole

plus clarithromycin plus amoxicillin with clarithromycin plus amoxicillin. Two studies (1 and 2) were

conducted in patients with an active duodenal ulcer, and the other study (3) was conducted in patients

with a history of a duodenal ulcer in the past 5 years but without an ulcer present at the time of

enrollment. The dose regimen in the studies was omeprazole 20 mg twice daily plus clarithromycin 500

mg twice daily plus amoxicillin 1 g twice daily for 10 days; or clarithromycin 500 mg twice daily, plus

amoxicillin 1 g twice daily for 10 days. In studies 1 and 2, patients who took the omeprazole regimen

also received an additional 18 days of omeprazole 20 mg once daily. Endpoints studied were

eradication of H. pylori and duodenal ulcer healing (studies 1 and 2 only). H. pylori status was

determined by CLOtest

, histology and culture in all three studies. For a given patient, H. pylori was

considered eradicated if at least two of these tests were negative, and none was positive.

The combination of omeprazole plus clarithromycin plus amoxicillin was effective in eradicating H.

pylori.

Table 6

Per-Protocol and Intent-to-Treat H. pylori Eradication Rates

% of Patients Cured [95% Confidence Interval]

Omeprazole+clarithromycin+amoxicillin Clarithromycin+amoxicillin

Per-Protocol † Intent-to-Treat ‡ Per-Protocol † Intnet-to-Treat ‡

(p ≤ 0.01)

Study 1

*77 [64,86]

(n=64)

*69 [57,79]

(n=80)

43 [31, 56]

(n=67)

37 [27, 48]

(n=84)

Study 2

*78 [67,88]

(n=65)

*73 [61, 82]

(n=77)

41 [29, 54]

(n=68)

36 [26, 47]

(n=83)

Study 3

*90 [80, 96]

(n=69)

*83 [74, 91]

(n=84)

33 [24, 44]

(n=93)

32 [23, 42]

(n=99)

† Patients were included in teh analysis if they had confirmed duodenal ulcer disease (active ulcer,

studies 1 and 2: history of ulcer within 5 years, study 3) and H. pylori infection at baseline defined as at

least two of three positive endoscopic tests from CLOtest

, histology, and/or culture. Patients were

included in the analysis if they completed teh study. Additionally, if patients dropped out of the study

due to an adverse event related to teh study drug, they were in cluded in the analysis as failures of

therapy. The impact of eradication on ulcer recurrence has not been assessed in patients with a past

history of ulcer.

Patients were included in the analysis if they had documented H. pylori infection at baseline and had

confirmed duodenal ulcer disease. All dropouts were included as failures of therapy.

*(p<0.05) versus clarithromycin plus amoxicillin.

Dual Therapy (omeprazole /clarithromycin)

Four randomized, double-blind, multi-center studies (4, 5, 6, and 7) evaluated omeprazole 40 mg once

daily plus clarithromycin 500 mg three times daily for 14 days, followed by omeprazole 20 mg once

daily, (studies 4, 5, and 7) or by omeprazole 40 mg once daily (Study 6) for an additional 14 days in

patients with active duodenal ulcer associated with H. pylori. Studies 4 and 5 were conducted in the U.S.

and Canada and enrolled 242 and 256 patients, respectively. H. pylori infection and duodenal ulcer were

confirmed in 219 patients in Study 4 and 228 patients in Study 5. These studies compared the

combination regimen to omeprazole and clarithromycin monotherapies. Studies 6 and 7 were conducted

in Europe and enrolled 154 and 215 patients, respectively. H. pylori infection and duodenal ulcer were

confirmed in 148 patients in study 6 and 208 patients in Study 7. These studies compared the

combination regimen with omeprazole monotherapy. The results for the efficacy analyses for these

studies are described below. H. pylori eradication was defined as no positive test (culture or histology)

at 4 weeks following the end of treatment, and two negative tests were required to be considered

eradicated of H. pylori. In the per-protocol analysis, the following patients were excluded: dropouts,

patients with missing H. pylori tests post-treatment, and patients that were not assessed for H. pylori

eradication because they were found to have an ulcer at the end of treatment.

The combination of omeprazole and clarithromycin was effective in eradicating H. pylori.

Table 7

H. pylori Eradication Rates (Per-Protocol Analyssi at 4 to 6 Weeks)

% of Patients Cured [95% Confidence interval]

Omeprazole+

Clarithromycin

Omeprazole Clarithromycin

U.S. Studies

Study 4

74 [60, 85]†

(n=53)

0 [0, 7]

(n=54)

31 [18, 47]

(n=42)

Study 5

64 [51, 76]†

0 [0, 6]

(n=59)

39 [24, 55]

(n=44)

Non U.S. Studies

Study 6

83 [71, 92]

(n=60)

1 [0, 7]

(n=74)

Study 7

74 [64, 83]

1 [0,6]

Study 7

(n=86)

(n=90)

† Statistically significantly higher than clarithromycin monotherapy (p<0.05)

‡ Statistically significantly higher than omeprazoel monotherapy (p<0.05)

Ulcer healing was not significantly different when clarithromycin was added to omeprazole therapy

compared with omeprazole therapy alone.

The combination of omeprazole and clarithromycin was effective in eradicating H. pylori and reduced

duodenal ulcer recurrence.

Table 8

Duodenal Ulcer Recurrence Rates by

H. pylori Eradication Status

% of Patients with Ulcer Recurrence

H. pylori eradicated H. pylori not eradicated

U.S. Studies

6 months post-treatment

Study 4

(n=49)

(n=88)

Study 5

(n=53)

(n=106)

Non U.S. Studies

6 months post-treatment

Study 6

(n=43)

(n=78)

Study 7

(n=53)

(n=107)

12 months post-treatment

Study 6

(n=39)

(n=71)

H. pylori eradication status assessed at same time point as ulcer recurrence

† Combined results for omeprazole + clarithromycin, omeprazole, and clarithromycin treatment arms

14.2 Gastric Ulcer

In a U.S. multicenter, double-blind, study of omeprazole 40 mg once daily, 20 mg once daily, and

placebo in 520 patients with endoscopically diagnosed gastric ulcer, the following results were

obtained.

Treatment of Gastric Ulcer

% of Patients Healed

(All Patients Treated)

Omeprazole

20mg once daily

(n=202)

Omeprazole

40mg once daily

(n=214)

Placebo

(n=104)

Week 4 47.5**

55.6**

30.8

Week 8

74.8**

82.7

48.1

**,+

**(p<0.01) omeprazole 40mg or 20mg versus placebo

(p<0.05) omeprazole 40mg versus 20mg

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 daily, 20 mg once daily, and ranitidine 150 mg twice a day were

evaluated.

Treatment of Gastric Ulcer

% of Patients Healed

(All Patients Treated)

Omeprazole

20mg once daily

(n=200)

Omeprazole

40mg once daily

(n=187)

Ranitidine

150 twice daily

(n=199)

Week 4 63.5

78.1**

56.3

Week 8 81.5

91.4

78.4

**(p<0.01) omeprazole 40mg versus ranitidine

(p<0.01) omeprazole 40mg versus 20mg

14.3 Gastroesophageal Reflux Disease (GERD)

Symptomatic GERD

A placebo-controlled study was conducted in Scandinavia to compare the efficacy of omeprazole 20 mg

or 10 mg once daily for up to 4 weeks in the treatment of heartburn and other symptoms in GERD

patients without erosive esophagitis. Results are shown below.

% Successful Symptomatic Outcome

Omeprazole

20 mg a.m.

Omeprazole

10 mg a.m.

Placebo

a.m.

All patients

46*†

(n=205)

31†

(n=199)

(n=105)

Patients with confirmed GERD

(n=115)

36†

(n=109)

(n=59)

Defined as complete resolution of heartburn

*(p<0.005) versus 10mg

†(p<0.005) versus placebo

14.4 Erosive Esophagitis

In a U.S. multicenter double-blind placebo controlled study of 20 mg or 40 mg of omeprazole delayed-

release capsules in patients with symptoms of GERD and endoscopically diagnosed erosive esophagitis

of grade 2 or above, the percentage healing rates (per protocol) were as follows:

Week

20mg Omeprazole

(n=83)

40mg Omeprazole

(n=87)

Placebo

(n=43)

39**

45**

**,++

,†

74**

75**

**(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 H -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 H - 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 Of Healing 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

Omeprazole

20mg once daily

(n=138)

Omeprazole

20mg 3 days

per week

(n=137)

Placebo

(n=131)

Percent in

endoscopic

remission at 6 months

*(p<0.01) omeprazole 20mg once daily versus omeprazole 20mg 3 consecutive days per week or

placebo

In an international multicenter double-blind study, omeprazole 20 mg daily and 10 mg daily were

compared with 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

20mg 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

58

*(p=0.01) omeprazole 20 mg once daily, versus omeprazole 10 mg once daily or Ranitidine

(p=0.03) ompeprazole 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.

14.5 Pathological Hypersecretory Conditions

In open studies of 136 patients with pathological hypersecretory conditions, such as Zollinger-Ellison

(ZE) syndrome with or without multiple endocrine adenomas, omeprazole delayed-release capsules

significantly inhibited gastric acid secretion and controlled associated symptoms of diarrhea, anorexia,

and pain. Doses ranging from 20 mg every other day to 360 mg per day maintained basal acid secretion

below 10 mEq/hr in patients without prior gastric surgery, and below 5 mEq/hr in patients with prior

gastric surgery.

Initial doses were titrated to the individual patient need, and adjustments were necessary with time in

some patients [see Dosage and Administration (2) ] omeprazole was well tolerated at these high dose

levels for prolonged periods (> 5 years in some patients). In most ZE patients, serum gastrin levels were

not modified by omeprazole. However, in some patients serum gastrin increased to levels greater than

those present prior to initiation of omeprazole therapy. At least 11 patients with ZE syndrome on long-

term treatment with omeprazole developed gastric carcinoids. These findings are believed to be a

manifestation of the underlying condition, which is known to be associated with such tumors, rather than

the result of the administration of omeprazole. [See Adverse Reactions (6) ]

14.6 Pediatric GERD

Symptomatic GERD

The effectiveness of omeprazole for the treatment of nonerosive GERD in pediatric patients 2 to 16

years of age is based in part on data obtained from pediatric patients in an uncontrolled phase III study.

[See Use in Specific Populations (8.4)]

The study enrolled 113 pediatric patients 2 to 16 years of age with a history of symptoms suggestive of

nonerosive GERD. Patients were administered a single dose of omeprazole (10 mg or 20 mg, based on

body weight) for 4 weeks either as an intact capsule or as an open capsule in applesauce. Successful

response was defined as no moderate or severe episodes of either pain-related symptoms or

vomiting/regurgitation during the last 4 days of treatment. Results showed success rates of 60% (9/15;

10 mg omeprazole) and 59% (58/98; 20 mg omeprazole), respectively.

Healing of Erosive Esophagitis

In an uncontrolled, open-label dose-titration study, healing of erosive esophagitis in pediatric patients 1

to 16 years of age required doses that ranged from 0.7 to 3.5 mg/kg/day (80 mg/day). Doses were

initiated at 0.7 mg/kg/day. Doses were increased in increments of 0.7 mg/kg/day (if intraesophageal pH

showed a pH of < 4 for less than 6% of a 24-hour study). After titration, patients remained on treatment

for 3 months. Forty-four percent of the patients were healed on a dose of 0.7 mg/kg body weight; most

of the remaining patients were healed with 1.4 mg/kg after an additional 3 months’ treatment. Erosive

esophagitis was healed in 51 of 57 (90%) children who completed the first course of treatment in the

healing phase of the study. In addition, after 3 months of treatment, 33% of the children had no overall

symptoms, 57% had mild reflux symptoms, and 40% had less frequent regurgitation/vomiting.

Maintenance of Healing of Erosive Esophagitis

In an uncontrolled, open-label study of maintenance of healing of erosive esophagitis in 46 pediatric

patients, 54% of patients required half the healing dose. The remaining patients increased the healing

dose (0.7 to a maximum of 2.8 mg/kg/day) either for the entire maintenance period, or returned to half

the dose before completion. Of the 46 patients who entered the maintenance phase, 19 (41%) had no

relapse. In addition, maintenance therapy in erosive esophagitis patients resulted in 63% of patients

having no overall symptoms.

15 REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial

Susceptibility Tests for Bacteria That Grow Aerobically—Fifth Edition. Approved Standard NCCLS

Document M7-A5, Vol, 20, No. 2, NCCLS, Wayne, PA, January 2000.

16 HOW SUPPLIED/STORAGE AND HANDLING

Omeprazole delayed-release capsules, USP 40 mg are off-white to pale yellow, elliptical to spherical

pellets filled in size ‘Oel’ hard gelatin capsules with opaque yellow colored cap and opaque lavender

colored body, imprinted on cap ‘OMEPRAZOLE’ 40 mg and body ‘R159’ with black ink. The capsules

are supplied in bottles of 30, 60 and 90.

Bottles of 30 NDC 42549-658-30

Bottles of 60 NDC 42549-658-60

Bottles of 90 NDC 42549-658-90

Storage

Store delayed-release capsules in a tight container protected from light and moisture.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Relabeling and Repackaging by:

STAT Rx USA LLC

Gainesville, GA. 30501

17 PATIENT COUNSELING INFORMATION

Omeprazole delayed-release capsules should be taken before eating. Patients should be informed that

the omeprazole delayed-release capsules should be swallowed whole.

For patients who have difficulty swallowing capsules, the contents of an omeprazole delayed-release

capsule can be added to applesauce. One tablespoon of applesauce should be added to an empty bowl

and the capsule should be opened. All of the pellets inside the capsule should be carefully emptied on

the applesauce. The pellets should be mixed with the applesauce and then swallowed immediately with

a glass of cool water to ensure complete swallowing of the pellets. The applesauce used should not be

hot and should be soft enough to be swallowed without chewing. The pellets should not be chewed or

crushed. The pellets/applesauce mixture should not be stored for future use.

Principle Display Panel

Omeprazole Delayed-release Capsules, USP

40mg

Rx Only

Omeprazole Delayed-release Capsules, USP 40mg

Manufactured by:

Dr. Reddy's Laboratories Limited

Bachepalli - 502 325 INDIA

Relabeling and Repackaging by:

STAT Rx USA LLC

Gainesville, GA 30501

OMEPRAZOLE

omeprazole capsule, delayed release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:42549 -6 58 (NDC:55111-159 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

O MEPRAZO LE (UNII: KG6 0 48 4QX9 ) (OMEPRAZOLE - UNII:KG6 0 48 4QX9 )

OMEPRAZOLE

40 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CRO SPO VIDO NE (UNII: 6 8 40 19 6 0 MK)

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MANNITO L (UNII: 3OWL53L36 A)

MEGLUMINE (UNII: 6 HG8 UB2MUY)

METHACRYLIC ACID - ETHYL ACRYLATE CO PO LYMER ( 1:1) TYPE A (UNII: NX76 LV5T8 J)

PEG/PPG-3 0 /16 0 CO PO LYMER (UNII: 6 8 T8 I45V23)

PO VIDO NE (UNII: FZ9 8 9 GH9 4E)

TRIETHYL CITRATE (UNII: 8 Z9 6 QXD6 UM)

D&C RED NO . 2 8 (UNII: 76 7IP0 Y5NH)

FD&C BLUE NO . 1 (UNII: H3R47K3TBD)

FD&C RED NO . 4 0 (UNII: WZB9 127XOA)

FD&C YELLO W NO . 6 (UNII: H77VEI9 3A8 )

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

GELATIN (UNII: 2G8 6 QN327L)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

D&C YELLO W NO . 10 (UNII: 35SW5USQ3G)

FD&C BLUE NO . 1 (UNII: H3R47K3TBD)

FD&C BLUE NO . 2 (UNII: L0 6 K8 R7DQK)

FD&C RED NO . 4 0 (UNII: WZB9 127XOA)

BUTYL ALCO HO L (UNII: 8 PJ6 1P6 TS3)

SHELLAC (UNII: 46 N10 7B71O)

PRO PYLENE GLYCO L (UNII: 6 DC9 Q16 7V3)

ALCO HO L (UNII: 3K9 9 58 V9 0 M)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

Product Characteristics

Color

white (OFF-WHITE TO PALE YELLOW)

S core

no sco re

S hap e

CAPSULE

S iz e

23mm

Flavor

Imprint Code

OMEPRAZOLE;40 ;mg;R159

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:42549 -6 58 -30

30 in 1 BOTTLE

2

NDC:42549 -6 58 -6 0

6 0 in 1 BOTTLE

3

NDC:42549 -6 58 -9 0

9 0 in 1 BOTTLE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 78 49 0

0 4/17/20 0 9

Labeler -

ST AT Rx USA LLC (786036330)

Registrant -

PSS World Medical Inc. (101822682)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

STAT Rx USA LLC

78 6 0 36 330

relabel, repack

STAT Rx USA LLC

Revised: 2/2012

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