Omeprazole delayed-release capsules in combination with clarithromycin, are indicated for treatment of patients with H. pylori infection and duodenal ulcer disease to eradicate H. pylori .

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

Gastric Ulcer

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

Treatment of Gastroesophageal Reflux Disease (GERD)

Symptomatic GERD

Omeprazole delayed-release capsules are indicated for the treatment of heartburn and other symptoms associated with GERD.

Erosive Esophagitis

Omeprazole delayed-release capsules are indicated for the short-term treatment (4-8 weeks) of erosive esophagitis which has been diagnosed by endoscopy.

The efficacy of Omeprazole delayed-release capsules used for longer than 8 weeks in these patients has not been established.

Maintenance of Healing of Erosive Esophagitis

Omeprazole delayed-release capsules are indicated to maintain healing of erosive esophagitis. Controlled studies do not extend beyond 12 months.

Pathological Hypersecretory Conditions

Omeprazole delayed-release capsules are indicated for the long-term treatment of pathological hypersecretory conditions (eg, Zollinger-Ellison syndrome, multiple endocrine adenomas and systemic mastocytosis).

CONTRAINDICATIONS:

 Omeprazole delayed-release capsules are contraindicated in patients with known hypersensitivity to any component of the formulation.

Clarithromycin is contraindicated in patients with a known hypersensitivity to any macrolide antibiotic. (Please refer to full prescribing information for clarithromycin before prescribing.)

Amoxicillin is contraindicated in patients with a history of allergic reaction to any of the penicillins. (Please refer to full prescribing information for amoxicillin before prescribing.)

DESCRIPTION: The stability of Omeprazole is a function of pH; it is rapidly degraded in acid media, but has acceptable stability under alkaline conditions.  

CLINICAL PHARMACOLOGY:

 Pharmacokinetics and Metabolism:

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 to intravenous administration) is about 30-40% at doses of 20-40 mg, due in large part to presystemic metabolism. In healthy subjects the plasma half-life is 0.5 to 1 hour, and the total body clearance is 500-600 mL/min. Protein binding is approximately 95%.

Following single dose oral administration the majority of the dose (about 77%) was eliminated in urine as at least six metabolites. The remainder of the dose was recoverable in feces. This implies a significant biliary excretion of the metabolites of Omeprazole.

In patients with chronic hepatic disease, the bioavailability increased to approximately 100% compared to an I.V. dose, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly 3 hours compared to the half-life in normals of 0.5-1 hour. Plasma clearance averaged 70 mL/min, compared to a value of 500-600 mL/min in normal subjects.

In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and 62 mL/min/1.73 m ², the disposition of Omeprazole was very similar to that in healthy volunteers, although there was a slight increase in bioavailability.

The elimination rate of Omeprazole was somewhat decreased in the elderly, and bioavailability was increased. Nearly 70% of the dose was recovered in urine as metabolites of Omeprazole and no unchanged drug was detected.

Dose adjustment, particularly where maintenance of healing of erosive esophagitis is indicated, for the hepatically impaired and Asian subjects should be considered.

Omeprazole Delayed-Release Capsule 20 mg was not bioequivalent when administered with and without applesauce.

The pharmacokinetics of Omeprazole have been investigated in pediatric patients of different ages.

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 

Pharmacokinetics: Combination Therapy with Antimicrobials

Omeprazole 40 mg daily was given in combination with clarithromycin 500 mg every 8 hours to healthy adult male subjects. The steady state plasma concentrations of Omeprazole were increased (C _max , AUC _0-24 , and T _1/2 increases of 30%, 89% and 34% respectively) by the concomitant administration of clarithromycin.

The plasma levels of clarithromycin and 14-hydroxy-clarithromycin were increased by the concomitant administration of Omeprazole. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of Omeprazole.

Pharmacodynamics

Mechanism of Action: Omeprazole belongs to a new class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H ₂ histamine antagonistic properties, but that suppress gastric acid secretion by specific inhibition of the H ⁺ /K ⁺ ATPase enzyme system at the secretory surface of the gastric parietal cell. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.

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. 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.

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.

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. However, these studies are of insufficient duration and size to rule out the possible influence of long-term administration of Omeprazole on the development of any premalignant or malignant conditions.

Serum Gastrin Effects

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. Gastrin values returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy.

Other Effects

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.

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

Clinical Studies

Duodenal Ulcer Disease

Active Duodenal Ulcer:  the percentage of patients healed (per protocol) at 2 and 4 weeks was significantly higher with Omeprazole 20 mg once a day than with placebo (p </= 0.01).

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.

The percentage of patients healed (per protocol) at 4 weeks was significantly higher with Omeprazole 20 mg once a day than with ranitidine 150 mg b.i.d. (p < 0.01).

Healing occurred significantly faster in patients treated with Omeprazole than in those treated with ranitidine 150 mg b.i.d. (p < 0.01).

H. pylori Eradication in Patients with Duodenal Ulcer Disease Triple Therapy (Omeprazole /clarithromycin/amoxicillin) -- The dose regimen in the studies was Omeprazole 20 mg b.i.d. plus clarithromycin 500 mg b.i.d. plus amoxicillin 1 g b.i.d. for 10 days; or clarithromycin 500 mg b.i.d. plus amoxicillin 1 g b.i.d. for 10 days. Patients who took the Omeprazole regimen also received an additional 18 days of Omeprazole 20 mg q.d. Endpoints studied were eradication of H. pylori and duodenal ulcer healing. 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 .

† Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer, studies 126 and 127; history of ulcer within 5 years, study M96-446) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest®, histology, and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy. The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer.

‡ Patients were included in the analysis if they had documented H. pylori infection at baseline and had confirmed duodenal ulcer disease. All dropouts were included as failures of therapy.

*(p < 0.05) versus clarithromycin plus amoxicillin.

Dual Therapy (OMEPRAZOLE/clarithromycin) -- Omeprazole 40 mg q.d. plus clarithromycin 500 mg t.i.d. for 14 days, followed by Omeprazole 20 mg q.d. or by Omeprazole 40 mg q.d. for an additional 14 days in patients with active duodenal ulcer associated with H. pylori . These studies compared the combination regimen to Omeprazole and clarithromycin monotherapies. These studies compared the combination regimen to Omeprazole monotherapy. 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. The combination of Omeprazole and clarithromycin was effective in eradicating H. pylori.

Ulcer healing was not significantly different when clarithromycin was added to Omeprazole therapy compared to Omeprazole therapy alone.

The combination of Omeprazole and clarithromycin was effective in eradicating H. pylori and reduced duodenal ulcer recurrence.

Pathological Hypersecretory Conditions

In 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.

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.

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.

Helicobacter

Helicobacter pylori

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.  

WARNINGS: (See WARNINGS in prescribing information for clarithromycin  & amoxicillin.)

PRECAUTIONS:

 General

Symptomatic response to therapy with Omeprazole does not preclude the presence of gastric malignancy. Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with Omeprazole.

Information for Patients

Omeprazole delayed-release capsules should be taken before eating. 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/applesauce mixture should not be stored for future use.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 not mutagenic in an in vitro Ames Salmonella typhimurium assay, an in vitro mouse lymphoma cell assay and an in vivo rat liver DNA damage assay.

Pregnancy

Omeprazole: Pregnancy Category C

Clarithromycin:Pregnancy Category C

Nursing Mothers

It is not known whether Omeprazole is excreted in human milk. 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.

Pediatric Use

The safety and effectiveness of Omeprazole have been established in the age group 2 years to 16 years for the treatment of acid-related gastrointestinal diseases, including the treatment of symptomatic GERD, treatment of erosive esophagitis, and the maintenance of healing of erosive esophagitis. The safety and effectiveness of Omeprazole.  have not been established for pediatric patients less than 2 years of age.

Treatment of Gastroesophageal Reflux Disease (GERD)

Symptomatic GERD

In patients aged 2 years to 16 years with a history of symptoms suggestive of nonerosive GERD, Results showed success rates of 60% (10 mg Omeprazole) and 59% (20 mg Omeprazole) in reducing the number and intensity of either pain-related symptoms or vomiting/regurgitation episodes.

Erosive Esophagitis

In pediatric patients aged 1 to 16 years required doses that ranged from 0.7 to 3.5 mg/kg/day (80 mg/day). 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 addition, maintenance therapy in erosive esophagitis patients resulted in 63% of patients having no overall symptoms.

Safety

Omeprazole delayed-release capsules administered to pediatric patients was generally well tolerated with an adverse event profile resembling that in adults. Unique to the pediatric population, however, adverse events of the respiratory system were most frequently reported in both the 0 to 2 year and 2 to 16 year age groups (46.2% and 18.5%, respectively). Similarly, otitis media was frequently reported in the 0 to 2 year age group (22.6%), and accidental injuries were reported frequently in the 2 to 16 year age group (3.8%).

Geriatric Use

There were no differences in safety and effectiveness between the elderly and younger subjects. Pharmacokinetic studies have shown the elimination rate was somewhat decreased in the elderly and bioavailability was increased.

Drug Interactions:

Omeprazole can prolong the elimination of diazepam, warfarin and phenytoin, drugs that are metabolized by oxidation in the liver. 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 P-450 system (eg, cyclosporine, disulfiram, benzodiazepines). Patients should be monitored to determine if it is necessary to adjust the dosage of these drugs when taken concomitantly with Omeprazole.

Because of its profound and long lasting inhibition of gastric acid secretion, it is theoretically possible that Omeprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). In the clinical trials, antacids were used concomitantly with the administration of Omeprazole.

Combination Therapy with Clarithromycin

Co-administration of Omeprazole and clarithromycin have resulted in increases in plasma levels of Omeprazole, clarithromycin, and 14-hydroxy-clarithromycin.

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

There have been reports of an interaction between erythromycin and astemizole resulting in QT prolongation and torsades de pointes. Concomitant administration of erythromycin and astemizole is contraindicated. Because clarithromycin is also metabolized by cytochrome P450, concomitant administration of clarithromycin with astemizole is not recommended.

SIDE EFFECTS:

The following adverse reactions which occurred in 1% or more of Omeprazole-treated patients have been reported:

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 experiences peculiar to these drug combinations have been observed. Adverse experiences that have occurred have been limited to those that have been previously reported with Omeprazole, clarithromycin, or amoxicillin.

Triple Therapy (Omeprazole /clarithromycin/amoxicillin) -- The most frequent adverse experiences observed in clinical trials using combination therapy with Omeprazole, clarithromycin, and amoxicillin were diarrhea (14%), taste perversion (10%), and headache (7%).

Dual Therapy (Omeprazole /clarithromycin) -- Adverse experiences observed in controlled clinical trials using combination therapy with Omeprazole and clarithromycin which differed from those previously described for Omeprazole alone were: Taste perversion (15%), tongue discoloration (2%), rhinitis (2%), pharyngitis (1%) and flu syndrome (1%).

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. Symptoms were transient, and no serious clinical outcome has been reported when Omeprazole was taken alone. Omeprazole is extensively protein bound and is, therefore, not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive.

DOSAGE AND ADMINISTRATION:

Short-Term Treatment of Active Duodenal Ulcer

The recommended adult oral dose of Omeprazole is 20 mg once daily. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy.

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 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 20 mg once daily is recommended for ulcer healing and symptom relief.

Dual Therapy (OMEPRAZOLE/clarithromycin) -- The recommended adult oral regimen is Omeprazole 40 mg once daily plus clarithromycin 500 mg t.i.d. for 14 days. In patients with an ulcer present at the time of initiation of therapy, an additional 14 days of Omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief.

Gastric Ulcer

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

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.

Maintenance of Healing of Erosive Esophagitis

The recommended adult oral dose is 20 mg daily.

Pathological Hypersecretory Conditions

The dosage of Omeprazole in patients with pathological hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose is 60 mg once a day.

Pediatric Patients

For the treatment of GERD or other acid-related disorders, the recommended dose for pediatric patients 2 years of age and older is as follows:

Patient Weight                                Omeprazole Dose

< 20 kg                                         10 mg

>/= 20 kg                                      20 mg  

How Supplied: Each pack of Ruz-Omeprazole 20 mg capsules contains 14 capsules in one brown glass bottle.

storage: Store in a tight container protected from light and moisture. Store between 15°C and 30°C.

Reference: PDR 2000, page 617-621

                  USPDI for Professional Health Care, 2004, Page 2131-2134

                  Martindale 2005, Page 1278-1281