Dom-Omeprazole DR Product Monograph

ACTIONS AND CLINICAL PHARMACOLOGY

Omeprazole inhibits the gastric enzyme H⁺,K⁺-ATPase (the proton pump) which catalyzes the exchange of H⁺ and K⁺. Omeprazole is effective in the inhibition of both basal acid secretion and stimulated acid secretion. The inhibition is dose-dependent. Daily oral doses of omeprazole 20 mg and higher showed a consistent and effective acid control. Information from clinical trials in patients with duodenal ulcers in remission indicate that omeprazole magnesium 20 mg tablets demonstrate the same inhibition of stimulated acid secretion and similar effect on 24-hour intragastric pH as omeprazole magnesium 20 mg capsules. The mean decrease in peak acid output after pentagastrin stimulation was approximately 70%, after 5 days of dosing with omeprazole magnesium 20 mg tablet once daily.

The 20 mg tablet and the 20 mg capsule are not bioequivalent in terms of plasma omeprazole AUC, C_max and T_max. Omeprazole magnesium 20 mg tablets demonstrate, after repeated dosing, increased plasma omeprazole AUC (18%) and maximum concentration (41%) in comparison to omeprazole 20 mg given as capsules.

The omeprazole capsule (as a multiple unit formulation) is usually emptied gradually from the stomach into the intestine. In contrast to the capsule, the tablet (as a single unit formulation) will enter the intestine and dissolve as one unit. Consequently, the absorption and first pass metabolism of the tablet take place only during a very limited period. This may be one of the reasons for the difference observed in the pharmacokinetic variables of the two formulations.

Omeprazole magnesium tablets are absorbed rapidly. Food has no effect on the bioavailability of the tablet. Peak plasma levels occur on average within 2 hours.

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Omeprazole magnesium 20 mg tablets and omeprazole magnesium 20 mg capsules have an equivalent effect on the inhibition of stimulated acid secretion and on 24-hour intragastric pH. These data support the conclusion that omeprazole magnesium 20 mg tablet and capsule can be used with equivalent efficacy in the treatment of conditions where a reduction of gastric acid secretion is required.

The equivalence of two 10 mg omeprazole magnesium tablets to one 20 mg omeprazole magnesium tablet has been demonstrated by a bioequivalence study in healthy volunteers.

The antisecretory effect of omeprazole is directly proportional to the AUC; it is not dependent on the plasma concentration at any given time. Omeprazole is 95% bound to plasma proteins.

Treatment with omeprazole magnesium alone has been shown to suppress, but not eradicate Helicobacter pylori (H. pylori), a bacterium that is strongly associated with acid peptic disease.

Omeprazole undergoes first-pass metabolism by the cytochrome P-450 system, mainly in the liver, through CYP 2C19 and CYP 3A4. The CYP 2C19 isozyme, which is involved in the metabolism of all available proton pump inhibitors, exhibits polymorphism. Approximately 3% of the Caucasian population and 15-20% of Asian populations lack a functional CYP 2C19 enzyme and are called poor metabolisers.

Following i.v. administration and oral administration (capsules) of omeprazole, 80% of the dose is recovered as urinary metabolites. The remaining 20% is excreted in the feces.

INDICATIONS AND CLINICAL USE

Dom-OMEPRAZOLE DR (omeprazole magnesium) tablets are indicated in the treatment of conditions where a reduction of gastric acid secretion is required, such as:

• duodenal ulcer;
• gastric ulcer;
• NSAID-associated gastric and duodenal ulcers;
• reflux esophagitis;
• symptomatic gastroesophageal reflux disease (GERD) i.e., heartburn and regurgitation;
• dyspepsia^*: a complex of symptoms which may be caused by any of the organic diseases listed above, or upon investigation no identifiable organic cause is found (i.e., functional dyspepsia);
• Zollinger-Ellison syndrome (pathological hypersecretory condition);

^* A working definition of dyspepsia would include the presence of epigastric pain/discomfort, with or without heartburn and regurgitation which may be accompanied by nausea, vomiting, bloating, belching, flatulence, early satiety or post-prandial fullness. Symptoms may occur either during the day or throughout the night. ^Pr Dom-OMEPRAZOLE DR Product Monograph Page 4 o

CONTRAINDICATIONS

Hypersensitivity to omeprazole, substituted benzimidazoles or any of the components of this medication (see PHARMACEUTICAL INFORMATION).

WARNINGS

In the presence of any alarm symptom (e.g., significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment may alleviate symptoms and delay diagnosis.

Concomitant administration with atazanavir and nelfinavir is not recommended (see PRECAUTIONS, Drug Interactions).

Results from studies in healthy subjects have shown a pharmacokinetic/pharmacodynamic interaction between clopidogrel (300 mg loading dose/75mg daily maintenance dose) and omeprazole (80 mg once daily, i.e., four times the recommended dose) resulting in decreased exposure to the active metabolite of clopidogrel by an average of 46% and resulting in decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 16%. Based on these data, concomitant use of omeprazole and clopidogrel should be avoided. See PRECAUTIONS, Drug Interactions.

Concomitant use of Proton Pump Inhibitors (PPIs) with Methotrexate

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. A temporary withdrawal of the PPI may be considered in some patients receiving treatments with high dose methotrexate (see PRECAUTIONS, Drug Interactions).

Use in Pregnancy

The safety of omeprazole in pregnancy has not been established. Omeprazole magnesium tablets should not be administered to pregnant women unless the expected benefits outweigh the potential risks.

Nursing Mothers

It is not known if omeprazole is secreted in human milk. Omeprazole magnesium tablets should not be given to nursing mothers unless its use is considered essential.

Use in Children

The safety and effectiveness of omeprazole magnesium tablets in children have not yet been established.

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PRECAUTIONS

General

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin and amoxicillin, which are used together with PPIs for the treatment of H. pylori, 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.

Decreased gastric acidity due to any means, including any proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to a slightly increased risk of gastrointestinal infections such as Salmonella, Campylobacter and possibly Clostridium difficile.

Use in the Elderly

Elderly subjects showed increased bioavailability (36%), reduced total plasma clearance (to 250 mL/min) and prolonged (50%) elimination half-life (to 1.0 hour) (data obtained from studies with i.v. administration of omeprazole and oral administration of omeprazole capsules). The daily dose in elderly patients should, as a rule, not exceed 20 mg (see DOSAGE AND ADMINISTRATION).

Geriatrics (>71 years of age): Benefits of use of PPIs should be weighed against the increased risk of fractures as patients in this category may already be at high risk for osteoporosis related fractures. If the use of PPIs is required, they should be managed carefully according to established treatment guidelines (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS).

Patients with Hepatic Insufficiency

Patients with impaired liver function showed a 75% increase in bioavailability, reduced total plasma clearance (to 67 mL/min), and a four-fold prolongation of the elimination half-life (to 2.8 hours) (data obtained from studies with i.v. administration of omeprazole and oral administration of omeprazole capsules). A dose of 20 mg omeprazole capsules given once daily to these patients for 4 weeks was well tolerated, with no accumulation of omeprazole or its metabolites. The daily dose in patients with severe liver disease should, as a rule, not exceed 20 mg (see DOSAGE AND ADMINISTRATION).

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Patients with Renal Insufficiency

The disposition of intact omeprazole is unchanged in patients with impaired renal function, and no dose adjustment is needed in these patients (data obtained from studies with i.v. administration of omeprazole and oral administration of omeprazole capsules) (see DOSAGE AND ADMINISTRATION).

Information on the bioavailability of omeprazole magnesium 20 mg tablet in elderly patients, in patients with hepatic insufficiency, and in patients with renal insufficiency, as well as information or drug interactions are not currently available.

Carcinogenesis

The rat carcinogenicity study (24 months) revealed a gradual development from gastric ECL-cell hyperplasia to carcinoids at the end of their normal life-span during administration with 14 -140 mg/kg/day of omeprazole. No metastasis developed. No carcinoids developed during 18 months’ high-dose treatment of mice (14 -140 mg/kg/day). Similarly, administration of omeprazole up to 28 mg/kg/day in dogs for 7 years did not cause any carcinoids.

The gastric carcinoids in rats were related to sustained hypergastrinemia secondary to acid inhibition and not to omeprazole per se (see TOXICOLOGY). Similar observations have been made after administration of histamine H₂-receptor blockers and also in partially fundectomized rats.

Short-term treatment and long-term treatment with omeprazole capsules in a limited number of patients for up to 6 years have not resulted in any significant pathological changes in gastric oxyntic endocrine cells.

Endocrine and Metabolism

Hypomagnesaemia, Hypokalemia and Hypocalcemia: The chronic use of PPIs may lead to hypomagnesaemia. Moreover, hypokalemia and hypocalcemia have been reported in the literature as accompanying electrolyte disorders.

Musculoskeletal and Connective Tissue

Bone Fracture: Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS).

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Drug Interactions

The gastric acid suppression during treatment with omeprazole and other proton pump inhibitors might decrease or increase the absorption of drugs with gastric pH dependent absorption. Thus, it can be predicted that the absorption of drugs such as ketoconazole, itraconazole and erlotinib can decrease during omeprazole treatment, as it does during treatment with other acid secretion inhibitors or antacids.

Omeprazole is metabolized by the cytochrome P-450 system (CYP), mainly in the liver. The pharmacokinetics of the following drugs, which are also metabolized through the cytochrome P-450 system, have been evaluated during concomitant use of omeprazole capsules in humans: aminopyrine, antipyrine, clopidogrel, diazepam, phenytoin, warfarin (or other vitamin K antagonists), cilostazol*, theophylline, voriconazole, digoxin, propranolol, metoprolol, lidocaine, quinidine, ethanol, piroxicam, diclofenac and naproxen.

*not marketed in Canada

Omeprazole inhibits CYP 2C19, the major omeprazole metabolizing enzyme, and is partially metabolized by CYP 3A4. Drugs known to inhibit CYP 2C19 or CYP 3A4 or both (such as clarythromycin and voriconazole) may lead to increased omeprazole serum levels by decreasing the rate of omeprazole’s metabolism. Drugs known to induce CYP 2C19 or CYP 3A4 or both (such as rifampin and St John’s Wort) may lead to decreased omeprazole serum levels by increasing omeprazole’s rate of metabolism.

Aminopyrine and Antipyrine

After 14 days’ administration of 60 mg omeprazole once daily, the clearance of aminopyrine was reduced by 19%; the clearance of antipyrine was reduced by 14%. After 14 days’ administration of 30 mg once daily, no significant changes in clearance were noted.

Clopidogrel

Results from studies in healthy subjects have shown a pharmacokinetic/pharmacodynamic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole (80 mg once daily, ie, four times the recommended dose) resulting in decreased exposure to the active metabolite of clopidogrel by an average of 46%, and resulting in decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 16%.

It is, however, uncertain to what extent this interaction is clinically important. One prospective, randomized (but incomplete) study (in over 3 760 patients comparing placebo with omeprazole 20 mg in patients treated with clopidogrel and ASA and non-randomized, post-hoc analyses of data from large, prospective, randomized clinical outcome studies (in over 47 000 patients) did not show any evidence of an increased risk for adverse cardiovascular outcome when clopidogrel and PPIs, including omeprazole, were given concomitantly.

Results from a number of observational studies are inconsistent with regard to increased risk or no increased risk for CV thromboembolic events when clopidogrel is given together with a PPI. ^Pr Dom-OMEPRAZOLE DR Product Monograph Page 8 o

When clopidogrel was given together with a fixed dose combination of esomeprazole 20 mg + ASA 81 mg compared to clopidogrel alone in a study in healthy subjects there was a decreased exposure by almost 40% of the active metabolite of clopidogrel. However, the maximum levels of inhibition of (ADP induced) platelet aggregation in these subjects were the same in the clopidogrel and the clopidogrel + the combined (esomeprazole + ASA) product groups, likely due to the concomitant administration of low dose ASA (see WARNINGS).

Diazepam, Phenytoin, Warfarin (or other vitamin K antagonists) and Cilostazol* As omeprazole magnesium is metabolized through cytochrome P-450 2C19, it can alter the metabolism and prolong elimination of diazepam, warfarin (R-warfarin), phenytoin and cilostazol*.

*not marketed in Canada

Diazepam

Following repeated dosing with omeprazole 40 mg once daily, the clearance of diazepam was decreased by 54%. The corresponding decrease after omeprazole 20 mg was 26%.

Warfarin (or other vitamin K antagonists)

Concomitant administration of omeprazole 20 mg in healthy subjects had no effect on plasma concentrations of the (S)-enantiomer of warfarin, but caused a slight, though statistically significant increase (12%) in the less potent (R)-enantiomer concentrations. A small but statistically significant increase (11%) in the anticoagulant effect of warfarin was also seen. In patients receiving warfarin or other vitamin K antagonists, monitoring of INR (International Normalised Ratio) is recommended and a reduction of the warfarin (or other vitamin K antagonist) dose may be necessary. Concomitant treatment with omeprazole 20 mg daily did not change coagulation time in patients on continuous treatment with warfarin.

Phenytoin

Following three weeks’ treatment with omeprazole 20 mg once daily, the steady-state plasma levels of phenytoin in epileptic patients already receiving concomitant phenytoin treatment were not significantly affected. Urinary excretion of phenytoin and its main metabolite were also unchanged.

After single intravenous and oral doses of omeprazole capsules 40 mg in young, healthy volunteers, the clearance of phenytoin was decreased by 15-20%, and half-life was prolonged by 20-30%. Following repeated dosing with omeprazole 40 mg once daily, the elimination half-life of phenytoin was increased by 27%. Thus, there appears to be a dose-dependent inhibition of elimination of phenytoin by omeprazole.

Patients receiving phenytoin and warfarin (or other vitamin K antagonists) should be monitored to determine if it is necessary to adjust the dosage of these drugs when taken concomitantly with omeprazole.

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Results from a range of interaction studies with omeprazole magnesium versus other drugs indicate that omeprazole, 20-40 mg given repeatedly, has no influence on other clinically relevant isoforms of CYP, as shown by the lack of metabolic interaction with substrates for CYP 1A2 (caffeine, phenacetin, theophylline), CYP 2C9 (S-warfarin), CYP 2D6 (metoprolol, propranolol), CYP 2E1 (ethanol), and CYP 3A (cyclosporin, lidocaine, quinidine, estradiol).

Cilostazol* Omeprazole, given in doses of 40 mg to health subjects in a cross-over study, increased C_max and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites, 3,4-dihydrocilostazol, by 29% and 69% respectively.

*not marketed in Canada

Methotrexate

Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted (see WARNINGS).

Antiretroviral Drugs

Omeprazole, like other acid-reducing agents, has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. A change in gastric pH may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP 2C19.

Reports indicate that omeprazole has a significant impact on atazanavir exposure, decreasing AUC, Cmax and Cmin. This interaction is only partially overcome by the addition of ritonavir to the atazanavir treatment regimen. Similarly, decreased serum levels of nelfinavir have also been reported when given together with omeprazole. Concomitant administration of omeprazole with atazanavir and nelfinavir is therefore not recommended. For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported. There are also some antiretroviral drugs where unchanged serum levels have been reported when given with omeprazole (see WARNINGS).

Tacrolimus

Although no clinical studies have been undertaken, there is a possibility that the concomitant administration of omeprazole and tacrolimus may increase serum levels of tacrolimus.

Theophylline

No effects on oral or i.v. theophylline kinetics have been observed after repeated once-daily doses of 40 mg omeprazole.

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Voriconazole

Concomitant administration of omeprazole and a CYP 2C19 and CYP 3A4 inhibitor, voriconazole, resulted in more than doubling of the omeprazole exposure. However, a dose adjustment of omeprazole is not required.

Digoxin

The absorption of digoxin can increase during treatment with omeprazole and other drugs that reduce gastric acidity. Concomitant treatment with omeprazole (20 mg daily) and digoxin in ten healthy subjects increased the bioavailability of digoxin by an average of 10% (up to 30% in two out of ten subjects).

Propranolol and Metoprolol

No effects on propranolol kinetics were observed in a steady-state trial with 20 mg of omeprazole daily. Similarly, no effects on steady-state plasma levels of metoprolol were observed after concomitant treatment with 40 mg omeprazole daily.

Lidocaine

No interaction with a single intravenous dose of lidocaine or its active metabolite, MEGX, was found after one week’s pre-treatment with omeprazole 40 mg once daily. There were no interactions between omeprazole and lidocaine or MEGX concerning pharmacokinetic variables.

Quinidine

After one week of omeprazole 40 mg once daily, no effect was observed on the kinetics or pharmacodynamics of quinidine.

Ethanol

There was no significant effect on the pharmacokinetics of ethanol after omeprazole 20 mg.

Piroxicam, Diclofenac and Naproxen

There was no significant effect on the steady-state pharmacokinetics of piroxicam, diclofenac, and naproxen following repeated dosing with omeprazole 20 mg, in healthy volunteers.

Antacids

No interaction with antacids administered concomitantly with omeprazole (given as capsules) has been found.

Food

No interaction with food after repeated dosing of omeprazole magnesium tablets has been found.

Laboratory Tests

During treatment with antisecretory drugs serum gastrin increases in response to the decreased acid secretion. Also chromogranin A (CgA) increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. Literature reports indicate that proton pump inhibitor treatment should be stopped 5 to 14 days before CgA measurement. Measurements should be repeated if levels have not normalized by this time. ^Pr Dom-OMEPRAZOLE DR Product Monograph Page 11

Other Interactions

As demonstrated with other PPIs, prolonged use may impair the absorption of protein-bound Vitamin B₁₂ and may contribute to the development of Vitamin B₁₂ deficiency.

ADVERSE REACTIONS

Omeprazole is well tolerated. Most adverse reactions have been mild and transient, and have shown no consistent relationship with treatment. Adverse events have been recorded during controlled clinical investigations in 2764 patients exposed to omeprazole (data taken from controlled clinical studies with omeprazole capsules) or reported from routine use. In a controlled clinical trial comparing omeprazole to placebo, the prevalence of adverse events with omeprazole 40 mg once daily was similar to that with placebo. In short-term comparative double-blind studies with histamine H₂-receptor antagonists, there was no significant difference in the prevalence of adverse events between omeprazole capsules and the H₂-receptor antagonists. An extensive evaluation of laboratory variables has not revealed any significant changes during omeprazole treatment which are considered to be clinically important.

The following adverse events (at a rate of more than 1%) have been reported in individuals receiving omeprazole capsules in controlled clinical situations: diarrhea (2.8%); headache (2.6%); flatulence (2.3%); abdominal pain (1.7%); constipation (1.3%); and dizziness/vertigo (1.1%).

The following is a list of adverse events reported in clinical trials or reported from routine use. Events are classified within body system categories. The following definitions of frequencies are used: common: ≥ 1/100; uncommon: ≥ 1/1000 and <1/100; rare: <1/1000, and very rare: <1/10000.

Central and Peripheral Nervous System: Common: headache. Uncommon: dizziness, paresthesia, somnolence, insomnia and vertigo. Rare: reversible mental confusion, agitation, aggression, depression and hallucination occurring predominantly in severely ill patients.

Endocrine: Rare: gynaecomastia.

Gastrointestinal: Common: diarrhoea, constipation, abdominal pain, nausea/vomiting and flatulence. Rare: dry mouth, stomatitis, gastrointestinal candidiasis

and microscopic colitis.

Hematological: Rare: leukopenia, thrombocytopenia, agranulocytosis and pancytopenia.

Hepatic: Uncommon: increased liver enzyme levels. Rare: encephalopathy in patients with pre-existing severe liver disease; hepatitis with or without jaundice and hepatic failure.

Musculoskeletal: Rare: arthralgia, muscular weakness and myalgia.

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Skin: Uncommon: rash, dermatitis and/or pruritus, and uticaria. Rare: photosensitivity, erythema multiforme, Stevens-Johnsons syndrome, toxic epidermal necrolysis (TEN) and alopecia.

Other Adverse Events: Uncommon: malaise, hypersensitive reactions including urticaria Rare: hypersensitive reactions including angioedema, fever, bronchospasm and interstitial nephritis and anaphylactic shock; increased sweating, peripheral edema, blurred vision, taste disturbances and hyponatraemia. Very rare: hypomagnesaemia (severe hypomagnesaemia may result in hypocalcaemia).

Clinical experience with the use of omeprazole magnesium 20 mg tablet is limited. In two short term studies (20 mg tablet once daily for a maximum duration of 7 days) in a limited number of patients with duodenal ulcer in remission, the adverse event profile seen with omeprazole magnesium 20 mg tablet is similar to that seen with omeprazole magnesium 20 mg capsule.

Gastrointestinal: Withdrawal of long-term PPI therapy can lead to aggravation of acid related symptoms and may result in rebound acid hypersecretion.

Musculoskeletal and Connective Tissue: Osteoporosis and osteoporosis-related fractures have been reported with multiple daily doses and long-term PPI therapy.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

No information is available on the effects of higher doses in man, and specific recommendations for treatment cannot be given. Single oral doses of up to 400 mg of omeprazole capsules have not resulted in any severe symptoms, and no specific treatment has been needed. As in all cases where overdosing is suspected, treatment should be supportive and symptomatic. Any unabsorbed material should be removed from the gastrointestinal tract, and the patient should be carefully monitored.

The oral LD₅₀ of omeprazole in male and female rats and mice was greater than 4000 mg/kg. In dogs, the only sign of acute toxicity was vomiting, which occurred at doses of approximately 600 mg/kg (see TOXICOLOGY).

DOSAGE AND ADMINISTRATION

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

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Duodenal Ulcer

Acute Therapy: The recommended adult oral dose is 20 mg given once daily. Healing usually occurs within 2 weeks. For patients not healed after this initial course of therapy, an additional 2 weeks of treatment is recommended.

Refractory Patients: In patients with duodenal ulcer refractory to other treatment regimens, the recommended adult doses are 20 mg-40 mg given once daily. Healing is usually achieved within 4 weeks in such patients.

Maintenance Therapy for Duodenal Ulcer: The recommended Dom-OMEPRAZOLE DR (omeprazole magnesium) dose is 10 mg once daily, increased to 20-40 mg once daily as necessary.

Gastric Ulcer

Acute Therapy: The recommended adult dose is 20 mg given once daily. Healing usually occurs within 4 weeks. For patients not healed after this initial course of therapy, an additional 4 weeks of treatment is recommended.

Refractory Patients: In patients with gastric ulcer refractory to other treatment regimens, the recommended adult dose is 40 mg given once daily. Healing is usually achieved within 8 weeks.

Maintenance Therapy for Gastric Ulcer: The recommended Dom-OMEPRAZOLE DR dose is 20 mg once daily, increased to 40 mg once daily as necessary.

Reflux Esophagitis

Acute Therapy: The recommended adult dose is 20 mg given once daily. In most patients, healing occurs within 4 weeks. For patients not healed after this initial course of therapy, an additional 4 weeks of treatment is recommended.

Refractory Patients: For patients with reflux esophagitis refractory to other treatment regimens, the recommended adult dose is 40 mg given once daily. Healing is usually achieved within 8 weeks.

Maintenance Therapy for Reflux Esophagitis: For the long-term management of patients with healed reflux esophagitis, 10 mg omeprazole (given as capsules) once daily has been found to be effective in controlled clinical trials of 12 months’ duration, and in continuous maintenance treatment, in a limited number of patients, for a period of up to 6 years. Therefore, the recommended adult dose of Dom-OMEPRAZOLE DR tablets for maintenance treatment of patients with healed reflux esophagitis is 10 mg given once daily. In the case of recurrence, the dose can be increased to 20-40 mg once daily.

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Symptomatic Gastroesophageal Reflux Disease (i.e., Heartburn and Regurgitation)

The recommended adult dose is 20 mg given once daily. Symptom relief should be rapid. If symptom control is not achieved after 4 weeks, further investigation is recommended. Since some patients may respond adequately to 10 mg given once daily, individual dose adjustment can be considered. For the maintenance of symptom relief in patients with gastroesophageal reflux disease (i.e., heartburn and regurgitation) the recommended adult dose is 10 mg given once daily.

NSAID-Associated Gastric or Duodenal Ulcers

Acute Therapy: In patients with NSAID-associated gastric or duodenal ulcers, the recommended adult dose is 20 mg given once daily. Symptom resolution is rapid and healing usually occurs within 4 weeks. For those patients not healed after this initial course of therapy, an additional 4 weeks of treatment is recommended.

Maintenance Therapy: For the prevention of relapse in patients with NSAID-associated gastric or duodenal ulcers, the recommended adult dose is 20 mg given once daily, for up to 6 months.

Dyspepsia

Prior to treating patients presenting with dyspeptic symptoms, it should be determined that these symptoms are originating from the upper gastrointestinal tract. Patients presenting with alarm symptoms (see WARNINGS), and older patients who are at a greater risk of having a serious organic disease, should be investigated prior to the initiation of therapy. If the dyspeptic symptoms are known to be related to a diagnosis of organic disease, the appropriate treatment regimen listed in the sections above should be employed.

If the dyspeptic symptoms are not known to be related to an organic disease, the recommended daily dose of Dom-OMEPRAZOLE DR is 20 mg once daily for 4 weeks. If after 2 weeks’ treatment the patient does not respond to therapy, or there is an early clinical indication of a lack of efficacy, the patient should be thoroughly investigated in order to rule out organic disease (see WARNINGS). If there are indications of a clinical response following the initial 2 weeks of treatment, Dom-OMEPRAZOLE DR may be continued for an additional 2 weeks. Patients may respond adequately to 10 mg once daily therefore, individual dose adjustment may be considered.

Epigastric pain/discomfort (with or without heartburn and regurgitation) as predominant symptoms, are likely to respond to acid suppression therapy. In all cases, patients who do not respond to 4 weeks’ treatment, or whose symptoms recur shortly after discontinuation of treatment, with Dom-OMEPRAZOLE DR should be investigated for underlying organic diseases.

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Zollinger-Ellison Syndrome

The dose used in the treatment of Zollinger-Ellison syndrome will vary with the individual patient.

The recommended initial dose is 60 mg, given once daily. More than 90% of patients with the severe form of the disease and inadequate response to other therapies have been adequately controlled with doses of 20-120 mg omeprazole capsules daily. With doses greater than 80 mg, the dose should be divided and given twice daily. Doses should be adjusted to the individual patient’s need and should continue as long as clinically indicated. Doses up to 120 mg omeprazole capsules three times daily have been administered.

Patients with Renal Insufficiency: No dose adjustment is required (see PRECAUTIONS).

Patients with Hepatic Insufficiency: No dose adjustment is required. The daily dose should not exceed 20 mg (see PRECAUTIONS).

Elderly Patients: No dose adjustment is required. The daily dose should not exceed 20 mg (see PRECAUTIONS).

The tablets should be swallowed whole with sufficient water.

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PHARMACEUTICAL INFORMATION

Composition

Active:

omeprazole magnesium 10.3 mg (corresponds to 10 mg omeprazole/tablet)

20.6 mg (corresponds to 20 mg omeprazole/tablet)

Nonmedicinal:

Colloidal silicon dioxide, copovidone, croscarmellose sodium, eudragit, FD&C Blue No.1, FD&C Red No.40, FD&C yellow No.6, lactose, lecithin, microcrystalline cellulose, propylene glycol, shellac glaze, simethicone, sodium lauryl sulfate, sodium stearyl fumarate, talc, titanium dioxide, triethyl citrate and red iron oxide. In addition to the non-medicinal ingredients listed above, the 10 mg strength contains also iron oxide yellow No. 10.

Stability and Storage Recommendations

Omeprazole magnesium tablets are moisture sensitive and are therefore provided in blister packages suitable for direct distribution to the patient. Store between 15ºC and 25ºC. Protect from moisture.

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Omeprazole magnesium tablets are also provided in HDPE bottles. Store between 15°C and 30°C. Protect from moisture.

AVAILABILITY OF DOSAGE FORMS

Dom-OMEPRAZOLE DR 10 mg: Pink, biconvex, round, coated tablet, ink-printed in black with "P 10" on one side and plain on the other side. Available in HDPE bottles of 100 tablets and in blister packages of 30 tablets.

Dom-OMEPRAZOLE DR 20 mg: Red-brown, biconvex, round, coated tablet, ink-printed in black with "P 20" on one side and nothing on the other side. Available in HDPE bottles of 100 tablets and 500 tablets and in blister packages of 30 tablets.