Losec (Omeprazole Magnesium)

LOSEC®

Astra

Omeprazole Magnesium

H KATPase Inhibitor

Note: When used in combination with amoxicillin, clarithromycin or metronidazole, the product monographs for those agents must be consulted and followed.

Action And Clinical Pharmacology: Omeprazole inhibits the gastric enzyme H KATPase (the proton pump) which catalyzes the exchange of Hand K It is effective in the inhibition of both basal acid secretion and stimulated acid secretion. The inhibition is dose dependent. Daily oral doses of 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 20 mg tablets demonstrate the same inhibition of stimulated acid secretion and similar effect on 24-hour intragastric pH as omeprazole 20 mg capsules. The mean decrease in peak acid output after pentagastrin stimulation was approximately 70%, after 5 days of dosing with omeprazole 20 mg tablet once daily.

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

Treatment with omeprazole alone has been shown to suppress, but not eradicate H. pylori, a bacterium that is strongly associated with acid peptic disease. Approximately 90 to 100% of patients with duodenal ulcers, and 80% of patients with gastric ulcer, are infected with H. pylori. Clinical evidence indicates a synergistic effect between omeprazole and certain antibiotics in achieving eradication of H. pylori. Eradication of H. pylori is associated with symptom relief, healing of mucosal lesions, decreased rate of duodenal ulcer recurrence and long-term remission of peptic ulcer disease, and reducing the need for prolonged antisecretory therapy.

There is no statistically significant change in the bioavailability (AUC, Cmax) of amoxicillin during concomitant treatment with omeprazole, in healthy volunteers.

There is an increase in the bioavailability (AUC) and half-life of omeprazole, and bioavailability (AUC) and Cmax of clarithromycin, during concomitant administration, in healthy volunteers.

There is no statistically significant change in the bioavailability (AUC, Cmax) of metronidazole during concomitant treatment with omeprazole, in healthy volunteers.

Omeprazole tablets are absorbed rapidly. Food has no effect on the bioavailability of the tablet. Peak plasma levels occur on average within 2 hours. The 20 mg tablet and the 20 mg capsule are not bioequivalent in terms of plasma omeprazole AUC, Cmax and Tmax. Omeprazole 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.

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.

Omeprazole undergoes first-pass metabolism by the cytochrome P-450 2C19 system, mainly in the liver. 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.

Omeprazole 20 mg tablets and 20 mg capsules have an equivalent pharmacodynamic effect assessed by the inhibition of stimulated acid secretion and effect on 24-hour intragastric pH.

Indications And Clinical Uses: 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; Zollinger-Ellison syndrome (pathological hypersecretory condition); eradication of H. pylori.

Omeprazole, in combination with clarithromycin and either amoxicillin or metronidazole, is indicated for the treatment of patients with peptic ulcer disease associated with H. pylori infection. The optimal timing for eradication therapy in patients whose ulcer is not clinically active (i.e., asymptomatic) remains to be determined.

Patients who fail to have their infection eradicated may be considered to have H. pylori resistant to the antimicrobials used in the eradication regimen. Therefore, therapy involving alternative effective antimicrobial agents should be considered (if re-treating).

It has been demonstrated that resistance to metronidazole is a negative predictive factor, decreasing the eradication rate of H. pylori obtained with triple therapy (omeprazole, metronidazole and clarithromycin) by 10 to 20%. The addition of omeprazole to metronidazole and clarithromycin appears to reduce the effect of primary resistance and the development of secondary resistance compared to antimicrobials alone.

Contra-Indications: Hypersensitivity to omeprazole or any of the components of this medication (see Supplied).

Manufacturers’ Warnings In Clinical States: When gastric ulcer is suspected, the possibility of malignancy should be excluded before therapy with omeprazole is instituted, as treatment with this drug may alleviate symptoms and delay diagnosis.

Pregnancy: The safety in pregnancy has not been established. Omeprazole should not be administered to pregnant women unless the expected benefits outweigh the potential risks.

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

Children: The safety and effectiveness of omeprazole in children have not yet been established.

Precautions: Geriatrics: Elderly subjects showed increased bioavailability (36%), reduced total plasma clearance (to 250 mL/min) and prolonged (50%) elimination half-life (to 1 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).

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 4-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).

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).

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

Carcinogenicity: 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 to 140 mg/kg/day of omeprazole. No metastasis developed. No carcinoids developed during 18 months’ high-dose treatment of mice (14 to 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. Similar observations have been made after administration of histamine H2-receptor blockers and also in partially fundectomised 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.

Drug Interactions: The absorption of some drugs might be altered due to the decreased intragastric acidity. Thus, it can be predicted that the absorption of ketoconazole will 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, diazepam, phenytoin, warfarin, theophylline, propranolol, metoprolol, lidocaine, quinidine, ethanol, piroxicam, diclofenac and naproxen.

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.

Diazepam, Warfarin and Phenytoin: As omeprazole is metabolized through cytochrome P-450 2C19, it can alter the metabolism and prolong elimination of diazepam, warfarin (R-warfarin) and phenytoin.

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: 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. Concomitant treatment with omeprazole 20 mg daily did not change coagulation time in patients on continuous treatment with warfarin.

Phenytoin: Following 3 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 i.v. and oral doses of omeprazole capsules 40 mg in young, healthy volunteers, the clearance of phenytoin was decreased by 15 to 20%, and half-life was prolonged by 20 to 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 should be monitored to determine if it is necessary to adjust the dosage of these drugs when taken concomitantly with omeprazole.

Results from a range of interaction studies with omeprazole versus other drugs indicate that omeprazole, 20 to 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 (cyclosporine, lidocaine, quinidine, estradiol).

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

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 i.v. dose of lidocaine or its active metabolite, MEGX, was found after 1 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 1 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.

No interaction with food after repeated dosing of omeprazole tablets has been found. No interaction with antacids administered concomitantly with omeprazole (given as capsules) has been found.

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 2 764 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%).

In addition, the following adverse events were reported in clinical trials or were reported from routine use:

Skin: Rarely, rash and/or pruritus. In isolated cases photosensitivity, erythema multiforme and alopecia.

Musculoskeletal: In isolated cases arthralgia, muscular weakness and myalgia.

Central and Peripheral Nervous System: Rarely dizziness, paresthesia, somnolence, insomnia and vertigo. In isolated cases reversible mental confusion, agitation, depression and hallucination occurring predominantly in severely ill patients.

Gastrointestinal: nausea and vomiting. In isolated cases dry mouth, stomatitis and gastrointestinal candidiasis.

Hepatic: In rare cases, increased liver enzyme levels. In isolated cases encephalopathy in patients with pre-existing severe liver disease, hepatitis with or without jaundice and hepatic failure.

Endocrine: In isolated cases gynecomastia.

Hematologic: In isolated cases, patients have developed leukopenia and thrombocytopenia, agranulocytosis and pancytopenia.

Other: Rarely, malaise. Hypersensitive reactions including urticaria (rarely) and, in isolated cases, angioedema, fever, bronchospasm and interstitial nephritis and anaphylactic shock. In isolated cases increased sweating, peripheral edema, blurred vision and taste disturbances.

H. pylori Eradication Combination Therapy: The following adverse events (at a rate of more than 1%), were recorded during controlled clinical trials in 493 patients receiving omeprazole, amoxicillin and clarithromycin: diarrhea (28%), taste disturbances (15%), headache (5%), flatulence (4%), nausea (3%), abdominal pain (2%), ALT increased (1%), epigastric pain (1%), pharyngitis (1%) and glossitis (1%).

The following adverse events (at a rate of more than 1%) were recorded during controlled clinical trials in 494 patients receiving omeprazole, metronidazole and clarithromycin: taste disturbances (14%), diarrhea (13%), headache (6%), ALT increased (6%), flatulence (5%), nausea (5%), AST increased (5%), dyspepsia (3%), dry mouth (2%), dizziness/vertigo (2%), epigastric pain (1%), pharyngitis (1%), eructation (1%) and fatigue (1%).

Clinical experience with the use of omeprazole 20 mg tablet is limited. In 2 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 the omeprazole 20 mg tablet is similar to that seen with the omeprazole 20 mg capsule.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: 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 4 000 mg/kg. In dogs, the only sign of acute toxicity was vomiting which occurred at doses of approximately 600 mg/kg.

When used in combination with antibiotics, the prescribing information/product monograph for those antibiotics should be consulted.

Dosage And Administration: Omeprazole 20 mg tablets and omeprazole 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 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.

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 dose is 20 to 40 mg given once daily. Healing is usually achieved within 4 weeks in such patients.

Maintenance Therapy for Duodenal Ulcer: Over 95% of duodenal ulcer patients are H. pylori-positive, and should be treated with eradication therapy, as described below. A small percentage of patients who are H. pylori-negative will experience a disease recurrence and will require maintenance treatment with an antisecretory agent. The recommended omeprazole dose is 10 mg once daily, increased to 20 to 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: About 80% of gastric ulcer patients are H. pylori-positive, and should be treated with eradication therapy, as described below. A small percentage of patients who are H. pylori-negative will experience a disease recurrence and will require maintenance treatment with an antisecretory agent. The recommended omeprazole dose is 20 mg once daily, increased to 40 mg once daily as necessary.

NSAID-Associated Gastric or Duodenal Ulcers: The issue of whether or not eradication of H. pylori in patients with NSAID-associated ulcers might have beneficial preventive effects has not yet been settled.

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.

H. pylori Associated Peptic Ulcer Disease: Omeprazole, Amoxicillin and Clarithromycin Triple Therapy: The recommended dose for eradication of H. pylori is omeprazole 20 mg, amoxicillin 1 000 mg and clarithromycin 500 mg, all twice daily for 7 days.

Omeprazole, Metronidazole and Clarithromycin Triple Therapy: The recommended dose for eradication of H. pylori is omeprazole 20 mg, metronidazole 500 mg and clarithromycin 250 mg, all twice daily for 7 days.

To ensure healing and/or symptom control, further treatment with 20 mg omeprazole once daily for up to 3 weeks is recommended for patients with active duodenal ulcer, and with 20 to 40 mg omeprazole once daily for up to 12 weeks for patients with active gastric ulcer.

Patient compliance with treatment regimens for the eradication of H. pylori has been demonstrated to have a positive effect on eradication outcome. In clinical trials, patients treated with triple therapy regimens have shown high compliance rates.

Susceptibility testing (MIC values derived from the Agar dilution method) of H. pylori to metronidazole and clarithromycin is available for 486 primary isolates from patients with a history of duodenal ulcer in one European study. Resistance to metronidazole (MIC >8 mg/L) was detected in 131 strains (27%), while 9 strains (2%) were resistant to clarithromycin (MIC >1 mg/L). Secondary resistance to metronidazole developed in strains from 4 patients treated with omeprazole/metronidazole/clarithromyin. Similarly, in those patients treated with omeprazole/metronidazole/clarithromycin or omeprazole/amoxicillin/clarithromycin combinations, secondary resistance to clarithromycin developed in strains from 4 patients. For amoxicillin, the MIC values at pretherapy or post-therapy did not indicate any primary, or the development of secondary, resistance to H. pylori.

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 omeprazole 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 to 40 mg once daily.

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 respond adequately to 10 mg given once daily, individual dose adjustment should 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.

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 the patients with the severe form of the disease and inadequate response to other therapies have been adequately controlled with doses of 20 to 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 3 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).

Geriatrics: No dose adjustment is required. The daily dose should not exceed 20 mg (see Precautions).

The tablets should be swallowed whole with sufficient water.

Storage: Omeprazole tablets are moisture sensitive and are therefore provided in blister compliance packages suitable for direct distribution to the patient. Store in a dry place at controlled room temperature (15 to 30°C).

Availability And Storage: 10 mg: Each pink, circular and biconvex delayed release tablet, printed LOSEC10 on both sides, contains: omeprazole magnesium anhydrous 10.3 mg (equivalent to omeprazole 10 mg). Nonmedicinal ingredients: hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, microcrystalline cellulose, paraffin, polyethylene glycol, sodium starch glycolate, sodium stearyl fumarate, talc and titanium dioxide. Press-through blister compliance strips in cartons of 28. Dispense in original container.

20 mg: Each red-brown, circular, biconvex delayed release tablet, printed LOSEC20 on both sides, contains: omeprazole magnesium anhydrous 20.6 mg (equivalent to omeprazole 20 mg). Nonmedicinal ingredients: hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, microcrystalline cellulose, paraffin, polyethylene glycol, sodium starch glycolate, sodium stearyl fumarate, talc and titanium dioxide. Press-through blister compliance packs in cartons of 14 and 28 and in 10´10 unit dose blister packages. Dispense in the original container. (Shown in Product Recognition Section)

LOSEC® Astra Omeprazole Magnesium H KATPase Inhibitor Note: When used in combination with amoxicillin, clarithromycin or metronidazole, the product monographs for those agents must be consulted and followed.

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