Omeprazole STADA

Omeprazole STADA is indicated in adults and children over 1 year of age and > 10kg.

Omeprazole STADA gastro-resistant capsules are indicated in:

Adults:

- Treatment of duodenal ulcers

- Prevention of relapse of duodenal ulcers

- Treatment of gastric ulcers

- Prevention of relapse of gastric ulcers

- In combination with appropriate antibiotics, Helicobacter pylori (H. pylori) eradication in peptic ulcer disease

- Treatment of NSAID associated gastric and duodenal ulcers

- Prevention of NSAID associated gastric and duodenal ulcers in patients at risk

- Treatment of reflux esophagitis

- Long term management of patients with healed reflux esophagitis

- Treatment of symptomatic gastro-esophageal reflux disease

- Treatment of Zollinger-Ellison syndrome

Paedriatric population:

Children over 1 year of age and >10 kg

- Treatment of reflux esophagitis,

- Symptomatic treatment of heartburn and acid regurgitation in gastro-esophageal reflux disease

Children and adolescents over 4 years of age

- In combination with antibiotics in the treatment of duodenal ulcer caused by H. pylori

Posology in adults

Treatment of duodenal ulcers

The recommended dose in patients with an active duodenal ulcer is Omeprazole STADA 20 mg once daily. In most patients healing occurs within two weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further two weeks treatment period. In patients with a poorly responsive duodenal ulcer Omeprazole STADA 40mg once daily is recommended and healing is usually achieved within four weeks.

Prevention of relapse of duodenal ulcers

For the prevention of relapse of duodenal ulcer in H. pylori negative patients or when H. pylori eradication is not possible the recommended dose is Omeprazole STADA 20mg once daily. In some patients a daily dose of 10mg may be sufficient. In case of therapy failure, the dose can be increased to 40mg.

Treatment of gastric ulcers

The recommended dose is 20mg once daily. In most patients healing occurs within four weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further four weeks treatment period. In patients with a poorly responsive gastric ulcer Omeprazole STADA 40mg once daily is recommended and healing is usually achieved within eight weeks.

Prevention of relapse of gastric ulcers

For the prevention of relapse in patients with poorly responsive gastric ulcer the recommended dose is Omeprazole STADA 20mg once daily. If needed the dose can be increased to Omeprazole STADA 40mg once daily.

H. pylori eradication in peptic ulcer disease

For the eradication of H. pylori the selection of antibiotics should consider the individual patient's drug tolerance, and should be undertaken in accordance with national, regional and local resistance patterns and treatment guidelines.

- Omeprazole STADA 20 mg + clarithromycin 500 mg + amoxicillin 1000 mg, each twice daily for 1 week

or

- Omeprazole STADA 20 mg + clarithromycin 250 mg (alternatively 500mg) + metronidazole 400mg-(or 500 mg or tinidazole 500mg) each twice daily for one week

or

- Omeprazole STADA 40 mg once daily with amoxicillin 500 mg + metronidazole 400mg (or 500 mg or tinidazole 500mg) both three times a day for one week

In each regimen, if the patient is still H. pylori positive, therapy may be repeated.

Treatment of NSAID - associated gastric and duodenal ulcers:

For the treatment of NSAID -associated gastric and duodenal ulcers, the recommended dose is Omeprazole STADA 20 mg once daily. In most patients healing occurs within four weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further four weeks treatment period.

Prevention of NSAID -associated gastric and duodenal ulcers in patients at risk

For the prevention of NSAID -associated gastric ulcers and duodenal ulcers in patients at risk (age >60, previous history of gastric and duodenal ulcers, previous history of upper GI bleeding) the recommended dose is 20mg Omeprazole STADA once daily.

Treatment of reflux esophagitis

The recommended dose is Omeprazole STADA 20mg once daily. In most patients healing occurs within 4 weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further four weeks treatment period.

In patients with severe esophagitis Omeprazole STADA 40mg once daily is recommended and healing is usually achieved within eight weeks.

Long-term management of patients with healed reflux esophagitis

For the long-term management of patients with healed reflux esophagitis the recommended dose is Omeprazole STADA 10mg once daily. If needed, the dose can be increased to Omeprazole STADA 20-40mg once daily.

Treatment of symptomatic of gastro-esophageal reflux disease

The recommended dose is Omeprazole STADA 20mg daily. Patients may respond adequately to 10mg daily, and therefore individual dose adjustments should be considered. If symptom control has not be achieved after four weeks treatment with Omeprazole STADA 20mg daily, further investigation is recommended.

Treatment of Zollinger-Ellison syndrome

In patients with Zollinger-Ellison syndrome the dose should be individually adjusted and treatment continued as long as clinically indicated. The recommended initial dose is Omeprazole STADA 60mg daily. All patients with severe disease and inadequate response to other therapies have been effectively controlled and more than 90% of the patients maintained on doses of Omeprazole STADA 20-120mg daily. When the dose exceeds Omeprazole STADA 80mg daily, the dose should be divided and given twice daily.

Paediatric population

The safety and efficacy of Omeprazole STADA in children aged 0-12 months and < 10kg has not yet been established.

Children over 1 year of age and > 10 kg

Treatment of Reflux esophagitis

Symptomatic treatment of heartburn and acid regurgitation in gastro-esophageal reflux disease

The posology recommendations are as follows:

Reflux esophatitis

The treatment time is 4-8 weeks.

Symptomatic treatment of heartburn and acid regurgitation in gastro-esophageal reflux disease

The treatment time is 2-4 weeks. If symptom control has not been achieved after 2-4 weeks the patient should be investigated further.

Children and adolescents over 4 years of age

Treatment of duodenal ulcer caused by H pylori.

When selecting appropriate combination therapy, consideration should be given to official national, regional and local guidelines regarding bacterial resistance, duration of treatment (most commonly 7 days but sometimes up to 14 days) and appropriate use of antibacterial agents.

The treatment should be supervised by a specialist.

The posology recommendations are as follows:

Special Populations:

Renal impairment

Dose adjustment is not required in patients with impaired renal function.

Hepatic impairment

In patients with impaired hepatic function a daily dose of 10-20mg may be sufficient.

Elderly

Dose adjustment is not required in the elderly.

Method of administration:

It is recommended to take Omeprazole STADA capsules in the morning, preferably without food, swallowed whole with half a glass of water.

The capsules must not be crushed or chewed.

For patients with swallowing difficulties and for children who can drink or swallow semi-solid food:

Patients can open the capsule and swallow the contents with half a glass of water or after mixing the contents in a slightly acidic fluid e.g. fruit juice or apple sauce, or in non-carbonated water. Patients should be advised that the dispersion should be taken immediately (or within 30 minutes) and always be stirred just before drinking and rinsed down with half a glass of water.

Alternatively patients can suck the capsule and swallow the pellets with half a glass of water. The enteric-coated pellets must not be chewed.

Omeprazole STADA like other proton pump inhibitors (PPIs) must not be used concommitantly with nelfinavir.

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

Co-administration of atazanavir with proton pump inhibitors is not recommended. If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g. virus load) is recommended in combination with an increase in the dose of atazanavir to 400mg with 100mg of ritonavir; Omeprazole STADA 20mg should not be exceeded.

Omeprazole STADA as with all acid blocking medicines, may reduce the absorption of vitamin B₁₂ (cyanocobalamin) due to hypo or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B₁₂ absorption on long-term therapy.

Omeprazole STADA is a CYP2C19 inhibitor. When starting or ending treatment with Omeprazole STADA, the potential for interactions with drugs metabolized through CYP2C19 should be considered. An interaction is observed between clopidogrel and Omeprazole STADA. The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of Omeprazole STADA and clopidogrel should be discouraged.

Hypomagnesaemia

Severe hypomagnesaemia has been reported in patients treated with PPIs like Omeprazole STADA for at least three months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with digoxin or other medicines that may cause hypomagnesaemia (e.g. diuretics), healthcare professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment;

Proton pump inhibitors, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fractures by 10-40%. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of vitamin D and calcium.

Subacute cutaneous lupus erythematosus (SCLE)

Proton pump inhibitors are associated with very infrequent cases of SCLE. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the healthcare professional should consider stopping Omeprazole STADA. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Interference with laboratory tests

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, Omeprazole STADA treatment should be stopped for at least five days before CgA measurements. If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor treatment.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and in hospitalised patients possibly also Clostridium difficile.

As in all long-term treatments, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.

Paediatric population:

Some children with chronic illnesses may require long-term treatment although it is not recommended.

Omeprazole STADA has no or negligible influence on the ability to drive or use machines. Adverse drug reactions such as dizziness and visual disturbance may occur. If affected, patients should not drive or operate machinery.

The most common side effects (1-10% of patients) are headache, abdominal pain, constipation, diarrhoea, flatulence and nausea/vomiting.

The following adverse drug reactions have been identified or suspected in the clinical trials programme for Omeprazole STADA and post-marketing. None was found to be dose-related.

Adverse reactions listed below are classified according to the frequency and System Organ Class (SOC). Frequency categories are defined according to the following convention:

- very common (>1/10)

- common (>1/100 to<1/10)

- uncommon (>1/1,000 -to <1/100)

- rare (>1/10,000 to <1/1,000)

- very rare (<1/10,000)

- not known (cannot be estimated from the available data)

Paediatric Population

The safety of Omeprazole STADA has been assessed in a total of 310 children aged 0 to 16 years with acid-related disease. There are limited long term safety data from 46 children who received maintenance therapy of Omeprazole STADA during a clinical study for severe erosive oesophagitis for up to 749 days. The adverse event profile was generally the same as for adults in short- as well as in long-term treatment. There are no long term data regarding the effects of Omeprazole STADA treatment on puberty and growth.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

There is limited information available on the effects of overdoses of Omeprazole STADA in humans. In literature, doses of up to 560 mg have been described, and occasional reports have been received when single oral doses have been reached of up to 2,400 mg Omeprazole STADA (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported. Also apathy, depression and confusion have been described in single cases.

The symptoms described in connection with Omeprazole STADA overdose have been transient, and no serious outcome has been reported. The rate of elimination was unchanged (first order kinetics) with increased doses. Treatment, if needed, is symptomatic.

Pharmacotherapeutic group: Proton pump inhibitors, ATC-code: A02BC01

Mechanism of Action:

Omeprazole STADA, a racemic mixture of two enantiomers, reduces gastric acid secretion through a highly targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. It is rapidly acting and provides control through reversible inhibition of gastric acid secretion with once daily dosing.

Omeprazole STADA is a weak base and is concentrated and converted to the active form in the highly acidic environment of the intracellular canaliculi within the parietal cell, where it inhibits the enzyme H+, K+-ATPase - the acid pump. This effect on the final step of gastric acid formation process is dose-dependent and provides for highly effective inhibition of both basal acid secretion and stimulated acid secretion, irrespective of stimulus.

Pharmacodynamic effects:

All pharmacodynamic effects observed can be explained by the effect of Omeprazole STADA on acid secretion.

Clinical Efficacy and Safety:

Effect on gastric acid secretion:

Oral dosing with Omeprazole STADA once daily provides for rapid and effective inhibition of daytime and night-time gastric acid secretion with maximum effect being achieved within 4 days of treatment. With Omeprazole STADA 20mg, a mean decrease of at least 80% in 24-hour intragastric acidity is then maintained on duodenal ulcer patients, with the mean decrease in peak acid output after pentagastrin stimulation being about 70% 24 hours after dosing.

Oral dosing with Omeprazole STADA 20mg maintains an intragastric pH of > 3 for a mean time of 17 hours of the 24-hour period in duodenal ulcer patients.

As a consequence of reduced acid secretion and intragastric acidity, Omeprazole STADA dose-dependently reduces/normalizes acid exposure of the esophagus in patients with gastro-esophageal reflux disease. The inhibition of acid secretion is related to the area under the plasma concentration-time curve (AUC) of Omeprazole STADA and not the actual plasma concentration at a given time.

No tachyphylaxis has been observed during treatment with Omeprazole STADA.

Effect on H. pylori

H. pylori is associated with peptic ulcer disease, including duodenal and gastric ulcer disease. H. pylori is a major factor in the development of gastritis. H. pylori together with gastric acid are major factors in the development of peptic ulcer disease. H. pylori is a major factor in the development of atrophic gastritis which is associated with an increased risk of developing gastric cancer.

Eradication of H. pylori with Omeprazole STADA and antimicrobials is associated with high rates of healing and long-term remission of peptic ulcers.

Dual therapies have been tested and have been found to be less effective than triple therapies. They could however be considered in cases where known hypersensitivity precludes the use of any triple combination.

Other effects related to acid inhibition

During long-term treatment gastric glandular cysts have been reported in somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.

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

During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion. Also CgA increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours.

Available published evidence suggests that proton pump inhibitors should be discontinued between 5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range.

An increased number of ECL cells possibly related to the increased serum gastrin levels, have been observed in some patients (both children and adults) during long term treatment with Omeprazole STADA. The findings are considered to be of no clinical significance.

Paediatric population

In a non-controlled study in children (1 to 16 years of age) with severe reflux esophagitis, Omeprazole STADA at doses of 0.7 to 1.4 mg/kg improved esophagitis level in 90 % of the cases and significantly reduced reflux symptoms. In a single-blind study, children aged 0-24 months with clinically diagnosed gastro-esophageal reflux disease were treated with 0.5, 1.0 or 1.5 mg Omeprazole STADA/kg. The frequency of vomiting/regurgitation episodes decreased by 50 % after 8 weeks of treatment irrespective of the dose.

Eradication of Helicobacter pylori in children

A randomised, double-blind clinical study (Heliot study) concluded that Omeprazole STADA in combination with two antibiotics (amoxicillin and clarithromycin) was safe and effective in the treatment of H. pylori infection in children of 4 years old and above with a gastritis: H. pylori eradication rate: 74 % (23/31 patients) with Omeprazole STADA + amoxicillin + clarithromycin versus 9.4 % (3/32 patients) with amoxicillin + clarithromycin. However, there was no evidence of clinical benefit demonstrated regarding dyspeptic symptoms. This study does not support any information for children aged less than 4 years old.

Absorption

Omeprazole STADA is acid labile and is therefore administered orally as enteric-coated granules in hard-gelatin capsules. Absorption of Omeprazole STADA is rapid, with peak-plasma levels occurring 1-2 hours after the dose. Absorption of Omeprazole STADA takes place in the small intestine and is usually completed within 3-6 hours. Concomitant intake of food has no influence on the bioavailability. The systemic availability (bioavailability) from a single oral dose of Omeprazole STADA is approximately 40%. After repeated once-daily administration, the bioavailability increases to about 60%.

Distribution

The apparent volume of distribution in healthy subjects is approximately 0.3l/kg body weight. Omeprazole STADA is 97% protein bound.

Biotransformation

Omeprazole STADA is completely metabolised, by the cytochrome P450 system (CYP). The major part of metabolism is dependent on the polymorphically expressed CYP 2C19 responsible for the formation of hydroxyOmeprazole STADA, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of Omeprazole STADA Sulphone. As a consequence of high affinity of Omeprazole STADA to CYP 2C19, there is the potential for competitive inhibition and metabolic drug-drug interactions with other substrates for CYP 2C19. However due to low affinity to CYP3A4, Omeprazole STADA has no potential to inhibit the metabolism of other CYP3A4 substrates. In addition Omeprazole STADA lacks an inhibitory effect on the main CYP enzymes.

Approximately 3% of the Caucasian population and 15-20% of the Asian population lack a functional CYP 2C19 enzyme and are called poor metabolisers. In such individuals the metabolism of Omeprazole STADA is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 20mg Omeprazole STADA the mean AUC was 5 to 10 times higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were also higher, by 3 to 5 times. These findings have no implications for the posology of Omeprazole STADA.

Elimination

The plasma elimination half life of Omeprazole STADA is usually shorter than one hour both after single and repeated oral once daily dosing. Omeprazole STADA is completely eliminated from plasma between doses with no tendency for accumulation during once daily administration. Almost 80% of an oral dose of Omeprazole STADA is excreted as metabolites in the urine, the remainder in the faeces, primarily originating from bile secretion.

The AUC of Omeprazole STADA increases with repeated administration. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. This time- and dose- dependency is due to a decrease of first pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by Omeprazole STADA and /or it's metabolites (e.g. the sulphone).

No metabolite has been found to have any effect on gastric acid secretion.

Special Populations

Impaired hepatic function

The metabolism of Omeprazole STADA in patients with liver dysfunction is impaired, resulting in an increased AUC. Omeprazole STADA has not shown any tendency to accumulate with once-daily dosing.

Impaired renal function

The pharmacokinetics of Omeprazole STADA, including systemic bioavailability and elimination rate, are unchanged in patients with reduced renal function.

Elderly

The metabolism rate of Omeprazole STADA is somewhat reduced in elderly subjects (75-79 years of age).

Paediatric patients

During treatment with the recommended doses to children from the age of 1 year, similar plasma concentrations were obtained as compared to adults. In children younger than 6 months, clearance of Omeprazole STADA is low due to low capacity to metabolise Omeprazole STADA.

Gastric ECL-cell hyperplasia and carcinoids have been observed in life-long studies in rats treated with Omeprazole STADA. These changes are the result of sustained hypergastrinaemia secondary to acid inhibition. Similar findings have been made after treatment with H₂-receptor antagonists, proton pump inhibitors and after partial fundectomy. Thus, these changes are not from a direct effect of any individual active substance.

Not applicable.

No special requirements for disposal.