SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Losec Acid Control 10 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each gastro-resistant tablet contains 10.3 mg omeprazole magnesium equivalent to 10 mg omeprazole.

Contains sucrose (19-20 mg).

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Gastro-resistant tablet. (tablet).

Light-pink, oblong, biconvex, film-coated tablets engraved with on one side and 10 mg on the other side, containing enteric-coated pellets (also called Multiple-Unit Pellet System MUPS®).

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of oesophageal reflux disease. In reflux oesophagitis the majority of patients are healed after 4 weeks. Symptom relief is rapid.

Treatment of duodenal and benign gastric ulcers including those complicating NSAID therapy.

Relief of reflux-like symptoms (e.g. heartburn) and/or ulcer-like symptoms (e.g. epigastric pain) associated with acid-related dyspepsia.

Treatment and prophylaxis of NSAID-associated benign gastric ulcers, duodenal ulcers and gastroduodenal erosions in patients with a previous history of gastroduodenal lesions who require continued NSAID treatment.

Relief of associated dyspeptic symptoms.

Helicobacter pylori eradication: Omeprazole should be used in combination with antibiotics for eradication of Helicobacter pylori (Hp) in peptic ulcer disease.

Relief of associated dyspeptic symptoms. Prophylaxis of acid aspiration.

Zollinger-Ellison syndrome.

Children over 1 year of age and > 10 kg

Reflux oesophagitis.

Symptomatic treatment of heartburn and acid regurgitation in gastroesophageal reflux disease.

4.2 Posology and method of administration Dosage

Adults

Oesophageal reflux disease including reflux oesophagitis:

The usual dosage is 20 mg Losec once daily. The majority of patients are healed after 4 weeks. For those patients not fully healed after the initial course, healing usually occurs during a further 4-8 weeks treatment.

Losec has also been used at a dose of 40 mg once daily in patients with reflux oesophagitis refractory to other therapy. Healing usually occurs within 8 weeks. Patients can be continued at a dosage of 20 mg once daily.

Acid reflux disease:

For long-term management, Losec 10 mg once daily is recommended, increasing to 20 mg if symptoms return.

Duodenal and benign gastric ulcers:

The usual dose is 20 mg Losec once daily. The majority of patients with duodenal ulcer are healed after 4 weeks. The majority of patients with benign gastric ulcer are healed after 8 weeks. In severe or recurrent cases the dose may be increased to 40 mg Losec daily. Long-term therapy for patients with a history of recurrent duodenal ulcer is recommended at a dosage of 20 mg Losec once daily.

For prevention of relapse in patients with duodenal ulcer the recommended dose is Losec 10 mg, once daily, increasing to 20 mg, once daily if symptoms return.

The following groups are at risk from recurrent ulcer relapse: those with Helicobacter pylori infection, younger patients (<60 years), those whose symptoms persist for more than one year and smokers. These patients will require initial long-term therapy with Losec 20 mg once daily, reducing to 10 mg once daily, if necessary.

Acid-related dyspepsia:

The usual dosage is Losec 10 mg or 20 mg once daily for 2-4 weeks depending on the severity and persistence of symptoms. Patients who do not respond after 4 weeks or who relapse shortly afterwards, should be investigated.

For the treatment of NSAID-associated gastric ulcers, duodenal ulcers or gastroduodenal erosions:

The recommended dosage of Losec is 20 mg once daily. Symptom resolution is rapid and 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 4 weeks treatment.

For the prophylaxis of NSAID-associated gastric ulcers, duodenal ulcers, gastroduodenal erosions and dyspeptic symptoms in patients with a previous history of gastroduodenal lesions who require continued NSAID treatment: The recommended dosage of Losec is 20 mg once daily.

Helicobacter pylori (Hp) eradication regimens in peptic ulcer disease:

Losec is recommended at a dose of 40 mg once daily or 20 mg twice daily in association with antimicrobial agents as detailed below:

Triple therapy regimens in duodenal ulcer disease:

Losec and the following antimicrobial combinations:

Amoxicillin 500 mg and metronidazole 400 mg both three times a day for one week

or

Clarithromycin 250 mg and metronidazole 400 mg (or tinidazole 500 mg) both twice a day for one week

or

Amoxicillin 1 g and clarithromycin 500 mg both twice a day for one week.

Dual therapy regimens in duodenal ulcer disease:

Losec and amoxicillin 750 mg to 1 g twice daily for two weeks.

Alternatively Losec and clarithromycin 500 mg three times a day for two weeks.

Dual therapy regimens in gastric ulcer disease:

Losec and amoxicillin 750 mg to 1 g twice daily for two weeks.

In each regimen if symptoms return and the patient is Hp positive, therapy may be repeated or one of the alternative regimens can be used; if the patient is Hp negative then see dosage instructions for acid reflux disease.

To ensure healing in patients with active peptic ulcer disease, see further dosage recommendations for duodenal and benign gastric ulcer.

Prophylaxis of acid aspiration:

For patients considered to be at risk of aspiration of the gastric contents during general anaesthesia, the recommended dosage is Losec 40 mg on the evening before surgery followed by Losec 40 mg 2-6 hours prior to surgery.

Zollinger-Ellison syndrome:

The recommended initial dosage is 60 mg Losec once daily. The dosage should be adjusted individually and treatment continued as long as clinically indicated. More than 90% of patients with severe disease and inadequate response to other therapies have been effectively controlled on doses of 20120 mg daily. With doses above 80 mg daily, the dose should be divided and given twice daily.

Elderly

Dose adjustment is not required in the elderly.

Children

Reflux oesophagitis:

The treatment time is 4-8 weeks.

Symptomatic treatment of heartburn and acid regurgitation in gastroesophageal 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.

The dosage recommendations are as follows:

Age    Weight

> 1 year of age    10-20 kg

20 mg once daily.

The dosage can increased to 40 mg once daily if needed.

Children over 4 years of age

In combination with antibiotics in treatment of duodenal ulcer caused by Helicobacter pylori. When selecting appropriate combination therapy consideration should be given to official local guidance 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.

Dosage

Combination with two antibiotics: Losec 10 mg, amoxicillin 25 mg/kg body weight and clarithromycin 7.5 mg/kg body weight are all administered together 2 times daily for 1 week.

Combination with    two    antibiotics:    Losec    20    mg,

amoxicillin 750 mg and clarithromycin 7.5 mg/kg body weight are all administered 2 times daily for 1 week.

Combination with    two    antibiotics:    Losec    20    mg,

amoxicillin 1 g and clarithromycin 500 mg are all administered 2 times daily for 1 week.

Impaired renal function

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

As bioavailability and half-life can increase in patients with impaired hepatic function, the dose requires adjustment with a maximum daily dose of 20 mg.

For patients (including children aged 1 year and above who can drink or swallow semi-solid food) who are unable to swallow Losec

The tablets may be dispersed in 10 ml of non-carbonated water and then suspended in a small amount of any fruit juice with a pH less than 5 e.g. apple, orange, pineapple or in apple sauce or yoghurt after gentle mixing. Do not use milk or carbonated water. The dispersion should be taken immediately or within 30 minutes. Stir the dispersion just before drinking and rinse it down with half a glass of water. There is no evidence to support the use of sodium bicarbonate buffer as a delivery form. It is important that the tablets should not be crushed or chewed.

4.3 Contraindications

Known hypersensitivity to omeprazole or to any of the other constituents of the formulation.

When gastric ulcer is suspected, the possibility of malignancy should be excluded before treatment with Losec is instituted, as treatment may alleviate symptoms and delay diagnosis.

Omeprazole like other PPIs should not be administered with atazanavir (see section 4.5).

4.4 Special warnings and precautions for use

When treatment with Losec tablets is instituted, patients on previous Losec capsules therapy should be monitored for any reports of ‘flare up’ of disease symptoms.

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

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 fracture by 1040%. 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.

Hypomagnesaemia

Severe hypomagnesaemia has been reported in patients treated with PPIs like omeprazole 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 drugs that may cause hypomagnesaemia (e.g., diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

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

4.5 Interaction with other medicinal products and other forms of interaction

Due to the decreased intragastric acidity, the absorption of ketoconazole or itraconazole may be reduced during omeprazole treatment as it is during treatment with other acid secretion inhibitors.

As omeprazole is metabolised in the liver through cytochrome P450 it can prolong the elimination of diazepam, phenytoin, warfarin and other vitamin K antagonists which are in part substrates for this enzyme.

Monitoring of patients receiving phenytoin is recommended and a reduction of the phenytoin dose may be necessary. However concomitant treatment with omeprazole 20 mg daily did not change the blood concentration of phenytoin in patients on continuous treatment with phenytoin. In patients receiving warfarin or other vitamin K antagonists, monitoring of INR 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, however, not change coagulation time in patients on continuous treatment with warfarin.

Plasma concentrations of omeprazole and clarithromycin are increased during concomitant administration. This is considered to be a useful interaction during H. pylori eradication. There is no interaction with metronidazole or amoxicillin. These antimicrobials are used together with omeprazole for eradication of Helicobacter pylori.

There is no evidence of an interaction with phenacetin, theophylline, caffeine, propranolol, metoprolol, ciclosporin, lidocaine, quinidine, estradiol or antacids. The absorption of omeprazole is not affected by alcohol or food.

There is no evidence of an interaction with piroxicam, diclofenac or naproxen. This is considered useful when patients are required to continue these treatments.

Simultaneous treatment with omeprazole and digoxin in healthy subjects lead to a 10 % increase in the bioavailability of digoxin as a consequence of the increased intragastric pH.

Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a substantial reduction in atazanavir exposure (approximately 75 % decrease in AUC, C_max, and C_min). Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. PPIs including omeprazole should not be co-administered with atazanavir (see section 4.3).

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

Concomitant administration of omeprazole and a CYP2C19 and CYP3A4 inhibitor, voriconazole, resulted in more than doubling of the omeprazole exposure. Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) C_max and AUC_T by 15 % and 41 %, respectively. A dose adjustment of omeprazole is not regularly required in either of these situations. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.

4.6 Pregnancy and lactation Pregnancy

Results from three prospective epidemiological studies indicate no adverse effects of omeprazole on pregnancy or on the health of the foetus/newborn child. Losec can be used during pregnancy.

Lactation

Omeprazole is excreted in breast milk but is not likely to influence the child when therapeutic doses are used.

4.7 Effects on ability to drive and use machines

No effects are foreseen.

4.8 Undesirable effects

Omeprazole is well tolerated and adverse reactions have generally been mild and reversible. The following have been reported as adverse events in clinical trials or reported from routine use, but in many cases a relationship to treatment with omeprazole has not been established.

The following definitions of frequencies are used: Common    > 1/100

Gynaecomastia.

Dry mouth, stomatitis and gastrointestinal candidiasis.

Leukopenia, thrombocytopenia, agranulocytosis and pancytopenia.

Encephalopathy in patients with pre-existing severe liver disease, hepatitis with or without jaundice, hepatic failure.

Arthritic and myalgic symptoms and muscular weakness.

Impotence.

Photosensitivity, bullous eruption erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), alopecia.

Hypersensitivity reactions e.g. angioedema, fever, bronchospasm, interstitial nephritis and anaphylactic shock. Increased sweating, peripheral oedema, blurred vision, taste disturbance and hyponatraemia. Hypomagnesaemia (see section 4.4)

The safety of omeprazole 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 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 treatment on puberty and growth.

4.9 Overdose

Rare reports have been received of overdosage with omeprazole. In the literature, doses of up to 560 mg have been described and occasional reports have been received when single oral doses have reached up to 2400 mg omeprazole (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported from overdosage with omeprazole. Also apathy, depression and confusion have been described in single cases.

The symptoms described in connection to omeprazole overdosage have been transient, and no serious outcome due to omeprazole has been reported. The rate of elimination was unchanged (first order kinetics) with increased doses and no specific treatment has been needed.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Omeprazole reduces gastric acid secretion through a unique mechanism of action. It is a specific inhibitor of the gastric proton pump in the parietal cell. It is rapidly acting and produces reversible control of gastric acid secretion with once daily dosing.

Oral dosing with 20 mg Losec once daily, provides for rapid and effective inhibition of gastric acid secretion with maximum effect being achieved within 4 days of treatment. In duodenal ulcer patients, a mean decrease of approximately

80 % in 24 hour intragastric acidity is then maintained, with the mean decrease in peak acid output after pentagastrin stimulation being about 70 %, 24 hours after dosing with omeprazole.

Clinical data for omeprazole in the prophylaxis of NSAID induced gastroduodenal lesions are derived from clinical studies of up to 6 months duration.

Helicobacter pylori (Hp) is associated with acid peptic disease including duodenal ulcer (DU) and gastric ulcer (GU) in which about 95 % and 80 % of patients respectively are infected with this bacterium. Hp is implicated as a major contributing factor in the development of gastritis and ulcers in such patients. Recent evidence also suggests a causative link between Hp and gastric carcinoma.

Omeprazole has been shown to have a bactericidal effect on Hp in-vitro.

Eradication of Hp with omeprazole and antimicrobials is associated with rapid symptom relief, high rates of healing of any mucosal lesions, and long-term remission of peptic ulcer disease thus reducing complications such as gastrointestinal bleeding as well as the need for prolonged anti-secretory treatment.

In clinical data in patients with acute peptic ulcer, omeprazole Hp eradication therapy improved patients' quality of life.

During long-term treatment an increased frequency of gastric glandular cysts have been reported. These changes are a physiological consequence of pronounced inhibition of acid secretion. The cysts are benign and appear to be reversible. No other treatment-related mucosal changes have been observed in patients treated continuously with omeprazole for periods up to 5 years.

Paediatric data

In a non-controlled study in children (1 to 16 years of age) with severe reflux oesophagitis, omeprazole at doses of 0.7 to 1.4 mg/kg improved oesophagitis level in 90 % of the cases and significantly reduced reflux symptoms. In a single-blind study, children aged 0-24 months with clinically diagnosed GERD were treated with 0.5, 1.0 or 1.5 mg omeprazole/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) has concluded to the efficacy and an acceptable safety for omeprazole associated to two antibiotics (amoxicillin and clarithromycin) in the treatment of Helicobacter pylori infection in children of 4 years old and above with a gastritis: Helicobacter pylori eradication rate: 74.2 % (23/31 patients) with omeprazole + 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.

Site and mechanism of action

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

All pharmacodynamic effects observed are explained by the effect of omeprazole on acid secretion.

5.2 Pharmacokinetic properties Absorption and distribution

Omeprazole and omeprazole magnesium are acid labile and are administered orally as enteric-coated granules in capsules or tablets. Bioequivalence between Losec Capsules and Losec Tablets based on omeprazole plasma concentration-time curve (AUC) has been demonstrated. Absorption of omeprazole takes place in the small intestine and is usually completed within 3-6 hours. The systemic bioavailability of omeprazole from a single oral dose of omeprazole is approximately 35 %. After repeated once daily administration, the bioavailability increases to about 60 %. Concomitant intake of food has no influence on the bioavailability. The plasma protein binding of omeprazole is about 95 %.

Metabolism and elimination

The average half-life of the terminal phase of the plasma concentration-time curve is approximately 40 minutes. There is no change in half-life during treatment. The inhibition of acid secretion is related to the area under the plasma concentration-time curve (AUC) but not to the actual plasma concentration at a given time.

Omeprazole is entirely metabolised, mainly in the liver. Identified metabolites in plasma are the sulphone, the sulphide and hydroxy-omeprazole, these metabolites have no significant effect on acid secretion. About 80 % of the metabolites are excreted in the urine and the rest in the faeces. The two main urinary metabolites are hydroxy-omeprazole and the corresponding carboxylic acid.

The systemic bioavailability of omeprazole is not significantly altered in patients with reduced renal function. The area under the plasma concentration-time curve is increased in patients with impaired liver function, but no tendency to accumulation of omeprazole has been found.

Children

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 is low due to low capacity to metabolise omeprazole.

5.3 Preclinical safety data Animal Toxicology

Gastric ECL-cell hyperplasia and carcinoids, have been observed in life-long studies in rats treated with omeprazole or subjected to partial fundectomy.

These changes are the result of sustained hypergastrinaemia secondary to acid inhibition, and not from a direct effect of any individual drug.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline cellulose

Glycerol monostearate Hydroxypropylcellulose

Hypromellose Magnesium stearate

Methyl acrylic acid-ethyl acrylate co-polymer (1:1) dispersion 30 per cent

Sugar spheres

Synthetic paraffin

Macrogol

Polysorbate

Crospovidone

Sodium stearyl fumarate

Sodium hydroxide*

Talc

Triethyl citrate Iron oxide Titanium dioxide.

* May be added as a pH adjuster.

6.2 Incompatibilities

None known.

6.3    Shelf life

3 years.

6.4    Special precautions for storage

Do not store above 25 °C.

Store in the original container.

6.5    Nature and contents of container

Press-through Aluminium-Polyamide-PVC/ Aluminium foil calendarised blister packs.

Packs of 7, 14, 28, 56 and 560 tablets.