MEPRADEC 10 mg GASTRO-RESISTANT CAPSULES

Omeprazole........................10 mg

For excipients, see section 6.1.

Capsule, hard.

Omeprazole 10 mg Gastro-Resistant Capsule is a hard gelatin capsule with an opaque beige body, marked "10" and an opaque beige cap, marked "DP".

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

Treatment of oesophageal reflux disease. In reflux oesophagitis the majority of patients are healed after 4 weeks. Symptomatic relief is rapid. Relief of reflux-like symptoms (e.g., heartburn) and/or ulcer-like symptoms (e.g., epigastric pain) associated with acid-related dyspepsia.

Relief of associated dyspeptic symptoms.

Zollinger-Ellison syndrome.

Prophylaxis of acid aspiration.

The capsules should be swallowed whole with plenty of liquid (e.g., water or fruit juice) prior to a meal. It is important that the capsules should not be crushed or chewed.

Duodenal & Benign Gastric Ulcers: The usual dose is 20 mg 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 daily.

Long-term therapy for patients with a history of recurrent duodenal ulcer is recommended at a dosage of 20 mg once daily.

For the prevention of relapse in patients with duodenal ulcer the recommended dose is 10 mg once daily, increasing to 20 mg once daily if symptoms recur. The following groups are at risk from recurrent ulcer relapse: those with Helicobacter pylori infection, younger patients (under 60 years), those whose symptoms persist for more than one year and smokers. These patients will require initial long-term therapy with 20 mg once daily, reducing to 10 mg once daily if necessary.

Treatment of NSAID-associated Gastric Ulcers, Duodenal Ulcers or Gastroduodenal Erosions: The recommended dosage 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.

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 is 20 mg once daily.

Oesophageal Reflux Disease including Reflux Oesophagitis: The usual dosage is 20 mg 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. Omeprazole Capsules can also be used at a dose of 40 mg once daily in patients with reflux oesophagitis refractory to other therapy. Healing usually occurs within 8 weeks. Treatment for these patients can be continued at a dosage of 20 mg once daily.

Acid Reflux Disease: For long-term management 10 mg once daily is recommended, increasing to 20 mg if symptoms return.

Acid-Related Dyspepsia: The usual dose is 10 mg or 20 mg once daily for 2-4 weeks depend- ing on the severity and persistence of symptoms. Patients who do not respond after 4 weeks or who relapse shortly afterwards should be investigated.

Zollinger-Ellison Syndrome: The dosage should be adjusted individually. The recommended initial dosage is 60 mg once daily and treatment is 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 20-120 mg daily. With doses above 80 mg daily, the dose should be divided and given twice daily.

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

Elderly: Dose adjustment is not required in the elderly.

Children: The formulation is not suitable for children.

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.

Known hypersensitivity to Omeprazole or to any of the other ingredients.

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

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 leads to a slightly increased risk of gastrointestinal infections such as salmonella or campylobacter.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

As omeprazole is metabolized in the liver through cytochrome P450 it can delay the elimination of diazepam, phenytoin and warfarin. Monitoring of patients receiving warfarin or Phenytoin is recommended and a reduction of the warfarin or 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. Similarly, concomitant treatment with Omeprazole 20 mg daily did not change coagulation time in patients on continuous treatment with warfarin. Interactions with other medicinal products which are also metabolized via the cytochrome P-450 isoenzyme of group 2C cannot be excluded (e.g., hexobarbital).

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.

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

Omeprazole as so far tested has no influence on the metabolism of the following substances: amoxicillin, antacids, caffeine, ciclosporin, diclofenac, estradiol, lidocaine, metoprolol, naproxen, phenacetin, piroxicam, propranolol, quinidine, theophylline.

Alcohol and food do not affect the absorption of omeprazole.

Pregnancy

The analysis of the results from three epidemiological studies has revealed no evidence of adverse events of omeprazole on pregnancy or on the health of the foetus/new-born child.

Omeprazole can be used in pregnancy.

Lactation

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

No effects on ability to drive and use machines have been observed.

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.

Skin rash, urticaria and pruritus have been reported, usually resolving after discontinuation of treatment. In addition photosensitivity, bullous eruption, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema and alopecia have been reported in isolated cases.

Diarrhoea and headache have been reported and may be severe enough to require discontinuation of therapy in a small number of patients. In the majority of cases the symptoms resolved after discontinuation of therapy.

Other gastrointestinal reactions have included constipation, nausea/vomiting, flatulence and abdominal pain. Dry mouth, stomatitis and candidiasis have been reported in isolated cases.

Paraesthesia has been reported. Dizziness, light-headedness and feeling faint have been associated with treatment, but all usually resolve on cessation of therapy. Also reported are somnolence, insomnia and vertigo. Reversible mental confusion, agitation, depression and hallucinations have occurred predominantly in severely ill patients.

Arthritic and myalgic symptoms as well as muscle weakness have been reported and have usually resolved when therapy is stopped.

In isolated cases, the following have been reported: blurred vision, taste disturbances, aggression, peripheral oedema, hyponatraemia, increased sweating, gynaecomastia, impotence, leucopenia, thrombocytopenia, agranulocytosis, pancytopenia, anaphylactic shock, malaise, fever, bronchospasm, encephalopathy in patients with pre-existing severe liver disease, hepatitis with or without jaundice, rarely hepatic failure and interstitial nephritis which has resulted in acute renal failure.

Increases in liver enzymes have been observed.

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, diarrhea 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.

Omeprazole, a substituted benzimidazole, is a selective proton pump inhibitor which inhibits directly and in dose-dependent fashion the H+/K+-ATPase of the parietal cells of the stomach responsible for gastric acid secretion. By this selective intracellular attack, independently from membrane located receptors like histamine H2-, muscarine M1- or gastrineric receptors, Omeprazole belongs to an independent class of inhibitors which block the terminal secretion process. By its mode of action, Omeprazole reduces not only basal but also stimulus-induced acid secretion, independently of the kind of stimulus. Omeprazole thus increases the pH-value and reduces the secretory volume.

Oral dosing with 20 mg Omeprazole once daily produces inhibition of gastric acid secretion within 1-2 hours of the first dose. The maximum effect is achieved within 4 days of starting treatment after which the degree of inhibition remains constant. The mean decrease in pentagastrin-stimulated peak acid output twenty-four hours after dosing is about 70%.

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

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 of up to 5 years.

Site and Mechanism of Action: Omeprazole is a weak base and is concentrated and converted to the active form by protonation 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.

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 is approxi-mately 35%. After repeated once-daily administration, the bioavailability increases to about 60%. Concomitant intake of food has no influence on bioavailability. The plasma protein binding of omeprazole is about 95%.

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 actual plasma concentration at a time.

Omeprazole is entirely metabolized, 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.

Available data from children (1 year and older) suggest that the pharmacokinetics within the recommended doses are similar to those reported in adults. At steady state, lower plasma levels of omeprazole were seen in some children.

Omeprazole is a well established drug for which there are adequate published safety data. Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or toxicity to reproduction.

Carcinogenic Potential: 2 years' carcinogenicity studies in rats (i.e., life-long treatment) showed development of ECL-cell-carcinoids; but rats which have been treated with high doses of Omeprazole over a year have not shown any carcinoids in the later 1-year period. The mechanism for the build-up of the stomach carcinoids has been investigated very carefully and various studies lead to the conclusion that this is a secondary reaction due to the extreme increased serum gastrin levels of the rats during the treatment period. These changes are the result of sustained hypergastrinaemia secondary to acid inhibition and not from a direct effect of any individual drug. Similar development of ECL-cell-carcinoids were observed in rats subjected to partial fundectomy. ECL-cell-carcinoids were not seen in mice or dog studies.

Core Excipients: lactose (monohydrate), sodium starch glycollate, sodium stearate, sodium stearyl fumarate.

Enteric Coating: hypromellose acetate succinate, Sepisperse AP-3527 containing: propylene glycol, titanium dioxide (E-171), red iron oxide (E-172), hypromellose and yellow iron oxide (E-172), talc, triethyl citrate, monoethanolamine, sodium lauryl sulphate.

Polish: carnauba wax.

Hard Gelatin Capsule: gelatin, titanium dioxide (E-171), yellow iron oxide (E-172), black iron oxide (E-172), red iron oxide (E-172).

Not applicable.

2 years

Store in the original package; do not store above 30°C.

The capsules are presented in aluminium/aluminium blisters, strips of which are contained within a printed cardboard carton. Each carton contains 28 capsules.

Not applicable.

DEXCEL-PHARMA LIMITED

1 Cottesbrooke Park, Heartlands Business Park,

Daventry, Northamptonshire NN11 8YL

United Kingdom

PL 14017/0049

27 July 2004

11 September 2008