Data Sheet
Omeprazole capsules
Omeprazole 10 mg, 20 mg, 40 mg
Presentation
Omeprazole capsules 10 mg are hard gelatine size 3 capsules with rich yellow opaque body printed with "R157" in black ink, and a purple opaque cap printed with "Omeprazole 10 mg" in black ink. Each capsule contains omeprazole 10 mg as enteric coated pellets.
Omeprazole capsules 20 mg: hard gelatine size 2 capsules with a light grey opaque body printed with "R158" in black ink, and a purple opaque cap printed with "Omeprazole 20 mg" in black ink. Each capsule contains omeprazole 20 mg as enteric coated pellets.
Omeprazole capsules 40 mg: hard gelatine size 0 capsules with a purple opaque body printed with "R159" in black ink, and a rich yellow opaque cap printed with "Omeprazole 40 mg" in black ink. Each capsule contains omeprazole 40 mg as enteric coated pellets.
Uses
Actions
Omeprazole, a racemic mixture of two active 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 rapid acting and provides control through reversible inhibition of gastric acid secretion with once daily dosing.
Site and mechanism of action
Omeprazole 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 the gastric acid formation process is dose-dependent and provides for highly effective inhibition of both basal acid secretion and stimulated acid secretion, irrespective of the stimulus.
All pharmacodynamic effects observed can be explained by the effect of omeprazole on acid secretion.
Effect on gastric acid secretion
Oral dosing with omeprazole capsules 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 capsules 20 mg, a mean decrease of at least 80% in 24-hour intragastric acidity is then maintained in duodenal ulcer patients, with the mean decrease in peak acid output after pentagastrin stimulation being about 70% twenty-four hours after dosing.
Oral dosing with omeprazole capsules 20 mg 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 dose-dependently reduces/normalises acid exposure of the oesophagus in patients with gastro-oesophageal reflux disease.
The inhibition of acid secretion is related to the area under the plasma concentration-time curve (AUC) of omeprazole and not to the actual plasma concentration at a given time.
No tachyphylaxis has been observed during treatment with omeprazole.
Effect on Helicobacter pylori
Helicobacter pylori is associated with acid peptic disease, including duodenal and gastric ulcer disease, in which about 95% and 70% of patients respectively are infected with this bacterium. 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 has been found to play a causal role in the development of gastric carcinoma.
Omeprazole has a bactericidal effect on H.pylori in vitro.
Eradication of H.pylori 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.
Other effects related to acid inhibition
During long-term treatment gastric glandular cysts have been reported in a 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 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 and Campylobacter.
Pharmacokinetics
Absorption and distribution
Omeprazole is acid labile and is therefore administered orally as enteric-coated pellets in capsules or tablets.
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 capsules is approximately 35%. After repeated once daily administration, the bioavailability increases to about 60%. The apparent volume of distribution in healthy subjects is approximately 0.3 L/kg and a similar value is also seen in patients with renal insufficiency. In elderly patients, and in patients with hepatic insufficiency, the volume of distribution is slightly decreased. Concomitant intake of food has no influence on the bioavailability. The plasma protein binding of omeprazole is about 95%.
Metabolism and excretion
After oral administration, the plasma elimination half-life of omeprazole is usually shorter than one hour and there is no change in half-life during long-term treatment.
Omeprazole is completely metabolised by the cytochrome P450 system (CYP), mainly in the liver. The major part of its metabolism is dependent on the polymorphically expressed, specific isoform CYP2C19 (S-mephenytoin hydroxylase), responsible for the formation of hydroxyomeprazole, the major metabolite in plasma. In accordance with this, as a consequence of competitive inhibition, there is a potential for metabolic drug-drug interactions between omeprazole and other substrates for CYP2C19.
No metabolite has been found to have any effect on gastric acid secretion. Almost 80% of an orally given dose is excreted as metabolites in the urine, and the remainder is found in the faeces, primarily originating from bile secretion.
The systemic bioavailability and elimination of omeprazole is unchanged in patients with reduced renal function. The area under the plasma concentration-time curve, and the elimination half-life are increased in patients with impaired liver function, but omeprazole has not shown any tendency to accumulate with once daily dosing.
Children
Available data from children (1 year and older) suggests that the pharmacokinetics, within the recommended dosages (see Dosage and Administration) is similar to those reported in adults.
Indications
Omeprazole capsules are indicated for the treatment of:
- reflux oesophagitis
- duodenal ulcer
- gastric ulcer
- NSAID-associated gastric and duodenal ulcers or erosions
- Acid related dyspepsia
- Zollinger-Ellison syndrome.
In the treatment of peptic ulceration, the eradication of H.pylori, as the causative organism, must be a high priority.
Accordingly, omeprazole capsules should be used as part of combination therapy for the eradication of H.pylori.
Maintenance
Omeprazole capsules are indicated for maintenance treatment of:
- reflux oesophagitis
- duodenal ulcer
- gastric ulcer
- Zollinger-Ellison syndrome.
Dosage and Administration
Omeprazole capsules are recommended to be given in the morning and swallowed whole with half a glass of water. The contents of the capsule should not be chewed or crushed.
For patients with swallowing difficulties and for children who can drink or swallow semi-solid food
For patients with swallowing difficulties the capsule can be opened and the contents swallowed directly with half a glass of liquid or after mixing the contents in a slightly acidic fluid e.g. fruit juice, yoghurt or in non carbonated water. The dispersion should be taken immediately or within 30 minutes. Alternatively patients can suck the capsule and swallow the pellets with liquid. The pellets must not be chewed or crushed.
Reflux oesophagitis
The recommended dosage is omeprazole capsules 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 period.
In patients with severe reflux oesophagitis 40 mg once daily is recommended and healing is usually achieved within 8 weeks.
For the long-term management of patients with healed reflux oesophagitis the recommended dose is 10 mg once daily. If needed the dose can be increased to 20-40 mg once daily.
Severe reflux oesophagitis in children from one year and older
The management of severe reflux oesophagitis should be diagnosed or recommended by a specialist paediatrician or gastroenterologist.
| The recommended dosage regime for healing is: | |
|---|---|
| Weight | Dosage |
| 10-20 kg | 10 mg daily |
| > 20 kg | 20 mg daily |
If needed dosage may be increased to 20 mg and 40 mg respectively.
Helicobacter pylori (Hp) eradication regimens in peptic ulcer disease
Triple therapy regimens
Omeprazole capsules 20 mg, amoxicillin 1 g and clarithromycin 500 mg, all twice a day for one week
or
Omeprazole capsules 20 mg, clarithromycin 250 mg and metronidazole 400 mg (or tinidazole 500 mg), all twice a day for one week
or
Omeprazole capsules 40 mg once daily with amoxicillin 500 mg and metronidazole 400 mg both three times a day for one week.
Dual therapy regimens
Omeprazole capsules 40-80 mg daily with amoxicillin 1.5 g daily in divided doses for two weeks. In clinical studies daily doses of 1.5-3 g of amoxicillin have been used
or
Omeprazole capsules 40 mg once daily and clarithromycin 500 mg three times a day for two weeks.
To ensure healing in patients with active peptic ulcer disease, see further dosage recommendations for duodenal and gastric ulcer.
In each regimen if the patient is still Hp positive, therapy may be repeated.
Duodenal ulcer
The recommended dosage in patients with an active duodenal ulcer is omeprazole capsules 20 mg once daily. Symptom resolution is rapid and in most patients healing occurs within 2 weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further 2 week treatment period.
In patients with poorly responsive duodenal ulcer 40 mg once daily is recommended and healing is usually achieved within 4 weeks.
For the prevention of relapse in patients with duodenal ulcer disease the recommended dose is 10 mg once daily. If needed the dose can be increased to 20-40 mg once daily.
For NSAID-associated duodenal ulcers see "NSAID-Associated Gastroduodenal Lesions".
Gastric ulcer
The recommended dosage is omeprazole capsules 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 period.
In patients with poorly responsive gastric ulcer 40 mg once daily is recommended and healing is usually achieved within 8 weeks.
For the prevention of relapse in patients with poorly responsive gastric ulcer the recommended dose is 20 mg once daily. If needed the dose can be increased to 40 mg once daily.
For NSAID-associated gastric ulcers see "NSAID-Associated Gastroduodenal Lesions".
NSAID-associated gastroduodenal lesions
For NSAID-associated gastric ulcers, duodenal ulcers or gastroduodenal erosions in patients with or without continued NSAID treatment, the recommended dosage of omeprazole capsules 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 period.
For the prevention of NSAID-associated gastric ulcers, duodenal ulcers, gastroduodenal erosions and dyspeptic symptoms the recommended dosage is 20 mg once daily.
Symptoms of Acid-related dyspepsia
For the 24-hour relief, and prevention of symptoms in patients with epigastric pain/discomfort with or without heartburn and indigestion, 20 mg once daily in the morning for 14 -28 days*. If symptom control has not been achieved after 4 weeks treatment with 20 mg daily, further investigation is recommended.
*Patients may respond adequately to 10 mg daily and this dose could be considered as a starting dose.
Zollinger-Ellison syndrome
In patients with Zollinger-Ellison syndrome the dosage should be individually adjusted and treatment continued as long as is clinically indicated. The recommended initial dosage is omeprazole capsules 60 mg 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 20-120 mg daily. When doses exceed 80 mg daily, the dose should be divided and given twice daily.
Impaired Renal Function
Dose adjustment is not needed in patients with impaired renal function.
Impaired Hepatic Function
As bioavailability and plasma half-life of omeprazole are increased in patients with impaired hepatic function a daily dose of 10 - 20 mg may be sufficient.
Elderly
Dose adjustment is not needed in the elderly.
Contraindications
Known hypersensitivity to omeprazole.
Warnings and Precautions
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, the possibility of malignancy should be excluded as treatment may alleviate symptoms and delay diagnosis.
Use in Pregnancy and Lactation
Results from three prospective epidemiological studies indicate no adverse effects of omeprazole on pregnancy or on the health of the foetus/newborn child. Omeprazole capsules can be used during pregnancy.
Omeprazole is excreted in breast milk but is not likely to influence the child when therapeutic doses are used.
Effects on ability to drive and use machines
Omeprazole capsules are not likely to affect the ability to drive or use machines.
Adverse Effects
Omeprazole capsules are well tolerated and adverse reactions have generally been mild and reversible. The following events 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 |
|---|---|
| Uncommon | ≥1/1,000 and <1/100 |
| Rare | <1/1,000 |
| Common | Central and peripheral nervous system: | Headache |
|---|---|---|
| Gastrointestinal: | Diarrhoea, constipation, abdominal pain, nausea/vomiting and flatulence | |
| Uncommon | Central and peripheral nervous system: | Dizziness, paraesthesia, somnolence, insomnia and vertigo |
| Hepatic: | Increased liver enzymes | |
| Skin: | Rash, dermatitis and/or pruritis. Urticaria | |
| Other: | Malaise | |
| Rare | Central and peripheral nervous system: | Reversible mental confusion, agitation, aggression, depression and halluncinations, predominantly in severely ill patients |
| Endocrine: | Gynaecomastia | |
| Gastrointestinal: | Dry mouth, stomatitis and gastrointestinal candidiasis | |
| Haematological: | Leukopenia, thrombocytopenia, agranulocytosis and pancytopenia. | |
| Hepatic: | Encephalopathy in patients with pre-existing severe liver disease; hepatitis with or without jaundice, hepatic failure | |
| Musculoskeletal: | Arthralgia, muscular weakness and myalgia | |
| Skin: | Photosensitivity, erythema multiforme, Stevens-Johnson syndrome,
toxic epidermal necrolysis (TEN), alopecia Hypersensitivity reactions eg. angioedema, fever, bronchospasm, interstitial nephritis and anaphylactic shock. |
|
| Other: | Increased sweating, peripheral oedema, blurred vision, taste disturbance and hyponatraemia. |
Interactions
The absorption of some medicines might be altered due to the decreased intragastric acidity. The absorption of ketoconazole and itraconazole can decrease during omeprazole treatment, as it does during treatment with other acid secretion inhibitors or antacids.
No interaction with food or concomitantly administered antacids has been found.
As omeprazole is metabolised in the liver through cytochrome P450 2C19 (CYP2C19), it can prolong the elimination of diazepam, phenytoin, warfarin (R-warfarin) and other vitamin K antagonists which are all in part substrates for this enzyme.
Monitoring of patients receiving phenytoin is recommended and a reduction of phenytoin dose may be necessary. However concomitant treatment with omeprazole capsules 20 mg daily did not change the blood concentration of phenytoin in patients on continuous treatment with this medicine. 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 capsules 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 but there is no interaction with metronidazole or amoxicillin. These antimicrobials are used together with omeprazole for eradication of Helicobacter pylori.
Concomitant administration of omeprazole has been reported to reduce the plasma levels of atazanavir.
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. However, a dose adjustment of omeprazole was not required.
Results from a range of interaction studies with omeprazole capsules versus other medicines indicate that omeprazole, 20-40 mg daily, has no influence on any other relevant isoforms of CYP, as shown by the lack of metabolic interaction with substrates for CYP1A2 (caffeine, phenacetin, theophylline), CYP2C9 (S-warfarin, piroxicam, diclofenac and naproxen), CYP2D6 (metoprolol, propranolol), CYP2E1 (ethanol), and CYP3A (cyclosporin, lidocaine, quinidine, estradiol, erythromycin, budesonide).
Overdosage
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 2,400 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.
Pharmaceutical Precautions
Store below 25°C.
Medicine Classification
Prescription Medicine.
Package Quantities
10 mg: Cartons of aluminium blisters containing 7, 14, 28, 30 or 56 capsules. HDPE bottles of 30 capsules
20 mg: Cartons of aluminium blisters containing 7, 14, 28, 30, 56 or 112 capsules. HDPE bottles of 30 capsules.
40 mg: Cartons of aluminium blisters containing 7, 14, 28 or 30 capsules. HDPE bottles of 30 capsules.
Not all pack sizes may be marketed.
Further Information
Composition
Each capsule contains: omeprazole 10 mg, 20 mg or 40 mg.
Excipients
Mannitol, Crospovidone, Hypromellose, Poloxamer, Meglumine, Povidone, Methacrylic acid ethyl acrylate copolymer, Triethyl citrate, Magnesium stearate,
10 and 40 mg Gelatin capsules (Erythrosin, Patent blue V, Titanium dioxide, Yellow iron oxide, Titanium dioxide, Gelatin, printing ink)
20 mg Gelatin capsules (Erythrosin, Patent blue V, Titanium dioxide, Black iron oxide, Titanium dioxide, Gelatin, printing ink)
Preclinical safety data
Gastric ECL-cell hyperplasia and carcinoids, have been observed in life-long studies in rats treated with omeprazole. 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 drug.
Name and Address
Affordable Healthcare Ltd
Level 6, AMI House
63 Albert Street
PO Box 911-267
AUCKLAND
Tel: (09) 356 7000
Fax: (09) 356 7001
Date of Preparation
26 February 2008