There is limited information available on the effects of overdoses of Omeprazol Pensazole 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 Omeprazol Pensazole (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 Omeprazol Pensazole 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.
Omeprazol Pensazole like other proton pump inhibitors (PPIs) must not be used concommitantly with nelfinavir.
Not applicable.
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 Omeprazol Pensazole 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)
| SOC/ Frequency | Adverse reaction |
| Blood and lymphatic system disorders | |
| Rare: | Leukopenia, thrombocytopenia |
| Very rare: | Pancytopenia, agranulocytosis |
| Immune system disorders | |
| Rare: | Hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/ shock |
| Metabolism and nutrition disorders | |
| Rare: | Hyponataemia |
| Not Known: | Hypomagneseamia; severe hypomagnesaemia may result in hypocalcaemia Hypomagnesaemia may also be associated with hypokalaemia. |
| Psychiatric disorders | |
| Uncommon: | Insomnia |
| Rare: | Agitation, confusion, depression |
| Very Rare: | Aggression, hallucinations. |
| Nervous system disorders | |
| Common: | Headache |
| Uncommon: | Dizziness, paresthesia, somnolence |
| Rare: | Taste disturbance |
| Eye disorders | |
| Rare: | Blurred vision |
| Ear and labyrinth disorders | |
| Uncommon: | Vertigo |
| Respiratory, thoracic and mediastinal disorders | |
| Rare: | Bronchospasm |
| Gastrointestinal disorders | |
| Common: | Abdominal pain, constipation, diarrhoea, flatulence, nausea and vomiting fundic gland polyps (benign) |
| Rare: | Dry mouth, stomatitis, gastrointestinal candidiasis |
| Not known: | Microscopic colitis |
| Hepatobiliary disorders | |
| Uncommon: | Increased liver enzymes |
| Rare: | Hepatitis with or without jaundice |
| Very Rare: | Hepatic failure, encephalopathy in patients with pre-existing liver disease |
| Skin and subcutaneous tissue disorders | |
| Uncommon: | Dermatitis, pruritus, rash, urticaria |
| Rare: | Alopecia, photosensitivity |
| Very Rare: | Erythema multiforme, Stevens-Johnsonsyndrome, toxic epidermal necrolysis (TEN) |
| Not known | Subacute cutaneous lupus erythematosus |
| Musculoskeletal and connective tissue disorders | |
| Uncommon: | Fracture of the hip, wrist or spine |
| Rare: | Arthralgia, myalgia |
| Very Rare: | Muscular weakness |
| Renal and urinary disorders: | |
| Rare: | Interstitial nephritis |
| Reproductive System and breast disorders: | |
| Very Rare: | Gynaecomastia |
| General disorders and administration site conditions | |
| Uncommon: | Malaise, peripheral oedema |
| Rare: | Increased sweating. |
Paediatric Population
The safety of Omeprazol Pensazole 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 Omeprazol Pensazole 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 Omeprazol Pensazole 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.
Gastric ECL-cell hyperplasia and carcinoids have been observed in life-long studies in rats treated with Omeprazol Pensazole. 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.
Pharmacotherapeutic group: Proton pump inhibitors, ATC-code: A02BC01
Mechanism of Action:
Omeprazol Pensazole, 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.
Omeprazol Pensazole 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 Omeprazol Pensazole on acid secretion.
Clinical Efficacy and Safety:
Effect on gastric acid secretion:
Oral dosing with Omeprazol Pensazole 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 Omeprazol Pensazole 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 Omeprazol Pensazole 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, Omeprazol Pensazole 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 Omeprazol Pensazole and not the actual plasma concentration at a given time.
No tachyphylaxis has been observed during treatment with Omeprazol Pensazole.
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 Omeprazol Pensazole 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 Omeprazol Pensazole. 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, Omeprazol Pensazole 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 Omeprazol Pensazole/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 Omeprazol Pensazole 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 Omeprazol Pensazole + 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
Omeprazol Pensazole is acid labile and is therefore administered orally as enteric-coated granules in hard-gelatin capsules. Absorption of Omeprazol Pensazole is rapid, with peak-plasma levels occurring 1-2 hours after the dose. Absorption of Omeprazol Pensazole 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 Omeprazol Pensazole 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. Omeprazol Pensazole is 97% protein bound.
Biotransformation
Omeprazol Pensazole 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 hydroxyOmeprazol Pensazole, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of Omeprazol Pensazole Sulphone. As a consequence of high affinity of Omeprazol Pensazole 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, Omeprazol Pensazole has no potential to inhibit the metabolism of other CYP3A4 substrates. In addition Omeprazol Pensazole 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 Omeprazol Pensazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 20mg Omeprazol Pensazole 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 Omeprazol Pensazole.
Elimination
The plasma elimination half life of Omeprazol Pensazole is usually shorter than one hour both after single and repeated oral once daily dosing. Omeprazol Pensazole is completely eliminated from plasma between doses with no tendency for accumulation during once daily administration. Almost 80% of an oral dose of Omeprazol Pensazole is excreted as metabolites in the urine, the remainder in the faeces, primarily originating from bile secretion.
The AUC of Omeprazol Pensazole 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 Omeprazol Pensazole 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 Omeprazol Pensazole in patients with liver dysfunction is impaired, resulting in an increased AUC. Omeprazol Pensazole has not shown any tendency to accumulate with once-daily dosing.
Impaired renal function
The pharmacokinetics of Omeprazol Pensazole, including systemic bioavailability and elimination rate, are unchanged in patients with reduced renal function.
Elderly
The metabolism rate of Omeprazol Pensazole 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 Omeprazol Pensazole is low due to low capacity to metabolise Omeprazol Pensazole.
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; Omeprazol Pensazole 20mg should not be exceeded.
Omeprazol Pensazole 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.
Omeprazol Pensazole is a CYP2C19 inhibitor. When starting or ending treatment with Omeprazol Pensazole, the potential for interactions with drugs metabolized through CYP2C19 should be considered. An interaction is observed between clopidogrel and Omeprazol Pensazole. The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of Omeprazol Pensazole and clopidogrel should be discouraged.
Hypomagnesaemia
Severe hypomagnesaemia has been reported in patients treated with PPIs like Omeprazol Pensazole 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 Omeprazol Pensazole. 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, Omeprazol Pensazole 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.
Omeprazol Pensazole 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.
No special requirements for disposal.
