- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
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
Alternative to oral therapyIn patients where the use of oral medicinal products is inappropriate, Omeprazole IV 40 mg once daily is recommended. In patients with Zollinger-Ellison Syndrome the recommended initial dose of Omeprazole given intravenously is 60 mg daily. Higher daily doses may be required and the dose should be adjusted individually. When doses exceed 60 mg daily, the dose should be divided and given twice daily.Omeprazole is to be administered in an intravenous infusion for 20-30 minutes.For instructions on reconstitution of the product before administration, see section 6.6.
Impaired renal functionDose adjustment is not needed in patients with impaired renal function (see section 5.2).
Impaired hepatic functionIn patients with impaired hepatic function a daily dose of 10-20 mg may be sufficient (see section 5.2).
Elderly (> 65 years old)Dose adjustment is not needed in the elderly (see section 5.2).
Paediatric patientsThere is limited experience with Omeprazole for intravenous use in children.
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 health care professional should consider stopping [nationally completed name]. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.As in all long-term treatments, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.This medicinal product is essentially 'sodium- free'. The total amount of sodium (Na+) in the reconstituted solution is less than 1 mmol (23 mg) per 40 mg dose.
Effects of omeprazole on the pharmacokinetics of other active substances
Active substances with pH dependent absorptionThe decreased intragastric acidity during treatment with omeprazole might increase or decrease the absorption of active substances with a gastric pH dependent absorption.
Nelfinavir, atazanavirThe plasma levels of nelfinavir and atazanavir are decreased in case of co-administration with omeprazole.Concomitant administration of omeprazole with nelfinavir is contraindicated (see section 4.3).Co-administration of omeprazole (40 mg once daily) reduced mean nelvinavir exposure by ca. 40% and the mean exposure of the pharmacologically active metabolite M8 was reduced by ca. 75-90%. The interaction may also involve CYP2C19 inhibition.Concomitant administration of omeprazole with atazanavir is not recommended (see section 4.4).Concomitant administration of omeprazole (40 mg once daily) and atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a 75% decrease of the atazanavir exposure. Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. The co-administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared to atazanavir 300 mg/ritonavir 100 mg once daily.
DigoxinConcomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10%. Digoxin toxicity has been rarely reported. However caution should be exercised when omeprazole is given at high doses in elderly patients. Therapeutic drug monitoring of digoxin should be then be reinforced.
ClopidogrelIn a crossover clinical study, clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) was diminished by 47% (24 hours) and 30% (Day 5) when clopidogrel and omeprazole were administered together. In another study it was shown that administering clopidogrel and omeprazole at different times did not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19. Inconsistent data on the clinical implications of this PK/PD interaction in terms of major cardiovascular events have been reported from observational and clinical studies.
Other active substancesThe absorption of posaconazole, erlotinib, ketoconazol and itraconazol is significantly reduced and thus clinical efficacy may be impaired. For posaconazol and erlotinib concomitant use should be avoided.Active substances metabolised by CYP2C19Omeprazole is a moderate inhibitor of CYP2C19, the major omeprazole metabolising enzyme. Thus, the metabolism of concomitant active substances also metabolised by CYP2C19, may be decreased and the systemic exposure to these substances increased. Examples of such drugs are R-warfarin and other vitamin K antagonists, cilostazol, diazepam and phenytoin.
CilostazolOmeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively.
PhenytoinMonitoring phenytoin plasma concentration is recommended during the first two weeks after initiating omeprazole treatment and, if a phenytoin dose adjustment is made, monitoring and a further dose adjustment should occur upon ending omeprazole treatment.
SaquinavirConcomitant administration of omeprazole with saquinavir/ritonavir resulted in increased plasma levels up to approximately 70% for saquinavir associated with good tolerability in HIV-infected patients.
TacrolimusConcomitant administration of omeprazole has been reported to increase the serum levels of tacrolimus. A reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and dosage of tacrolimus adjusted if needed.
Effects of other active substances on the pharmacokinetics of omeprazole
Inhibitors of CYP2C19 and/or CYP3A4Since omeprazole is metabolised by CYP2C19 and CYP3A4, active substances known to inhibit CYP2C19 or CYP3A4 (such as clarithromycin and voriconazole) may lead to increased omeprazole serum levels by decreasing omeprazole's rate of metabolism. Concomitant voriconazole treatment resulted in more than doubling of the omeprazole exposure. As high doses of omeprazole have been well-tolerated adjustment of the omeprazole dose is not generally required. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.
Inducers of CYP2C19 and/or CYP3A4Active substances known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St John's wort) may lead to decreased omeprazole serum levels by increasing omeprazole's rate of metabolism.
|Blood and lymphatic system disorders|
|Very rare:||Agranulocytosis, pancytopenia|
|Immune system disorders|
|Rare:||Hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/shock|
|Metabolism and nutrition disorders|
|Very rare:||Hypomagnesaemia (see section 4.4).|
|Rare:||Agitation, confusion, depression|
|Very rare:||Aggression, hallucinations|
|Nervous system disorders|
|Uncommon:||Dizziness, paraesthesia, somnolence|
|Ear and labyrinth disorders|
|Respiratory, thoracic and mediastinal disorders|
|Common:||Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting|
|Rare:||Dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis|
|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|
|Very rare:||Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis(TEN)|
|Not known:||Subacute cutaneous lupus erythematosus (see section 4.4)|
|Musculoskeletal and connective tissue disorders|
|Uncommon:||Fracture of the hip, wrist or spine (see section 4.4)|
|Very rare:||Muscular weakness|
|Renal and urinary disorders|
|Reproductive system and breast disorders|
|General disorders and administration site conditions|
|Uncommon:||Malaise, peripheral oedema|
Reporting of suspected adverse reactionsReporting 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 (www.mhra.gov.uk/yellowcard).
Mechanism of actionOmeprazole, 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 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 stimulus.
Pharmacodynamic effectsAll pharmacodynamic effects observed can be explained by the effect of omeprazole on acid secretion.
Effect on gastric acid secretionIntravenous omeprazole produces a dose dependent inhibition of gastric acid secretion in humans. In order to immediately achieve a similar reduction of intragastric acidity as after repeated dosing with 20 mg orally, a first dose of 40 mg intravenously is recommended. This results in an immediate decrease in intragastric acidity and a mean decrease over 24 hours of approximately 90% for both IV injection and IV infusion.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 H. pyloriH. 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 and antimicrobials is associated with high rates of healing and long-term remission of peptic ulcers.
Other effects related to acid inhibitionDuring 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.
DistributionThe apparent volume of distribution in healthy subjects is approximately 0.3 l/kg body weight. Omeprazole is 97% plasma protein bound.
Metabolism:Omeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of its metabolism is dependent on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulphone. As a consequence of high affinity of omeprazole to CYP2C19, there is a potential for competitive inhibition and metabolic drug-drug interactions with other substrates for CYP2C19. However, due to low affinity to CYP3A4, omeprazole has no potential to inhibit the metabolism of other CYP3A4 substrates. In addition, omeprazole lacks an inhibitory effect on the main CYP enzymes.Approximately 3% of the Caucasian population and 1520% of Asian populations lack a functional CYP2C19 enzyme and are called poor metabolisers. In such individuals the metabolism of omeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 20 mg omeprazole, 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.
ExcretionTotal plasma clearance is about 30-40 l/h after a single dose. The plasma elimination half-life of omeprazole is usually shorter than one hour both after single and repeated once-daily dosing. Omeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration. Almost 80% of a dose of omeprazole is excreted as metabolites in the urine, the remainder in the faeces, primarily originating from bile secretion.The AUC of omeprazole 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 and/or its metabolites (e.g. the sulphone).No metabolite has been found to have any effect on gastric acid secretion.
Impaired hepatic functionThe metabolism of omeprazole in patients with liver dysfunction is impaired, resulting in an increased AUC. Omeprazole has not shown any tendency to accumulate with once-daily dosing.
Impaired renal functionThe pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are unchanged in patients with reduced renal function.
ElderlyThe metabolism rate of omeprazole is somewhat reduced in elderly subjects (75-79 years of age).
Preparation1. With a syringe draw 5 ml of infusion solution from the 100 ml infusion bottle or bag.2. Add this volume to the vial with the freeze-dried omeprazole, mix thoroughly making sure all omeprazole is dissolved.3. Draw the omeprazole solution back into the syringe.4. Transfer the solution into the infusion bag or bottle.5. Repeat steps 1-4 to make sure all omeprazole is transferred from the vial into the infusion bag or bottle.
Alternative preparation for infusions in flexible containers1. Use a double-ended transfer needle and attach to the injection membrane of the infusion bag. Connect the other needle-end from the vial with freeze-dried omeprazole.2. Dissolve the omeprazole substance by pumping the infusion solution back and forward between the infusion bag and the vial.3. Make sure all omeprazole is dissolved.The solution for infusion is to be administered in an intravenous infusion for 20-30 minutes.Any unused product or waste material should be disposed of in accordance with local requirements.
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