Source: Health Products Regulatory Authority (IE) Revision Year: 2023 Publisher: Pharmaco (N.Z.) Ltd, 4 Fisher Crescent, Mt Wellington, Auckland 1060, Telephone: 0800 804 079
Known hypersensitivity to omeprazole, substituted benzimidazoles or any other constituent of the formulation.
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, the possibility of malignancy should be excluded as treatment may alleviate symptoms and delay diagnosis.
Concomitant administration of omeprazole and medicines such as atazanavir and nelfinavir is not recommended (see section 4.5 Interactions).
Concomitant use of omeprazole and clopidogrel should be avoided see section 4.5 Interactions).
Some published studies have shown that withdrawal of long-term proton pump inhibitor (PPI) therapy can lead to aggravation of acid-related symptoms and may result in rebound acid hypersecretion. The causal relationship with omeprazole has not been fully established.
Some published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with a small increased risk for osteoporosis related fractures. However, in other similar observational studies no such increased risk was found.
In randomized, double-blind and controlled clinical studies on omeprazole and esomeprazole (including two open long-term studies of up to more than 12 years) there are no indications that PPIs are associated with osteoporotic fractures.
Although a causal relationship between omeprazole/esomeprazole and osteoporotic fractures has not been established, patients at risk for developing osteoporosis or osteoporotic fractures are advised to have appropriate clinical monitoring in accordance with current clinical guidelines for these conditions.
Symptomatic hypomagnesaemia has been reported rarely in patients treated with long-term PPI medication. In some severe cases hypocalcaemia was also reported. Severe hypomagnesaemia may result in serious adverse events such as tetany, seizures and potentially also arrhythmias. In some patients, treatment of hypomagnesaemia with magnesium replacement was not sufficient to correct the magnesium imbalance and discontinuation of the PPI was required. In patients later retreated with the same or different PPI, hypomagnesaemia returned within a shorter time period. For patients expected to be on prolonged treatment or who take PPIs with other medicines such as digoxin or medicines that may cause hypomagnesaemia, consideration should be given to monitoring magnesium levels prior to initiation and periodically thereafter.
The decreased intragastric acidity during treatment with omeprazole might increase or decrease the absorption of active substances with a gastric pH dependent absorption.
Omeprazole has been reported to interact with some antiretroviral medicines. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral medicine. Other possible interaction mechanisms are via CYP 2C19. For some antiretroviral medicines, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Concomitant administration with omeprazole and medicines such as atazanavir and nelfinavir is therefore not recommended.
Co-administration of omeprazole (20 mg) with citalopram (20 mg single dose) doubles the AUC of the S-isomer of citalopram, but the R-isomer of citalopram is not affected. A reduction in the dose of citalopram may be necessary based on clinical judgement. For patients taking omeprazole, the citalopram dose should not exceed the maximum dose of 20 mg/day.
Co-administration of omeprazole (30 mg) with escitalopram (20 mg single dose) increased the plasma levels (approximately 50%) and terminal half-life (31%) of escitalopram. A reduction in the dose of escitalopram may be necessary based on clinical judgement.
Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (up to 30% in two out of ten subjects).
Results from studies in healthy subjects have shown a pharmacokinetic/pharmacodynamic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole (80 mg p.o. daily, i.e. four times the recommended dose) resulting in decreased exposure to the active metabolite of clopidogrel by an average of 46%, and resulting in decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 16%.
It is, however, uncertain to what extent this interaction is clinically important. One prospective, randomised (but incomplete) study (in over 3760 patients comparing placebo with omeprazole 20 mg in patients treated with clopidogrel and ASA) and non-randomised, post-hoc analyses of data from large, prospective, randomised clinical outcome studies (in over 47000 patients) did not show any evidence of an increased risk for adverse cardiovascular outcome when clopidogrel and PPIs, including omeprazole, were given concomitantly.
Results from a number of observational studies are inconsistent with regard to increased risk or no increased risk for CV thromboembolic events when clopidogrel is given together with a PPI.
When clopidogrel was given together with a fixed dose combination of esomeprazole 20 mg + ASA 81 mg compared to clopidogrel alone in a study in healthy subjects there was a decreased exposure by almost 40% of the active metabolite of clopidogrel. However, the maximum levels of inhibition of (ADP induced) platelet aggregation in these subjects were the same in the clopidogrel and the clopidogrel + the combined (esomeprazole + ASA) product groups, likely due to the concomitant administration of low dose ASA.
The absorption of erlotinib, ketoconazole and itraconazole is significantly reduced and thus clinical efficacy may be impaired. For posaconazole and erlotinib concomitant use should be avoided.
Omeprazole inhibits CYP2C19, the major omeprazole metabolising enzyme. Thus, the metabolism of concomitant medicines also metabolised by CYP2C19, such as diazepam, phenytoin, warfarin (R-warfarin) or other vitamin K antagonists and cilostazol, may be delayed.
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 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 20 mg daily did, however, not change coagulation time in patients on continuous treatment with warfarin.
Omeprazole, 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.
Omeprazole is partly metabolised also by CYP3A4, but omeprazole does not inhibit this enzyme. Thus, omeprazole does not affect the metabolism of medicines metabolised by CYP3A4, such as cyclosporin, lignocaine, quinidine, oestradiol, erythromycin and budesonide.
Results from a range of interaction studies with omeprazole versus other medicines demonstrate that omeprazole, 20-40 mg daily, has no significant influence on any other CYP enzymes relevant for medicine metabolism, as shown by the lack of metabolic interaction with substrates for CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as Swarfarin, piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol, propranolol), CYP2E1 (such as ethanol).
Concomitant administration of omeprazole has been reported to increase the serum levels of tacrolimus.
When given together with proton pump inhibitors, methotrexate levels have been reported to increase in some patients. In high-dose methotrexate administration a temporary withdrawal of omeprazole may need to be considered.
For other antiretroviral medicines, such as saquinavir, elevated serum levels have been reported. There are also some antiretroviral medicines of which unchanged serum levels have been reported when given with omeprazole.
Since omeprazole is metabolised by CYP2C19 and CYP3A4, medicines known to inhibit CYP 2C19 or CYP 3A4 or both (such as clarithromycin and voriconazole) may lead to increased omeprazole serum levels by decreasing the rate of omeprazole’s metabolism. Concomitant voriconazole treatment resulted in more than doubling of the omeprazole exposure. Since high doses of omeprazole have been well-tolerated, adjustment of the omeprazole dose is not required during temporary concomitant use.
Medicines known to induce CYP 2C19 or CYP 3A4 or both (such as rifampicin and St John’s wort) may lead to decreased omeprazole serum levels by increasing omeprazole’s rate of metabolism.
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.
Omeprazole is excreted in breast milk but is not likely to influence the child when therapeutic doses are used.
LOSEC is not likely to affect the ability to drive or use machines.
The following adverse reactions have been identified or suspected in the clinical trials programme for omeprazole and post-marketing. None was found to be dose-related. The reactions are classified according to frequency (common ≥1/100 to <1/10; uncommon ≥1/1000 to <1/100; rare ≥1/10000 to <1/1000; very rare <1/10000).
Rare: Leukopenia, thrombocytopenia, agranulocytosis, pancytopenia
Rare: Hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/shock
Rare: Hyponatraemia
Very Rare: Hypomagnesaemia, severe hypomagnesaemia may result in hypocalcaemia. Hypomagnesaemia may also result in hypokalaemia.
Uncommon: Insomnia
Rare: Agitation, aggression, confusion, depression, hallucinations
Common: Headache
Uncommon: Dizziness, paraesthesia, somnolence
Rare: Taste disturbance
Rare: Blurred vision
Uncommon: Vertigo
Rare: Bronchospasm
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, hepatic failure, encephalopathy in patients with pre-existing liver disease
Uncommon: Dermatitis, pruritus, rash, urticaria
Rare: Alopecia, photosensitivity, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS)
Rare: Arthralgia, myalgia, muscular weakness
Rare: Interstitial nephritis
Rare: Gynaecomastia
Uncommon: Malaise
Rare: Increased sweating, peripheral oedema
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via https://nzphvc.otago.ac.nz/reporting/.
None known when instructions in section 4.2 Dosage and Method of Administration are followed.
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