Source: Health Products Regulatory Authority (IE) Revision Year: 2019 Publisher: Xeolas Pharmaceuticals Limited, Hamilton Building, DCU, Glasnevin, Dublin 9, Ireland
Hypersensitivity to the active substance, substituted benzimidazoles or to any of the excipients listed in section 6.1.
Omeprazole like other proton pump inhibitors (PPIs) must not be used concomitantly with nelfinavir (see section 4.5).
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, malignancy should be excluded, as treatment may alleviate symptoms and delay diagnosis.
Co-administration of atazanavir with proton pump inhibitors is not recommended (see section 4.5). 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 400 mg with 100 mg of ritonavir; omeprazole 20 mg should not be exceeded.
Omeprazole, as 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.
Omeprazole is a CYP2C19 inhibitor. When starting or ending treatment with omeprazole, the potential for interactions with drugs metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and omeprazole (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of omeprazole and clopidogrel should be discouraged.
Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPIs) like omeprazole 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 drugs 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 fracture 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.
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 Omeprazole. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.
Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, omeprazole treatment should be stopped for at least 5 days before CgA measurements (see section 5.1). 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.
Some children with chronic illnesses may require long-term treatment although it is not recommended.
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 (see section 5.1).
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 contains 17.2 mg (0.75 mmol) of sodium per ml or 86mg (3.75 mmol) of sodium per 5ml dose, equivalent (for 5ml dose) to 4.3% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
This medicine contains 54.3 mg (1.39 mmol) potassium per ml or 271.5 mg (6.95mmol) of potassium per 5ml dose. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.
This medicinal product contains sodium methyl para hydroxybenzoate, which may cause allergic reactions (possibly delayed).
This medicine contains 5 mg sodium benzoate in each 1 ml.
This product contains maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Effects of omeprazole on the pharmacokinetics of other active substances
Active substances with pH dependent absorption
The decreased intragastric acidity during treatment with omeprazole might increase or decrease the absorption of active
substances with a gastric pH dependent absorption.
Nelfinavir, atazanavir
The 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.
Digoxin
Concomitant 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.
Clopidogrel
Results from studies in healthy subjects have shown a pharmacokinetic (PK)/pharmacodynamic (PD) interaction between
clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole (80 mg p.o. daily) resulting in a decreased
exposure to the active metabolite of clopidogrel by an average of 46% and a decreased maximum inhibition of (ADP induced)
platelet aggregation by an average of 16%.
Inconsistent data on the clinical implications of a PK/PD interaction of omeprazole in terms of major cardiovascular events have
been reported from both observational and clinical studies. As a precaution, concomitant use of omeprazole and clopidogrel
should be discouraged (see section 4.4).
Other active substances
The absorption of posaconazole, erlotinib, ketoconazole and itraconazole is significantly reduced and thus clinical efficacy may
be impaired. For posaconazole and erlotinib concomitant use should be avoided.
Active substances metabolised by CYP2C19
Omeprazole 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.
Cilostazol
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.
Phenytoin
Monitoring 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.
Unknown mechanism
Saquinavir
Concomitant 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.
Tacrolimus
Concomitant 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.
Methotrexate
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.
Effects of other active substances on the pharmacokinetics of omeprazole
Inhibitors CYP2C19 and/or CYP3A4
Since 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 CYP3A4
Active 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.
Results from three prospective epidemiological studies (more than 1000 exposed outcomes) indicate no adverse effects of omeprazole on pregnancy or on the health of the foetus/newborn child. Omeprazole can be used during pregnancy.
Omeprazole is excreted in breast milk but is not likely to influence the child when therapeutic doses are used.
Animal studies with the racemic mixture omeprazole, given by oral administration do not indicate effects with respect to fertility.
Omeprazole Oral Suspension is not likely to affect the ability to drive or use machines. Adverse drug reactions such as dizziness and visual disturbances may occur (see section 4.8). If affected, patients should not drive or operate machinery.
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 omeprazole and post-marketing. None was found to be dose-related. Adverse reactions listed below are classified according to 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).
Rare: Leukopenia, thrombocytopenia
Very rare: Agranulocytosis, pancytopenia
Rare: Hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/shock
Rare: Hyponatraemia
Not known: Hypomagnesaemia; severe hypomagnesaemia may result in hypocalcaemia. Hypomagnesaemia may also be associated with hypokalaemia.
Uncommon: Insomnia
Rare: Agitation, confusion, depression
Very rare: Aggression, 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, fundic gland polyps (benign)
Rare: Dry mouth, stomatitis, gastrointestinal candidiasis
Not known: Microscopic colitis
Uncommon: Increased liver enzymes
Rare: Hepatitis with or without jaundice
Very rare: Hepatic failure, encephalopathy in patients with pre-existing liver disease
Uncommon: Dermatitis, pruritus, rash, urticaria
Rare: Alopecia, photosensitivity
Very rare: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN)
Not known: Subacute cutaneous lupus erythematosus (see section 4.4)
Uncommon: Fracture of the hip, wrist or spine
Rare: Arthralgia, myalgia
Very rare: Muscular weakness
Rare: Interstitial nephritis
Very rare: Gynaecomastia
Uncommon: Malaise, peripheral oedema
Rare: Increased sweating
The safety of omeprazole 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 omeprazole during a clinical study for severe erosive esophagitis 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 omeprazole treatment on puberty and growth.
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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.
Not applicable.
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