Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Sandoz Ltd, Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR, United Kingdom
Hypersensitivity to omeprazole, substituted benzimidazoles or to any of the excipients.
Omeprazole like other proton pump inhibitors (PPIs) should not be used concomitantly with nelfinavir (see section 4.5).
In the presence of any alarm symptoms (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 medicinal products, 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 medicinal products 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.
Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter (see section 5.1).
Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors 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 proton pump inhibitor.
For patients expected to be on prolonged treatment or who take proton pump inhibitors with digoxin or medicinal products that may cause hypomagnesaemia (e.g. diuretics), health care professionals should consider measuring magnesium levels before starting proton pump inhibitor 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 for intravenous. 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 for intravenous 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.
As in all long-term treatments, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.
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 nelfinavir 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 then be reinforced.
Clopidogrel:
In 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 substances:
The 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.
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 medicinal products 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.
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.
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.
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 events 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.
Omeprazole is not likely to affect the ability to drive or use machines. Adverse 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 adverse events (1-10% of patients) are headache, abdominal pain, constipation, diarrhoea, flatulence and nausea/vomiting.
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. 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
Very rare: Hypomagnesaemia (see section 4.4)
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, 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 (see section 4.4)
Rare: Arthralgia, myalgia
Very rare: Muscular weakness
Rare: Interstitial nephritis
Very rare: Gynaecomastia
Uncommon: Malaise, peripheral oedema
Rare: Increased sweating
Irreversible visual impairment has been reported in isolated cases of critically ill patients who have received omeprazole intravenous injection, especially at high doses, but no causal relationship has been established.
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 (www.mhra.gov.uk/yellowcard).
Omeprazole powder for solution for infusion should not be mixed with other medicinal products than those mentioned in section 6.6.
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