Losec Mups 10 & 20 & 40 mg FC tablets.

Adults: LOSEC MUPS tablets are indicated for the treatment of duodenal ulcer including prevention of relapse, gastric ulcer, reflux oesophagitis, including long term management of patients with reflux oesophagitis, Zollinger-Ellison Syndrome, and for the symptomatic relief of heartburn in patients with gastroesophageal reflux disease and the short-term relief of functional dyspepsia.

LOSEC MUPS tablets are indicated for H. pylori -positive duodenal ulcers, as part of the eradication programme with appropriate antibiotics. Treatment of NSAID associated gastric and/or duodenal ulcer and erosions and a reduction of the risk to develop gastric and/or duodenal ulcer/erosions and a risk of reduction for relapse of a previously healed gastric and/or duodenal ulcer/erosions in patients on NSAIDs treatment.

Children: Short term (up to 3 months) treatment of severe ulcerative reflux oesophagitis resistant to previous medical treatment.

Posology

Duodenal ulcer : The recommended dosage is 20 mg once daily for two to four weeks. In some duodenal ulcer patients, refractory to other treatment regimens, 40 mg once daily may be effective. For the prevention of relapse in patients with duodenal ulcer the recommended dose is 10 mg once daily. If needed the dose can be increased to 20 u2013 40 mg once daily.

LOSEC MUPS tablets are indicated for H. pylori -positive duodenal ulcers, as part of the eradication programme with appropriate antibiotics. For NSAID associated duodenal ulcers, see u201cNSAID associated gastroduodenal lesionsu201d.

Gastric ulcer and reflux oesophagitis : The recommended dosage is 20 mg once daily for four to eight weeks. In some patients with gastric ulcer or reflux oesophagitis refractory to other treatment regimens, 40 mg once daily may be effective. For the long-term management of patients with reflux oesophagitis, the recommended dose is 10 mg once daily. If needed the dose can be increased to 20 u2013 40 mg once daily. In patients with severe or symptomatic recurrent reflux oesophagitis treatment can be continued with LOSEC MUPS at a dosage of 20 mg once daily. For NSAID associated gastric ulcers, see u201cNSAID associated gastroduodenal lesionsu201d.

Severe ulcerative reflux oesophagitis in children from one year and older: The recommended dosage regime is: Weight: 10 u2013 20 kg LOSEC MUPS 10 mg once daily > 20 kg LOSEC MUPS 20 mg once daily If needed, dosage may be increased to 20 mg and 40 mg respectively.

NSAID associated gastroduodenal lesions: NSAID associated gastric ulcers, duodenal ulcers or gastroduodenal erosions in patients with or without continued NSAID treatment, the recommended dosage of LOSEC MUPS is 20 mg once daily. Symptom resolution is rapid and, in most patients, healing occurs within 4 weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further 4 weeks treatment period. For the prevention of NSAID associated gastric ulcers, duodenal ulcers, gastroduodenal erosions and dyspeptic symptoms, the recommended dosage of LOSEC MUPS is 20 mg once daily.

Symptomatic gastroesophageal reflux disease: The recommended dosage is 20 mg daily. Patients may respond adequately to 10 mg daily, and therefore individual dose adjustment should be considered. If symptom control has not been achieved after four weeks treatment with 20 mg daily, further investigation is recommended.

Functional dyspepsia: For the relief of symptoms in patients with epigastric pain/discomfort with or without heartburn, the recommended dosage is 20 mg once daily. Patients may respond adequately to 10 mg daily and therefore this dose could be considered as a starting dose. If symptom control has not been achieved after 2 weeks treatment with 20 mg daily, further investigation is recommended.

Zollinger-Ellison Syndrome: The recommended initial dosage is 60 mg once daily. The dosage should be adjusted individually, and treatment continued as long as is clinically indicated. Patients with severe disease have been effectively controlled on LOSEC MUPS with more than 90 % maintained on doses of 20 mg to 120 mg daily. With doses above 80 mg daily, the dose should be divided and given twice daily.

Special populations

Elderly: No dose adjustment is necessary in the elderly.

Impaired renal function: No dose adjustment is required in patients with impaired renal function.

Impaired hepatic function: As bioavailability and plasma half-life of omeprazole are increased in patients with impaired hepatic function, a daily dose of 10 u2013 20 mg is generally sufficient. The long-term safety of LOSEC MUPS in patients with renal and hepatic impairment has not been established.

Paediatric population

Children: There is very limited experience with LOSEC MUPS in children.

Method of administration

Oral administration: LOSEC MUPS tablets are recommended to be given in the morning and swallowed whole with half a glass of liquid. The tablets should not be chewed or crushed. For patients with swallowing difficulties the tablets may be dispersed in half a glass of non-carbonated water or fruit juices. Stir until the tablets disintegrate and drink the liquid with the pellets immediately or within 30 minutes. Rinse the glass with half a glass of fluid and drink. The pellets must not be chewed or crushed.

• Known hypersensitivity to omeprazole, substituted benzimidazoles or to any of the excipients (see section 6.1).

LOSEC MUPS is not indicated for mild gastrointestinal complaints such as nervous dyspepsia. Prior to treatment the possibility of malignancy or gastric ulcer or a malignant disease of the oesophagus should be excluded as the treatment with LOSEC MUPS may alleviate the symptoms of malignant ulcers and can thus delay diagnosis.

Concomitant administration with omeprazole and medicines such as atazanavir and nelfinavir is not recommended (see section 4.5). 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 %. Based on these data, concomitant use of omeprazole and clopidogrel should be avoided (see section 4.5).

Some published observational studies suggest that the use of the use of LOSEC 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 proton pump inhibitors (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. PPIs, 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 PPIs may increase the overall risk of fracture by 10 u2013 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) PPIs 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 provider should consider stopping LOSEC. SCLE after previous treatment with a PPI may increase the risk of SCLE with other PPIs.

Renal impairment Acute interstitial nephritis (AIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms ranging from those of hypersensitivity reactions to nonspecific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue LOSEC and evaluate patients with suspected AIN.

Severe hypomagnesaemia has been reported in patients treated with PPIs like LOSEC 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 medicines that may cause hypomagnesaemia (e.g. diuretics), healthcare providers should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

Omeprazole, as in LOSEC MUPS, is a CYP2C19 inhibitor. When starting or ending treatment with LOSEC MUPS, the potential for interactions with medicines 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 cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported very rarely and rarely, respectively in association with omeprazole treatment.

Interference with laboratory tests Increased Chromogranin A (CgA) levels 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 the 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 PPIs 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.

Sugar spheres LOSEC MUPS contain sugar spheres which may have an effect on the glycaemic control of patients with diabetes mellitus. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase- isomaltase insufficiency should not take this medicine.

Effects of omeprazole on the pharmacokinetics of other medicines

Active substances with pH dependant absorption The gastric acid suppression during treatment with LOSEC might decrease or increase the absorption of medicines with a gastric pH dependent absorption.

Nelfinavir, atazanavir 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 CYP2C19. 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. 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.

Digoxin Absorption of medicines such as digoxin can increase during treatment with omeprazole. 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). Digoxin toxicity has rarely been reported. However, caution should be exercised when omeprazole is given at high doses in elderly patients. Therapeutic monitoring of digoxin should be reinforced.

Clopidogrel 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. 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 medicines, such as posaconazole, ketoconazole, itraconazole, erlotinib 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 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 LOSEC 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 LOSEC 20 mg daily did, however, not change coagulation time in patients on continuous treatment with warfarin.

Cilostazol Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased C max 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.

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, lidocaine, quinidine, estradiol, erythromycin, and budesonide. Results from a range of interaction studies with omeprazole versus other medicines demonstrate that omeprazole, 20 u2013 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 S-warfarin, piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol, propranolol), CYP2E1 (such as ethanol).

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 medicines on the pharmacokinetics of omeprazole

Inhibitors of CYP2C19 and/or CYP3A4 Since omeprazole is metabolised by CYP2C19 and CYP3A4, medicines known to inhibit CYP2C19 or CYP3A4 or both (such as clarithromycin and voriconazole) may lead to increased omeprazole serum levels by decreasing the rate of omeprazoleu2019s 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 generally required during temporary concomitant use. 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 Medicines known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St Johnu2019s Wort) may lead to decreased omeprazole serum levels by increasing omeprazoleu2019s rate of metabolism.

Pregnancy 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.

Breastfeeding Omeprazole is excreted in breast milk but is not likely to influence the child when therapeutic doses are used.

Fertility Animal studies with the racemic mixture omeprazole, given by oral administration do not indicate effects with respect to fertility.

Adverse drug reactions such as dizziness and visual disturbances may occur (see section 4.8). If affected, patients should not drive or operate machinery.

a. Summary of the safety profile The most common side effects (1 u2013 10 % of patients) are headache, abdominal pain, constipation, diarrhoea, flatulence and nausea/vomiting. Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP) have been reported in association with omeprazole treatment (see section 4.4).

b. Tabulated list of adverse reactions The following events have been reported as adverse events in clinical trials or reported adverse reactions from post marketing surveillance. None was found to be dose related. The reactions are classified according to frequency (very common ( u2265 1/10); common ( u2265 1/100 to <1/10); uncommon ( u2265 1/1 000 to <1/100); rare u2265 1/10 000 to <1/1 000; very rare <1/10 000), not known (cannot be estimated from the available data).

MedDRA system organ class Frequency Adverse reactions Blood and lymphatic system disorders Rare Leukopenia, thrombocytopenia, agranulocytosis, pancytopenia Immune system disorders Rare Hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/shock Metabolism and nutrition disorders Rare Hyponatraemia Very Rare Hypomagnesaemia, severe hypomagnesaemia may result in hypocalcaemia Not known Hypomagnesaemia may also be associated with hypokalaemia Psychiatric disorders Uncommon Insomnia Rare Agitation, confusion, depression, hallucinations, aggression Nervous system disorders Common Headache Uncommon Dizziness, paraesthesia, light-headedness, 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/vomiting, fundic gland polyps (benign) Rare Dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis Hepatobiliary disorders Uncommon Increased liver enzymes Rare Hepatitis with or without jaundice, hepatic failure, encephalopathy in patients with pre-existing liver disease Skin and subcutaneous tissue disorders Uncommon Dermatitis, pruritus, urticaria, rash Rare Alopecia, photosensitivity, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), bullous eruption, acute generalized exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS) Not known Subacute cutaneous lupus erythematosus (see section 4.4) Musculoskeletal and connective tissue and bone disorders Uncommon Fracture of the hip, wrist or spine Rare Arthralgia, myalgia, muscular weakness Renal and urinary disorders Rare Interstitial nephritis (with possible progression to renal failure) Reproductive system and breast disorders Rare Gynaecomastia General disorders and administration site conditions Uncommon Malaise Rare Increased sweating, peripheral oedema c. Description of selected adverse reactions 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 increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with omeprazole may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter . 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.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety App (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

Rare reports have been received of overdosage with omeprazole. In the literature doses of up to 560 mg have been described and occasional reports have been received when single oral doses have reached up to 2 400 mg omeprazole (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported from overdosage with omeprazole. Also, apathy, depression and confusion have been described in single cases. The symptoms described in connection with omeprazole overdosage have been transient, and no serious outcome due to omeprazole has been reported. The rate of elimination was unchanged (first order kinetics) with increased doses and no specific treatment has been needed. Treatment is symptomatic and supportive.