Nexium Control

Tablets

Composition :

Each gastro-resistant tablet contains 20 mg of esomeprazole (as magnesium trihydrate). Excipient (s) with known effect : Each gastro-resistant tablet contains 28 mg of sucrose. For the full list of excipients, see section 6.1.

Excipients

Glycerol monostearate 40-55, hyprolose, hypromellose, iron oxide (red-brown) (E 172), iron oxide (yellow) (E 172) magnesium stearate, copolymerized methacrylic acid ethyl acrylate (1: 1) 30% dispersion, microcrystalline cellulose , synthetic paraffin, macrogol 6000, polysorbate 80, crospovidone (Type A), sodium stearyl fumarate, sugar spheres (sucrose), talc, titanium dioxide (E 171), triethyl citrate.

Therapeutic indications

Nexium Control is indicated in adults for the short-term treatment of reflux symptoms (e.g. heartburn and acid regurgitation).

Contraindications

Hypersensitivity to esomeprazole, benzimidazole substitutes or to any of the excipients (see section 6.1). Esomeprazole should not be used concomitantly with nelfinavir (see section 4.5).

Dosage

Posology The recommended dose is 20 mg of esomeprazole (one tablet) per day. It may be necessary to take the tablets for 2-3 consecutive days to improve symptoms. The duration of treatment is up to 2 weeks. Once symptoms have completely disappeared, treatment should be stopped. If resolution of symptoms is not achieved within 2 weeks of continuous treatment, the patient should consult a physician. Special populations Patients with renal impairment No dose adjustment is required in patients with impaired renal function. Given the limited experience in patients with severe renal insufficiency, such patients should be treated with caution (see section 5.2). Patients with hepatic impairment No dose adjustment is required in patients with mild or moderate hepatic impairment. However, patients with severe hepatic impairment should be advised by a physician before taking Nexium Control (see sections 4.4 and 5.2). Elderly patients (≥65 years old) No dose adjustment is necessary in elderly patients. Pediatric population There is no indication for a specific use of NEXIUM Control in the pediatric population below 18 years of age in the indication: “short-term treatment of reflux symptoms (eg heartburn and acid regurgitation)”. Method of administration The tablets should be swallowed whole with half a glass of water. The tablets should not be chewed or crushed. Alternatively, the tablet can be dispersed in half a glass of still water. Other liquids should not be used as the gastro-resistant coating may dissolve. The water should be mixed until the tablet disperses. The liquid with the granules should be drunk immediately or within 30 minutes. The glass should be rinsed with half a glass of water and the water drunk. The granules must not be chewed or crushed.

Warnings and Precautions

General Patients should be instructed to consult a physician if: • They have significant unintentional restoration of silhouette, recurrent vomiting, dysphagia, haematemesis or melaena and when gastric ulcer is suspected or present, the malignant nature of the ulcer should be excluded as esomeprazole therapy may alleviate symptoms and delay diagnosis. • Have had a previous stomach ulcer or gastrointestinal surgery. • Have been on continuous symptomatic treatment of dyspepsia or heartburn for 4 or more weeks. • Have jaundice or severe liver disease. • Are over the age of 55 with new or recently changed symptoms. Patients with long-term recurring symptoms of dyspepsia or heartburn should see their doctor at regular intervals. In particular, patients over the age of 55 who are taking daily non-prescription treatments for dyspepsia and heartburn should inform their doctor or pharmacist. Patients should not take Nexium Control as a long-term preventative drug. Treatment with proton pump inhibitors (PPIs) may lead to a slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter, and possibly also Clostridium difficile in hospitalized patients (see section 5.1). Patients should consult their doctor before taking this medicine if they are to undergo an endoscopy or urea breath test. Combination with other medicinal products Co-administration of esomeprazole and atazanavir is not recommended (see section 4.5). If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir. The dose of 20 mg of esomeprazole should not be exceeded. Esomeprazole is a CYP2C19 inhibitor. At the start or end of esomeprazole treatment, the potential interaction with medicinal products metabolised by CYP2C19 should be considered. An interaction was observed between clopidogrel and esomeprazole. The clinical relevance of this interaction is uncertain. The use of esomeprazole with clopidogrel should be discouraged (see section 4.5). Patients should not take another PPI or H2 antagonist concomitantly. Sucrose This medicine contains sugar (sucrose) spheres. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. Interference with laboratory tests An increased level of Chromogranin A (CgA) may interfere with investigations for neuroendocrine tumors. To avoid this interference, esomeprazole treatment should be temporarily interrupted for five days before CgA determination.

Interactions

Interaction studies have only been performed in adults. Influence of esomeprazole on the pharmacokinetics of other medicinal products Since esomeprazole is an enantiomer of omeprazole it is advisable to consider the interactions observed with omeprazole. Protease inhibitors Interactions have been reported between omeprazole and some protease inhibitors. The clinical relevance and mechanisms of these interactions are not always known. An increase in gastric pH during omeprazole treatment may change the absorption of protease inhibitors. Other possible mechanisms of interaction occur through inhibition of CYP2C19. For atazanavir and nelfinavir, decreased serum levels have been reported when administered with omeprazole and concomitant administration is not recommended. Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg / ritonavir 100 mg in healthy volunteers results in a substantial reduction in atazanavir exposure (approximately 75% decrease in AUC, Cmax and Cmin) . Increasing the atazanavir dose to 400 mg does not compensate for the impact of omeprazole on atazanavir exposure. Co-administration of omeprazole (20 mg once daily (qd)) with atazanavir 400 mg / ritonavir 100 mg to healthy volunteers resulted in an approximately 30% decrease in atazanavir exposure compared to the exposure observed with atazanavir 300 mg / ritonavir 100 mg qd without omeprazole 20 mg qd. Co-administration of omeprazole (40 mg qd) reduced the mean AUC, Cmax and Cmin of nelfinavir by 36-39% and the mean AUC, Cmax and Cmin of the pharmacologically active metabolite M8 were reduced by 75-92%. Due to the pharmacodynamic effects and similar pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration of esomeprazole and atazanavir is not recommended and concomitant administration of esomeprazole and nelfinavir is contraindicated (see sections 4.3 and 4.4). Increased serum levels (80-100%) of saquinavir (co-administered with ritonavir) have been reported during concomitant treatment with omeprazole (40 mg qd). Treatment with omeprazole 20 mg qd had no effect on the exposure of darunavir (co-administered with ritonavir) and amprenavir (co-administered with ritonavir). Treatment with esomeprazole 20 mg qd had no effect on amprenavir exposure (with and without co-administration with ritonavir). Treatment with omeprazole 40 mg qd had no effect on lopinavir exposure (co-administered with ritonavir). Methotrexate Methotrexate levels have been reported to increase in some patients when given together with PPI. In the presence of high doses of methotrexate, temporary withdrawal of esomeprazole may need to be considered. Tacrolimus Increased serum levels of tacrolimus have been reported with concomitant administration of esomeprazole and tacrolimus. Strengthened monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and tacrolimus dosage adjusted as necessary. Medicinal products with pH dependent absorption Suppression of gastric acidity during treatment with esomeprazole and other PPIs may decrease or increase the absorption of medicinal products with pH dependent gastric absorption. The absorption of medicinal products such as ketoconazole, itraconazole and erlotinib may decrease during treatment with esomeprazole and the absorption of digoxin may increase during treatment with esomeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (up to 30% in two of ten subjects). Digoxin toxicity has rarely been reported. However, caution should be exercised when esomeprazole is administered in high doses to elderly patients. Monitoring of the therapeutic effect of digoxin therefore needs to be strengthened. Medicinal products metabolised by CYP2C19 Esomeprazole inhibits CYP2C19, the major esomeprazole metabolising enzyme. Therefore, when esomeprazole is combined with other medicinal products metabolised via CYP2C19, such as warfarin, phenytoin, citalopram, imipramine, clomipramine, diazepam, etc., the plasma concentrations of these medicinal products may be increased and a dose reduction may be required. In the case of clopidogrel, a prodrug converted to its active metabolite by CYP2C19, the plasma concentration of the active metabolite may be reduced. Warfarin Concomitant administration of 40 mg esomeprazole to patients receiving warfarin in a clinical study showed that clotting times remained within a normal range. However, some isolated cases of increased INR of clinical relevance have been reported post-marketing during concomitant treatment. Monitoring is recommended at the initiation and termination of concomitant treatment with esomeprazole during treatment with warfarin or other coumarin derivatives. Clopidogrel Results from studies in healthy volunteers showed a pharmacokinetic (PK) / pharmacodynamic (PD) interaction between clopidogrel (loading dose 300 mg / daily maintenance dose 75 mg) and esomeprazole (40 mg orally daily) resulting in in a decreased exposure to the active metabolite of clopidogrel of on average 40%, and resulting in a decrease in maximal inhibition of platelet aggregation (induced ADP) of on average 14%. In a study in healthy subjects, an almost 40% decrease in exposure to the active metabolite of clopidogrel was observed when a fixed dose combination of esomeprazole 20 mg + ASA 81 mg and clopidogrel was administered, compared to clopidogrel alone. However, in these subjects the maximum levels of inhibition of platelet aggregation (induced ADP) were the same in both groups. Non-unique data from observational and clinical studies have been reported on the clinical implications of this PK / PD interaction in terms of major cardiovascular events. As a precaution, concomitant use of esomeprazole and clopidogrel should be discouraged. Phenytoin Concomitant administration of 40 mg esomeprazole results in a 13% increase in trough plasma levels of phenytoin in epileptic patients. It is recommended that phenytoin plasma concentrations be monitored when treatment with esomeprazole is initiated or discontinued. Voriconazole Omeoprazole (40 mg once daily) increased the Cmax and AUCτ of voriconazole (a CYP2C19 substrate) by 15% and 41%, respectively. Cilostazol Omeoprazole as well as esomeprazole act as inhibitors of CYP2C19. Omeprazole, given in doses of 40 mg to healthy subjects in a crossover study, increased the Cmax and AUC of cilostazol by 18% and 26% respectively, and of one of its active metabolites by 29% and 69% respectively. Cisapride In healthy volunteers, concomitant administration of 40 mg esomeprazole resulted in a 32% elevation of the area under the plasma concentration / time curve (AUC) and a 31% prolongation of the elimination half-life (t1 / 2) but not a significant increase in peak plasma concentrations of cisapride. The mild QTc interval prolongation observed after administration of cisapride alone is not further prolonged when cisapride is administered in combination with esomeprazole. Diazepam Concomitant administration of 30 mg esomeprazole resulted in a 45% reduction in clearance of the CYP2C19 substrate diazepam. Medicinal products studied with no clinically relevant interactions Amoxicillin and quinidine Esomeprazole has been shown to have no clinically relevant effect on the pharmacokinetics of amoxicillin and quinidine. Naproxen or rofecoxib Studies evaluating the concomitant administration of esomeprazole with naproxen or rofecoxib did not reveal any clinically relevant pharmacokinetic interactions in short-term studies. Influence of other medicinal products on the pharmacokinetics of esomeprazole Medicinal products inhibiting CYP2C19 and / or CYP3A4 Esomeprazole is metabolised via CYP2C19 and CYP3A4. Concomitant treatment of esomeprazole with a CYP3A4 inhibitor, clarithromycin (500 mg twice daily (bid)), results in a doubling of the exposure (AUC) to esomeprazole. Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4 can lead to more than doubled exposure of esomeprazole. Voriconazole, inhibitor of CYP2C19 and CYP3A4, raises the AUCτ of omeprazole by 280%. A dose adjustment of esomeprazole is not routinely required in either of the above mentioned situations. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated. Medicinal products that induce CYP2C19 and / or CYP3A4 Medicinal products known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St. John's wort (Hypericum perforatum)) may lead to decreased serum levels of esomeprazole for 'increased metabolism of esomeprazole.

Side effects

Summary of the safety profile Headache, abdominal pain, diarrhea and nausea are among the most commonly reported adverse reactions in clinical trials (and also from post-marketing use). Furthermore, the safety profile is similar for different formulations, treatment indications, age groups and patient populations. No dose related adverse reactions were identified. Tabulated list of adverse reactions The following adverse reactions have been identified or suspected during clinical trials with esomeprazole and post-marketing. Reactions have been classified according to the MedDRA convention on frequency: very common> 1/10; common ≥1 / 100, <1/10; uncommon ≥1 / 1,000 to <1/100; rare ≥1 / 10,000, <1 / 1,000; very rare <1 / 10,000; not known (frequency cannot be estimated from the available data).

Reporting of suspected adverse reactions Reporting suspected adverse reactions that occur after authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to the Italian Medicines Agency, website: http://www.agenziafarmaco.gov.it/it/responsabili.

Pregnancy and breastfeeding