Emanera 20 Mg/40 Mg Capsules

EMANERA 20 mg and 40 mg capsules are indicated in adults for:

• Gastro-oesophageal Reflux Disease (GORD):
• treatment of erosive reflux oesophagitis
• long-term management of patients with healed oesophagitis to prevent relapse
• symptomatic treatment of Gastro-oesophageal Reflux Disease (GORD)
• In combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori:
• healing of Helicobacter pylori associated duodenal ulcer and
• prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcer disease.
• Patients requiring continued NSAID therapy:
• healing of gastric ulcers associated with NSAID therapy.
• prevention of gastric and duodenal ulcers associated with NSAID therapy, in patients at risk.
• Treatment of Zollinger Ellison Syndrome
• In combination with antibiotics in treatment of duodenal ulcer caused by Helicobacter pylori

Gastro-oesophageal Reflux Disease (GORD):

• treatment of erosive reflux oesophagitis 40 mg once daily for 4 weeks
• An additional 4 week treatment is recommended for patients in whom oesophagitis has not healed or who have persistent symptoms.
• long-term management of patients with healed oesophagitis to prevent relapse 20 mg once daily.
• symptomatic treatment of Gastro-oesophageal Reflux Disease (GORD) 20 mg once daily in patients without oesophagitis. If symptom control has not been achieved after 4 weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using an on-demand regimen, taking 20 mg once daily, when needed.
• In combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori and healing of Helicobacter pylori associated duodenal ulcer and prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcer disease 20 mg EMANERA with 1 g amoxicillin and 500 mg clarithromycin (as per local protocol or guideline), all twice daily for 7 days.
• Patients requiring continued NSAID therapy:
• healing of gastric ulcers associated with NSAID therapy the usual dose is 20 mg once daily. The treatment duration is 4 u2013 8 weeks.
• prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk 20 mg or 40 mg once daily.
• Pathological hypersecretory conditions including Zollinger-Ellison syndrome and idiopathic hypersecretion: The recommended initial dosage is EMANERA 40 mg twice daily. The dosage should then be individually adjusted, and treatment continued as long as clinically indicated. Doses up to 120 mg twice daily have been administered.
• Adolescents 12-18 years:
• Gastro-oesophageal Reflux Disease (GORD):
• treatment of erosive reflux oesophagitis 40mg once daily for 4 weeks
• An additional 4 week treatment is recommended for patients in whom oesophagitis has not healed or who have persistent symptoms.
• long-term management of patients with healed oesophagitis to prevent relapse 20 mg once daily.
• Symptomatic treatment of Gastro-oesophageal Reflux Disease (GORD) 20 mg once daily in patients without oesophagitis. If symptom control has not been achieved after 4 weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using 20 mg once daily under medical supervision.
• Treatment of duodenal ulcer caused by Helicobacter pylori When selecting appropriate combination therapy, consideration should be given to official national, regional and local guidance regarding bacterial resistance, duration of treatment (most commonly 7 days but sometimes up to 14 days), and appropriate use of antibacterial agents. The treatment should be supervised by a specialist.
• The posology recommendation is:
• Weight Posology
• 30 - 40 kg Combination with two antibiotics: EMANERA 20 mg, amoxicillin 750 mg and clarithromycin 7.5 mg/kg body weight are all administered together twice daily for one week.
• > 40 kg Combination with two antibiotics: EMANERA 20 mg, amoxicillin 1 g and clarithromycin 500 mg are all administered together twice daily for one week.
• Children: EMANERA should not be used in children younger than 1 year since no data is available.
• Impaired renal function: Dose adjustment is not required in patients with impaired renal function. Due to limited experience in patients with severe renal insufficiency, such patients should be treated with caution.
• Impaired hepatic function: Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, a maximum daily dose of 20 mg EMANERA should be used.
• Elderly: Dose adjustment is not required in the elderly.
• Method of administration: The capsules should be swallowed whole with some water. The capsules should not be chewed or crushed.
• For patients who have difficulty in swallowing, the capsules can also be opened and the pellets mixed in half a glass of non-carbonated water. No other liquids should be used as the enteric coating may be dissolved. Drink the water with the pellets immediately or within 30 minutes. Rinse the glass with half a glass of water and drink. The pellets must not be chewed or crushed.
• For patients who cannot swallow, the capsules can be opened and pellets mixed in non-carbonated water and administered through a gastric tube. It is important that the appropriateness of the selected syringe and tube is carefully tested before use (see section 6.6).
• Do not eat the desiccant capsule provided in the container.

Hypersensitivity to esomeprazole, substituted benzimidazoles or to any of the excipients listed in section 6.1. EMANERA should not be used concomitantly with atazanavir or nelfinavir (see section 4.5).

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 with EMANERA may alleviate symptoms and delay diagnosis.

Long term use: Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.

On demand treatment: Patients on on-demand treatment should be instructed to contact their medical doctor if their symptoms change in character.

Helicobacter pylori eradication: When prescribing esomeprazole for eradication of Helicobacter pylori possible active substance interactions for all components in the triple therapy should be considered. Clarithromycin is a potent inhibitor of CYP3A4 and hence contraindications and interactions for clarithromycin should be considered when the triple therapy is used in patients concurrently taking other medicinal products metabolised via CYP3A4 such as cisapride.

Gastrointestinal infections: Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter (see section 5.1).

Absorption of vitamin B12: Esomeprazole 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.

Hypomagnesaemia: Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPIs) like esomeprazole 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.

Risk of fracture: 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 10u201340%. 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.

Combination with other medicines: Esomeprazole is a CYP2C19 inhibitor. When starting or ending treatment with esomeprazole, the potential for interactions with drugs metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and esomeprazole (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of esomeprazole and clopidogrel should be discouraged.

When prescribing esomeprazole for on demand therapy, the implications for interactions with other pharmaceuticals, due to fluctuating plasma concentrations of esomeprazole should be considered. (see section 4.5).

Interference with laboratory tests: Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, EMANERA 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.

Subacute cutaneous lupus erythematosus (SCLE): 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 EMANERA. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Tubulointerstitial nephritis: Increased risk of subclinical acute or chronic interstitial nephritis associated with protein pump inhibitors (PPIu2019s) leading to chronic renal inflammation and reduced renal function. The preferred term to describe the histological findings of tubular injury being u201ctubulointerstitial nephritisu201d. Acute tubulointerstitial nephritis is characterised by an inflammatory reaction within the tubulointerstitial space of the kidney. Acute interstitial inflammatory reactions are associated with damage to the tubulointerstitium, leading to acute kidney injury. Tubulointerstitial nephritis may be medicine-related, infectious, systemic, autoimmune, genetic, and idiopathic with the most common cause being related to a medication or medicine exposure. The risk of tubulointerstitial nephritis leading to chronic inflammation and reduced renal function associated with the use of protein pump inhibitors such as EMANERA, is a class effect.

Effects of EMANERA on the pharmacokinetics of other medicines

Protease inhibitors: Omeprazole has been reported to interact with some protease inhibitors. The clinical importance and the mechanisms behind these reported interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the protease inhibitors. Other possible interaction mechanisms are via inhibition of CYP 2C19. For atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole and concomitant administration is not recommended. Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a substantial reduction in atazanavir exposure (approximately 75% decrease in AUC, Cmax and Cmin). 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 with the exposure observed with atazanavir 300 mg/ritonavir 100 mg once daily without omeprazole 20 mg once daily. Co-administration of omeprazole (40 mg once daily) reduced mean nelfinavir AUC, Cmax and Cmin by 36-39 % and mean AUC, Cmax and Cmin for the pharmacologically active metabolite M8 was reduced by 75- 92%. Due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration with esomeprazole and atazanavir or nelfinavir is contraindicated (see section 4.3).

For saquinavir (with concomitant ritonavir), increased serum levels (80-100%) have been reported during concomitant omeprazole treatment (40 mg once daily). Treatment with omeprazole 20 mg once daily had no effect on the exposure of darunavir (with concomitant ritonavir) and amprenavir (with concomitant ritonavir). Treatment with esomeprazole 20 mg once daily had no effect on the exposure of amprenavir (with and without concomitant ritonavir). Treatment with omeprazole 40 mg once daily had no effect on the exposure of lopinavir (with concomitant ritonavir).

Methotrexate: When given together with PPIs, methotrexate levels have been reported to increase in some patients. In high-dose methotrexate administration a temporary withdrawal of esomeprazole may need to be considered.

Tacrolimus: Concomitant administration of esomeprazole 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.

Medicines with pH dependent absorption: Gastric acid suppression during treatment with esomeprazole and other PPIs might decrease or increase the absorption of medicinal products with a gastric pH dependent absorption. As with other medicinal products that decrease intragastric acidity, the absorption of medicinal products such as ketoconazole, itraconazole and erlotinib can decrease and the absorption of digoxin can 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 out of ten subjects). Digoxin toxicity has been rarely reported. However, caution should be exercised when esomeprazole is given at high doses in elderly patients. Therapeutic drug monitoring of digoxin should then be reinforced.

Medicines metabolised by CYP2C19: Esomeprazole inhibits CYP2C19, the major esomeprazole metabolising enzyme. Thus, when esomeprazole is combined with active substances metabolised by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin etc., the plasma concentrations of these active substances may be increased, and a dose reduction could be needed. This should be considered especially when prescribing esomeprazole for on demand therapy.

Diazepam: Concomitant administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam.

Phenytoin: Concomitant administration of 40 mg esomeprazole resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients. It is recommended to monitor the plasma concentrations of phenytoin when treatment with esomeprazole is introduced or withdrawn.

Voriconazole: Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) Cmax and AUCu03c4 by 15% and 41%, respectively.

Cilostazol: Omeprazole as well as esomeprazole act as inhibitors of CYP2C19. 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.

Cisapride: In healthy volunteers, concomitant administration of 40 mg esomeprazole resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life (tu00bd) but no significant increase in peak plasma levels of cisapride. The slightly prolonged QTc interval observed after administration of cisapride alone, was not further prolonged when cisapride was given in combination with esomeprazole (see also section 4.4).

Warfarin: Concomitant administration of 40 mg esomeprazole to warfarin-treated patients in a clinical trial showed that coagulation times were within the accepted range. However, post-marketing, a few isolated cases of elevated INR of clinical significance have been reported during concomitant treatment. Monitoring is recommended when initiating and ending concomitant esomeprazole treatment during treatment with warfarin or other coumarine derivatives.

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 esomeprazole (40 mg p.o. daily) resulting in decreased exposure to the active metabolite of clopidogrel by an average of 40% and resulting in decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 14%. 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. Inconsistent data on the clinical implications of a PK/PD interaction of esomeprazole in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution concomitant use of clopidogrel should be discouraged.

Investigated medicines with no clinically relevant interaction: Amoxicillin and quinidine. Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine. Naproxen or rofecoxib: Studies evaluating concomitant administration of esomeprazole and either naproxen or rofecoxib did not identify any clinically relevant pharmacokinetic interactions during short-term studies.

Effects of other medicines on the pharmacokinetics of EMANERA: Medicines which inhibit CYP2C19 and/or CYP3A4: Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant administration of esomeprazole and a CYP3A4 inhibitor, clarithromycin (500 mg b.i.d.), resulted in a doubling of the exposure (AUC) to esomeprazole. Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP 3A4 may result in more than doubling of the esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor voriconazole increased omeprazole AUCu03c4 by 280%. A dose adjustment of esomeprazole is not regularly required in either of these situations. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.

Medicines which induce CYP2C19 and/or CYP3A4: Medicines known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St. Johnu2019s wort) may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism.

Paediatric population: Interaction studies have only been performed in adults.

Safety during pregnancy and lactation has not been established.

EMANERA may cause dizziness and blurred vision, thereby affecting the ability to drive or use machinery.

Summary of the safety profile: Headache, abdominal pain, diarrhoea and nausea are among those adverse reactions that have been most commonly reported in clinical trials (and also from post-marketing use). In addition, the safety profile is similar for different formulations, treatment indications, age groups and patient populations. No dose-related adverse reactions have been identified.

Tabulated summary of adverse reactions: The following adverse drug reactions have been identified or suspected in the clinical trials programme for esomeprazole and post-marketing. None was found to be dose-related.

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. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

No specific antidote is known. EMANERA is extensively plasma protein bound and is therefore not readily dialysable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.