NEXIUM - PACKAGE LEAFLET - LEAFLETS

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Nexium - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life

Active ingredients: Esomeprazole

Nexium 10 mg gastro-resistant granules for oral suspension, in sachet

Nexium package inserts are available for pack sizes:

Nexium 10 mg gastro-resistant granules for oral suspension, in sachet
Nexium 20 mg gastro-resistant tablets, Nexium 40 mg gastro-resistant tablets
NEXIUM 40 mg powder for solution for injection / infusion

Why is Nexium used? What is it for?

Nexium contains a substance called esomeprazole, which belongs to a group of medicines called proton pump inhibitors. These medicines work by reducing the amount of acid produced by your stomach.

Nexium is used for the treatment of "gastroesophageal reflux disease".

Gastro-oesophageal reflux is when acid from the stomach escapes into the esophagus causing pain, inflammation and heartburn. Heartburn consists of a burning sensation that rises from the stomach or chest towards the neck.
In children, symptoms may include stomach contents returning to the mouth (regurgitation), feeling sick (vomiting) and poor weight gain.

Contraindications When Nexium should not be used

Do not take Nexium

if you are allergic (hypersensitive) to esomeprazole or other similar proton pump inhibitors (eg pantoprazole, lansoprazole, rabeprazole, omeprazole), or to any of the other ingredients of gastro-resistant Nexium granules.
if you are taking a medicine containing nelfinavir (used to treat HIV).

Precautions for use What you need to know before taking Nexium

Take special care with Nexium

if you have liver problems please tell your doctor, as he may prescribe a lower dose
if you have kidney problems please tell your doctor.

Nexium can mask the symptoms of other diseases. Therefore, if any of the following happen to you while you are taking Nexium, tell your doctor immediately:

Loses a lot of weight for no reason.
You have stomach pains or indigestion.
Start vomiting repeatedly.
You have trouble swallowing.
You vomit blood or have black stools (blood-stained stools).

If you have been prescribed Nexium on an "as needed" basis, contact your doctor if symptoms persist or if their characteristics change. On-demand treatment has not been studied in children and is therefore not recommended in this patient group.

If you take a proton pump inhibitor such as Nexium, especially for longer than one year, you may have a slightly increased risk of hip, wrist or spine fracture. If you have osteoporosis or are taking corticosteroids (which may increase the risk of osteoporosis) consult your doctor.

Interactions Which drugs or foods can modify the effect of Nexium

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Nexium can affect the way some other medicines work and some medicines can have an effect on Nexium.

In particular, tell your doctor or pharmacist if you are taking any of the following medicines:

Atazanavir (used to treat HIV). Do not take Nexium if you are taking nelfinavir.
Clopidogrel (used to prevent blood clots)
Ketoconazole, itraconazole or voriconazole (used to treat infections caused by fungi).
Erlotinib (used to treat cancer).
Diazepam (used for the treatment of anxiety or for muscle relaxation).
Citalopram, imipramine or clomipramine (used to treat depression).
Phenytoin (used in epilepsy).
Warfarin or coumarin (medicines called anticoagulants which are used to thin the blood).
Cilostazol (used to treat intermittent claudication - pain in the legs when walking, which is caused by insufficient blood supply).
Cisapride (used for indigestion and heartburn).
Clarithromycin (used to treat infections).
Digoxin (used for heart problems).
Methotrexate (a medicine used in high-dose chemotherapy to treat cancer) - if you are taking a high dose of methotrexate, your doctor may temporarily stop your treatment with Nexium.
Tacrolimus (used in organ transplants)
Rifampicin (used to treat tuberculosis).
St. John's wort (Hypericum perforatum) (used to treat depression).

Taking Nexium gastro-resistant granules with food and drink

Nexium gastro-resistant granules can be taken with or without food.

Warnings It is important to know that:

Pregnancy and breastfeeding

Before taking Nexium, tell your doctor or pharmacist if you are pregnant or trying to get pregnant. Your doctor will tell you if you can take Nexium during this time. Nexium should not be taken while breastfeeding.

Driving and using machines

Nexium is unlikely to affect your ability to drive or use tools or machines.

Important information about some of the ingredients of Nexium

Nexium contains sucrose and glucose which are both types of sugars. It is therefore important to have thorough oral hygiene and to regularly clean your teeth with a toothbrush.

If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking Nexium.

Dose, Method and Time of Administration How to use Nexium: Posology

Always take Nexium exactly as your doctor has told you. If in doubt, you should consult your doctor or pharmacist.

Your medicine comes as granules contained in a sachet. Each sachet contains 10 mg of esomeprazole. Your doctor will tell you how many sachets to take per day. Your doctor will also tell you how long to take them.

Empty the contents of the sachet or sachets into a glass containing water. Do not use sparkling water. The amount of water depends on the number of sachets your doctor has told you to take at a time.
Use 15 milliliters (ml) of water (3 teaspoons) for each sachet. This means you will need 15ml for one sachet and 30ml for two sachets.
Mix the granules in the water.
Let the contents thicken for a few minutes.
Mix again and drink the contents. The granules must not be chewed or crushed. Do not leave the content longer than 30 minutes before drinking it.
If after taking traces of the product remain in the glass, add more water, mix and drink the contents immediately.

Nexium gastro-resistant granules can be taken with or without food.

If you are tube fed (gastric), your doctor or nurse will give you Nexium through the tube. Information for your doctor or nurse is at the end of this leaflet.

Children

Nexium is not recommended for children under 1 year of age.
Children between the ages of 1 and 11 can take Nexium. The usual dose is one sachet (10 mg) or two sachets (20 mg) once a day. The dose for children is calculated based on the child's weight and the doctor will decide on the correct dose.

Adults and adolescents from 12 years of age

The usual dose is two sachets (20 mg) or 4 sachets (40 mg) once a day.

Senior citizens

There is no need to change the dose if you are elderly.

Patients with liver or kidney problems

In patients with severe liver problems, the maximum daily dose of Nexium is 2 sachets (20 mg). In children aged 1-11 years with severe liver problems, the maximum daily dose of 10 mg should not be exceeded.
No special dose reductions are required in patients with kidney problems. However, if you have severe kidney problems your doctor may want to have some tests done.

Overdose What to do if you have taken too much Nexium

If you take more Nexium than you should

If you have taken more Nexium than prescribed by your doctor, contact your doctor for a consultation.

If you forget to take Nexium

If you forget to take a dose of Nexium, take it as soon as you remember. If it is almost time for your next dose, wait until the usual time. Do not take a double dose to make up for a forgotten dose.

If you have any further questions on the use of Nexium, ask your doctor or pharmacist

Side Effects What are the side effects of Nexium

Like all medicines, Nexium can cause side effects, although not everybody gets them.

Allergic reactions

A severe allergic reaction (anaphylaxis) is a rare side effect that affects less than 1 in 1,000 people who take Nexium.

You may notice wheezing, swelling of the face or body, rash, fainting or difficulty swallowing. If this happens to you, stop taking Nexium and contact your doctor immediately.

Other side effects include:

Common (affects less than 1 in 10 people):

Headache.
Effects on the stomach or intestines: diarrhea, stomach pain, constipation, flatulence.
Nausea or vomiting.

Uncommon (affects less than 1 in 100 people):

Swelling in the feet and ankles.
Disturbed sleep (insomnia).
Dizziness, pins and needles, sleepiness.
Dizziness.
Dry mouth
Changes in blood tests that check how the liver is working.
Skin rash, hives and itching.
Fracture of the hip, wrist or spine (if Nexium is used in high doses and for prolonged periods)

Rare (affects less than 1 in 1,000 people):

Blood problems such as reduced number of white blood cells and platelets.
Low levels of sodium in the blood.
Feeling agitated, confused or depressed.
Changes in taste.
Vision problems such as blurred vision.
Sudden wheezing or shortness of breath (bronchospasm).
Inflammation of the inside of the mouth.
An infection called "thrush" which can affect the gut and is caused by a fungus.
Hepatitis with or without jaundice.
Hair loss (alopecia).
Skin rash on sun exposure.
Joint pain (arthralgia) or muscle pain (myalgia).
General feeling of being unwell and lack of strength.
Increased sweating.

Very rare (affects less than 1 in 10,000 people):

Change in the number of blood cells, including agranulocytosis (lack of white blood cells).
Aggression.
Seeing, feeling or hearing things that are not there (hallucinations).
Severe liver problems leading to liver failure and inflammation of the brain.
ciche or peeling of the skin. This may be associated with high fever and joint pain (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis).
Muscle weakness.
Severe kidney problems.
Breast enlargement in men.

Not known (frequency cannot be estimated from the available data)

If you take Nexium for more than three months, your blood levels of magnesium may drop. Low magnesium levels can manifest themselves with fatigue, involuntary muscle contractions, disorientation, convulsions, dizziness, increased heart rate. If you have any of these symptoms, please consult your doctor immediately. Low levels of magnesium can also lead to a reduction in potassium or calcium levels in the blood. Your doctor should decide whether to check your blood magnesium levels periodically.
Inflammation of the intestines (which can lead to diarrhea).

Nexium, in very rare cases, can affect white blood cells leading to immunodeficiency. If you have an "infection with symptoms such as fever with severe deterioration of your general physical condition or fever with symptoms of local infection such as pain in the neck, throat or mouth, or difficulty urinating, you should see your doctor as soon as possible. that lack of white blood cells (agranulocytosis) can be ruled out by a blood test It is important for you to give information about the medicines you are taking.

Do not worry about the list of possible side effects above. You may not get any. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or the pharmacist.

Expiry and Retention

This medicinal product does not require any special storage conditions.

Keep out of the reach and sight of children.
Do not use Nexium after the expiry date which is stated on the carton and sachet. The expiry date refers to the last day of the month.
The reconstituted suspension should be taken within 30 minutes

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

What Nexium gastro-resistant granules for oral suspension contains

The active ingredient is esomeprazole. Each sachet contains 10 mg of esomeprazole (as magnesium trihydrate).

The excipients are:

Esomeprazole granules:

Glycerol monostearate 40-55

Hydroxypropyl cellulose

Hypromellose

Magnesium stearate

Copolymer methacrylic acid ethyl acrylate (1: 1) dispersion at 30%

Polysorbate 80 Sucrose in spheres (sucrose and corn starch)

Talc

Triethyl citrate

Inert granules:

Citric acid anhydrous (for pH adjustment)

Crospovidone

Glucose

Hydroxypropyl cellulose

Yellow iron oxide (E 172)

Xanthan gum.

What Nexium looks like and contents of the pack

Each sachet of Nexium contains pale yellow fine granules. Brown granules may be visible. The oral suspension is a thick, yellow liquid containing suspended granules.

Each pack contains 28 sachets.

The following information is intended for medical or healthcare professionals only

Information on administration to patients with a nasogastric or gastric tube:

To administer the 10 mg dose, add the contents of a 10 mg sachet to 15 ml of water.
To administer the 20 mg dose, add the contents of two 10 mg sachets to 30 ml of water.
Mix.
Leave to thicken for a few minutes.
Mix again.
Pick up the suspension with a syringe.
Inject through the tube, 6 French in diameter or larger, into the stomach within 30 minutes of reconstitution.
Refill the syringe with 15 ml of water for the 10 mg dose and with 30 ml of water for the 20 mg dose.
Shake and inject the remaining contents of the nasogastric or gastric tube into the stomach. Unused suspension should be discarded

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Nexium can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

NEXIUM 10 MG FOOD-RESISTANT GRANULATE FOR ORAL SUSPENSION, IN SACHET

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each sachet contains: 10 mg of esomeprazole (as magnesium trihydrate).

Excipients: sucrose 6.8 mg and glucose 2.8 mg.

For the full list of excipients see section 6.1.

03.0 PHARMACEUTICAL FORM

Gastro-resistant granules for oral suspension, in sachet.

Pale yellow fine granules. Brown granules may be visible.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Nexium oral suspension is primarily indicated for the treatment of gastroesophageal reflux disease (GERD) in children 1 to 11 years of age.

Gastroesophageal reflux disease (GERD)

- treatment of endoscopically demonstrated erosive reflux esophagitis

- symptomatic treatment of gastroesophageal reflux disease (GERD)

Nexium oral suspension can also be used in patients who have difficulty swallowing Nexium gastro-resistant dispersible tablets. For indications in patients aged 12 years and older, please refer to the Summary of Product Characteristics of Nexium gastro-resistant tablets.

04.2 Posology and method of administration

Dosage:

Pediatric population:

Children from 1 to 11 years of age with a body weight> 10 kg

Gastroesophageal reflux disease (GERD)

- Endoscopically demonstrated treatment of erosive reflux esophagitis

Weight ≥ 10 -

Weight ≥ 20 kg: 10 mg or 20 mg once daily for 8 weeks.

- Symptomatic treatment of gastroesophageal reflux disease (GERD)

10 mg once daily for up to 8 weeks.

Doses above 1 mg / kg / day have not been studied.

Children under 1 year of age

The experience of treatment with esomeprazole in children below 1 year of age is limited and therefore treatment is not recommended in this age group (see section 5.1).

Adults and adolescents from 12 years of age

For posology in patients aged 12 years and older, please refer to the Summary of Product Characteristics of Nexium gastro-resistant tablets.

Special populations

Patients with impaired renal function

Dosage adjustments are not required in patients with impaired renal function.

In view of the limited clinical experience, patients with severe renal impairment should be treated with caution (see section 5.2).

Patients with impaired liver function

No dose adjustment is required in patients with mild or moderate hepatic impairment. In patients ≥ 12 years of age with severe hepatic impairment, the maximum dose of 20 mg of Nexium should not be exceeded. In children aged 1-11 years with severe hepatic impairment the maximum dose of 10 mg should not be exceeded (see section 5.2).

Method of administration

For the 10 mg dose, empty the contents of one 10 mg sachet into a glass containing 15 ml of water.

For the 20 mg dose, empty the contents of two 10 mg sachets into a glass containing 30 ml of water.

Do not use sparkling water.

Mix the contents until the granules are dispersed and leave to thicken for a few minutes. Mix again and drink the contents within 30 minutes. The granules must not be chewed or crushed. Rinse the glass with 15 ml of water to take all the granules.

For patients with a nasogastric or gastric tube: see section 6.6 for preparation and instructions for administration.

04.3 Contraindications

Known hypersensitivity to esomeprazole, to benzimidazole substitutes or to any other component of the formulation.

Esomeprazole should not be used concomitantly with nelfinavir (see section 4.5).

04.4 Special warnings and appropriate precautions for use

In the presence of any alarming symptoms (eg significant unintended weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, the malignant nature of the ulcer should be ruled out in how Nexium therapy could alleviate symptoms and delay diagnosis.

Patients who have been treated for a long time (especially those who have been treated for more than a year) should be monitored regularly. Long-term treatment is indicated in adults and adolescents (12 years of age and older, see section 4.1).

Patients on an on-demand regimen should be instructed to contact their physician if the symptoms experienced take on a different character. On-demand treatment has not been studied in children and is therefore not indicated in this patient group.

The implications of fluctuating plasma concentrations of esomeprazole for interactions with other drugs should be considered in patients on this regimen (see section 4.5).

The medicinal product contains sucrose and glucose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

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

Co-administration of esomeprazole and atazanavir is not recommended (see section 4.5). If the combination of atazanavir with a proton pump inhibitor is 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 esomeprazole should not exceed 20 mg.

Esomeprazole, like all acid-blocking drugs, can reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. risk for reduced absorption of vitamin B12.

Esomeprazole is an inhibitor of CYP2C19. Potential interaction with drugs metabolised by CYP2C19 should be considered at the start or end of treatment with esomeprazole. An interaction between clopidogrel and omeprazole was observed (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of esomeprazole and clopidogrel should be discouraged.

Proton pump inhibitors (PPIs) such as esomeprazole have been shown to cause severe hypomagnesaemia in patients treated for at least three months and in many cases for one year. Serious symptoms of hypomagnesaemia include fatigue, tetany, delirium, convulsions, dizziness, and ventricular arrhythmia. They can initially manifest insidiously and be neglected. Hypomagnesaemia in most patients improves after taking magnesium and discontinuing the proton pump inhibitor. Healthcare professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment. treatment in patients on therapy for a long time or on digoxin therapy or medicines that can cause hypomagnesaemia (e.g. diuretics).

Proton pump inhibitors, especially when used in high doses and for prolonged periods (> 1 year), may cause a slightly increased risk of hip, wrist and spine fractures, especially in elderly patients or in the presence of other known risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fracture by 10% to 40%. This increase may be partly due to other risk factors. Patients at risk of osteoporosis should receive treatment according to current clinical practice guidelines and must take an "adequate amount of vitamin D and calcium.

Interference with laboratory tests

An increased level of CgA can interfere with investigations for neuroendocrine tumors. To avoid this interference, esomeprazole treatment should be temporarily stopped for at least five days prior to CgA determination.

04.5 Interactions with other medicinal products and other forms of interaction

Influence of esomeprazole on the pharmacokinetics of other drugs

Medicinal products with pH dependent absorption

Suppression of gastric acidity related to treatment with esomeprazole and other proton pump inhibitors may decrease or increase the absorption of medicinal products with pH dependent gastric absorption. As observed with other medicinal products that reduce intragastric acidity, the absorption of medicinal products such as ketoconazole, itraconazole and erlotinib may decrease 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). & EACUTE; toxicity to digoxin has been rarely reported. However, caution should be exercised when esomeprazole is administered in high doses to elderly patients. Monitoring of the therapeutic use of digoxin therefore needs to be reinforced.

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 alter the absorption of protease inhibitors.Other possible mechanisms of interaction occur through inhibition of CYP2C19. Decreased serum levels of atazanavir and nelfinavir have been reported when administered with omeprazole and therefore concomitant administration is not recommended. Concomitant administration of omeprazole (40 mg / day) 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 did not compensate for the impact of omeprazole on atazanavir exposure. Co-administration of omeprazole (20 mg / day) with atazanavir 400 mg / ritonavir 100 mg in healthy volunteers resulted in a approximately 30% decrease in atazanavir exposure compared to exposure observed with atazanavir 300 mg / ritonavir 100 mg / day without omeprazole 20 mg / day. Co-administration of omeprazole (40 mg / day) decreased AUC , the mean Cmax and Cmin of nelfinavir by 36-39% and the mean AUC, Cmax and Cmin of the pharmacologically active metabolite M8 by 75-92%. Increased serum levels (80-100%) of saquinavir ( co-administered with ritonavir) during concomitant treatment with omeprazole (40 mg / day). Treatment with omeprazole 20 mg / day had no effect on the exposure of darunavir (co-administered with ritonavir) and amprenavir (co-administered with ritonavir). -administration with ritonavir). Treatment with esomeprazole 20 mg / day had no effect on the exposure of amprenavir (with and without co-administration with ritonavir). Treatment with omeprazole 40 mg / day had no effect on the exposure of lopinavir (when co-administered with ritonavir). Co-administration of esomeprazole and atazanavir is not recommended and co-administration of esomeprazole and nelfinavir is contraindicated due to the pharmacodynamic effects and similar pharmacokinetic properties of omeprazole and esomeprazole.

Drugs metabolised by CYP2C19

Esomeprazole inhibits its main metabolising enzyme, CYP2C19. When esomeprazole is combined with other drugs metabolised via CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., plasma concentrations of these drugs may be increased and doses may need to be reduced. This should be particularly taken into account when esomeprazole is prescribed as needed. Concomitant administration of esomeprazole 30 mg promotes a 45% reduction in clearance of the CYP2C19 substrate diazepam. Concomitant administration of esomeprazole 40 mg promotes a better elevation of phenytoin trough plasma levels by 13%. Monitoring phenytoin plasma concentrations is recommended when starting or stopping treatment with esomeprazole. omeprazole (40 mg / day) increases the Cmax and AUC of voriconazole (substrate of CYP2C19) by 15% and 41% respectively.

Concomitant administration of 40 mg esomeprazole to patients receiving warfarin showed that clotting times remained within a normal range in a clinical study. However, after the marketing of the product, during concomitant treatment, some isolated cases of increased INR values of clinical relevance have been reported. Monitoring of the patient at the initiation and termination of concomitant treatment with esomeprazole during therapy with warfarin or other coumarin derivatives is recommended.

Omeprazole as well as esomeprazole act as inhibitors of CYP2C19. Omeprazole, given in doses of 40 mg to healthy subjects in a cross 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.

In healthy volunteers, concomitant administration of esomeprazole 40 mg and cisapride promotes a 32% elevation in the area under the plasma concentration / time curve (AUC) and a 31% prolongation of the elimination half-life (t½), but not a significant increase in peak plasma concentrations of cisapride. The slight prolongation of the QTc interval observed after administration of cisapride alone is not further prolonged following the combination of cisapride and esomeprazole.

Esomeprazole has been shown to have no clinically relevant effect on the pharmacokinetics of amoxicillin and quinidine.

No clinically relevant pharmacokinetic interactions were shown in short-term studies evaluating the concomitant administration of esomeprazole with naproxen or rofecoxib.

In a cross-over clinical study, clopidogrel (300 mg loading dose followed by 75 mg / day) was administered for 5 days as monotherapy and with omeprazole (80 mg administered together with clopidogrel). Exposure to the active metabolite of clopidogrel decreased by 46% (day 1) and 42% (day 5) when clopidogrel and omeprazole were co-administered. When clopidogrel and omeprazole were co-administered there was a decrease in 47% (24 hours) and 30% (day 5) of mean inhibition of platelet aggregation (PAH). In another study it was shown that administering clopidogrel and omeprazole at different times does not prevent their interaction, which appears to be driven by the inhibitory action of omeprazole on CYP2C19. Non-unique data from observational and clinical studies have been reported on the clinical implications of this pharmacokinetic / pharmacodynamic interaction in terms of major cardiovascular events.

Mechanism unknown

Methotrexate levels have been reported to increase in some patients when given together with proton pump inhibitors. In the presence of high doses of methotrexate, temporary withdrawal of esomeprazole may need to be considered.

Influence of other drugs on the pharmacokinetics of esomeprazole

Esomeprazole is metabolised via CYP2C19 and CYP3A4. Concomitant treatment with esomeprazole and a CYP3A4 inhibitor, clarithromycin (500 mg bid) results in a doubling of the exposure (AUC) of esomeprazole. Concomitant administration of esomeprazole and an inhibitor Combined CYP2C19 and CYP3A4 may lead to more than double the exposure of esomeprazole. Voriconazole, inhibitor of CYP2C19 and CYP3A4, raises the AUC of omeprazole by 280%. A dose adjustment of esomeprazole is not routinely required in either of the above mentioned situations, however, it should be considered in patients with severe hepatic impairment and in cases where long-term treatment is indicated. Long-term treatment is indicated in adults and adolescents (12 years of age and older, see section 4.1).

Drugs known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St. John's wort) may lead to decreased esomeprazole serum levels due to increased metabolism of esomeprazole.

04.6 Pregnancy and lactation

Clinical data on exposure in pregnancy are insufficient for Nexium. No malformations or foetotoxic effects have been observed with omeprazole, racemic mixture in epidemiological studies involving a large number of pregnant women. Animal studies with esomeprazole do not indicate harmful effects. direct or indirect effects on embryo-fetal development Studies conducted in animals with the racemic mixture do not indicate direct or indirect harmful effects on pregnancy, parturition or postnatal development Prescribing of the drug to pregnant women should be done with caution.

It is not known whether esomeprazole is excreted in breast milk. Studies in breastfeeding women have not been conducted, therefore Nexium should not be used during breastfeeding.

04.7 Effects on ability to drive and use machines

No effect was observed.

04.8 Undesirable effects

The following adverse reactions have been identified or suspected during clinical trials with esomeprazole and post-marketing. None of these were dose-related. The reactions have been classified according to frequency: very common> 1/10; common ≥1 / 100,

General disorders and administration site conditions

Rare: malaise, increased sweating

Respiratory, thoracic and mediastinal disorders

Rare: bronchospasm

Disorders of the blood and lymphatic system

Rare: leukopenia, thrombocytopenia

Very rare: agranulocytosis, pancytopenia

Nervous system disorders

Common: headache

Uncommon: dizziness, paraesthesia, somnolence

Rare: taste disturbances

Disorders of the immune system

Rare: hypersensitivity reactions such as fever, angioedema and anaphylactic reaction / shock

Skin and subcutaneous tissue disorders

Uncommon: dermatitis, pruritus, rash, urticaria

Rare: alopecia, photosensitivity

Very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN)

Hepatobiliary disorders

Uncommon: elevated liver enzyme values

Rare: hepatitis with or without jaundice

Very rare: hepatic failure, encephalopathy in patients with pre-existing liver disease

Gastrointestinal disorders

Common: abdominal pain, constipation, diarrhea, flatulence, nausea / vomiting

Uncommon: dry mouth

Rare: stomatitis, gastrointestinal candidiasis

Not known: Microscopic colitis

Metabolism and nutrition disorders

Uncommon: peripheral edema

Rare: hyponatremia

Not known: hypomagnesaemia (see section 4.4); severe hypomagnesaemia may be related to hypocalcemia.

Musculoskeletal and connective tissue disorders

Uncommon: fracture of the hip, wrist or spine (see section 4.4)

Rare: arthralgia, myalgia

Very rare: muscle weakness

Renal and urinary disorders

Very rare: interstitial nephritis

Psychiatric disorders

Uncommon: insomnia

Rare: agitation, confusion, depression

Very rare: aggression, hallucinations

Diseases of the reproductive system and breast

Very rare: gynaecomastia

Eye disorders

Rare: blurred vision

Ear and labyrinth disorders

Uncommon: dizziness

04.9 Overdose

Experience with intentional overdose is currently very limited. Gastrointestinal symptoms and weakness have been described in connection with the intake of 280 mg. Single doses of 80 mg of esomeprazole caused no consequences. A specific antidote is not known. Esomeprazole is extensively bound to plasma proteins and therefore is not readily dialysable. As in all cases of overdose, treatment should be symptomatic with general supportive measures.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: acid pump inhibitors.

ATC code: A02BC05.

Esomeprazole is the S isomer of omeprazole and reduces gastric acid secretion by a specific and selective mechanism of action. Esomeprazole is a specific inhibitor of the acid pump in the parietal cell. Both omeprazole isomers, R and S, have similar pharmacodynamic activity.

Site and mechanism of action

Esomeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the intracellular canaliculi of the parietal cell, where it inhibits the enzyme H + K + -ATPase - acid pump, promoting an inhibition of the basal acid secretion and stimulated.

Effects on gastric acid secretion

After oral administration of 20 mg and 40 mg esomeprazole, the effect on acid secretion occurs within 1 hour. After repeated dosing with 20 mg esomeprazole once daily for 5 days, the mean peak acid secretion after pentagastrin stimulation it is reduced by 90% when evaluated 6-7 hours after the fifth day dose.

After 5 days of oral administration with esomeprazole 20 mg and 40 mg, the intragastric pH is maintained at values above 4 for a mean time of 13 and 17 hours out of 24, respectively, in patients with symptomatic gastroesophageal reflux disease.

The proportion of patients who maintain intragastric pH above 4 for at least 8, 12, and 16 hours is 76%, 54%, and 24% for 20 mg esomeprazole, respectively, and 97%, 92%, respectively. and 56% for 40 mg esomeprazole.

A correlation between drug exposure and inhibition of acid secretion has been demonstrated using AUC as a surrogate parameter for plasma concentration.

Therapeutic effects on acid inhibition

Esomeprazole 40 mg promotes healing of reflux oesophagitis in approximately 78% of patients after 4 weeks and in 93% after 8 weeks.

Other effects related to acid inhibition

During treatment with antisecretory drugs, an elevation of serum gastrin levels has been observed in response to decreased acid secretion. The level of Chromogranin A (CgA) also increases due to decreased gastric acidity.

An increase in ECL cell numbers, possibly related to increased gastrin levels, has been observed in some patients during long-term treatment with esomeprazole.

During long-term treatment with antisecretory drugs, an increase in the frequency of appearance of gastric glandular cysts was observed, which represent the physiological consequence of the pronounced inhibition of acid secretion. These formations are benign in nature and appear reversible.

Decreased gastric acidity by any means including proton pump inhibitors increases gastric bacterial counts normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to a slightly increased risk of gastrointestinal infections Salmonella And Campylobacter and possibly also from Clostridium difficile in hospitalized patients.

Pediatric population

Children with gastroesophageal reflux disease (GERD) from 1 to 11 years of age

In a multicenter parallel group study, 109 patients with endoscopically proven GERD (1 to 11 years of age) were treated with Nexium once daily for 8 weeks to assess safety and tolerability. The dosage per patient body weight was as follows:

weight

weight ≥ 20 kg: 10 mg or 20 mg of esomeprazole once daily.

Patients were endoscopically characterized for the presence or absence of erosive esophagitis. 53 patients had erosive esophagitis at baseline. Of the 45 patients undergoing endoscopic follow-up, 42 (93.3%) had resolved (88.9%) or improved (4.4%) their erosive esophagitis after 8 weeks of treatment.

Children with GERD from 0 to 11 months of age

The efficacy and safety of esomeprazole in patients with signs and symptoms of GERD were evaluated in a placebo-controlled study (98 patients aged 1 to 11 months).

1 mg / kg esomeprazole was administered once daily for two weeks (open-label phase) and 80 patients were included for an additional 4 weeks (double-blind phase for assessment of treatment interruptions). Regarding the primary endpoint time to discontinuation due to worsening of symptoms, there were no significant differences between esomeprazole and placebo.

In a placebo-controlled study (52 patients less than 1 month of age) efficacy and safety were evaluated in patients with symptoms of GERD. 0.5 mg / kg of esomeprazole was administered once daily for a minimum of There were no significant differences between esomeprazole and placebo in the primary endpoint, change from baseline in the number of symptomatic GERD episodes.

The results of the pediatric studies also showed that treatment with 0.5 mg / kg and 1.0 mg / kg esomeprazole in infants aged less than 1 month and aged 1 to 11 months, respectively, reduced the percentage time average with intra-esophageal pH

The safety profile was found to be similar to that observed in adults.

In a study in pediatric patients with gastroesophageal reflux disease (GERD) (from ECL cell hyperplasia with no known clinical significance and with no development of atrophic gastritis or carcinoid tumors.

05.2 Pharmacokinetic properties

Absorption and distribution

Esomeprazole is sensitive to the acidic environment and is administered orally in the form of gastro-resistant granules. In vivo conversion to R-isomer is irrelevant. Absorption of esomeprazole is rapid, with peak plasma levels occurring approximately 1-2 hours after dosing. Total bioavailability is 64% after a single 40 mg administration and reaches 89% after administration. repeated every day. For the 20 mg dose of esomeprazole, the corresponding values are 50% and 68%, respectively. The apparent steady-state volume of distribution in healthy subjects is approximately 0.22 L / kg body weight. 97% of esomeprazole is bound to plasma proteins.

Food intake delays and decreases the absorption of esomeprazole, although this has no significant influence on the effect of esomeprazole on intragastric acidity.

Metabolism and elimination

Esomeprazole is completely metabolised by the cytochrome P450 (CYP) system. Most of the metabolism of esomeprazole is dependent on the polymorphically expressed CYP2C19, responsible for the formation of the hydroxy- and desmethyl metabolites of esomeprazole. The remainder depends on another specific isoform, CYP3A4, responsible for the formation of esomeprazole sulfonate which is the main plasma metabolite.

The parameters below reflect mainly the pharmacokinetics in individuals who are metabolisers with a functioning CYP2C19 enzyme.

Total plasma clearance is approximately 17 L / h after a single dose and approximately 9 L / h after repeated administration. The plasma elimination half-life of esomeprazole is approximately 1.3 hours after repeated daily dosing. The pharmacokinetics of esomeprazole have been studied at doses up to 40 mg b.i.d. The area under the plasma concentration / time curve increases with repeated administration of esomeprazole. This increase is dose dependent and leads to an increase in AUC more than dose proportional after repeated administration. This dose-dependence and time-dependence are due to the decrease in first pass metabolism and systemic clearance, possibly due to "inhibition of" CYP2C19 enzyme caused by esomeprazole and / or its sulfonate metabolite. In the time interval between administrations, esomeprazole is completely cleared from plasma and has no tendency to accumulate when administered once daily.

The major metabolites of esomeprazole have no effect on acid secretion. Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the faeces. Less than 1% of the parent drug is found in the urine.

Special patient population

Approximately 2.9 ± 1.5% of the population, termed poor metabolisers, have insufficient function of the CYP2C19 enzyme. In these individuals the metabolism of esomeprazole is likely to be primarily catalysed by CYP3A4. After repeated daily administration of 40 mg esomeprazole, the mean area under the plasma concentration / time curve was approximately 100% higher in poor metabolisers than in subjects with functional CYP2C19 enzyme (extensive metabolisers). The mean peak plasma concentration was increased by approximately 60%.

These observations have no implications for the posology of esomeprazole.

The metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years).

After a single administration of 40 mg esomeprazole, the mean area under the plasma concentration / time curve is approximately 30% higher in women than in men. After repeated daily dosing, no gender difference was observed. These observations have no implications for the posology of esomeprazole.

The metabolism of esomeprazole in patients with mild to moderate hepatic dysfunction may be impaired. The metabolic rate is decreased in patients with severe hepatic dysfunction resulting in a doubling of the area under the plasma concentration / time curve of esomeprazole. Hence in patients with dysfunction. the maximum dose of 20 mg should not be exceeded. Esomeprazole and its major metabolites show no tendency to accumulate when administered once daily.

No studies have been conducted in patients with impaired renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be affected in patients with impaired renal function.

Pediatric population

Teenagers from 12 to 18 years of age:

After repeated administration of 20 mg and 40 mg esomeprazole, the total exposure (AUC) and the time to reach maximum plasma drug concentration (tmax) in adolescents aged 12-18 years were similar to those seen in adults.

Children from 1 to 11 years of age:

After repeated dosing of 10 mg esomeprazole, the total exposure (AUC) observed within the age range of 1 to 11 years was similar, and the exposure was similar to that in adolescents and adults treated with the dose. of 20 mg. After repeated administration of 20 mg esomeprazole, the total exposure (AUC) was higher in children 6 to 11 years of age than that observed in adolescents and adults treated with the same dose.

05.3 Preclinical safety data

Conventional preclinical studies of toxicity, genotoxicity and reproductive toxicity with repeated administration have shown no particular risk for humans. Carcinogenicity studies in rats treated with the racemic mixture have shown hyperplasia of gastric ECL cells and carcinoids. These changes observed in rats are the result of "elevated and pronounced hypergastrinaemia secondary to" acid inhibition and were observed in rats after prolonged treatment with gastric acid secretion inhibitors.

Compared to that observed in adult animals, no new or unexpected toxic effects were observed in rats and juvenile dogs following administration of esomeprazole for 3 months.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Esomeprazole granules:

Glycerol monostearate 40-55

Hydroxypropyl cellulose

Hypromellose

Magnesium stearate

Methacrylic acid ethyl acrylate copolymer (1: 1) dispersion at 30%

Polysorbate 80

Sucrose beads (sucrose and corn starch)

Talc

Triethyl citrate

Inert granules:

Citric acid anhydrous (for pH adjustment)

Crospovidone

Glucose

Hydroxypropyl cellulose

Yellow iron oxide (E172)

Xanthan gum.

06.2 Incompatibility

Not relevant.

06.3 Period of validity

3 years.

The product must be taken within 30 minutes of reconstitution.

06.4 Special precautions for storage

There are no special storage instructions.

06.5 Nature of the immediate packaging and contents of the package

Pack of 28 sachets.

Sachets (containing granules) made up of 3 layers: polyethylene terephthalate (PET), aluminum, low density polyethylene (LDPE) which protects the granules from humidity.