NEXIUM CONTROL - PACKAGE LEAFLET - LEAFLETS

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Nexium Control - Package Leaflet

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

Active ingredients: Esomeprazole

Nexium Control 20 mg gastro-resistant tablets

Indications Why is Nexium Control used? What is it for?

Nexium Control contains the active substance esomeprazole. It belongs to a group of medicines called 'proton pump inhibitors'. These work by reducing the amount of acid produced by the stomach.

This medicine is used in adults for the short-term treatment of reflux symptoms (for example, heartburn and acid regurgitation).

Reflux is the backflow of acid from the stomach into the esophagus ("food canal") which can become inflamed and painful. This can cause symptoms such as a painful sensation in the chest rising to the throat (heartburn) and a sour taste in the mouth (acid regurgitation).

Nexium Control is not designed to bring immediate relief. You may need to take the tablets for 2-3 consecutive days before you feel better. Talk to your doctor if you don't feel better or if you feel worse after 14 days.

Contraindications When Nexium Control should not be used

Do not take Nexium Control

if you are allergic to esomeprazole or any of the other ingredients of this medicine
if you are allergic to medicines containing other proton pump inhibitors (e.g. pantoprazole, lansoprazole, rabeprazole or omeprazole).
if you are taking a medicine containing nelfinavir (used to treat HIV infections)

You should not take this medicine if it falls into any of the above cases. If in doubt, consult your doctor or pharmacist before taking this medicine.

Precautions for use What you need to know before taking Nexium Control

Talk to your doctor before taking Nexium Control if:

You have had a "stomach ulcer or had stomach surgery in the past."
You have been on continuous treatment for 4 or more weeks for reflux or heartburn.
You have jaundice (yellowing of the skin and eyes) or severe liver problems.
You have severe kidney problems.
She is over 55 and has had new or recently changed reflux symptoms or needs indigestion or heartburn remedies daily without a prescription.
Talk to your doctor immediately before taking or after taking this medicine, if you notice any of the following symptoms, which could be signs of another, more serious illness.
Loses a lot of weight for no reason.
You have trouble or pain in swallowing.
Stomach pain or signs of indigestion such as nausea, fullness, bloating appear, especially after food.
He starts vomiting food or blood, which can appear as dark as coffee grounds in his vomit.
The stools are black (blood-stained stools).
Have severe or persistent diarrhea esomeprazole has been associated with a small increased risk of infectious diarrhea.

Get urgent advice from your doctor if you feel chest pain accompanied by lightheadedness, sweating, dizziness or shoulder pain and shortness of breath. This could be a symptom of a serious heart problem.

Call your doctor before taking this medicine if:

You must undergo an endoscopy or urea breath test.
You must have a specific blood test (Chromogranin A)

If any of the above apply to you (or if you are unsure), please contact your doctor immediately.

Children and adolescents

This medicine should not be used in children and adolescents under the age of 18.

Interactions Which drugs or foods may change the effect of Nexium Control

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is because this medicine can affect the way some medicines work and some medicines can have an effect on it.

You should not take this medicine if you are also taking a medicine containing nelfinavir (used to treat HIV infection).

You should specifically tell your doctor or pharmacist if you are taking clopidogrel (used to prevent blood clots).

You should not take this medicine with other medicines that limit the amount of acid produced in the stomach such as proton pump inhibitors (e.g. pantoprazole, lansoprazole, rabeprazole or omeprazole) or H2 antagonists (e.g. ranitidine or famotidine).

If necessary, you can take this medicine with antacids (e.g. magaldrate, alginic acid, sodium bicarbonate, aluminum hydroxide, magnesium carbonate or combinations thereof).

Tell your doctor or pharmacist if you are taking any of the following medicines:

Ketoconazole and itraconazole (used to treat infections caused by a fungus)
Voriconazole (used to treat infections caused by a fungus) and clarithromycin (used to treat infections). Your doctor may adjust the dose of Nexium Control if you also have severe liver problems and are being treated for a long time.
Erlotinib (used for cancer treatment)
Methotrexate (used to treat cancer and rheumatic diseases)
Digoxin (used for heart problems)
Atazanavir, saquinavir (used to treat HIV infection)
Citalopram, imipramine or clomipramine (used to treat depression)
Diazepam (used for the treatment of anxiety, for muscle relaxation or in epilepsy)
Phenytoin (used to treat epilepsy)
Medicines used to thin the blood, such as warfarin. Your doctor may need to monitor you when starting or stopping treatment with Nexium Control
Cilostazol (used to treat intermittent claudication - a condition in which poor blood supply to the leg muscles causes pain and difficulty walking)
Cisapride (used for indigestion and heartburn)
Rifampicin (used to treat tuberculosis)
Tacrolimus (in case of organ transplant)
St. John's wort (Hypericum perforatum) (used to treat depression)

Warnings It is important to know that:

Pregnancy and breastfeeding

As a precautionary measure, you should preferably avoid the use of Nexium Control during pregnancy. You should not use this medicine while breastfeeding.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

Nexium Control has a low probability of affecting the ability to drive or use machines. However, side effects such as dizziness and visual disturbances are uncommon (see section 4). If they appear, you should not drive or operate machinery.

Nexium Control contains sucrose

Nexium Control contains sugar spheres, which contain sucrose, a type of sugar. If you have been told by your doctor that you have an "intolerance to some sugars, consult your doctor before taking the medicine.

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

Always take this medicine exactly as described in this leaflet or as directed by your doctor or pharmacist. If in doubt, consult your doctor or pharmacist.

How much to take

The recommended dose is one tablet a day.
Do not take more than this recommended dose of one tablet (20 mg) per day, even if you do not feel immediate improvement.
You may need to take the tablets for two to three consecutive days before your reflux symptoms (for example, heartburn and acid regurgitation) improve.
The duration of treatment is up to 14 days.
When the reflux symptoms have completely disappeared you should stop taking this medicine.
If your reflux symptoms worsen or do not improve after taking this medicine for 14 consecutive days you should consult your doctor.

If you frequently experience persistent or long-lasting recurring symptoms, even after treatment with this medicine, please contact your doctor.

Taking the medicine

You can take the tablet at any time of the day with food or on an empty stomach.
Swallow the tablet whole with a glass of water. Do not chew or crush the tablet. This is because the tablet contains coated granules, which protect the medicine from stomach acid. It is therefore important not to damage the granules.

Alternative method of taking the medicine

Put the tablet in a glass of still (non-carbonated) water. Do not use any other liquids.
Stir until the tablet dissolves (the mixture will not be clear) then drink the mixture immediately or within 30 minutes. Always stir the mixture just before drinking it.
To make sure that you have drunk all of the medicine, rinse the glass thoroughly with half a glass of water and drink. The solid particles contain the medicine - do not chew or crush them.

Overdose What to do if you have taken too much Nexium Control

If you take more Nexium Control than you should

If you take more Nexium Control than recommended, tell your doctor or pharmacist immediately. Symptoms such as diarrhea, stomach pain, constipation, feeling or being sick and tired may occur.

If you forget to take Nexium Control

If you forget to take a dose, take it as soon as you remember on the same day. Do not take a double dose to make up for a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Side Effects What are the side effects of Nexium Control

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

If you notice any of the following serious side effects, stop taking Nexium Control and contact your doctor immediately:

Sudden wheezing, swelling of the lips, tongue and throat, rash, fainting or difficulty in swallowing (severe allergic reaction, rarely seen).
Skin redness with blisters or peeling. Severe blistering and bleeding can also appear in the lips, eyes, mouth, nose and genitals. This may be "Stevens-Johnson syndrome" or "toxic epidermal necrolysis", which are very rarely seen.
Yellow skin, dark urine and tiredness which may be symptoms of liver problems, rarely seen.

See your doctor as soon as possible if you have any of the following signs of infection:

This medicine affects white blood cells in very rare cases leading to immunodeficiency. If you experience an "infection with symptoms such as fever with severe deterioration in general health or fever with symptoms of local infection such as pain in the neck, throat or mouth or difficulty in urinating, you should see your doctor as soon as possible so that a lack of white blood cells (agranulocytosis) can be ruled out by carrying out a blood test, in which case it is important that you tell your doctor about the medicine you are taking.

Other side effects include:

Common (may affect up to 1 in 10 people)

Headache.
Effects on the stomach or intestines: diarrhea, stomach pain, constipation, wind (flatulence).
Feeling sick (nausea) or being sick (vomiting).

Uncommon (may affect up to 1 in 100 people)

Swelling in the feet and ankles.
Disturbed sleep (insomnia), sleepiness.
Dizziness, tingling sensation like "pinpricks".
Feeling of spinning (vertigo).
Dry mouth
Changes in blood tests that check how the liver is working.
Skin rash, skin wheals (hives) and itchy skin.

Rare (affects up to 1 in 1,000 people)

Blood problems such as a reduced number of white blood cells or platelets. This can cause weakness, bruising, or make infections easier.
Low levels of sodium in the blood. This can cause weakness, being sick (vomiting) and cramps.
Feeling agitated, confused or depressed.
Changes in taste.
Vision problems such as blurred vision.
Sudden wheezing or shortness of breath (bronchospasm).
Inflammation inside the mouth.
An infection called "thrush" which can affect the gut and is caused by a fungus.
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 up to 1 in 10,000 people)

Low numbers of red blood cells, white blood cells, and platelets (a condition called pancytopenia).
Aggression.
Seeing, feeling or hearing things that are not there (hallucinations).
Severe liver problems leading to liver failure and inflammation of the brain. ? Muscle weakness.
Severe kidney problems.
Breast enlargement in men.

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

Low levels of magnesium in the blood. This can cause fatigue, malaise (vomiting), involuntary muscle contractions, tremors and changes in heart rhythm (arrhythmia). If you have very low levels of magnesium, you may also experience low blood levels of calcium and / or potassium.
Inflammation of the intestines (which can lead to diarrhea).

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP / EXP. The expiry date refers to the last day of that month. Do not store above 30 ° C.

Keep this medicine in the original package to protect it from moisture.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Contents of the pack and other information

What Nexium Control contains

The active ingredient is esomeprazole. Each tablet contains 20 mg of esomeprazole (as magnesium trihydrate).
The other ingredients are: glycerol monostearate 40-55, hyprolose, hypromellose, iron oxide (red-brown E 172), iron oxide (yellow E172), magnesium stearate, methacrylic acid copolymer ethyl acrylate (1: 1) dispersion at 30%, microcrystalline cellulose, synthetic paraffin, macrogol 6000, polysorbate 80, crospovidone (type A), sodium stearyl fumarate, sugar spheres (sucrose), talc, titanium dioxide (E 171) and triethyl citrate.

What Nexium Control looks like and contents of the pack

Nexium Control gastro-resistant tablets are light pink, oblong, biconvex and marked "20 mg" on one side and A / EH on the other side.

Nexium Control is available in blister packs of 7 and 14 gastro-resistant tablets.

Not all pack sizes may be marketed.

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 Control 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 CONTROL 20 MG FOOD-RESISTANT TABLETS

02.0 QUALITATIVE AND QUANTITATIVE 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.

03.0 PHARMACEUTICAL FORM

Gastro-resistant tablet.

Light pink, elongated, biconvex, film-coated tablet marked "20 mg" on one side and A / EH on the other side.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

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

04.2 Posology and method of administration

Dosage

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 necessary 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 necessary 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 drinking water. The granules must not be chewed or crushed.

04.3 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).

04.4 Special warnings and appropriate precautions for use

General

Patients should be instructed to consult a physician if:

• Have 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 excluded as esomeprazole therapy may alleviate symptoms and delay diagnosis.

• Have had a previous "gastric 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 treatment 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 those fromSalmonella And Campylobacter, and possibly also from 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 medicines

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 conjunction with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir. The 20 mg dose of esomeprazole should not be exceeded.

Esomeprazole is an inhibitor of CYP2C19. At the start or end of treatment with esomeprazole, 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 concurrently.

Sucrose

This medicine contains sugar spheres (sucrose). 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) can interfere with investigations for neuroendocrine tumors. To avoid this interference, esomeprazole treatment should be temporarily interrupted for five days before CgA determination.

04.5 Interactions with other medicinal products and other forms of interaction

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 modify 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) . An increase in 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 in volunteers healthy patients 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 "AUC, mean Cmax and Cmin of nelfinavir by 36-39% and" AUC, mean Cmax and Cmin of the pharmacologically active metabolite M8 were reduced by 75-92%. Due to 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 the exposure of amprenavir (with and without co-administration with ritonavir). Treatment with omeprazole 40 mg qd had no effect on the exposure of lopinavir (when co-administered with ritonavir). ).

Methotrexate

In some patients, methotrexate levels have been reported to increase 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 if necessary.

Medicines with pH dependent absorption

Suppression of gastric acidity during treatment with esomeprazole and other PPIs may decrease or increase the absorption of drugs 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 should therefore be reinforced.

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 (300 mg loading dose / 75 mg daily maintenance dose) and esomeprazole (40 mg orally daily) resulting in a decreased exposure to the active metabolite of clopidogrel averaging 40%, resulting in a decrease in maximal inhibition of platelet aggregation (induced ADP) averaging 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 to monitor phenytoin plasma concentrations when starting or stopping treatment with esomeprazole.

Voriconazole

Omeoprazole (40 mg once daily) increased the Cmax and AUC 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% increase in 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 slight prolongation of the QTc interval 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 relevant clinical 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 that inhibit 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 AUC 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

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

04.6 Pregnancy and lactation

Pregnancy

A modest amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicates no malformation or fetus / neonatal toxicity of esomeprazole.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Nexium Control during pregnancy.

Feeding time

It is unknown whether esomeprazole / its metabolites are excreted in human milk. There is insufficient information on the effects of esomeprazole in newborns / infants. Esomeprazole should not be used during lactation.

Fertility

Animal studies with the racemic mixture of omeprazole, administered orally, show no effects on fertility.

04.7 Effects on ability to drive and use machines

Esomeprazole has minor effects on the ability to drive or use machines. Adverse reactions such as dizziness and visual disturbances are uncommon (see section 4.8). In the presence of these symptoms, patients should not drive or operate machinery.

04.8 Undesirable 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, groups. age and patient population No dose related adverse reactions identified.

Table 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,

common Uncommon Rare Very rare Not known Disorders of the blood and lymphatic system leukopenia, thrombocytopenia agranulocytosis, pancytopenia common Uncommon Rare Very rare Not known Disorders of the immune system hypersensitivity reactions such as fever, angioedema and anaphylactic reaction / shock Metabolism and nutrition disorders peripheral edema hyponatremia hypomagnesmia; severe hypomagnesaemia may be related to hypocalcemia; hypomagnesaemia can also lead to hypokalaemia Psychiatric disorders insomnia agitation, confusion, depression aggression, hallucinations Nervous system disorders headache dizziness, paraesthesia, somnolence taste disturbances Eye disorders blurred vision Ear and labyrinth disorders dizziness Respiratory, thoracic and mediastinal disorders bronchospasm Gastrointestinal disorders abdominal pain, constipation, diarrhea, flatulence, nausea / vomiting dry mouth stomatitis, gastrointestinal candidiasis microscopic colitis Hepatobiliary disorders increase in the value of liver enzymes hepatitis with or without jaundice liver failure, hepatic encephalopathy in patients with pre-existing liver disease Skin and subcutaneous tissue disorders dermatitis, itching, rash, urticaria alopecia, photosensitivity erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN) Musculoskeletal and connective tissue disorders arthralgia, myalgia muscle weakness Renal and urinary disorders interstitial nephritis Diseases of the reproductive system and breast gynecomastia General disorders and administration site conditions malaise, increased sweating

Reporting of suspected adverse reactions

The reporting of 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: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.

04.9 Overdose

There is currently very limited experience with intentional overdose. The symptoms described in connection with the intake of 280 mg were gastrointestinal symptoms and weakness. Single doses of 80 mg esomeprazole did not cause any consequences. A specific antidote is not known. Esomeprazole is extensively bound to plasma proteins and therefore is not quickly dialyzable. Treatment should be symptomatic and supportive measures should generally be used.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: drugs for acid related disorders, acid pump inhibitors, ATC code: A02BC05.

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

Mechanism of action

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

Pharmacodynamic effects

After oral administration of esomeprazole 20 mg and 40 mg the onset of effect occurs within one hour. After repeated dosing with esomeprazole 20 mg once daily for five 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 five days of oral administration with 20 mg and 40 mg esomeprazole, the intragastric pH is maintained above 4 for a mean time of 13 and 17 hours out of 24, respectively, in patients with symptomatic gastroesophageal reflux disease (GERD). The proportion of patients who maintained intragastric pH above 4 for at least 8, 12 and 16 hours was 76%, 54% and 24% for esomeprazole 20 mg, respectively. Corresponding values for esomeprazole 40 mg were 97%, 92% and 56%.

Using AUC as a surrogate parameter for plasma concentration, a correlation between inhibition of acid secretion and drug exposure was demonstrated.

During treatment with antisecretory drugs, serum gastrin levels rise in response to decreased acid secretion. The level of CgA also increases due to decreased gastric acidity.

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

The reduction of gastric acidity due to any reason including PPIs increases the gastric bacterial load of bacteria normally present in the gastrointestinal tract. Treatment with PPIs may lead to a slightly increased risk of gastrointestinal infections such as those from SalmonellaAnd Campylobacter and possibly also from Clostridium difficile in hospitalized patients.

Clinical efficacy

Esomeprazole 20 mg has been shown to be effective in treating frequent heartburn in subjects receiving a dose every 24 hours for 2 weeks. In two pivotal, multicentre, randomized, double-blind, placebo-controlled studies, 234 subjects with a recent history of heartburn were treated with 20 mg esomeprazole for 4 weeks. Symptoms associated with acid reflux (such as heartburn and acid regurgitation) were evaluated retrospectively over 24 hours. In both studies, esomeprazole 20 mg was significantly better than placebo for the primary endpoint of complete resolution of heartburn, defined as no heartburn episodes in the 7 days prior to the final visit (33.9% -41.6% vs. placebo 11.9% -13.7%, (patient's diary, it was statistically significant both at week 1 (10 , 0% -15.2% vs placebo 0.9% -2.4%, p = 0.014, p

Other secondary endpoints supported the primary endpoint, including heartburn relief at weeks 1 and 2, percentage of 24-hour heartburn-free days at weeks 1 and 2, mean heartburn severity at weeks 1 and 2, and time to obtain the first resolution of heartburn within 24 hours and during the night as well as a lasting resolution of heartburn, compared to placebo. Approximately 78% of patients receiving esomeprazole 20 mg reported resolution of heartburn within the first week of treatment compared with 52-58% for placebo. The time to achieve durable resolution of heartburn, defined as the first 7 consecutive days without heartburn recorded, was significantly shorter in the 20 mg esomeprazole group (39.7% -48.7% by day 14 vs placebo 11.0 % -20.2%). Median time to first resolution of heartburn was 1 day, statistically significant compared to placebo in one study (p = 0.048) and close to significance in the other (p = 0.069). Approximately 80% of the nights were free. heartburn in all treatment periods and 90% of nights were heartburn-free in week 2 of each study compared with 72.4-78.3% in the placebo group. The investigators 'ratings of heartburn resolution were consistent with the subjects' ratings and showed statistically significant differences between esomeprazole (34.7% -41.8%) and placebo (8.0% -11.4%). The researchers also found that esomeprazole was significantly more effective than placebo in resolving acid regurgitation (58.5% -63.6% vs placebo 28.3% -37.4%) during the week 2 assessment.

Following the Overall Treatment Assessment (OTE) of patients at week 2 of therapy, 78.0-80.7% of patients taking esomeprazole 20 mg reported improvement in their condition compared to 72.4-78.3 % of the placebo group. Most of these considered the importance of this change from Important to Extremely Important in carrying out their daily activities (79-86% at week 2).

05.2 Pharmacokinetic properties

Absorption

Esomeprazole is sensitive to the acidic environment and is administered orally as 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 dose and increases to 89% after repeated daily dosing. For the 20 mg dose of esomeprazole the corresponding values are 50% and 68%, respectively. L Food intake delays and decreases the absorption of esomeprazole although this has no significant influence on the effect of esomeprazole on intragastric acidity.

Distribution

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.

Biotransformation

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. another specific isoform, CYP3A4, responsible for the formation of esomeprazole sulfonate, the main plasma metabolite.

Elimination

The parameters below mainly reflect the pharmacokinetics in individuals with functional CYP2C19 enzyme, extensive metabolisers.

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 is approximately 1.3 hours after repeated daily dosing. Esomeprazole is completely cleared from plasma between doses with no tendency to accumulate when given once daily. The major metabolites of esomeprazole have no effect. on gastric acid secretion. Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder is found in the faeces. Less than 1% of the parent drug is found in the urine.

Linearity / Non-linearity

The pharmacokinetics of esomeprazole have been studied in 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 a more than dose proportional increase in AUC after repeated administration. This dose-dependence and time-dependence are due to the decrease in first pass metabolism and systemic clearance probably due to inhibition of the CYP2C19 enzyme caused by esomeprazole and / or its sulphonate metabolite.

Special patient population

Slow metabolisers

Approximately 2.9 ± 1.5% of the population have insufficient function of the CYP2C19 enzyme and are referred to as poor metabolisers. In these individuals the metabolism of esomeprazole is likely to be primarily catalysed by CYP3A4. After repeated daily dosing 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 approximately 60% higher.

These observations have no implications for the posology of esomeprazole.

Sex

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

Hepatic impairment

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

Renal impairment

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.

Elderly patients (≥65 years old)

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

05.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development.

Adverse reactions not observed in clinical studies, but found in animals exposed to levels similar to those of clinical exposure and with possible clinical relevance, are the following:

Carcinogenicity studies in rats treated with the racemic mixture revealed a "hyperplasia of gastric ECL cells and carcinoids. These gastric effects observed in rats are the result of a" high, pronounced hypergastrinaemia secondary to reduced gastric acid production and were observed in the rat after long-term treatment with gastric acid secretion inhibitors.