Active ingredients: Esomeprazole
Esopral 20 mg gastro-resistant tablets
Esopral 40 mg gastro-resistant tablets
Indications Why is Esopral used? What is it for?
Esopral contains a medicine called esomeprazole. It belongs to a group of medicines called 'proton pump inhibitors' which work by reducing the amount of acid produced in the stomach.
Esopral is used to treat the following ailments:
- "Gastroesophageal reflux disease" (GERD). It occurs when acid from the stomach escapes into the esophagus (the tube that connects the throat to the stomach), causing pain, inflammation and burning.
- Stomach or upper bowel ulcers infected with bacteria called "Helicobacter pylori". If you have these conditions, your doctor may also prescribe antibiotics to treat the infection and allow the ulcer to heal.
- Stomach ulcers caused by medicines called NSAIDs (Non-Steroidal Anti-Inflammatory Drugs). Esopral can also be used to prevent stomach ulcers from forming while taking NSAIDs.
- Excess stomach acid caused by a tumor in the pancreas (Zollinger-Ellison syndrome).
- Prolonged treatment of re-bleeding of ulcers, after prevention with intravenous administration of Esopral.
Contraindications When Esopral should not be used
Do not take Esopral:
- if you are allergic (hypersensitive) to esomeprazole or any of the other ingredients of this medicine
- if you are allergic to other proton pump inhibitor medicines (e.g. pantoprazole, lansoprazole, rabeprazole, omeprazole).
- if you are taking a medicine containing nelfinavir (used to treat HIV).
You should not take Esopral if it falls into any of the above cases. If in doubt, consult your doctor or pharmacist before taking Esopral.
Precautions for use What you need to know before taking Esopral
Take special care with Esopral
Talk to your doctor or pharmacist before taking Esopral if:
- You have severe liver problems.
- You have severe kidney problems.
Esopral can mask the symptoms of other diseases. Therefore, if any of the following happen to you before you start taking or while you are taking Esopral, tell your doctor immediately:
- You lose a lot of weight for no reason or have trouble swallowing.
- Stomach pain or indigestion occurs.
- Start vomiting food or blood.
- The stools are black (blood-stained stools).
If you have been prescribed Esopral "as needed", contact your doctor if symptoms persist or change in characteristics.
If you take a proton pump inhibitor such as Esopral, especially for longer than one year, you may have a slightly increased risk of fracture of the hip, wrist or spine. If you have osteoporosis or are taking corticosteroids (which may increase the risk of osteoporosis) consult your doctor.
Interactions Which drugs or foods may change the effect of Esopral
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This is because Esopral can affect the way some medicines work and some medicines can have an effect on Esopral.
You should not take Esopral tablets if you are taking a medicine containing nelfinavir (used to treat HIV).
Tell your doctor or pharmacist if you are taking any of the following medicines:
- Atazanavir (used to treat HIV).
- Clopidogrel (used to prevent blood clots)
- Ketoconazole, itraconazole or voriconazole (used to treat infections caused by fungi).
- Erlotinib (used to treat cancer).
- Citalopram, imipramine or clomipramine (used to treat depression).
- Diazepam (used for the treatment of anxiety, for muscle relaxation or in epilepsy).
- Phenytoin (used in epilepsy). If you are taking phenytoin, your doctor will need to monitor you when starting or stopping treatment with Esopral.
- Medicines used to thin the blood, such as warfarin. Your doctor may monitor you when you start or stop taking Esopral.
- 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).
- 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 Esopral.
- Tacrolimus (used in organ transplants)
- Rifampicin (used to treat tuberculosis).
- St. John's wort (Hypericum perforatum) (used to treat depression).
If your doctor has prescribed antibiotics such as amoxicillin and clarithromycin with Esopral to treat ulcers caused by Helicobacter pylori infection, it is very important that you tell your doctor about other medicines.
Warnings It is important to know that:
Pregnancy and breastfeeding
Before taking Esopral, tell your doctor if you are pregnant or want to become pregnant. Ask your doctor or pharmacist for advice before taking any medicine. Your doctor will decide whether you can take Esopral during this time.
It is not known if Esopral passes into breast milk, so you should not take Esopral if you are breastfeeding.
Taking Esopral with food and drink
The tablets can be taken on a full stomach or on an empty stomach.
Driving and using machines
Esopral is unlikely to affect your ability to drive or use any tools or machines.
Important information about some of the ingredients of Esopral
Esopral gastro-resistant tablets contain sucrose which is a type of sugar. If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.
Dosage and method of use How to use Esopral: Dosage
Always take Esopral exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
- Esopral gastro-resistant tablets are not recommended for children under 12 years of age.
- If you have been taking this medicine for a long time, your doctor will monitor you (particularly if you have been taking the medicine for more than a year).
- If your doctor has told you to take the medicine when needed, as needed, please tell your doctor if your symptoms change.
Taking the medicine
- You can take the tablets at any time of the day.
- You can take the tablets on a full stomach or on an empty stomach.
- Swallow the tablets whole with a drink of water. Do not chew or crush the tablets as they contain coated granules which protect the medicine from stomach acid. It is therefore important not to damage the granules.
What to do if you have trouble swallowing the tablets
If you have trouble swallowing the tablets:
- Put the tablets in a glass of still water. Other liquids should not be used.
- Stir until the tablets dissolve (the mixture will not have a clear appearance). Drink immediately or at least within 30 minutes. Always mix them before drinking.
- To make sure that you have taken all of the medicine, rinse the glass thoroughly by filling it halfway with water and drink. The solid particles contain the medicine and should not be chewed or crushed.
- If you are absolutely unable to swallow, the tablet can be mixed with some water, inserted into a syringe and administered through a tube directly into the stomach (gastric tube).
How much medication to take
- Your doctor will advise you on the number of tablets to take and for how long. This is a function of your physical condition, age and liver condition.
- Usual doses are given below.
Treatment of heartburn caused by gastroesophageal reflux disease (GERD):
Adults and children from 12 years of age:
- If your doctor has found your esophagus slightly damaged, the usual dose is one Esopral 40 mg gastro-resistant tablet once a day for 4 weeks. Your doctor may tell you to continue the treatment, taking the same dose, for an additional 4 weeks, in case your esophagus has not healed.
- After the esophagus has healed, the usual dose is one Esopral 20 mg gastro-resistant tablet once a day.
- If the esophagus is not damaged, the usual dose is one Esopral 20 mg gastro-resistant tablet each day. When your symptoms are under control, your doctor will inform you that you can take the medicine when needed, up to a maximum of one gastro-resistant tablet. of Esopral 20 mg per day.
- If you have severe liver problems, your doctor will give you a lower dose.
Treatment of ulcers caused by Helicobacter pylori infection and prevention of their reappearance:
- Adults from 18 years of age onwards: the usual dose is one Esopral 20 mg gastro-resistant tablet twice a day for one week.
- Your doctor will also tell you to take antibiotics called amoxicillin and clarithromycin.
Treatment of gastric ulcers caused by NSAIDs (Non-Steroidal Anti-Inflammatory Drugs):
- Adults 18 years and older: the usual dose is one Esopral 20 mg gastro-resistant tablet once a day for 4 to 8 weeks.
Prevention of stomach ulcers if you are taking NSAIDs (Non-Steroidal Anti-Inflammatory Drugs):
- Adults from 18 years of age onwards: the usual dose is one Esopral 20 mg gastro-resistant tablet once a day.
Treatment of excess stomach acid caused by a growth in the pancreas (Zollinger-Ellison syndrome):
- Adults from 18 years of age onwards: the usual dose is 40 mg tablets twice a day.
- Your doctor will adjust the dose according to your need and will also decide how long to continue the treatment. The maximum dose is 80 mg twice a day.
Prolonged treatment of re-bleeding of ulcers, after prevention with intravenous administration of Esopral:
The usual dose is one Esopral 40 mg tablet once a day for 4 weeks.
Overdose What to do if you have taken too much Esopral
If you take more Esopral than you should
If you have taken more Esopral than prescribed by your doctor, tell your doctor or pharmacist immediately.
If you forget to take Esopral
- If you forget to take a dose of Esopral, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose.
- Do not take a double dose (two doses simultaneously) to make up for a forgotten dose.
Side Effects What are the side effects of Esopral
Like all medicines, Esopral can cause side effects, although not everybody gets them.
If you notice any of the following serious side effects, stop taking Esopral and contact your doctor immediately:
- Sudden wheezing, swelling of the lips, tongue and throat or body, rash, fainting or difficulty in swallowing (severe allergic reaction).
- 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".
- Yellow skin, dark urine, and tiredness can be symptoms of liver problems.
These effects are rare, affecting less than 1 in 1,000 people.
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 Esopral is used in high doses and for prolonged periods).
Rare (affects less than 1 in 1,000 people):
- Blood problems, for example a reduced number of white blood cells and platelets. This can cause weakness, bruising, or make infections easier.
- Low levels of sodium in the blood. This can cause weakness, vomiting and cramps.
- Feeling agitated, confused or depressed.
- Changes in taste.
- Problems with your eyesight, 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.
- Liver problems, including jaundice which can cause yellow skin, dark urine and tiredness.
- 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):
- Changes 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.
- Sudden onset of severe rash or blistering 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 Esopral for more than three months, your blood levels of magnesium may go down. 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).
Esopral can, in very rare cases, affect the 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. so that the lack of white blood cells (agranulocytosis) can be ruled out through 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
- Keep out of the reach and sight of children.
- Do not store above 30 ° C.
- Store in the original package (blister) or keep the container tightly closed (bottle) in order to protect from moisture.
- Do not use the tablets after the expiry date (EXP) which is stated on the carton, wallet or blister. The expiry date refers to the last day of the month.
- 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 Esopral contains
The active ingredient is esomeprazole. Esopral gastro-resistant tablets are present in 2 strengths containing 20 mg or 40 mg of esomeprazole (as magnesium trihydrate).
The other ingredients are: glycerol monostearate 40-55, hyprolose, hypromellose, iron oxide (red-brown, yellow) (E172, only for 20 mg tablets), magnesium stearate, methacrylic acid copolymer ethyl acrylate (1: 1) dispersion at 30%, microcrystalline cellulose, synthetic paraffin, macrogols, polysorbate 80, crospovidone, sodium stearyl fumarate, sucrose spheres (sucrose and corn starch), talc, titanium dioxide (E171), triethyl citrate.
What Esopral looks like and contents of the pack
- Esopral 20 mg gastro-resistant tablets are light pink with A / EH on one side and 20 mg on the other.
- Esopral 40 mg gastro-resistant tablets are pink with A / EI on one side and 40 mg on the other.
- The tablets are in blister packs, wallets and / or bottles containing
- 20 mg, 40 mg: bottle of 2-5-7-14-15-28-30-56-60-100-140 (28x5) tablets.
- 20 mg, 40 mg blister or wallet blister of 3-7-7x1-14-15-25x1-28-30-50x1-56-60-90- 98-100x1-140 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.
01.0 NAME OF THE MEDICINAL PRODUCT
ESOPRAL - GASTRORESISTANT TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 tablet contains: 20 mg or 40 mg of esomeprazole (as magnesium trihydrate).
Excipients:
Esopral 20 mg: sucrose 28 mg.
Esopral 40 mg: sucrose 30 mg.
For the full list of excipients see section 6.1.
03.0 PHARMACEUTICAL FORM
Gastro-resistant tablet.
20 mg: light pink, elongated, biconvex, film-coated tablet. The tablet is marked 20 mg on one side and A / EH on the other.
40 mg: Pink, elongated, biconvex, film-coated tablet. The tablet bears 40 mg on one side and A / EI on the other.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Esopral tablets are indicated for:
Gastroesophageal reflux disease (GERD)
- treatment of erosive reflux esophagitis
- long-term maintenance for the prevention of relapses in patients in whom the healing of esophagitis has been achieved
- symptomatic treatment of gastroesophageal reflux disease (GERD)
In combination with antibacterials in an appropriate therapeutic regimen for the "eradication of"Helicobacter pylori And
- healing of the duodenal ulcer associated with Helicobacter pylori And
- prevention of relapse of peptic ulcers in patients with associated ulcers Helicobacter pylori.
Patients requiring continued NSAID treatment
- healing of gastric ulcers associated with NSAID therapy
- prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk.
Prolonged treatment of re-bleeding of peptic ulcers, after prevention induced by intravenous administration.
Treatment of Zollinger Ellison syndrome.
04.2 Posology and method of administration
The tablets should be swallowed whole with the help of liquids.
Do not chew or crush the tablets.
In patients who have difficulty swallowing, the tablets can also be dispersed in half a glass of still water. Do not use any other liquids as this could dissolve the gastro-resistant coating. Stir until the tablet disperses and drink the liquid with the granules immediately or within 30 minutes. Rinse the glass by filling it halfway with water and drinking its contents. The granules must not be chewed or crushed.
For patients who cannot swallow, it is possible to disperse the tablets in still water and administer them through a gastric tube. It is important to carefully check the appropriateness of the syringe and tube.
For instructions on preparation and administration see section 6.6.
Adults and adolescents from 12 years of age
Gastroesophageal reflux disease (GERD)
Treatment of erosive reflux esophagitis
40 mg once daily for 4 weeks.
In case of unhealed oesophagitis or persistence of symptoms it is recommended to prolong the treatment for another 4 weeks.
Long-term maintenance treatment for the prevention of relapse in patients with healing of esophagitis
20 mg once a day.
Symptomatic treatment of gastroesophageal reflux disease (GERD)
20 mg once daily in patients who do not have oesophagitis. If symptom control is not achieved after 4 weeks of therapy, the patient should perform further clinical investigations. Once symptoms have resolved, subsequent symptom control can be achieved by taking 20 mg once daily. In adults, a regimen of 20 mg once daily may be used as needed, when needed. In patients treated with NSAIDs at risk of developing gastric and duodenal ulcers, subsequent symptom control by adopting an on-demand regimen is not recommended.
Adults
In combination with antibacterials in an appropriate therapeutic regimen for the "eradication of"Helicobacter pylori And
Healing of the duodenal ulcer associated with Helicobacter pylori
P. Revision of relapses of peptic ulcers in patients with associated ulcers Helicobacter pylori.
20 mg of Esopral with 1 g of amoxicillin and 500 mg of clarithromycin, 2 times a day for 7 days.
Patients requiring continued NSAID treatment
Healing of gastric ulcers associated with NSAID therapy: the usual dose is 20 mg once daily for 4-8 weeks.
Prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk: 20 mg once daily.
Prolonged treatment of re-bleeding of peptic ulcers, after prevention induced by intravenous administration
40 mg once daily for 4 weeks after IV administration-induced prevention re-bleeding of peptic ulcers.
Treatment of Zollinger Ellison syndrome
The recommended starting dosage is 40 mg of Esopral twice a day.
Dosage should be individually adjusted and treatment continued for as long as clinically indicated. Based on the available clinical data, most patients can be controlled with doses of 80 to 160 mg per day of esomeprazole. Doses higher than 80 mg / day must be divided into two daily administrations.
Children under 12 years of age
Esopral should not be used in children less than 12 years of age as no data are available.
Patients with impaired renal function
No dose adjustments are 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 hepatic function
No dose adjustment is required in patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment the maximum dose of 20 mg of Esopral should not be exceeded (see section 5.2).
Senior citizens
No dose adjustments are required in the elderly.
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 much Esopral 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.
Patients on an on-demand regimen should be instructed to contact their physician if the symptoms experienced take on a different character. In patients following this regimen, the implications of fluctuating plasma concentrations of esomeprazole for interactions with other drugs should be considered (see section 4.5).
In patients who are prescribed esomeprazole for the "eradication of"Helicobacter pylori Possible interactions with all components of triple therapy should be considered. Clarithromycin is a potent inhibitor of CYP3A4, therefore contraindications and interactions of clarithromycin should be considered if triple therapy is initiated in patients already being treated with other drugs metabolised via CYP3A4, such as cisapride.
This medicinal product contains sucrose. 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 gastrointestinal infections, such as those from Salmonella And Campylobacter (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 esomeprazole 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 initiating PPI treatment and periodically during treatment in patients on prolonged therapy or on therapy with digoxin or drugs that can cause hypomagnesaemia (eg 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 Chromogranin A (CgA) can interfere with investigations for neuroendocrine tumors. To avoid this interference, esomeprazole treatment should be stopped for at least 5 days before CgA determination (see section 5.1).
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, absorption of medicinal products such as ketoconazole, itraconazole and erlotinib may decrease and digoxin absorption 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 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 treatment with omeprazole may modify 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 the 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 (CYP2C19 substrate ) 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, 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 therapy with warfarin or other coumarin derivatives.
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% increase in the area under the plasma concentration / time curve (AUC) and a 31% prolongation of the elimination half-life (t ½), 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 (see section 4.4).
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.
Results from studies in healthy subjects showed a "pharmacokinetic (PK) / pharmacodynamic (PD) interaction between clopidogrel (loading dose 300 mg / maintenance dose 75 mg per day) and esomeprazole (40 mg po per day), resulting in a mean decrease of 40% in exposure to the active metabolite of clopidogrel and a mean decrease of 14% in maximal inhibition (ADP induced) of platelet aggregation.
A study in healthy subjects showed that exposure to the active metabolite of clopidogrel decreased by almost 40% when clopidogrel is co-administered with a fixed dose of the combination esomeprazole 20 mg + ASA 81 mg compared to when given alone. However, in these subjects, the maximum level of inhibition (ADP induced) of platelet aggregation was the same in the clopidogrel and clopidogrel + combination (esomeprazole + ASA) groups.
Diverging data from observational and clinical studies have been reported on the clinical implications of a PK / PD interaction of esomeprazole in terms of major cardiovascular events. As a precaution, concomitant use of clopidogrel should be discouraged.
Mechanism unknown
Serum levels of tacrolimus have been reported to increase when administered together with esomeprazole.
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.
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
For Esopral, clinical data on exposure in pregnancy are insufficient. 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 Esopral 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,
Disorders of the blood and lymphatic system
Rare: leukopenia, thrombocytopenia
Very rare: agranulocytosis, pancytopenia
Disorders of the immune system
Rare: hypersensitivity reactions such as fever, angioedema and anaphylactic reaction / shock
Metabolism and nutrition disorders
Uncommon: peripheral edema
Rare: hyponatremia
Not known: hypomagnesaemia (see section 4.4.); severe hypomagnesaemia may be related to hypocalcemia. Hypomagnesaemia can also be associated with hypokalaemia.
Psychiatric disorders
Uncommon: insomnia
Rare: agitation, confusion, depression
Very rare: aggression, hallucinations
Nervous system disorders
Common: headache
Uncommon: dizziness, paraesthesia, somnolence
Rare: taste disturbances
Eye disorders
Rare: blurred vision
Ear and labyrinth disorders
Uncommon: dizziness
Respiratory, thoracic and mediastinal disorders
Rare: bronchospasm
Gastrointestinal disorders
Common: abdominal pain, constipation, diarrhea, flatulence, nausea / vomiting
Uncommon: dry mouth
Rare: stomatitis, gastrointestinal candidiasis
Not known: microscopic colitis
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
Skin and subcutaneous tissue disorders
Uncommon: dermatitis, pruritus, rash, urticaria
Rare: alopecia, photosensitivity
Very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN)
Musculoskeletal and connective tissue disorders
Uncommon: fracture of the hip, wrist or spine (see section 4.4. Special warnings and precautions for use).
Rare: arthralgia, myalgia
Very rare: muscle weakness
Renal and urinary disorders
Very rare: interstitial nephritis; renal failure has been reported concomitantly in some patients.
Diseases of the reproductive system and breast
Very rare: gynaecomastia
General disorders and administration site conditions
Rare: malaise, increased sweating
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: proton 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 strongly 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 and stimulated acid secretion .
Effects on gastric acid secretion
After oral administration of esomeprazole 20 mg and 40 mg the effect on acid secretion occurs within 1 hour. After repeated dosing with esomeprazole 20 mg once daily for 5 days, the mean peak acid secretion after pentagastrin stimulation is reduced. 90% when assessed 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 esomeprazole 20 mg, and 97%, 92% and 56% for esomeprazole, respectively. 40 mg.
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.
One week of treatment with esomeprazole 20 mg b.i.d. in association with appropriate antibiotics promotes the "eradication of"Helicobacter pylori in about 90% of patients.
After performing the eradication treatment for 1 week it is not necessary to continue monotherapy with antisecretory drugs for ulcer healing and resolution of symptoms in patients with uncomplicated duodenal ulcer.
In a randomized, placebo-controlled, double-blind clinical trial, patients with endoscopically confirmed bleeding peptic ulcer classified as Forrest Ia, Ib, IIa or IIb (9%, 43%, 38% and 10%, respectively) were randomized. to be treated with Esopral solution for infusion (n = 375) or placebo (n = 389). Following endoscopic haemostasis, patients were treated with 80 mg of esomeprazole as an intravenous bolus infusion for 30 minutes, followed by continuous infusion of 8 mg / hour of esomeprazole or placebo for 72 hours. After the initial 72 hour period. hours, all patients were treated open label with Esopral 40 mg orally for 27 days for acid suppression. Re-bleeding within 3 days was observed in 5.9% of patients in the Esopral group compared with 10.3 % in the placebo group 30 days after treatment, re-bleeding occurred in 7.7% of patients in the Esopral group versus 13.6% of patients in the placebo group.
Other effects related to acid inhibition
During treatment with antisecretory medicinal products, an elevation of serum gastrin levels has been observed in response to decreased acid secretion. CgA also increases due to decreased gastric acidity. The increased level of CgA may interfere with investigations for neuroendocrine tumors. Reports from the literature indicate that treatment with the proton pump inhibitor should be stopped at least 5 days before the start of CgA measurements.If CgA and gastrin levels are not normalized after 5 days, measurements should be repeated 14 days after stopping esomeprazole treatment.
An increase in ECL cell numbers, possibly related to increased gastrin levels, has been observed in both children and adults during long-term treatment with esomeprazole. The results are considered to be of no clinical relevance.
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.
Reduction of gastric acidity for any reason, including proton pump inhibitors, raises the gastric bacterial load of bacteria normally found in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to a slightly increased risk of infections gastrointestinal, such as those from Salmonella And Campylobacter and possibly also from Clostridium difficile in hospitalized patients.
In two studies with ranitidine, used as an active comparator, Esopral demonstrated a better effect in healing gastric ulcers in patients taking non-steroidal anti-inflammatory drugs, including selective COX-2.
In two studies with placebo, used as a comparison, Esopral demonstrated a better effect in the prevention of gastric and duodenal ulcers in patients taking non-steroidal anti-inflammatory drugs (over 60 years of age and / or with a history of ulcer), including COX -2 selective.
Pediatric population
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. The total bioavailability is 64% after a single 40 mg administration and reaches 89% after repeated daily administration. For the 20 mg dosage of esomeprazole the corresponding values are 50% and 68% respectively. apparent distribution at steady state 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. another specific isoform, CYP3A4, responsible for the formation of esomeprazole sulfonate which is the main plasma metabolite.
The parameters below mainly reflect the pharmacokinetics in individuals who are rapid metabolisers equipped with a functional 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 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, possibly due to inhibition of the CYP2C19 enzyme caused by "esomeprazole and / or its sulphonate metabolite. doses, esomeprazole is completely cleared from plasma and has no tendency to accumulate when given 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 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 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 were not observed. observations have no implications for esomeprazole posology.
Patients with organ dysfunction
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 in patients with severe dysfunction the maximum dose of 20 mg should not be exceeded. Esomeprazole and its major metabolites show no tendency to accumulate when given 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 renal impairment.
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 12-18 year old subjects were similar to those observed in adults for both. doses of esomeprazole.
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.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Glycerol monostearate 40-55,
hyprolose,
hypromellose,
iron oxide (20 mg and 40 mg tablets: red-brown; 20 mg tablets: yellow) (E 172),
magnesium stearate,
copolymerized methacrylic acid ethyl acrylate (1: 1) dispersion at 30%,
microcrystalline cellulose,
synthetic paraffin,
macrogula,
polysorbate 80,
crospovidone,
sodium stearyl fumarate,
granular sugar (sucrose and corn starch),
talc,
titanium dioxide (E 171),
triethyl citrate.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
In climatic zones III and IV: 2 years for 40 mg tablets and 18 months for 20 mg tablets.
06.4 Special precautions for storage
Do not store above 30 ° C.
Keep the bottle tightly closed to protect the medicine from moisture.
Store in the original blister to protect from moisture.
06.5 Nature of the immediate packaging and contents of the package
Tamper-proof polyethylene bottle with polypropylene screw cap supplied with desiccant cap.
Aluminum blister.
20 mg, 40 mg: bottles of: 2, 5, 7, 14, 15, 28, 30, 56, 60, 100, 140 (5x28) tablets.
20 mg, 40 mg: blister and or wallet packs of: 3, 7, 7x1, 14, 15, 25x1, 28, 30, 50x1, 56, 60, 90, 98, 100x1, 140 tablets
Not all pack sizes may be marketed
06.6 Instructions for use and handling
Administration through gastric tube
1) Place the tablet in an appropriate syringe and fill the syringe with approximately 25 mL of water and approximately 5 mL of air. In some tubes, in order to prevent blockage by the granules, a dispersion in 50 mL is required. of water.
2) Disperse the tablet by shaking the syringe immediately for about 2 minutes.
3) Hold the syringe pointing up and check the cone for obstructions.
4) Insert the tube into the syringe maintaining the position described above.
5) Shake the syringe and place it with the cone facing down. Immediately inject 5-10 mL into the tube. Reverse the position of the syringe after injection and shake (the syringe must be held with the cone up to prevent clogging).
6) Turn the syringe cone down and immediately inject another 5-10 ml into the tube. The procedure must be repeated until the syringe is empty.
7) If you need to rinse the sediment left in the syringe, fill the syringe with 25 ml of water and 5 ml of air and repeat the operations from step 5. For some tubes it is necessary to use 50 ml.
07.0 MARKETING AUTHORIZATION HOLDER
Bracco S.p.A. - Via E. Folli, 50 - 20134 Milan.
08.0 MARKETING AUTHORIZATION NUMBER
AIC 035433263 - "20 mg gastro-resistant tablets" 2 tablets in bottle
AIC 035433275 - "20 mg gastro-resistant tablets" 5 tablets in bottle
AIC 035433287 - "20 mg gastro-resistant tablets" 7 tablets in bottle
AIC 035433299 - "20 mg gastro-resistant tablets" 14 tablets in bottle
AIC 035433301 - "20 mg gastro-resistant tablets" 15 tablets in bottle
AIC 035433313 - "20 mg gastro-resistant tablets" 28 tablets in bottle
AIC 035433325 - "20 mg gastro-resistant tablets" 30 tablets in bottle
AIC 035433337 - "20 mg gastro-resistant tablets" 56 tablets in bottle
AIC 035433349 - "20 mg gastro-resistant tablets" 60 tablets in bottle
AIC 035433352 - "20 mg gastro-resistant tablets" 100 tablets in bottle
AIC 035433477 - "20 mg gastro-resistant tablets" 140 (28x5) tablets in bottle
AIC 035433489 - "20 mg gastro-resistant tablets" 3 tablets in AL / AL blister
AIC 035433491 - "20 mg gastro-resistant tablets" 7 tablets in AL / AL blister
AIC 035433010 - "20 mg gastro-resistant tablets" 7x1 tablets in AL / AL blister
AIC 035433022 - "20 mg gastro-resistant tablets" 14 tablets in AL / AL blister
AIC 035433034 - "20 mg gastro-resistant tablets" 15 tablets in AL / AL blister
AIC 035433046 - "20 mg gastro-resistant tablets" 25x1 tablets in AL / AL blister
AIC 035433059 - "20 mg gastro-resistant tablets" 28 tablets in AL / AL blister
AIC 035433061 - "20 mg gastro-resistant tablets" 30 tablets in AL / AL blister
AIC 035433073 - "20 mg gastro-resistant tablets" 50x1 tablets in AL / AL blister
AIC 035433085 - "20 mg gastro-resistant tablets" 56 tablets in AL / AL blister
AIC 035433097 - "20 mg gastro-resistant tablets" 60 tablets in AL / AL blister
AIC 035433109 - "20 mg gastro-resistant tablets" 90 tablets in AL / AL blister
AIC 035433111 - "20 mg gastro-resistant tablets" 98 tablets in AL / AL blister
AIC 035433123 - "20 mg gastro-resistant tablets" 100x1 tablets in AL / AL blister
AIC 035433135 - "20 mg gastro-resistant tablets" 140 tablets in AL / AL blister
AIC 035433364 - "40 mg gastro-resistant tablets" 2 tablets in bottle
AIC 035433376 - "40 mg gastro-resistant tablets" 5 tablets in bottle
AIC 035433388 - "40 mg gastro-resistant tablets" 7 tablets in bottle
AIC 035433390 - "40 mg gastro-resistant tablets" 14 tablets in bottle
AIC 035433402 - "40 mg gastro-resistant tablets" 15 tablets in bottle
AIC 035433414 - "40 mg gastro-resistant tablets" 28 tablets in bottle
AIC 035433426 - "40 mg gastro-resistant tablets" 30 tablets in bottle
AIC 035433438 - "40 mg gastro-resistant tablets" 56 tablets in bottle
AIC 035433440 - "40 mg gastro-resistant tablets" 60 tablets in bottle
AIC 035433453 - "40 mg gastro-resistant tablets" 100 tablets in bottle
AIC 035433465 - "40 mg gastro-resistant tablets" 140 (28x5) tablets in bottle
AIC 035433147 - "40 mg gastro-resistant tablets" 3 tablets in AL / AL blister
AIC 035433150 - "40 mg gastro-resistant tablets" 7 tablets in AL / AL blister
AIC 035433162 - "40 mg gastro-resistant tablets" 7x1 tablets in AL / AL blister
035433174 - "40 mg gastro-resistant tablets" 14 tablets in AL / AL blister
AIC 035433186 - "40 mg gastro-resistant tablets" 15 tablets in AL / AL blister
AIC 035433198 - "40 mg gastro-resistant tablets" 25x1 tablets in AL / AL blister
AIC 035433200 - "40 mg gastro-resistant tablets" 28 tablets in AL / AL blister
AIC 035433212 - "40 mg gastro-resistant tablets" 30 tablets in AL / AL blister
AIC 035433224 - "40 mg gastro-resistant tablets" 50x1 tablets in AL / AL blister
AIC 035433236 - "40 mg gastro-resistant tablets" 56 tablets in AL / AL blister
AIC 035433248 - "40 mg gastro-resistant tablets" 60 tablets in AL / AL blister
AIC 035433251 - "40 mg gastro-resistant tablets" 90 tablets in AL / AL blister
AIC 035433503 - "40 mg gastro-resistant tablets" 98 tablets in AL / AL blister
AIC 035433515 - "40 mg gastro-resistant tablets" 100x1 tablets in AL / AL blister
AIC 035433527 - "40 mg gastro-resistant tablets" 140 tablets in AL / AL blister
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 5 February 2002.
Date of last renewal: March 2011.
10.0 DATE OF REVISION OF THE TEXT
May 2014
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