Protec - Package Leaflet

Active principles: Omeprazole

PROTEC 20 mg hard gastro-resistant capsules

Indications Why is Protec used? What is it for?

PROTEC contains the active substance omeprazole. It belongs to a group of medicines called 'proton pump inhibitors' which work by reducing the amount of acid produced in the stomach.

PROTEC is used to treat the following conditions:

In adults:

• Gastro-oesophageal reflux disease (GERD). This disease occurs when acid escapes from the stomach and passes into the esophagus (the tube that connects the throat to the stomach) causing pain, inflammation and heartburn.
• Ulcers in the upper intestine (duodenal ulcer) or stomach (gastric ulcer).
• Ulcers infected with a bacterium called 'Helicobacter pylori'. If you have this disease, your doctor may also prescribe antibiotics to treat the infection and allow the ulcer to heal.
• Ulcers caused by medicines called NSAIDs (Non-Steroidal Anti-Inflammatory Drugs). PROTEC can also be used to prevent ulcers from forming if you are taking NSAIDs.
• Excessive stomach acid caused by tissue growth in the pancreas (Zollinger-Ellison syndrome).

In children:

Children older than 1 year and with a body weight greater than or equal to 10 kg

• Gastro-oesophageal reflux disease (GERD). This disease occurs when acid escapes from the stomach and passes into the esophagus (the tube that connects the throat to the stomach) causing pain, inflammation and heartburn.

Symptoms of this disease in children also include stomach contents returning to the mouth (regurgitation), being sick (vomiting) and poor weight gain.

Children over 4 years of age and adolescents

• Ulcers infected with a bacterium called 'Helicobacter pylori'. If the child has this disease, the doctor may also prescribe antibiotics to treat the infection and allow the ulcer to heal.

Contraindications When Protec should not be used

Do not take PROTEC

• if you are allergic (hypersensitive) to omeprazole or any of the other ingredients of PROTEC.
• if you are allergic to medicines containing other proton pump inhibitors (e.g. pantoprazole, lansoprazole, rabeprazole, esomeprazole).
• if you are taking a medicine containing nelfinavir (used for HIV infections). If you are unsure, ask your doctor or pharmacist before taking PROTEC.

Precautions for use What you need to know before taking Protec

Take special care with PROTEC

PROTEC can hide the symptoms of other diseases. Therefore, if you experience the symptoms described below before taking PROTEC or while you are taking it, contact your doctor immediately:

• Unexplained weight loss and swallowing problems.
• Stomach pain or indigestion.
• Vomiting of food or blood.
• Dark discolouration of the stool (presence of blood in the stool).
• Severe or persistent diarrhea, because omeprazole has been associated with a slight increase in contagious diarrhea.
• Severe liver problems.

If you have been taking PROTEC for a long time (more than 1 year) your doctor will prescribe regular checkups. Tell your doctor if you notice any new and unusual symptoms.

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

Interactions Which drugs or foods can change the effect of Protec

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This is important because PROTEC can affect the way some medicines work and some medicines can affect the way PROTEC works.

Do not take PROTEC if you are taking a medicine containing nelfinavir (used to treat HIV infections).

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

• Ketoconazole, itraconazole or voriconazole (used to treat infections caused by fungi)
• Digoxin (used to treat heart problems)
• Diazepam (used to treat anxiety, to relax muscles or for epilepsy).
• Phenytoin (used for epilepsy). If you are taking phenytoin, your doctor will monitor you at the beginning and at the end of PROTEC treatment.
• Medicines used to thin the blood, such as warfarin or other vitamin K blockers. Your doctor will monitor you at the beginning and end of PROTEC treatment.
• Rifampicin (used to treat tuberculosis)
• Atazanavir (used to treat HIV infection)
• Tacrolimus (used in organ transplants)
• St. John's wort (Hypericum perforatum) (used to treat mild depression)
• Cilostazol (used to treat intermittent claudication)
• Saquinavir (used to treat HIV infections)
• Clopidogrel (used to prevent blood clots - thrombi -)
• Erlotinib (used for cancer treatment)
• Methotrexate (a chemotherapy medicine used in high doses to treat cancer)

if you are taking methotrexate in high doses, your doctor may have you temporarily stop treatment with PROTEC.

If your doctor has prescribed the antibiotics amoxicillin and clarithromycin together with PROTEC for the treatment of ulcers caused by Helicobacter pylori infections, it is very important that you tell if you are taking any other medicines.

Taking PROTEC with food and drink

The capsules can be taken with food or on an empty stomach.

Warnings It is important to know that:

Pregnancy and breastfeeding

Before taking PROTEC tell your doctor if you are pregnant or want to become pregnant. Your doctor will decide whether you can take PROTEC during this time.

Your doctor will decide whether you can take PROTEC if you are breastfeeding.

Driving and using machines

PROTEC is unlikely to affect the ability to drive or use tools or machines. Adverse drug reactions such as dizziness and visual disturbances may occur. If you suffer from this, you should not drive or use machines.

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

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

Your doctor will tell you how many capsules to take and for how long. This will depend on your condition and age.

The usual doses are given below.

Adults:

For the treatment of GERD symptoms, such as heartburn and acid regurgitation:

• If your doctor has told you that your esophagus is slightly damaged, the usual dose is 20 mg once a day for 4 to 8 weeks. Your doctor may increase the dose to 40 mg for another 8 weeks if the gullet has not yet completely healed.
• The usual dose once the gullet has healed is 10 mg once a day.
• If the esophagus is not damaged, the usual dose is 10 mg once a day.

For the treatment of ulcer in the upper part of the intestine (duodenal ulcer):

• The usual dose is 20 mg once a day for 2 weeks. Your doctor may extend this dose for another 2 weeks if the ulcer has not yet healed.
• If the ulcer does not fully heal, the dose can be increased to 40 mg once daily for 4 weeks.

For the treatment of stomach ulcers (gastric ulcer):

• The usual dose is 20 mg once a day for 4 weeks. Your doctor may extend this dose for another 4 weeks if the ulcer has not yet healed.
• If the ulcer does not fully heal, the dose can be increased to 40 mg once daily for 8 weeks.

To prevent the reappearance of duodenal and gastric ulcers:

• The usual dose is 10 mg or 20 mg once a day. Your doctor may increase the dose to 40 mg once a day.

For the treatment of duodenal and gastric ulcers caused by taking NSAIDs (Non Steroidal Anti-Inflammatory Drugs):

• The usual dose is 20 mg once a day for 4-8 weeks.

To prevent the formation of duodenal and stomach ulcers if you are using NSAIDs:

• The usual dose is 20 mg once a day.

For the treatment of ulcers caused by Helicobacter pylori infection and prevention of their reappearance:

• The usual dose is 20 mg of PROTEC twice a day for one week.
• Your doctor will also tell you to take two antibiotics including amoxicillin, clarithromycin and metronidazole.

For the treatment of excessive stomach acid caused by a tissue growth in the pancreas (Zollinger-Ellison syndrome):

• The usual dose is 60 mg per day.
• Your doctor will adjust the dose according to your needs and will also decide how long you need to take the medicine for.

Children:

For the treatment of GERD symptoms, such as heartburn and acid regurgitation:

• PROTEC can be taken by children over 1 year of age and weighing more than 10 kg. The dose for children is based on the child's weight and the doctor will decide the correct dose.

For the treatment and prevention of the recurrence of ulcers caused by Helicobacter pylori infection:

• PROTEC can be taken by children over 4 years of age. The dose for children is based on the child's weight and the doctor will decide the correct dose.
• Your doctor will also prescribe two antibiotics called amoxicillin and clarithromycin for your child.

Taking this medicine

• It is recommended to take the capsules in the morning.
• The capsules can be taken with food or on an empty stomach.
• The capsules should be swallowed whole with half a glass of water. The capsules should not be chewed or crushed, as they contain granules coated in such a way as to prevent the medicine from being broken down by stomach acid. It is important not to damage the granules.

What to do if you or the child have trouble swallowing the capsules

If you or the child have trouble swallowing the capsules:

• Open the capsules and swallow the contents directly with half a glass of water or pour the contents into a glass of water (non-fizzy), acidic fruit juice (e.g. apple, orange or pineapple) or apple puree.
• Always shake the contents before drinking (the mixture will not be clear), then drink the preparation immediately or within 30 minutes.
• To make sure that you have taken all of the medicine, rinse the glass very well with half a glass of water and drink the contents. The solid particles contain the medicine - do not chew or crush them.

Overdose What to do if you have taken too much Protec

If you take more PROTEC than you should

If you take more PROTEC than prescribed by your doctor, contact your doctor or pharmacist immediately.

If you forget to take PROTEC

If you forget to take a dose, take it as soon as you remember it. However, if it is almost time for your next dose, skip the missed dose. Do not take a double dose to make up for a forgotten dose.

Side Effects What are the side effects of Protec

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

If you notice any of the following rare but serious side effects, stop taking PROTEC 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 blistering or peeling. Severe blistering may also appear with bleeding of the lips, eyes, mouth, nose and genitals. This could be "Stevens-Johnson syndrome" or "toxic epidermal necrolysis". Yellow skin, dark urine, and tiredness could be symptoms of liver problems.

Side effects can occur with a certain frequency, as defined below:

• Very common affects more than 1 in 10 patients
• Common affects 1 to 10 users in 100
• Uncommon affects 1 to 10 users in 1.000
• Rare affects 1 to 10 users in 10.000
• Very rare affects less than 1 in 10.000 patients
• Not known Frequency cannot be estimated from the available data

The other side effects include:

Common side effects

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

Uncommon side effects

• Swelling of the feet and ankles.
• Disturbed sleep (insomnia).
• Dizziness, tingling, feeling sleepy.
• Sensation of spinning (vertigo).
• Changes in blood tests related to liver function.
• Rash, rash with swelling of the skin (hives) and itchy skin.
• General feeling of being unwell and lack of energy
• If you take a proton pump inhibitor such as PROTEC, especially for longer than one year, you may have a slightly increased risk of hip, wrist or spine fractures. If you have osteoporosis or are taking corticosteroids (which can increase the risk of osteoporosis), please consult your doctor.

Rare side effects

• Changes in the composition of the blood, such as a reduction in the number of white blood cells or platelets. This can cause weakness and easy bruising, or it can make infections more likely.
• Allergic reactions, sometimes very serious, including swelling of the lips, tongue and throat, fever, wheezing.
• Low levels of sodium in the blood. This can cause weakness, being sick (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).
• Dry mouth
• Inflammation inside 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 exposure to the sun.
• Joint pain (arthralgia) or muscle pain (myalgia).
• Severe kidney problems (interstitial nephritis).
• Increased sweating

Very rare side effects

• Changes in blood cell counts, including agranulocytosis (lack of white blood cells)
• Aggression.
• Seeing, feeling or hearing about unreal events (hallucinations).
• Severe liver problems up to liver failure and inflammation of the brain.
• Sudden onset of severe rash or blistering and peeling of the skin. These effects may be associated with high fever and joint pain (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis)
• Muscle weakness.
• Chest enlargement in men.

Not known

• Inflammation of the intestine (resulting in diarrhea).
• If you take PROTEC for more than three months, your blood levels of magnesium may drop.

Low magnesium levels can manifest themselves with fatigue, involuntary muscle contractions, disorientation, convulsions, dizziness, increased heart rate. If you get any of these symptoms, please see your doctor immediately. Low levels of magnesium can also lead to a decrease in potassium or calcium levels in the blood. Your doctor should decide whether to check your blood magnesium levels periodically.

• Reduction in blood calcium levels (hypocalcaemia). The reduction in blood calcium levels can result from very low levels of magnesium.

In very rare cases PROTEC can affect white blood cells leading to an immunodeficiency. If you develop an infection with symptoms such as fever with a severe deterioration in general health 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, in to rule out a lack of white blood cells (agranulocytosis) by carrying out a blood test. It is important that in this case you tell your doctor about the medication you are taking.

Don't worry about the list of possible side effects. He may not manifest 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 pharmacist.

Reporting of side effects

Expiry and Retention

• Keep PROTEC out of the reach and sight of children.
• Do not use PROTEC after the expiry date which is stated on the pack after Expiry. The expiry date refers to the last day of that month.
• Store at a temperature not exceeding 30 ° C
• Store the blister in the original package in order to protect from moisture.
• 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 PROTEC contains

- The active substance is omeprazole. PROTEC gastro-resistant hard capsules contains 20 mg omeprazole.

- The excipients: core: microcrystalline cellulose, low substituted hydroxypropyl cellulose, mannitol, croscarmellose sodium, polysorbate 80, povidone K-30, arginine, sodium laurilsulfate, glycine, light magnesium carbonate. Coating: hypromellose, methacrylic acid-ethyl acrylate copolymer, triethyl citrate, sodium hydroxide, titanium dioxide, talc. Capsule: gelatin, indigo carmine (E-132), titanium dioxide, water.

What PROTEC looks like and contents of the pack

• PROTEC 20 mg light blue gastro-resistant hard capsules.

Pack sizes - Protec 20 mg hard gastro-resistant capsules: blister pack containing 14 hard capsules.

Learn more about Protec are available in the "Summary of Characteristics" tab.

01.0 NAME OF THE MEDICINAL PRODUCT

PROTEC 20 MG CAPSULE RIGIDE GASTRORESISTENTI

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each gastro-resistant hard capsule contains:

active principle: omeprazole 20 mg.

For the full list of excipients, see section 6.1

03.0 PHARMACEUTICAL FORM

Hard capsules containing gastro-resistant granules.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

PROTEC is available exclusively as a 20 mg gastro-resistant hard capsule formulation.

PROTEC capsules are indicated for:

Adults

• Treatment of duodenal ulcers

• Prevention of relapse of duodenal ulcers

• Treatment of gastric ulcers

• Prevention of recurrence of gastric ulcers

• Eradication of Helicobacter pylori (H. pylori) in peptic ulcer, in combination with appropriate antibiotic therapy

• Treatment of gastric and duodenal ulcers associated with the use of NSAIDs

• Prevention of gastric and duodenal ulcers associated with the use of NSAIDs in patients at risk

• Treatment of reflux oesophagitis

• Long-term management of patients with healed reflux oesophagitis

• Treatment of symptomatic gastroesophageal reflux disease

• Treatment of Zollinger-Ellison syndrome

Pediatric use

Children over 1 year of age and with a body weight ≥ 10 kg

• Treatment of reflux oesophagitis

• Symptomatic treatment of heartburn and acid regurgitation in gastroesophageal reflux disease

Children and adolescents over 4 years of age

• Treatment of duodenal ulcer caused by H. pylori, in combination with antibiotic therapy

04.2 Posology and method of administration

We recommend taking the product in the morning, swallowing the capsules whole with the help of liquids. The contents of the capsule must not be chewed or crushed. There was no evidence of interaction between omeprazole and food intake.

ADULTS

Duodenal ulcer

The recommended dose is 1 capsule of PROTEC 20 mg per day.

In most patients, a rapid improvement of painful symptoms is achieved within 24-48 hours, while ulcer healing is achieved, in most cases, within 2 weeks of starting treatment.

In the case of ulcers that have not completely healed, healing is generally achieved by prolonging the treatment for another 2 weeks. In patients with severe duodenal ulcer healing was achieved with PROTEC 40 mg (2 x 20 mg capsules) in a single daily administration, usually within 4 weeks.

Prevention of relapse of duodenal ulcer

For the prevention of relapse of duodenal ulcer in H. pylori negative patients or when H. pylori eradication is not possible, the recommended dose is PROTEC 20 mg once daily. In some patients a dose of 10 mg may be sufficient. In case of therapeutic failure, the dose can be increased to 40 mg.

Gastric ulcer

The recommended dose is 1 capsule of PROTEC 20 mg per day.

The duration of treatment for most patients is 4 weeks. Only in cases of ulcers that have not completely healed, an extension to 6-8 weeks will be necessary.

In patients with severe gastric ulcer healing was achieved with PROTEC 40 mg in a single daily administration, generally within 8 weeks.

Prevention of relapse in patients with gastric ulcer

For the prevention of relapse in patients with poorly responsive gastric ulcer, the recommended dose is PROTEC 20 mg once daily. If necessary, the dose can be increased to 2 capsules of PROTEC 20 mg once a day.

Eradication of H. pylori in peptic ulcer

For the eradication of H. pylori, antibiotic selection should be based on the patient's individual drug tolerance and therapy should be undertaken according to local, regional, national resistance patterns and treatment guidelines.

• PROTEC 20 mg + clarithromycin 500 mg + amoxicillin 1.000 mg, each twice daily for one week, or

• PROTEC 20 mg + clarithromycin 250 mg (alternatively 500 mg) + metronidazole 400 mg (or 500 mg or tinidazole 500 mg), each twice daily for one week or

• PROTEC 40 mg once daily with amoxicillin 500 mg and metronidazole 400 mg (or 500 mg or tinidazole 500 mg), both three times daily for one week.

For each of the regimens, if the patient still tests positive for H. pylori, the therapy can be repeated.

Gastric and duodenal ulcers and erosive gastropathies associated with the continued intake of non-steroidal anti-inflammatory drugs (NSAIDs)

The recommended dose is 1 capsule of PROTEC 20 mg per day. Rapid improvement in symptoms and healing is achieved in most patients within 4 weeks.

In patients who are not completely healed, healing is usually achieved by prolonging the treatment for another 4 weeks.

Prevention of gastric and duodenal ulcers associated with the use of NSAIDs in patients at risk

For the prevention of NSAID-associated gastric or duodenal ulcers in patients at risk (age> 60, history of gastric and duodenal ulcers, history of upper gastrointestinal bleeding) the recommended dose is PROTEC 20 mg once daily.

Reflux esophagitis

The recommended dose is 1 capsule of PROTEC of 20 mg per day for 4 weeks; in resistant cases it will be necessary to prolong the therapy to 6-8 weeks. In patients unresponsive to this dosage it may be necessary to increase the dose to 40 mg of PROTEC in a single daily administration to achieve healing, usually within 8 weeks.

Long-term management of patients with healed reflux oesophagitis

For the long-term management of patients with healed reflux oesophagitis, the recommended dose is PROTEC 10 mg once daily. If necessary, the dose can be increased to PROTEC 20-40 mg once daily.

Gastro-oesophageal reflux disease

The recommended dose for short-term treatment and maintenance of remission of gastroesophageal reflux disease is 1 capsule of PROTEC 20 mg per day. Since patients may respond adequately even to administration of 10 mg / day, individual dose adjustment may be appropriate.

Functional non-ulcer dyspepsia

In subjects with no more than 45 years of age without alarm index (anemia, weight loss, etc.) with dyspepsia with problems of ulcer-like symptoms (fasting or night epigastric pain) an initial dose of 1 capsule of PROTEC of 20 is recommended. mg per day for 4 weeks.

Since patients can respond adequately even to administration of 10 mg / day, it is possible to use this dose in the initial phase of the disease.

In subjects over 45 years of age with the aforementioned alarm indices, it is advisable to carry out an endoscopic investigation to exclude the presence of organic pathology.

Zollinger-Ellison syndrome

The recommended starting dose is 60 mg of homeoprazole in a single daily administration (3 capsules of 20 mg). Thereafter, the dosage should be individually adjusted and continued for as long as clinically indicated. Effective control was maintained with doses between 90 mg and 20 mg / day in more than 120% of patients with severe disease, who had responded poorly to other therapies. Daily dosages above 80 mg should be divided into two daily administrations.

CHILDREN

Children over 1 year of age and with a body weight ≥ 10 kg

Treatment of reflux esophagitis

Symptomatic treatment of heartburn and acid regurgitation in gastroesophageal reflux disease

The recommended doses are as follows:

Reflux esophagitis: The treatment period is 4-8 weeks.

Symptomatic treatment of heartburn and acid regurgitation in gastroesophageal reflux disease: treatment lasts 2-4 weeks. If symptomatic control is not achieved after 2-4 weeks, the patient should be further investigated.

Children and adolescents over 4 years of age

Treatment of duodenal ulcer caused by H. pylori: Official local, regional and national guidelines regarding bacterial resistance, duration of treatment (most commonly 7 days, but sometimes up to at 14 days) and the appropriate use of antibiotics.

The treatment must be carried out under the supervision of a specialist.

The recommended posology is as follows:

Special populations

Impaired renal function

No dosage adjustment is required in patients with impaired renal function (see section 5.2).

Impaired liver function

In patients with impaired hepatic function, a daily dose of 10-20 mg may be sufficient (see section 5.2).

Elderly (> 65 years)

No dosage adjustment is required in elderly patients (see section 5.2).

Method of administration

It is recommended to take PROTEC capsules in the morning, preferably on an empty stomach, swallowed whole with half a glass of water. The capsules should not be chewed or crushed.

For patients with swallowing difficulties and for children who can drink or swallow semi-solid foods

Patients can open the capsule and swallow the contents with half a glass of water, or mixed with slightly acidic liquids such as fruit juice or apple puree or still water. Patients should be advised that in such cases the dispersion should be swallowed immediately (or within 30 minutes) and that it should always be mixed just before drinking. Rinse the bottom with half a glass of water and drink the contents.

Alternatively, patients can dissolve the capsule in the mouth and swallow the contained granules with half a glass of water. The gastro-resistant granules must not be chewed.

04.3 Contraindications

Hypersensitivity to omeprazole, benzimidazole substitutes or to any of the excipients.

Omeprazole, like other proton pump inhibitors (PPIs), should not be administered concomitantly with nelfinavir (see section 4.5).

04.4 Special warnings and appropriate precautions for use

In the presence of some alarming symptoms (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, malignant nature of the ulcer should be ruled out. how the symptomatic response to therapy could delay a correct diagnosis.

Co-administration of atazanavir and proton pump inhibitors is not recommended (see section 4.5). If the combination of atazanavir and proton pump inhibitor is judged unavoidable, careful clinical monitoring (eg viral load) is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir; the dose of omeprazole should not exceed 20 mg.

Omeprazole, like all acid-suppressive medicines, can reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be taken into consideration in patients with low reserves or risk factors for reduced vitamin B12 absorption in case of long-term therapy.

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

Some children with chronic conditions may need long-term treatment although it is not recommended.

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

As with all long-term treatments, especially if the duration of treatment is greater than 1 year, patients should be monitored regularly.

Ipomagnesiemia

Proton pump inhibitors (PPIs) such as omeprazole have been observed 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 improves in most patients 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 medicinal products that can cause hypomagnesaemia (e.g. diuretics).

Proton pump inhibitors, especially when used in high doses and for prolonged periods (> 1 year), may cause a slightly increased risk of hip, wrist and spine fractures, especially in elderly patients or in the presence of other known risk factors. Observational studies suggest that proton pump inhibitors could 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 care according to current clinical practice guidelines and should take adequate amounts of vitamin D and calcium.

04.5 Interactions with other medicinal products and other forms of interaction

Active ingredients with pH-dependent absorption

Gastric pH-dependent absorption of active substances may be increased or decreased by decreased intragastric acidity during treatment with omeprazole.

Nelfinavir, atazanavir

Plasma levels of nelfinavir and atazanavir decrease when omeprazole is co-administered.

Concomitant administration of omeprazole and nelfinavir is contraindicated (see section 4.3). Co-administration of omeprazole (40 mg once daily) reduced the mean exposure of nelfinavir by approximately 40% and reduced the mean exposure of the pharmacologically active metabolite M8 by approximately 75-90%. The interaction may also involve CYP2C19 inhibition.

Concomitant administration of omeprazole and atazanavir is not recommended (see section 4.4). Co-administration of omeprazole (40 mg once daily) and atazanavir 300 mg / ritonavir 100 mg to healthy volunteers resulted in a 75% reduction in atazanavir exposure. Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. Co-administration of omeprazole (20 mg once daily) and atazanavir 400 mg / ritonavir 100 mg to healthy volunteers resulted in an approximately 30% reduction in atazanavir exposure compared to atazanavir 300 mg / ritonavir 100 mg once. per day.

Digoxin

Concomitant treatment with omeprazole (20 mg / day) and digoxin in healthy subjects resulted in a 10% increase in the bioavailability of digoxin. Digoxin toxicity has rarely been reported. However, caution is advised when using high doses of omeprazole in elderly patients. Therapeutic monitoring of digoxin should therefore be increased.

Clopidogrel

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

Other active ingredients

Absorption of posaconazole, erlotinib, ketoconazole and itraconazole is significantly reduced and therefore clinical efficacy may be compromised. Concomitant use of posaconazole and erlotinib should be avoided.

Active substances metabolised by CYP2C19

Omeprazole is a moderate inhibitor of its main metabolising enzyme, CYP2C19. Therefore, the metabolism of concomitant active substances also metabolised by CYP2C19 may be decreased and systemic exposure to these substances increased. Examples of such drugs are R-warfarin and other vitamin K antagonists, cilostazol, diazepam and phenytoin.

Cilostazolo

Omeprazole, given as 40 mg to healthy volunteers in a cross-over study, increased the Cmax and AUC of cilostazol by 18% and 26%, respectively, and one of its active metabolites by 29% and 69, respectively. %.

Phenytoin

Monitoring of phenytoin plasma concentration is recommended during the first two weeks after initiation of omeprazole treatment and, if a phenytoin dose adjustment is required, monitoring and further dose adjustment is recommended when ending treatment. with omeprazole.

Mechanism unknown

Saquinavir

Concomitant administration of omeprazole and saquinavir / ritonavir resulted in increased plasma levels of saquinavir up to approximately 70% with good tolerability in HIV-positive patients.

Tacrolimus

Concomitant administration of omeprazole has been reported to increase the serum levels of tacrolimus. Monitoring of tacrolimus concentrations and renal function (creatinine clearance) should be increased and, if necessary, the tacrolimus dosage adjusted.

Influence of other active substances on the pharmacokinetics of omeprazole

CYP2C19 and / or CYP3A4 inhibitors

Since omeprazole is metabolised by CYP2C19 and CYP3A4, the active substances inhibitors of CYP2C19 or CYP3A4 (such as clarithromycin and voriconazole) may increase the serum levels of omeprazole, decreasing its rate of metabolism. Co-administration of voriconazole results in more than doubled exposure to omeprazole. Since the administration of high doses of omeprazole was well tolerated, no dose adjustment of omeprazole is generally necessary. However, dose adjustment should be considered in patients with severe hepatic impairment and in the case of long-term treatment.

Inducers of CYP2C19 and / or CYP3A4

Active substances inducing CYP2C19 or CYP3A4 or both (such as rifampicin and St. John's wort) may lead to a decrease in the serum levels of omeprazole, increasing its rate of metabolism.

Interaction with food

There was no evidence of interaction between omeprazole and food intake.

04.6 Pregnancy and breastfeeding

The results of three prospective epidemiological studies (more than 1000 exposed patient outcomes) indicate no adverse effects of omeprazole on pregnancy or on the health of the fetus / newborn. Omeprazole can be used during pregnancy.

Omeprazole is excreted in breast milk but is unlikely to affect the infant when administered in therapeutic doses.

04.7 Effects on ability to drive and use machines

Although omeprazole is unlikely to normally affect the ability to drive or use machines, the patient should be informed of the possible, although uncommon, dizziness or somnolence (see section 4.8).

04.8 Undesirable effects

The most common side effects (1-10% of patients) are headache, abdominal pain, constipation, diarrhea, flatulence, nausea / vomiting.

The following adverse reactions, identified or suspected, have been highlighted during clinical trials with omeprazole and post-marketing. In no case was a correlation with the administered drug dose established. Undesirable effects are classified according to frequency and Organ Classification System (SOC). Frequency categories are defined using the following convention: Very common (≥1 / 10), Common (≥1 / 100 to

Pediatric population

The safety of omeprazole was evaluated in a total of 310 children aged 0 to 16 years with acid-related disease. Limited long-term data are available in 46 children who received omeprazole maintenance therapy for up to 749 days in a clinical study in severe erosive oesophagitis. The adverse event profile was found to be generally the same as in adults in both short-term and long-term treatment. There are no long-term data regarding the effects of omeprazole treatment on puberty and growth.

04.9 Overdose

There have been rare reports of overdose with omeprazole. Doses up to 560 mg are reported in the literature and there have been occasional reports of single oral doses up to 2400 mg of omeprazole (120 times the usually recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhea and headache have been reported following overdose with omeprazole. In individual cases, apathy, depression and confusion were observed.

The symptoms described in connection with omeprazole overdose have been transient and no serious consequences have been reported.

With increasing doses the elimination rate did not change (first order kinetics) and it was not necessary to establish a specific therapy.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: proton pump inhibitor

ATC code: A02BC01.

Omeprazole, the racemic form of two active enantiomers, reduces gastric acid secretion by a highly specialized mechanism of action. Omeprazole is a specific inhibitor of the proton pump in the gastric parietal cell.

Omeprazole acts rapidly and promotes reversible control of inhibition of acid secretion with only once daily administration.

Site and mechanism of action

Omeprazole is a weak base and is concentrated and converted to the active form in the strongly acidic environment of the intracellular canaliculi within the parietal cell, where it inhibits the H +, K + -ATPase - proton pump. This action on the last stage of the hydrochloric acid formation process is dose-dependent and causes a highly effective inhibition of acid secretion, both of the basal and of the stimulated one, regardless of the stimulus used.

All observed pharmacodynamic effects are due to the activity of omeprazole on acid secretion.

Effects on gastric acid secretion

The oral administration of omeprazole once a day allows a rapid and effective inhibition of day and night gastric acid secretion, which reaches its maximum within the first 4 days of treatment.

In patients suffering from duodenal ulcer the administration of 20 mg of omeprazole maintained an average reduction of 24% in intragastric acidity over 80 hours; 24 hours after the administration of omeprazole the peak of acid secretion, after stimulation with pentagastrin, is on average reduced by about 70%.

Oral administration of 20 mg of omeprazole maintains the intragastric pH at ≥ 3 for a mean time of 17 hours over 24 hours in patients with duodenal ulcer.

As a consequence of the reduction of acid secretion and intragastric acidity, omeprazole dose-dependently reduces / normalizes the acid exposure of the esophagus in patients with gastroesophageal reflux disease.

The inhibition of acid secretion is related to the plasma concentration / time curve (AUC) but not to the actual plasma concentration at a given time.

No tachyphylaxis was observed during treatment with omeprazole.

Effects on Helicobacter pylori

Helicobacter pylori is associated with peptic acid disease which includes duodenal ulcer disease and gastric ulcer disease in which approximately 95% and 70% of patients are infected with this bacterium, respectively.

Helicobacter pylori is considered to be the main culprit in the development of gastritis.

Helicobacter pylori together with gastric acid secretion are the most important factors for the development of peptic ulcer disease.

Helicobacter pylori is the most important factor in the development of atrophic gastritis which is associated with an increased risk of developing gastric cancers.

The eradication of Helicobacter pylori with omeprazole and antimicrobials allows a rapid improvement of ulcer symptoms, a high rate of scarring, a long-term remission of peptic ulcer disease with a reduced incidence of complications such as bleeding from the gastrointestinal tract making it unnecessary long term treatment with antisecretors.

Eradication of Helicobacter pylori with omeprazole and antibiotics is also associated with the regression of atrophic gastritis and a reduced risk of developing gastric cancer.

The dual therapies studied showed less efficacy than the triple therapies. However, they can be taken into account if known hypersensitivity precludes the use of a triple combination.

Other effects related to acid inhibition

During long-term treatment with omeprazole, an increase in the frequency of occurrence of gastric glandular cysts, which are the physiological consequence of the pronounced inhibition of acid secretion, has been observed. Said cystic formations are benign and reversible in nature.

The decrease in gastric acidity of any origin, including that due to proton pump inhibitors, increases the gastric bacterial load normally present in the gastrointestinal tract. Treatment with acid-reducing drugs may cause a slightly increased risk of Salmonella and Campylobacter gastrointestinal infections.

Pediatric use

In an uncontrolled study with children (1 to 16 years of age) with severe reflux oesophagitis, omeprazole, at doses of 0,7 to 1,4 mg / kg, improved the degree of esophagitis in 90% of cases. and significantly reduced reflux symptoms. In a single-blind study, children aged 0-24 months with clinically diagnosed reflux oesophagitis were treated with 0,5, 1,0 or 1,5 mg omeprazole / kg. The frequency of vomiting / regurgitation episodes decreased by 50% after 8 weeks of treatment, regardless of dose.

Eradication of H. pylori in children

A double-blind, randomized clinical trial (Héliot study) established that omeprazole in combination with two antibiotics (amoxicillin and clarithromycin) is effective and safe in the treatment of H. pylori infection in children aged 4 years and over with gastritis: rate of eradication of H. pylori: 74,2% (23/31 patients) with omeprazole + amoxicillin + clarithromycin versus 9,4% (3/32 patients) with amoxicillin + clarithromycin. However, no clinical benefit has been shown with regard to dyspeptic symptoms. This study does not support information for children under the age of 4.

05.2 Pharmacokinetic properties

Absorption

Omeprazole is sensitive to the acidic environment, consequently the product granules contained in the capsule have a gastro-resistant film. Absorption of omeprazole is rapid, with maximum plasma levels visible approximately 1-2 hours after dosing. Absorption of omeprazole occurs in the small intestine and is completed in 3-6 hours. Concomitant food intake does not affect the bioavailability of the drug. Systemic bioavailability after single oral dose is approximately 40%; it increases to about 60% after repeated daily administrations.

Distribution

The apparent volume of distribution in healthy subjects is approximately 0,3 L / kg.

Bioavailability is not affected by simultaneous food intake.

About 97% of omeprazole is bound to plasma proteins.

Metabolism

Omeprazole is completely metabolised by the cytochrome P450 (CYP) system. Most of the metabolism of omeprazole is dependent on the specific polymorphically expressed CYP2C19 isoform responsible for the formation of hydroxyomeprazole which is the major plasma metabolite. The remaining part depends on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulfone. As a consequence of omeprazole's high affinity for CYP2C19, there is a potential for competitive inhibition and drug-drug metabolic interaction between omeprazole and other CYP2C19 substrates. However, due to its low affinity for CYP3A4, omeprazole does not have the ability to inhibit the metabolism of other CYP3A4 substrates. Furthermore, omeprazole has no inhibitory effect on major CYP enzymes.

Approximately 3% of the Caucasian population and 15-20% of the Asian population have a deficiency in the function of the CYP2C19 enzyme, thus being defined as poor metabolisers. In these individuals, the metabolism of omeprazole is probably more catalysed by CYP3A4. After repeated administration of omeprazole 20 mg once daily, the mean AUC was 5 to 10-fold higher in poor metabolisers than in subjects with a functional CYP2C19 enzyme (extensive metabolisers). Maximum plasma concentrations were 3 to 5 times higher. These results have no implications for the posology of omeprazole.

Excretion

The plasma elimination half-life of omeprazole is usually less than one hour after both single and repeated oral once-daily dosing. Omeprazole is completely cleared from the plasma between doses, and therefore there is no tendency for accumulation during once daily administration. Approximately 80% of an oral dose of omeprazole is excreted in the urine as metabolites, the remainder in the faeces originating primarily from biliary secretion.

The AUC of omeprazole increases after repeated administration. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. The time and dose dependence is due to a decrease in first pass metabolism and systemic clearance, possibly caused by an inhibition of the CYP2C19 enzyme by omeprazole and / or its metabolites (e.g. sulphone).

No effect of the metabolites on gastric acid secretion was observed.

Special patient populations

Kids

Available data in children (from 1 year of life onwards) suggest that, within the recommended doses (see section 4.2), the pharmacokinetics in the child are similar to that in adults.

Senior citizens

In the elderly, the volume of distribution is slightly reduced.

Patients with renal dysfunction

The apparent volume of distribution in patients with renal insufficiency is similar to that observed in healthy subjects.

The systemic bioavailability and elimination of omeprazole are not altered in patients with impaired renal function.

Patients with hepatic dysfunction

In patients with hepatic insufficiency the volume of distribution is slightly reduced.

The area under the plasma concentration / time curve was increased in patients with impaired hepatic function, but there was no tendency for the product to accumulate when administered once daily.

05.3 Preclinical safety data

Gastric ECL cell hyperplasia and carcinoids were detected in trials in rats treated for life with omeprazole. These changes are the result of high hypergastrinemia secondary to acid inhibition and have been observed both following treatment with H2 antagonists, proton pump inhibitors and after partial fundus resection. These changes are not a direct effect of any single drug.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

PROTEC 20 mg hard gastro-resistant capsules

Each capsule contains the following excipients: Core: microcrystalline cellulose, low-substituted hydroxypropylcellulose, mannitol, croscarmellose sodium, polysorbate 80, povidone K-30, arginine, sodium lauryl sulfate, glycine, light magnesium carbonate.

Coating: hypromellose, methacrylic acid-ethyl acrylate copolymer, triethyl citrate, sodium hydroxide, titanium dioxide, talc.

Capsule: gelatin, indigo carmine (E-132), titanium dioxide, water.

06.2 Incompatibility

Not applicable

06.3 Period of validity

In intact packaging: 2 years

The expiry date indicated refers to the product in intact and correctly stored packaging.

06.4 Special precautions for storage

Store at a temperature not exceeding 30 ° C

06.5 Nature of the immediate packaging and contents of the package

PVC-AL-PA / AL-AL blisters; box of 14 capsules.

06.6 Instructions for use and handling

See section 4.2 "Posology and method of administration".

07.0 MARKETING AUTHORIZATION HOLDER

AGIPS FARMACEUTICI Srl - Via Amendola, 4 - 16035 Rapallo (GE)

08.0 MARKETING AUTHORIZATION NUMBER

PROTEC 20 mg capsule rigide gastroresistenti, 14 capsule - A.I.C.: 037760016

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Date of first authorization: 31-12-2007

10.0 DATE OF REVISION OF THE TEXT

November 2012

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL