Losek - instructions for use, dose, side effects, contraindications

Omeprazole is a racemic mixture of two enantiomers, reduces the secretion of hydrochloric acid due to specific inhibition of the proton pump of parietal cells of the stomach. With a single application, the drug acts quickly and has a reversible inhibition of hydrochloric acid secretion.

Mechanism of action

Omeprazole is a weak base, transforms into an active form in the acidic environment of the tubules of the cells of the parietal layer of the gastric mucosa, where it activates and inhibits the H + / K + -ATPase-proton pump.The drug has a dose-dependent effect on the last stage of the synthesis of hydrochloric acid, inhibits both basal and stimulated secretion independently of the stimulating factor.

Effect on the secretion of hydrochloric acid in the stomach

Intravenous administration of omeprazole has a dose-dependent inhibition of hydrochloric acid secretion in humans. In order to achieve a rapid reduction in intragastric acidity, intravenous administration of 40 mg of omeprazole is recommended, followed by a rapid decrease in intragastric secretion, which is maintained for 24 hours.

The degree of oppression of hydrochloric acid secretion is proportional to the area under the "concentration-time" curve (AUC) omeprazole and is not proportional to the actual concentration of the drug in the blood at a given time.

During treatment with omeprazole tachyphylaxis was not noted.

In patients taking orally for a long time, drugs that reduce the secretion of the glands of the stomach, the formation of glandular cysts in the stomach was more often noted. These phenomena are caused by physiological changes due to inhibition of hydrochloric acid secretion.Cysts are benign and undergo reverse development.

During therapy with drugs that reduce the secretion of the glands of the stomach, an increase in the concentration of gastrin in the blood serum was detected. Due to a decrease in the secretion of hydrochloric acid, the concentration of chromogranin A (CgA) increases. An increase in CgA concentration may influence the results of the examinations to identify neuroendocrine tumors. To prevent this effect, therapy with proton pump inhibitors should be stopped 5 to 14 days before the CgA concentration test. If during this time the concentration of CgA did not return to the normal value, the study should be repeated.

In children and adult patients who took long-term omeprazole, there was an increase in the number of enterochromaffin-like cells, probably due to an increase in the concentration of gastrin in the blood serum. Clinical significance of this phenomenon is not.

Decrease in secretion of hydrochloric acid in the stomach under the influence of inhibitors of the proton pump or other drugs that reduce the secretion of the glands of the stomach, leads to an increase in the growth of normal intestinal microflora,which in turn can lead to a slight increase in the risk of developing intestinal infections caused by bacteria such as Salmonella spp., Campylobacter spp., and, in hospitalized patients, probably also Clostridium difficile.

Pharmacokinetics:

Distribution

The volume of distribution in healthy volunteers is 0.3 l / kg, a similar figure is determined in patients with renal insufficiency. In elderly patients and in patients with hepatic insufficiency, the volume of distribution is somewhat reduced. Omeprazole binds to plasma proteins by about 95%.

Metabolism and excretion

After intravenous administration, the mean half-life in the terminal phase is 40 minutes; the total clearance is from 0.3 to 0.6 l / min. During treatment there is no change in the half-life period.

Omeprazole is completely metabolized with the participation of the cytochrome P450 enzyme system (CYP). The metabolism of the drug depends mainly on the specific isoenzyme CYP2C19, which is responsible for the formation of the main metabolite - hydroxyomeprazole. The metabolism of the remainder is carried out by isoenzyme CYP3A4; thus forming a sulfo derivative of omeprazole. Metabolites have no effect on gastric acid secretion. About 80% of the intravenously administered dose is excreted as metabolites by the kidneys, and the rest by the intestine.

Peculiarities of pharmacokinetics in some patient groups

Approximately 3% of the population has reduced isoenzyme activity CYP2C19. In such patients, the metabolism of omeprazole is mainly performed by CYP3A4, and with the repeated admission of 20 mg of omeprazole, once a day, the average area under the concentration-time curve is 5-10 times higher than in patients with normal isoenzyme activity CYP2C19. The average value of the maximum plasma concentration in patients with reduced isoenzyme activity was increased approximately 3-5 times. The noted features do not affect the dose and method of application of the drug Losek®.

In patients with impaired renal function, excretion of omeprazole does not undergo any changes. There is an increase in the half-life in patients with impaired liver function, however, omeprazole Do not cumulate when taken once a day. The rate of metabolism of omeprazole in elderly patients (75-79 years) is somewhat reduced.

Indications:

Peptic ulcer of duodenum, peptic ulcer of stomach, reflux-esophagitis, treatment of Zollinger-Ellison syndrome.

Contraindications:

Hypersensitivity to omeprazole, a benzoimidazole derivative, or other components of the drug.

Children's age (experience is limited).

Omeprazole should not be used together with atazanavir and nelfinavir (see section "Interaction with other drugs and other forms of drug interaction").

Pregnancy and lactation:

Pregnancy

The results of epidemiological studies showed no side effects of omeprazole on the course of pregnancy, on the fetus or on the newborn. Losek® can be used during pregnancy.

Lactation

Omeprazole is excreted in breast milk. Influence on children, if any, is not known. In this regard, in case of need therapy with Losek® during lactation, the possibility of stopping breastfeeding should be considered.

Dosing and Administration:

If it is not possible to perform oral therapy for patients with peptic ulcer and duodenal ulcer or reflux esophagitis, it is recommended to administer infusion of Losek® preparation at a dose of 40 mg once a day.Patients with Zollinger-Ellison syndrome are recommended initial intravenous administration of Losek® at a dose of 60 mg per day.

Doses are selected individually, sometimes a higher dose is required. If the daily dose exceeds 60 mg, the dose should be divided into two injections.

Infusion of the drug Losek® is administered intravenously for 20-30 minutes. It is recommended to inject the solution for infusion immediately after its preparation.

Patients with impaired renal function

In patients with impaired renal function, there is no need to adjust the dose.

Patients with hepatic impairment

For patients with impaired liver function, a daily dose of 10-20 mg per day can be sufficient, since these patients have a half-life of omeprazole.

Elderly patients

There is no need to adjust the dose for elderly patients.

Children

There is limited experience with Losek® in children.

Instructions for preparing an infusion solution

The infusion solution is prepared by dissolving the lyophilized powder of omeprazole in 100 ml of a 5% infusion solution of dextrose or in 100 ml of an infusion 0.9% solution of sodium chloride.

Infusion solution on 5% Dextrose should be used within 6 hours. Infusion solution on a 0.9% solution of sodium chloride should be used within 12 hours.

Preparation

1. Draw 5 ml of the infusion solution from the vial or infusion bag with a syringe.

2. Introduce the infusion solution into a vial of lyophilized omeprazole powder, shake the vial until the drug dissolves completely.

3. Draw a syringe solution of omeprazole.

4. Transfer the solution of omeprazole to a vial or infusion bag.

5. Repeat steps 1-4 in order to transfer the entire preparation from the vial.

Alternative preparation of an infusion solution in a soft container

1. To prepare the solution, use a two-sided needle (adapter). With one end of the needle, pierce the membrane of the infusion bag, and connect the other end of the needle to the vial of lyophilized omeprazole.

2. Dissolve the powder of omeprazole, pumping the infusion solution from the bag into the bottle and back.

3. Make sure that the powder is completely dissolved, then disconnect the empty vial and remove the needle from the infusion bag.

Side effects:

The following side effects are independent of the dosing regimen of the drug, noted with omeprazole, both in clinical trials and in post-marketing studies.

The frequency of adverse reactions is given in the form of the following gradation: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000).

From the skin and subcutaneous tissues

Infrequently: dermatitis, itching, skin rash, hives;

Rarely: alopecia, photosensitivity reactions, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

From the musculoskeletal and connective tissue

Rarely: arthralgia, myalgia, muscle weakness.

From the nervous system

Often: headache;

Infrequently: dizziness, paresthesia, drowsiness;

Rarely: a taste disorder.

Disorders of the psyche

Infrequently: insomnia;

Rarely: increased excitability, aggressiveness, impaired consciousness, depression, hallucinations.

From the gastrointestinal tract

Often: abdominal pain, constipation, diarrhea, flatulence, nausea / vomiting;

Rarely: dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis.

From the liver and biliary tract

Infrequently: increased activity of "liver" enzymes;

Rarely: hepatitis with / without jaundice, liver failure, encephalopathy in patients with liver disease.

From the genitals and breast

Rarely: gynecomastia.

On the part of the blood and lymphatic system

Rarely: leukopenia, thrombocytopenia, agranulocytosis, pancytopenia.

From the immune system

Rarely: hypersensitivity reactions - fever, angioedema, anaphylactic reaction / anaphylactic shock.

From the respiratory system, organs of the chest and mediastinum

Rarely: bronchospasm.

From the side of the kidneys and urinary tract

Rarely: interstitial nephritis.

On the part of the hearing organ and labyrinthine violations

Infrequently: Vertigo.

From the side of the organ of vision

Rarely: blurred vision.

From the side of metabolism and nutrition

Rarely: hyponatremia;

Rarely: hypomagnesemia, hypocalcemia due to severe hypomagnesemia, hypokalemia due to hypomagnesemia.

General disorders

Infrequently: malaise;

Rarely: increased sweating, peripheral edema.

There have been reports of irreversible visual impairment in patients with severe concomitant diseases with intravenous injection of omeprazole in high doses.However, the causal relationship between impairment of vision and therapy with omeprazole has not been established.

Overdose:

In clinical studies, intravenous administration of the drug for one day to 270 mg and 650 mg for a three-day period without any consequences for the patient.

Symptoms: dizziness, blocking, headache, confusion, dilation of blood vessels, tachycardia, nausea, vomiting, flatulence, diarrhea.

Treatment: symptomatic. Hemodialysis is not effective enough.

Incompatibility

It is not noted if the instructions for preparing the infusion solution are followed (see section "Method of administration and dose").

Interaction:

Effect of omeprazole on the pharmacokinetics of other drugs.

The decrease in the secretion of hydrochloric acid in the stomach in the treatment with omeprazole and other inhibitors of the proton pump can lead to a decrease or increase in absorption of other drugs, the absorption of which depends on the acidity of the medium. Like other drugs that reduce the acidity of gastric juice, treatment with omeprazole may lead to a reduction in the absorption of ketoconazole, itraconazole and erlotinib, as well as an increase in the absorption of drugs such as digoxin. Joint use of omeprazole at a dose of 20 mg once a day and digoxin increases the bioavailability of digoxin by 10% (bioavailability of digoxin was increased by up to 30% in 20% of patients).

It was shown that omeprazole interacts with some antiretroviral drugs. The mechanisms and the clinical significance of these interactions are not always known. An increase in pH on the background of omeprazole therapy may affect the absorption of antiretroviral drugs. It is also possible to interact at the isoenzyme level CYP2C19. With the joint use of omeprazole and some antiretroviral drugs, such as atazanavir and nelfinavir, against the background of therapy with omeprazole, there is a decrease in their concentration in the serum. In this regard, the joint use of omeprazole with antiretroviral drugs, such as atazanavir and nelfinavir, Not recommended.

With the simultaneous use of omeprazole and saquinavir, an increase in the concentration of saquinavir in the serum was noted, while with use with some other antiretroviral drugs their concentration did not change.

Omeprazole inhibits CYP2C19 - the main isoenzyme involved in its metabolism. Joint use of omeprazole with other drugs, in the metabolism of which isoenzyme participates CYP2C19, such as diazepam, phenytoin, warfarin, other antagonists of vitamin K and cilostazol, can lead to a decrease in the metabolism of these drugs.

It is recommended to control the concentration of phenytoin in the plasma with the simultaneous administration of phenytoin and omeprazole; in some cases, a reduction in the dose of phenytoin may be required. At the same time, patients with long-term phenytoin, the combined use of omeprazole at a dose of 20 mg once a day did not cause a change in the concentration of phenytoin in the blood plasma.

When using omeprazole by patients receiving warfarin or other vitamin K antagonists, monitoring of INR (an internationally normalized relationship) is required; in some cases, you may need to reduce the dose of warfarin or another vitamin K antagonist. At the same time, in patients taking long-term warfarin, the joint use of omeprazole at a dose of 20 mg once a day did not cause a change in the coagulation time.

The use of omeprazole at a dose of 40 mg once a day led to an increase in stachas and areas under the concentration-time curve of cilostazol by 18% and 26%respectively; for one of the active metabolites of cilostazol, the increase was 29% and 69%, respectively.

The pharmacokinetic / pharmacodynamic interaction between clopidogrel (loading dose 300 mg and maintenance dose 75 mg / day) and omeprazole (80 mg / day oral), which leads to a decrease in the exposure of the active metabolite clopidogrel, on average, to 46% and a decrease in the maximum inhibition of ADP-induced platelet aggregation, on average, by 16%.

The clinical significance of this interaction is not clear. In a prospective study in patients who received placebo or omeprazole in a dose of 20 mg / day. concurrent with clopidogrel and acetylsalicylic acid (ACA) therapy, and in the analysis of clinical outcomes of large-scale randomized trials, there was no evidence of an increased risk of cardiovascular complications in the combined use of clopidogrel and proton pump inhibitors, including omeprazole.

The results of a number of observational studies are contradictory and do not give an unambiguous answer about the presence or absence of an increased risk of thromboembolic cardiovascular complications against the background of joint use of clopidogrel and proton pump inhibitors.

When clopidogrel together with a fixed combination of 20 mg of esomeprazole and 81 mg ASA exposure of the active metabolite of clopidogrel decreased by almost 40% compared to a monotherapy clopidogrel, with maximal levels of inhibition of ADP-induced platelet aggregation were identical, which is probably due to the simultaneous reception of ASA in a low dose.

Omeprazole does not affect the metabolism of drugs metabolized by the CYP3A4 isoenzyme such as, ciclosporin, lidocaine, quinidine, estradiol, erythromycin and budesonide.

No effects of omeprazole on the following drugs have been identified: caffeine, theophylline, quinidine, piroxicam, diclofenac, naproxen, metoprolol, propranolol and ethanol.

With the simultaneous use of omeprazole and tacrolimus, there was an increase in the concentration of tacrolimus in the blood serum.

Some patients reported increased concentrations of methotrexate against a background of combined use with proton pump inhibitors. When using high doses of methotrexate, consideration should be given to the possibility of a temporary withdrawal of omeprazole.

Effect of drugs on the pharmacokinetics of omeprazole.

In the metabolism of omeprazole, isozymes participate CYP2C19 and CYP3A4. The combined use of omeprazole and isozyme inhibitors CYP2C19 and CYP3A4, such as, clarithromycin and voriconazole, can lead to an increase in the concentration of omeprazole in the blood plasma by slowing the metabolism of omeprazole. The combined use of voriconazole and omeprazole results in a more than two-fold increase in the value AUC for omeprazole. Due to the good tolerability of high doses of omeprazole, with a short joint application of these drugs does not require correction of the dose of omeprazole. Medicines that induce isoenzymes CYP2C19 and CYP3A4, such as, rifampicin and preparations of St. John's wort perfumed, when combined with omeprazole may lead to a decrease in the concentration of omeprazole in the blood plasma due to the acceleration of the metabolism of omeprazole.

Special instructions:If you suspect a stomach ulcer in the early stages, you need to undergo an X-ray or endoscopy examination to establish the correct diagnosis and the appointment of an adequate treatment.

In the presence of any anxiety symptoms (for example,such as significant spontaneous weight loss, frequent vomiting, dysphagia, vomiting with blood or melena), and in the presence of gastric ulcer (or suspected gastric ulcer), the possibility of malignant growth should be excluded, since treatment with Losek® can lead to a smoothing of the symptoms and delay the diagnosis.

Pharmacokinetic / pharmacodynamic interaction between clopidogrel (loading dose 300 mg and maintenance dose 75 mg / day) and omeprazole (80 mg / d. leads to a decrease in the exposure of the active metabolite of clopidogrel by an average of 46% and a decrease in the maximum inhibition of ADP-induced platelet aggregation by an average of 16%. Therefore, simultaneous use of omeprazole and clopidogrel should be avoided (see section "Interaction with other drugs and other forms of drug interactions").

Separate observational studies indicate that proton pump inhibitor therapy may slightly increase the risk of osteoporosis-related fractures, but other similar studies have not shown an increased risk.

In randomized, double-blind, controlled clinical trials of omeprazole and esomeprazole, including two open trials with a duration of therapy of more than 12 years, the connection of fractures against osteoporosis with proton pump inhibitors was not confirmed.

Although the causal relationship between the use of omeprazole / esomeprazole with fractures against osteoporosis is not established, patients with a risk of developing osteoporosis or fractures against it should be under appropriate clinical supervision.

Effect on the ability to drive transp. cf. and fur:

Losek® does not affect the ability to drive vehicles and work with machinery.

Because dizziness and drowsiness may occur during Losek® therapy, care should be taken when driving vehicles and other mechanisms.

Form release / dosage:

Liofilizate for the preparation of a solution for infusions 40 mg.

Packaging:For 40 mg of active substance omeprazole in a glass bottle with a rubber stopper and an aluminum crimping ring and a plastic lid. 5 bottles in a plastic contour cell are placed in a cardboard box with instructions for use.

Storage conditions:

At temperatures below 25 ° C in the original packaging, protected from light. Keep out of the reach of children.

The vial without a cardboard package should be stored in a dark place with room lighting for a maximum of 24 hours.

Prepared solution: Infusion should be performed within 12 hours if physiological saline was used and for 6 hours if a solution of 5% dextrose was used.

Special precautions for storage

Lyophilizate for the preparation of solution for infusion should be dissolved in 100 ml infusion saline or in 100 ml of 5% infusion solution dextrose. Infusion should be performed within 12 hours, if physiological saline was used, for 6 hours if a solution of 5% dextrose was used.

Solutions are prepared with room lighting without special precautions.

Shelf life:

2 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:P N014082 / 01

Date of registration:10.08.2010

Expiration Date:Unlimited

Date of cancellation:2016-03-15

The owner of the registration certificate:AstraZeneca UK LtdAstraZeneca UK Ltd United Kingdom

Manufacturer: & nbsp

ASTRAZENECA, AB Sweden

Representation: & nbspAstraZeneca Pharmaceuticals Ltd.AstraZeneca Pharmaceuticals Ltd.

Information update date: & nbsp20.03.2018

Illustrated instructions

Instructions

Losek® (Losec®)