Adzole-DM

dyspepsia, accompanied by delayed emptying of the stomach, gastro-esophageal reflux, esophagitis (feeling of overflow in the epigastrium, feeling of bloating, pain in the upper abdomen, belching, flatulence, nausea, vomiting, heartburn with or without throwing stomach contents into the oral cavity),

gastroesophageal reflux disease,

nausea, vomiting, heartburn associated with gastroesophageal reflux disease, gastritis, gastric ulcer and duodenal ulcer, including after eradication therapy.

Treatment of dyspepsia and gastro-esophageal reflux that do not respond well to monotherapy with proton pump inhibitors or H antagonists₂- receptors.

Inside, on an empty stomach, 20-30 minutes before meals (the contents of the capsule can not be chewed), washed down with a small amount of water.

Omez^® JEM take 1 capsule / day in the morning.

The maximum daily dose is 1 capsule. Omez^® DSR, which corresponds to 20 mg of omeprazole and 30 mg of domperidone.

Special patient groups

Liver function disorders. In case of mild liver function disorders, no dosage adjustment is required.

Impaired renal function. No single dose adjustment is required.

Old age. Correction of the dosage regimen is not required.

Inside, drinking a small amount of water, 1 capsule. 2 times a day, 15-20 minutes before meals.

hypersensitivity to the components of the drug and benzimidazole,

prolactin-secreting pituitary tumor (prolactinoma),

lactose intolerance, lactase deficiency, glucose-galactose malabsorption,

sucrose/isomaltase deficiency, fructose intolerance,

concomitant administration of erlotinib, posaconazole, nelfinavir, atazanavir, oral forms of ketoconazole, erythromycin, or other CYP3A4 inhibitors that cause QT prolongation, such as fluconazole, voriconazole, clarithromycin, amiodarone, and telithromycin (see " Interaction»),

gastrointestinal bleeding, mechanical obstruction, or perforation, i.e. when stimulation of the gastrointestinal motility can be dangerous,

moderate to severe hepatic insufficiency,

pregnancy,

breastfeeding period,

children under 18 years of age.

With caution: the presence of a stomach ulcer (or suspected stomach ulcer), previous surgery on the gastrointestinal tract, the presence of alarming symptoms: significant spontaneous weight loss, repeated vomiting, vomiting with blood, fecal discoloration (tar — like stools-melena), swallowing disorders, the appearance of new symptoms or changes in existing symptoms from the gastrointestinal tract, the presence of severe electrolyte disorders or heart diseases, such as heart failure, osteoporosis, kidney failure.

hypersensitivity,

gastrointestinal bleeding,

mechanical obstruction of the gastrointestinal tract,

perforation of the stomach or intestines,

prolactin-secreting pituitary tumor (prolactinoma),

lactation period,

children's age.

With caution: kidney and / or liver failure, pregnancy.

Possible side effects are listed below by body system and frequency of occurrence for omeprazole and domperidone: very common (≥1/10), common (≥1/100, <1/10), infrequent (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000, including isolated cases and the frequency is not known).

Domperidone

On the part of the immune system: very rarely — anaphylactic reaction/anaphylactic shock, angioedema.

Mental disorders: very rarely-agitation, nervousness, increased excitability and irritability.

From the nervous system very rarely-extrapyramidal phenomena, convulsions, drowsiness, headache.

From the CCC side: very rarely-prolongation of the QT interval, ventricular tachycardia of the "pirouette" type, sudden coronary death (more likely for patients over 60 years of age taking more than 30 mg/day).

From the skin and subcutaneous tissues: very rarely-Quincke's edema, urticaria.

From the kidneys and urinary tract: very rarely-urinary retention.

Laboratory and instrumental data: very rarely-changes in the indicators of functional tests of the liver, an increase in the level of blood prolactin.

If you experience side effects that are not listed in this description, you should immediately inform your doctor.

Omeprazole

From the blood and lymphatic system: rarely-leukopenia, thrombocytopenia, very rarely-agranulocytosis, pancytopenia, eosinophilia.

On the part of the immune system: rarely-hypersensitivity reactions: fever, angioedema, anaphylactic reaction/anaphylactic shock.

From the side of metabolism and nutrition: rarely-hyponatremia, the frequency is unknown-hypomagnesemia, which in severe cases can lead to hypocalcemia, hypokalemia.

Mental disorders: infrequently-insomnia, rarely-increased excitability, depression, reversible confusion, very rarely-aggression, hallucinations.

From the nervous system: often-headache, infrequently-dizziness, paresthesia, drowsiness, rarely-taste disorders.

On the part of the visual organ: infrequently-visual disturbances, including a decrease in the visual fields, a decrease in the acuity and clarity of visual perception (usually pass after discontinuation of therapy).

On the part of the organ of hearing and labyrinth disorders: infrequently-disorders of auditory perception, including ringing in the ears (usually pass after the termination of therapy), vertigo (feeling of rotation of one's own body or surrounding objects).

From the respiratory system, chest and mediastinal organs: rarely-bronchospasm.

From the gastrointestinal tract: often — abdominal pain, constipation, diarrhea, flatulence, nausea, vomiting, rarely — dryness of the oral mucosa, stomatitis, gastrointestinal candidiasis, microscopic colitis, discoloration of the tongue to brown-black and the appearance of benign cysts of the salivary glands when used simultaneously with clarithromycin (phenomena are reversible after discontinuation of therapy), isolated cases — the formation of gastric glandular cysts during long-term treatment when used simultaneously with clarithromycin (a consequence of inhibition of the secretion of hydrochloric acid, is benign, reversible).

From the liver and biliary tract: infrequently-increased activity of liver enzymes and alkaline phosphatase (reversible), rarely-hepatitis (with or without jaundice), liver failure, encephalopathy in patients with previous severe liver diseases.

From the skin and subcutaneous tissues: infrequently-dermatitis, pruritus, skin rash, urticaria, rarely-alopecia, photosensitivity reactions in the form of redness of the skin after UV radiation, multiform exudative erythema, toxic epidermal necrolysis, Stevens-Johnson syndrome (severe erythema, characterized by the appearance of spots and blisters on the skin and mucous membranes against a background of high temperature and joint pain).

From the musculoskeletal system and connective tissue: infrequently - fractures of the vertebrae, wrist bones, femoral head associated with osteoporosis, rarely-arthralgia, myalgia, muscle weakness.

From the kidneys and urinary tract: rarely-interstitial nephritis.

From the genitals and breast: rarely-gynecomastia.

General disorders: infrequently-malaise, rarely-increased sweating, peripheral edema.

Domperidone

From the digestive system: transient spasms of the intestine.

From the nervous system: extrapyramidal disorders (in children and individuals with increased BBB permeability).

Allergic reactions: skin rash, urticaria.

Other: hyperprolactinemia (galactorrhea, gynecomastia).

Omeprazole

On the part of the digestive system: diarrhea or constipation, nausea, vomiting, flatulence, abdominal pain, dry mouth, taste disorders, stomatitis, transient increase in the activity of liver enzymes in plasma, in patients with previous severe liver disease — hepatitis (including jaundice), impaired liver function.

From the nervous system: headache, dizziness, agitation, drowsiness, insomnia, paresthesia, depression, hallucinations, in patients with severe concomitant somatic diseases, patients with previous severe liver disease-encephalopathy.

From the musculoskeletal system: muscle weakness, myalgia, arthralgia.

From the hematopoietic system: leukopenia, thrombocytopenia, in some cases — agranulocytosis, pancytopenia.

From the skin: itching, skin rash, in some cases — photosensitization, multiform exudative erythema, alopecia.

Allergic reactions: urticaria, angioedema, bronchospasm, interstitial nephritis, anaphylactic shock, fever.

Other: visual impairment, peripheral edema, increased sweating, gynecomastia, rarely-the formation of gastric glandular cysts during long-term treatment (a consequence of inhibition of hydrochloric acid secretion, is benign, reversible).

Symptoms: dizziness, confusion, apathy, drowsiness, headache, visual impairment, vascular dilatation, tachycardia, nausea, vomiting, flatulence, diarrhea, increased sweating, dry mouth. With an increase in the dose, the elimination rate of the drug did not change.

Treatment: administration of activated charcoal inside, gastric lavage, if necessary — symptomatic therapy and careful monitoring. Anticholinergics, drugs used to treat parkinsonism, or antihistamines may be effective in the occurrence of extrapyramidal reactions. Hemodialysis is not effective enough.

Domperidone

Symptoms: drowsiness, disorientation, and extrapyramidal reactions.

Treatment: reception of activated charcoal, in the event of extrapyramidal reactions-anticholinergic, antiparkinsonian, antihistamines.

Omeprazole

Symptoms: visual impairment, drowsiness, agitation, confusion, headache, increased sweating, dry mouth, nausea, arrhythmia.

Treatment: symptomatic. There is no specific antidote. Hemodialysis is not effective enough.

The combination of two active substances (domperidone and omeprazole) has a complex effect on the main components of the pathogenesis of GERD, dyspeptic disorders of various origins. Domperidone enhances and synchronizes physiological peristaltic waves, omeprazole reduces basal and stimulated hydrochloric acid secretion.

Domperidone

A dopamine antagonist, combines peripheral (gastrokinetic) action and antagonism to dopamine receptors in the trigger zone of the brain (central action), thanks to which it has an antiemetic effect, stimulates the release of prolactin from the pituitary gland and eliminates the inhibitory effect of dopamine on the motor function of the gastrointestinal tract, enhances and synchronizes peristaltic waves, thereby accelerates the natural emptying of the stomach and increases the pressure of the lower esophageal sphincter.

Omeprazole

The mechanism of action. Omeprazole is concentrated in the acidic environment of the secretory tubules of the parietal cells of the gastric mucosa, activates and inhibits the proton pump-the enzyme H /K - ATPASE, which provides a dose-dependent, highly effective inhibition of basal and stimulated hydrochloric acid secretion, regardless of the stimulating factor.

Effect on the acidity of the stomach. The maximum effect is achieved within 4 days of treatment. In patients with duodenal ulcer, omeprazole at a dose of 20 mg causes a steady decrease in 24-hour gastric acidity by at least 80%. At the same time, a decrease in the average C is achieved_max hydrochloric acid after stimulation with pentagastrin by 70% for 24 hours. In patients with duodenal ulcer, omeprazole at a dose of 20 mg with daily oral administration maintains an intragastric pH value of≥3 for an average of 17 h / day. The inhibition of hydrochloric acid secretion depends on the AUC of omeprazole, and not on the concentration of the drug in the plasma at a given time.

Action on Helicobacter pylori. Eradication Helicobacter pylori when using omeprazole together with antibacterial agents, it is accompanied by rapid elimination of symptoms, a high degree of healing of defects in the gastrointestinal mucosa and a long-term remission of peptic ulcer disease, which reduces the likelihood of complications such as bleeding as effectively as constant maintenance therapy.

Other effects. A decrease in the secretion of hydrochloric acid in the stomach leads to a slight increase in the risk of intestinal infections caused by Salmonella spp., Campylobacter spp. and Clostridium difficile. During treatment with drugs that reduce the secretion of gastric glands, the concentration of gastrin in the blood serum increases. Due to a decrease in the secretion of hydrochloric acid, the concentration of chromogranin A (CgA) increases (see "Special instructions").

Domperidone. Increases the duration of peristaltic contractions of the antrum and duodenum, accelerates gastric emptying in case of delay in this process, increases the tone of the lower esophageal sphincter, prevents nausea and vomiting. Stimulates the release of prolactin from the pituitary gland. The antiemetic effect may be due to a combination of peripheral (gastrokinetic) action and antagonism to dopamine receptors in the trigger zone of the brain. Domperidone has no effect on gastric secretion. Poorly penetrates through the BBB, so the use of domperidone is rarely accompanied by the development of extrapyramidal side effects, especially in adults

Omeprazole. It inhibits the enzyme H-K-ATPase (proton pump) in the parietal cells of the stomach and thus blocks the final stage of hydrochloric acid synthesis. This leads to a decrease in the level of basal and stimulated secretion, regardless of the nature of the stimulus. After a single oral administration of the drug, the effect of omeprazole occurs within 1 hour and continues for 24 hours, the maximum effect is achieved after 2 hours. After stopping the drug, secretory activity is completely restored after 3-5 days.

Ffarmacodinamica rationale of the combination. Omeprazole suppresses the secretion of hydrochloric acid, domperidone increases the tone of the lower esophageal sphincter and accelerates gastric emptying, thereby reducing the activity of aggressive factors of gastric juice and throwing gastric contents into the esophagus.

Domperidone

This dosage form provides a delayed release of the active substance. In tests of dissolution in an acidic medium, after 8 hours, from 75 to 83% of the nominal domperidone content in 1 capsule is determined, and after 12 hours - from 86 to 94%.

Absorption on an empty stomach fast. T_max - 30-60 min. Low bioavailability (15%) is associated with first-pass metabolism in the intestinal wall and liver.

Distribution. The binding to plasma proteins is 90%. Penetrates into various tissues, passes poorly through the BBB.

It is metabolized in the liver (including due to the first-pass effect) and the intestinal wall (by hydroxylation and N-disalkylation) with the participation of the isoenzymes CYP3A4, CYP1A2 and CYP2E1.

Output. 66% - through the intestine (unchanged — 10%), by the kidneys-33% (unchanged - 1%) in the form of glucuronides.

With pronounced CRF T_1/2 lengthens.

Omeprazole

High absorption of omeprazole, T_max it is 0.5-1 h. Bioavailability-30-40%, after constant intake once a day increases to 60%.

Distribution. Binding to plasma proteins-90-95%. V_d - 0.3 l / kg —

Metabolism. Part of omeprazole undergoes presystemic hepatic metabolism involving more CYP2C19 than CYP3A4 with the formation of inactive metabolites. Omeprazole, which is not included by the parietal cells in the formation of active metabolites, is completely metabolized in the liver. The total plasma clearance is 0.3–0.6 l/min.

Output. T_1/2 omeprazole is about 40 min. It is excreted by the kidneys (70-80%) and with bile (20-30%). With impaired liver function, the bioavailability of omeprazole increases and the plasma clearance of omeprazole decreases.

With impaired renal function or in elderly patients, there were no changes in the bioavailability of omeprazole.

Domperidone

Suction. After oral administration, domperidone is rapidly absorbed. It has a low bioavailability (about 15%). The reduced acidity of the gastric contents reduces the absorption of domperidone. Tmax in plasma — 1 h.

Distribution. Domperidone is widely distributed in various tissues, and its concentration is low in brain tissues. The binding to plasma proteins is 91-93%.

Metabolism. It undergoes intensive metabolism in the intestinal wall and liver.

Output. It is excreted through the intestine (66%) and kidneys (33%), in unchanged form, 10 and 1% of the dose is excreted, respectively. T_1/2 it is 7-9 hours, with severe renal insufficiency — it is prolonged.

Omeprazole

Omeprazole is rapidly absorbed from the gastrointestinal tract, T_max in plasma-0.5-1 h. Bioavailability is 30-40%. Binding to plasma proteins is about 90%. Omeprazole is almost completely metabolized in the liver. It is an inhibitor of the CYP2C19. T enzyme system_1/2 - 0.5-1 h. It is excreted by the kidneys (70-80%) and with bile (20-30%). In chronic renal failure, the excretion decreases in proportion to the decrease in creatinine clearance. In elderly patients, the excretion decreases, the bioavailability increases. In hepatic insufficiency, the bioavailability is 100%, T_1/2 — 3 hours.

Special studies of drug interactions of the drug Omez^® DSR with other drugs was not performed. For individual drugs, the following drug interactions were noted.

Substances with pH-dependent absorption

Like other drugs that reduce the acidity of gastric juice, treatment with omeprazole can lead to a decrease in the absorption of ketoconazole, itraconazole, posaconazole, erlotinib, iron preparations and cyanocobalamin. It is necessary to avoid their joint administration with the drug Omez^® JEM.

Antacid and antisecretory drugs

Cimetidine and sodium bicarbonate reduce the oral availability of domperidone.

Digoxin

The bioavailability of digoxin when co-administered with omeprazole increases by 10%. Caution should be exercised when using digoxin and Omez simultaneously^® JEM in elderly patients. The combined intake of domperidone and digoxin does not change the concentration of the latter.

Clopidogrel

According to the results of studies, there was an interaction between clopidogrel (loading dose of 300 mg, maintenance dose of 75 mg/day) and omeprazole (80 mg / day orally), which reduces the exposure of the active metabolite of clopidogrel and reduces the inhibition of platelet aggregation. Therefore, concomitant use of clopidogrel and omeprazole at a dose of 80 mg / day should be avoided.

Antiretroviral drugs

An increase in the pH value during omeprazole therapy may affect the absorption of antiretroviral drugs. Interaction at the level of the CYP2C19 isoenzyme is also possible. In this regard, the joint use of the drug Omez^® JEM with antiretroviral drugs such as atazanavir and nelfinavir is contraindicated. When used concomitantly with omeprazole, there is an increase in the plasma concentration of saquinavir/ritonavir to 70%, while the tolerability of treatment in patients with HIV infection does not worsen.

The overwhelming effect of HIV protease inhibitors on the CYP3A4 isoenzyme may cause an increase in the concentration of domperidone when they are co-administered with Omez^® JEM.

Tacrolimus

With the simultaneous use of omeprazole and tacrolimus, an increase in the concentration of tacrolimus in the blood serum was noted. It is necessary to monitor the Cl of creatinine and the concentration of tacrolimus in the blood plasma when it is used together with the drug Omez^® JEM.

Methotrexate

Proton pump inhibitors may slightly increase the concentration of methotrexate in the blood plasma. When treating high doses of methotrexate, you should temporarily stop taking the drug Omez^® JEM.

Drugs that are metabolized by the CYP2C19 isoenzyme

With simultaneous use with omeprazole, it is possible to increase the plasma concentration and increase the T_1/2 warfarin (R-warfarin), diazepam, phenytoin, cilostazole, imipramine, clomipramine, citalopram, hexobarbital, disulfiram, as well as other drugs that are metabolized in the liver with the participation of the CYP2C19 isoenzyme (it may be necessary to reduce the doses of these drugs). However, taking omeprazole 20 mg / day does not affect the concentration of phenytoin in the blood plasma in patients taking phenytoin for a long time. When using omeprazole in patients receiving warfarin or other vitamin K antagonists, monitoring of INR is necessary. At the same time, concomitant treatment with omeprazole at a daily dose of 20 mg does not lead to a change in the coagulation time in patients taking warfarin for a long time

Inhibitors of the CYP2C19 and/or CYP3A4 enzymes

Concomitant use with inhibitors of the CYP2C19 and/or CYP3A4 isoenzymes slows down the metabolism of omeprazole.

When omeprazole or domperidone is co-administered with clarithromycin or erythromycin, the concentration of omeprazole, as well as the concentration of domperidone in the blood plasma, increases.

The combined use of voriconazole and omeprazole leads to an increase in the AUC of omeprazole. Fluconazole, itraconazole, ketoconazole, and voriconazole also increase the plasma concentration of domperidone.

The overwhelming effect of HIV protease inhibitors on the CYP3A4 isoenzyme may cause an increase in the concentration of domperidone when they are co-administered with Omez^® JEM.

Clinical experience and research in vitro It is shown that it is possible to increase the concentration of domperidone in plasma with the combined use of such strong CYP3A4 inhibitors as calcium antagonists (diltiazem and verapamil), nefadozone and amiodarone.

In addition, when taking amiodarone, or when taking domperidone with ketoconazole, erythromycin may prolong the QT interval (see "Special instructions").

Inducers of the CYP2C19 and CYP3A4 enzymes

Inducers of CYP2C19 and CYP3A4 isoenzymes, such as rifampicin, preparations of St. John's wort (Hypericum perforatum), 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.

Anticholinergic drugs

Anticholinergic drugs can neutralize the effect of domperidone.

No effect on metabolism

Co-administration of omeprazole with amoxicillin or metronidazole does not affect the concentration of omeprazole in the blood plasma.

There was no clinically significant interaction of omeprazole with metoprolol, phenacetin, estradiol, budesonide, diclofenac, naproxen, piroxicam, S-warfarin.

No effect of omeprazole on antacids, theophylline, caffeine, quinidine, lidocaine, propranolol, and ethanol was found.

The use of domperidone against the background of taking paracetamol or digoxin did not affect the level of these drugs in the blood.

Domperidone is compatible with taking antipsychotic drugs( neuroleptics), dopaminergic receptor agonists (bromocriptine, L-dopa), because it inhibits their undesirable peripheral effects (nausea and vomiting) and does not affect their central effects.

Domperidone

Cimetidine, sodium bicarbonate, and other antacid and antisecretory drugs reduce the bioavailability of domperidone.

Anticholinergic agents neutralize the effect of domperidone.

Increase the concentration of domperidone in plasma: antifungal agents of the azole series, antibiotics from the group of macrolides, HIV protease inhibitors, nefazodone.

Omeprazole

It can reduce the absorption of esters, ampicillin, iron salts, itraconazole and ketoconazole (omeprazole increases the pH of the stomach). As an inhibitor of cytochrome P450, it can increase the concentration and reduce the excretion of diazepam, indirect anticoagulants, phenytoin (drugs that are metabolized in the liver by cytochrome CYP2C19), which in some cases may require a reduction in their doses. Increases the inhibitory effect on the hematopoietic system of other drugs.