Omez^® DSR (Capsules) Instructions for Use

Marketing Authorization Holder

Dr. Reddy’s Laboratories Ltd. (India)

Contact Information

Dr. Reddy’s Laboratories Ltd. (India)

ATC Code

A02BX (Other drugs for the treatment of gastric and duodenal ulcers and GERD)

Active Substances

Omeprazole (Rec.INN registered by WHO)

Domperidone (Rec.INN registered by WHO)

Dosage Form

Omez® DSR

Modified-release capsules 30 mg+20 mg: 10, 30, 80, or 100 pcs.

Dosage Form, Packaging, and Composition

Modified-release capsules hard gelatin, size No. 1, transparent, colorless, with black marking on the capsule cap and red marking “OMEZ-DSR” on the capsule body; the capsule contents are spherical pellets ranging from white to grayish-white and from brown to yellowish-brown in color.

Excipients: talc.

* Excipients (in the enteric-coated pellets) mannitol, lactose monohydrate, sodium lauryl sulfate, sodium phosphate dibasic, sucrose (25/30), sucrose, hypromellose 6 cps; coating hypromellose 6 cps; enteric coating methacrylic acid and ethyl acrylate copolymer [1:1] (methacrylic acid copolymer [type C]), sodium hydroxide, macrogol 6000, talc, titanium dioxide.

** Excipients (in the prolonged-release pellets) sugar spheres nonpareil, colloidal silicon dioxide, talc, hypromellose 5 cps; coating hypromellose 5 cps, talc, iron oxide yellow (E172), iron oxide red (E172), titanium dioxide; prolonged-release coating hypromellose 5 cps, ethylcellulose 10 cps, triacetin, talc.

Composition of sugar spheres nonpareil sucrose, corn starch, povidone K-30, hypromellose.

Composition of hard gelatin capsules No. 1: gelatin, water, sodium lauryl sulfate.

Composition of black ink for printing on the capsule cap anhydrous ethanol***, isopropanol, butanol, shellac, propylene glycol, iron oxide black (E172), purified water.

Composition of red ink for printing on the capsule body anhydrous ethanol***, isopropanol, butanol, shellac, iron oxide red (E172), ammonia solution, polysorbate 80, propylene glycol.

10 pcs. – blisters (1) – carton packs.
10 pcs. – blisters (3) – carton packs.
10 pcs. – blisters (8) – carton packs.
10 pcs. – blisters (10) – carton packs.

*** ethanol is not contained in the finished medicinal product, as it evaporates after the ink is applied.

Clinical-Pharmacological Group

Combined drug that regulates the motor function of the gastrointestinal tract and inhibits the secretion of hydrochloric acid

Pharmacotherapeutic Group

Drugs for the treatment of diseases associated with acidity disorders; antiulcer drugs and drugs for the treatment of gastroesophageal reflux

Pharmacological Action

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

Omeprazole

Mechanism of action

Omeprazole concentrates in the acidic environment of the secretory tubules of the parietal cells of the gastric mucosa, is activated, and inhibits the proton pump – the enzyme H⁺/K⁺-ATPase, which provides dose-dependent, highly effective inhibition of basal and stimulated secretion of hydrochloric acid, regardless of the stimulating factor.

Effect on gastric acidity

The maximum effect is achieved within 4 days of treatment. In patients with duodenal ulcer, Omeprazole at a dose of 20 mg causes a sustained reduction in 24-hour gastric acidity by at least 80%. This achieves a reduction in the mean maximum concentration of hydrochloric acid after pentagastrin stimulation by 70% over 24 hours. In patients with duodenal ulcer, Omeprazole 20 mg, when taken orally daily, maintains an intragastric environment acidity level of pH ≥3 for an average of 17 hours per day. Inhibition of hydrochloric acid secretion depends on the AUC of omeprazole, not on the plasma concentration of the drug at a given time.

Effect on Helicobacter pylori

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

Other effects

Reduced secretion of hydrochloric acid in the stomach leads to a slight increase in the risk of developing intestinal infections caused by Salmonella spp., Campylobacter spp. and Clostridium difficile. During treatment with drugs that reduce gastric secretion, the concentration of gastrin in the blood serum increases. Due to the decrease in hydrochloric acid secretion, the concentration of chromogranin A increases.

Domperidone

A dopamine antagonist, it combines peripheral (gastrokinetic) action and antagonism to dopamine receptors in the brain’s trigger zone (central action), due 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 accelerating natural gastric emptying and increasing the pressure of the lower esophageal sphincter.

Pharmacokinetics

Omeprazole

Absorption

Absorption of omeprazole is high, the time to reach maximum plasma concentration (T_max) is 0.5-1 h. Bioavailability is 30-40%, after continuous use once daily it increases to 60%.

Distribution

Plasma protein binding is 90-95%. V_d is 0.3 L/kg.

Metabolism

Part of omeprazole undergoes presystemic hepatic metabolism involving CYP2C19 to a greater extent than CYP3A4, forming inactive metabolites. Omeprazole not incorporated by parietal cells into the formation of active metabolites is completely metabolized in the liver. Total plasma clearance is 0.3-0.6 L/min.

Elimination

The T_1/2 of omeprazole is about 40 min. It is excreted by the kidneys (70-80%) and with bile (20-30%).

Pharmacokinetics in special clinical situations

In case of impaired liver function, the bioavailability of omeprazole increases and plasma clearance decreases.

In case of impaired renal function or in elderly patients, no changes in the bioavailability of omeprazole were noted.

Domperidone

This dosage form provides slow release of the active substance. In dissolution tests in an acidic environment, 75% to 83% of the nominal domperidone content in one capsule is determined after 8 hours, and 86% to 94% after 12 hours.

Absorption

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

Distribution

Plasma protein binding is 90%. It penetrates into various tissues and poorly passes through the blood-brain barrier.

Metabolism

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

Elimination

66% is excreted through the intestines (unchanged – 10%), by the kidneys – 33% (unchanged 1%) in the form of glucuronides.

Pharmacokinetics in special clinical situations

In severe chronic renal failure, T_1/2 is prolonged.

Indications

• Dyspepsia accompanied by delayed gastric emptying, gastroesophageal reflux, esophagitis (feeling of fullness in the epigastrium, feeling of bloating, pain in the upper abdomen; belching, flatulence; nausea, vomiting; heartburn with or without regurgitation of gastric contents into the oral cavity);
• Gastroesophageal reflux disease;
• Nausea, vomiting, heartburn associated with gastroesophageal reflux disease, gastritis, gastric and duodenal ulcers, including after eradication therapy.

ICD codes

Dosage Regimen

The drug is taken orally on an empty stomach, 20-30 minutes before meals (the capsule contents should not be chewed), with a small amount of water.

The recommended dose is 1 capsule once daily in the morning.

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

In mild hepatic impairment, no dose adjustment is required.

No adjustment of the single dose is required in renal impairment.

In elderly patients, no dose adjustment is required.

Adverse Reactions

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); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000, including isolated cases and frequency unknown).

Omeprazole

Blood and lymphatic system disorders rare – leukopenia, thrombocytopenia; very rare – agranulocytosis, pancytopenia, eosinophilia.

Immune system disorders: rare – hypersensitivity reactions (fever, angioedema, anaphylactic reaction/anaphylactic shock).

Metabolism and nutrition disorders rare – hyponatremia; frequency unknown – hypomagnesemia, which in severe cases can lead to hypocalcemia, hypokalemia.

Psychiatric disorders uncommon – insomnia; rare – increased excitability, depression, reversible confusion; very rare – aggression, hallucinations.

Nervous system disorders common – headache; uncommon – dizziness, paresthesia, somnolence; rare – taste disturbance.

Eye disorders uncommon – visual disturbances, including visual field defects, decreased visual acuity and clarity (usually resolve after discontinuation of therapy).

Ear and labyrinth disorders uncommon – hearing disturbances, including “tinnitus” (usually resolve after discontinuation of therapy), vertigo (sensation of spinning of one’s own body or surrounding objects).

Respiratory, thoracic and mediastinal disorders rare – bronchospasm.

Gastrointestinal disorders common – abdominal pain, constipation, diarrhea, flatulence, nausea, vomiting; rare – dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis, brownish-black discoloration of the tongue and appearance of benign salivary gland cysts with simultaneous use of clarithromycin (phenomena are reversible after discontinuation of therapy); isolated cases – formation of gastric glandular cysts during long-term treatment with simultaneous use of clarithromycin (a consequence of inhibition of hydrochloric acid secretion, benign, reversible in nature).

Hepatobiliary disorders uncommon – increased activity of liver enzymes and alkaline phosphatase (reversible); rare – hepatitis (with or without jaundice), liver failure, encephalopathy in patients with pre-existing severe liver disease.

Skin and subcutaneous tissue disorders uncommon – dermatitis, pruritus, skin rash, urticaria; rare – alopecia, photosensitivity reactions in the form of skin redness after UV exposure, erythema multiforme, 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 fever and joint pain).

Musculoskeletal and connective tissue disorders uncommon – fractures of vertebrae, wrist bones, femoral head associated with osteoporosis; rare – arthralgia, myalgia, muscle weakness.

Renal and urinary disorders: rare – interstitial nephritis.

Reproductive system and breast disorders rare – gynecomastia.

General disorders and administration site conditions uncommon – malaise; rare – increased sweating, peripheral edema.

Domperidone

Immune system disorders: very rare – anaphylactic reaction/anaphylactic shock, angioedema.

Psychiatric disorders very rare – agitation, nervousness, increased excitability and irritability.

Nervous system disorders very rare – extrapyramidal phenomena, convulsions, somnolence, headache.

Cardiac disorders very rare – QT interval prolongation, torsades de pointes ventricular tachycardia, sudden coronary death (more likely for patients over 60 years of age taking more than 30 mg/day).

Skin and subcutaneous tissue disorders very rare – angioedema, urticaria.

Renal and urinary disorders very rare – urinary retention.

Investigations very rare – changes in liver function tests, increased blood prolactin levels.

If side effects not listed in this leaflet occur, the patient should immediately inform the doctor.

Contraindications

• Hypersensitivity to the components of the drug and benzimidazoles;
• Prolactin-secreting pituitary tumor (prolactinoma);
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• Sucrase/isomaltase deficiency, fructose intolerance;
• Concomitant use of erlotinib, posaconazole, nelfinavir, atazanavir, oral forms of ketoconazole, erythromycin or other CYP3A4 inhibitors that cause QT interval prolongation, such as fluconazole, voriconazole, clarithromycin, amiodarone and telithromycin;
• Gastrointestinal bleeding, mechanical obstruction or perforation, i.e., when stimulation of gastrointestinal motility may be dangerous;
• Moderate and severe hepatic impairment;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years.

With caution

• In the presence of gastric ulcer (or suspicion of gastric ulcer), previous gastrointestinal surgery;
• In the presence of “alarm” symptoms: significant spontaneous weight loss, recurrent vomiting, vomiting with blood, change in stool color (tarry stools – melena), swallowing disorder;
• With the appearance of new symptoms or changes in existing gastrointestinal symptoms;
• In the presence of severe electrolyte disturbances or heart disease, such as heart failure);
• With osteoporosis;
• With renal failure.

Use in Pregnancy and Lactation

The use of the drug Omez^® DSR during pregnancy and breastfeeding is contraindicated.

Use in Hepatic Impairment

Contraindicated in moderate and severe hepatic impairment.

In mild hepatic impairment, no dose adjustment is required.

Use in Renal Impairment

The drug should be prescribed with caution in renal failure.

Pediatric Use

Contraindicated for use under 18 years of age.

Geriatric Use

In elderly patients, no dose adjustment is required.

Special Precautions

Lactose

The omeprazole pellets contain lactose, therefore Omez^® DSR should not be used in patients with lactose intolerance, galactosemia, and glucose and galactose malabsorption.

Cardiovascular system

The use of domperidone has been shown to be associated with an increased risk of ventricular arrhythmias or sudden coronary death, which is more likely for patients over 60 years of age at a daily domperidone dose of more than 30 mg. The use of domperidone and other drugs that lead to QT interval prolongation requires caution in patients with existing conduction disorders with QT prolongation, severe electrolyte imbalance, or congestive heart failure.

Osteoporosis

Patients at risk of developing osteoporosis or osteoporosis-related fractures should be under appropriate clinical supervision, although a causal relationship between omeprazole use and osteoporosis-related fractures has not been established.

Hypomagnesemia

There have been reports of severe hypomagnesemia in patients receiving proton pump inhibitor therapy, including omeprazole, for more than one year. Patients receiving long-term therapy with omeprazole, especially in combination with digoxin or other drugs that reduce plasma magnesium levels (diuretics), require regular monitoring of magnesium levels.

Effect on Laboratory Tests

An increase in chromogranin A (CgA) concentration due to reduced gastric acid secretion may affect the results of examinations for neuroendocrine tumors. To prevent this influence, proton pump inhibitor therapy should be discontinued 5 days before testing the CgA concentration.

Effect on Ability to Drive and Operate Machinery

Caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions while being treated with Omez^® DSR.

Overdose

Symptoms dizziness, confusion, apathy, drowsiness, headache, visual disturbance, vasodilation, tachycardia, nausea, vomiting, flatulence, diarrhea, increased sweating, dry mouth. When the dose was increased, the elimination rate of the drug did not change.

Treatment activated charcoal orally, gastric lavage; if necessary – symptomatic therapy and careful observation. Anticholinergic agents, drugs used to treat parkinsonism, or antihistamines may be effective if extrapyramidal reactions occur. Hemodialysis is not sufficiently effective.

Drug Interactions

No specific drug interaction studies of Omez^® DSR with other drugs have been conducted. For certain drugs, the following drug interactions have been noted.

Substances with pH-dependent absorption

Like other drugs that reduce gastric acidity, treatment with omeprazole may lead to reduced absorption of ketoconazole, itraconazole, posaconazole, erlotinib, iron preparations, and cyanocobalamin. Their concomitant use with Omez^® DSR should be avoided.

Antacid and Antisecretory Drugs

Cimetidine and sodium bicarbonate reduce the oral availability of domperidone.

Digoxin

The bioavailability of digoxin increases by 10% when used concomitantly with omeprazole. Caution should be exercised when using digoxin and Omez^® DSR concomitantly in elderly patients. Concomitant use of domperidone and digoxin does not alter the concentration of the latter.

Clopidogrel

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

Antiretroviral Drugs

An increase in pH 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 concomitant use of Omez^® DSR with antiretroviral drugs such as atazanavir and nelfinavir is contraindicated.

Concomitant use with omeprazole increases the plasma concentration of saquinavir/ritonavir by up to 70%, with no worsening of treatment tolerability in HIV-infected patients.

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

Tacrolimus

Concomitant use of omeprazole and tacrolimus has been noted to increase serum tacrolimus concentration. Creatinine clearance and plasma tacrolimus concentration should be monitored when used concomitantly with Omez^® DSR.

Methotrexate

Proton pump inhibitors may slightly increase the plasma concentration of methotrexate. When treating with high doses of methotrexate, Omez^® DSR should be temporarily discontinued.

Drugs metabolized by the CYP2C19 isoenzyme

Concomitant use with omeprazole may increase plasma concentration and prolong T_1/2 of warfarin (R-warfarin), diazepam, phenytoin, cilostazol, imipramine, clomipramine, citalopram, hexobarbital, disulfiram, and other drugs metabolized in the liver by the CYP2C19 isoenzyme (dose reduction of these drugs may be required). However, taking omeprazole 20 mg/day does not affect plasma phenytoin concentration in patients on long-term phenytoin. Monitoring of INR is required in patients taking warfarin or other vitamin K antagonists when using omeprazole. At the same time, concomitant treatment with omeprazole at a daily dose of 20 mg does not lead to a change in coagulation time in patients on long-term warfarin.

Inhibitors of CYP2C19 and/or CYP3A4 enzymes

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

When omeprazole or domperidone is taken concomitantly with clarithromycin or erythromycin, the plasma concentration of omeprazole, as well as domperidone, increases.

Concomitant 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 inhibitory effect of HIV protease inhibitors on the CYP3A4 isoenzyme may cause an increase in domperidone concentration when co-administered with Omez^® DSR.

Clinical experience and in vitro studies indicate that an increase in domperidone plasma concentration is possible when co-administered with such strong CYP3A4 inhibitors as calcium antagonists (diltiazem and verapamil), nefazodone, and amiodarone.

Furthermore, when taking amiodarone, or when domperidone is taken concomitantly with ketoconazole or erythromycin, the QT interval may be prolonged.

Inducers of CYP2C19 and CYP3A4 enzymes

Inducers of CYP2C19 and CYP3A4 isoenzymes, such as rifampicin and St. John’s wort (Hypericum perforatum) preparations, when used concomitantly with omeprazole, may lead to a decrease in omeprazole plasma concentration due to accelerated metabolism of omeprazole.

Anticholinergic Drugs

Anticholinergic drugs may neutralize the effect of domperidone.

No effect on metabolism

Concomitant use of omeprazole with amoxicillin or metronidazole does not affect the plasma concentration of omeprazole.

No clinically significant interaction of omeprazole with metoprolol, phenacetin, estradiol, budesonide, diclofenac, naproxen, piroxicam, S-warfarin has been established.

No effect of omeprazole on antacids, theophylline, caffeine, quinidine, lidocaine, propranolol, ethanol has been identified.

The use of domperidone during paracetamol or digoxin intake did not affect the blood levels of these drugs.

Domperidone is compatible with the use of antipsychotic drugs (neuroleptics), dopamine receptor agonists (bromocriptine, L-dopa), as it suppresses their undesirable peripheral effects (nausea and vomiting) and does not affect their central effects.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years. Do not use after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.