Omez d

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OMEZ D® (OMEZ D)

Composition:

Active substances: omeprazole and domperidone;

1 capsule contains: omeprazole 10 mg, domperidone 10 mg;

Excipients: microcrystalline cellulose, sodium starch glycolate (type A); colloidal anhydrous silicon dioxide; mannitol (E 421); sucrose; disodium hydrogen phosphate; sodium lauryl sulfate; magnesium stearate; talc; lactose monohydrate; calcium carbonate; hypromellose; propylene glycol; methacrylic acid copolymer (type C); polysorbates, diethyl phthalate; sodium hydroxide, cetyl alcohol, corn starch.

Pharmaceutical form. Hard capsules.

Main physicochemical properties: hard gelatin capsules with a cap ranging from blue to violet in color and the inscription OMEZ D in white, and a body from almost white to white with a logo printed in black, containing pellets and powder-like mass from almost white to white in color.

Pharmacotherapeutic group. Drugs for treatment of peptic ulcer and gastroesophageal reflux disease. ATC code A02BC.

Pharmacological Properties.

Pharmacodynamics.

A medicinal product whose action is determined by its constituent components. Omeprazole is an antisecretory antiulcer agent that reduces both spontaneous and stimulated gastric secretion by inhibiting H+/K+-ATPase (the proton pump), which is essential for hydrogen ion transport. It suppresses the final phase of basal and stimulated hydrochloric acid secretion regardless of the nature of the stimulus.

Domperidone is a dopamine receptor antagonist and a prokinetic agent. It practically does not penetrate the blood-brain barrier (BBB). It enhances the propagation of peristaltic contractions in the antral portion of the stomach and duodenum, increases gastric emptying rate, and enhances the tone of the lower esophageal sphincter. It does not interfere with digestive secretion. It exerts antiemetic effects due to both its gastrokinetic action and antagonism at dopamine receptors in the chemoreceptor trigger zone located outside the BBB.

Pharmacokinetics.

Omeprazole.

Omeprazole is rapidly absorbed. Maximum plasma concentration is reached within 1–2 hours after oral administration. Absorption of omeprazole occurs in the small intestine and is usually completed within 3–6 hours. Concomitant food intake does not affect omeprazole bioavailability. Systemic availability (bioavailability) of a single oral dose is approximately 40%. With repeated administration once daily, bioavailability increases to about 60%.

The apparent volume of distribution in healthy volunteers is approximately 0.3 L/kg body weight. Omeprazole is 97% bound to plasma proteins.

Omeprazole is completely metabolized by the cytochrome P450 (CYP) system, primarily via CYP2C19, which is responsible for forming hydroxyomeprazole as the main metabolite of omeprazole in plasma. The omeprazole sulfone metabolite is formed with the involvement of another isoenzyme, CYP3A4. Due to omeprazole's high affinity for CYP2C19, competitive inhibition of the metabolism of other substrates by this isoenzyme is possible. However, omeprazole has low affinity for CYP3A4 and therefore does not inhibit the metabolism of other CYP3A4 substrates. Nevertheless, omeprazole does not inhibit the major enzymes of the cytochrome P450 system. The elimination half-life of omeprazole in plasma, both after single and multiple dosing, is less than 1 hour. Omeprazole is completely eliminated from plasma between doses. With once-daily administration, no tendency toward drug accumulation is observed. Approximately 80% of the administered omeprazole dose is excreted in urine as metabolites. The remainder is excreted in feces via biliary secretion.

With repeated administration, the area under the concentration-time curve (AUC) for omeprazole increases. This increase is dose-dependent, but the relationship is not linear. The time- and dose-dependency results from reduced presystemic metabolism and systemic clearance, likely due to inhibition of CYP2C19 by omeprazole and/or its metabolites (e.g., the sulfone). Omeprazole metabolites do not affect gastric acid secretion.

Domperidone.

After oral administration on an empty stomach, domperidone is rapidly absorbed. Maximum plasma concentration is reached within 30–60 minutes. The low absolute bioavailability of domperidone (approximately 15%) after oral administration is due to extensive presystemic metabolism in the intestinal wall and liver. Although domperidone bioavailability increases in healthy volunteers when taken with food, patients with gastrointestinal complaints should take the drug 15–30 minutes before meals. Reduced gastric acidity impairs domperidone absorption. Bioavailability of the drug after oral administration is decreased by prior intake of cimetidine and sodium bicarbonate. When domperidone is taken after a meal, the time to maximum absorption is slightly delayed, while the area under the concentration-time curve increases.

Orally administered domperidone does not accumulate and does not induce its own metabolism. Maximum plasma concentration 90 minutes after a 30 mg daily dose administered for two weeks is almost the same as after the first dose (21 ng/mL compared to 18 ng/mL). Domperidone is 91–93% bound to plasma proteins.

Domperidone is rapidly and extensively metabolized in the liver via hydroxylation and N-dealkylation.

Approximately 31% and 66% of the orally administered dose are excreted in urine and feces, respectively. A small portion of the drug is excreted unchanged (10% in feces and 1% in urine). The elimination half-life from plasma after a single dose in healthy volunteers is 7–9 hours. This half-life is prolonged in patients with severe renal impairment.

Clinical characteristics.

Indications.

Functional dyspepsia, delayed gastric emptying, gastroparesis, reflux esophagitis, peptic ulcer disease of the stomach and duodenum.

Contraindications.

Hypersensitivity to domperidone, omeprazole, substituted benzimidazoles, or to any component of the drug. Prolactin-secreting pituitary tumor (prolactinoma). Gastrointestinal bleeding, mechanical intestinal obstruction, perforation of the stomach or intestine. Severe or moderate impairment of liver and/or kidney function. Patients with known prolongation of cardiac conduction intervals, particularly QTc, patients with significant electrolyte imbalances or underlying heart diseases such as congestive heart failure (see section "Special precautions"). Hepatic failure.

Concomitant use of ketoconazole, erythromycin, or other potent inhibitors of CYP3A4, and medicinal products that prolong the QT interval (except apomorphine), such as fluconazole, itraconazole, oral ketoconazole, posaconazole, ritonavir, saquinavir, telaprevir, voriconazole, clarithromycin, amiodarone, erythromycin, telithromycin (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction"). Concomitant use with nelfinavir and atazanavir.

Interaction with other medicinal products and other forms of interaction.

Domperidone.

Anticholinergic drugs may neutralize the antidyspeptic effect of domperidone.

Antacids and antisecretory drugs should not be taken simultaneously with domperidone, as they reduce its bioavailability after oral administration.

The main metabolic pathway of domperidone involves the CYP3A4 isoenzyme of the cytochrome P450 system; therefore, concomitant use of domperidone and drugs that significantly inhibit this isoenzyme may lead to increased plasma levels of domperidone.

Concomitant use with ketoconazole, erythromycin, or other potential inhibitors of CYP3A4 may result in QT interval prolongation.

When domperidone 10 mg four times daily is used concomitantly with ketoconazole 200 mg twice daily, QT interval prolongation averages 9.8 msec (ranging from 1.2 to 17.5 msec individually). When domperidone 10 mg four times daily is used concomitantly with erythromycin 500 mg three times daily, QT interval prolongation averages 9.9 msec (ranging from 1.6 to 14.3 msec individually). At steady state, this interaction increases Cmax and area under the concentration-time curve (AUC) for domperidone by approximately threefold. In these studies, monotherapy with domperidone 10 mg four times daily caused QT prolongation of 1.6 msec (ketoconazole interaction study) and 2.5 msec (erythromycin interaction study). Monotherapy with ketoconazole (200 mg twice daily) caused QT prolongation of 3.8 msec, and monotherapy with erythromycin (500 mg three times daily) caused QT prolongation of 4.9 msec.

Clinically significant changes in QT interval have been observed when domperidone was used concomitantly with potent CYP3A4 inhibitors capable of prolonging the QT interval. Therefore, concomitant use of domperidone with certain drugs is contraindicated (see section "Contraindications").

Concomitant use of the following medicinal products with domperidone is contraindicated.

All medicinal products that prolong the QT interval:

• Class IA antiarrhythmics (e.g., disopyramide, quinidine, hydroquinidine);
• Class III antiarrhythmics (e.g., amiodarone, dofetilide, dronedarone, ibutilide, sotalol);
• Some neuroleptics (e.g., haloperidol, pimozide, sertindole);
• Some antidepressants (e.g., citalopram, escitalopram);
• Some antibiotics (e.g., levofloxacin, moxifloxacin, erythromycin, spiramycin);
• Some antifungal agents (e.g., pentamidine);
• Some antimalarial agents (e.g., halofantrine, lumefantrine);
• Some gastrointestinal agents (e.g., cisapride, dolasetron, prucalopride);
• Some antihistamines (e.g., mequitazine, mizolastine);
• Some oncology drugs (e.g., toremifene, vandetanib, vincamine);
• Some other drugs (e.g., bepridil, methadone, diphenylamine);
• Apomorphine, except when benefit outweighs risks, and provided strict adherence to precautionary measures during concomitant use (see apomorphine product information, section "Contraindications").

Strong CYP3A4 inhibitors with which domperidone should not be used:

• Azole antifungals such as fluconazole*, itraconazole*, ketoconazole*, and voriconazole*;
• Macrolide antibiotics such as clarithromycin* and erythromycin;
• Protease inhibitors*;
• HIV protease inhibitors such as amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir, and saquinavir;
• Calcium channel blockers such as diltiazem and verapamil;
• Amiodarone*;
• Amisulpride;
• Nefazodone;
• Telithromycin*

(*prolong QTc interval).

Concomitant use of the following substances requires caution.

Use with caution with drugs that cause bradycardia and hypokalemia, and with the following macrolides that may cause QT prolongation: azithromycin and roxithromycin (clarithromycin is contraindicated as it is a potent CYP3A4 inhibitor).

Domperidone should be used cautiously concomitantly with potent CYP3A4 inhibitors that do not cause QT prolongation, such as indinavir, and patients should be closely monitored for signs or symptoms of adverse reactions.

Domperidone may be combined with:

• Neuroleptics, whose action it enhances;
• Dopaminergic agonists (bromocriptine, L-dopa), whose undesirable peripheral effects such as digestive disturbances, nausea, and vomiting it suppresses without neutralizing their main properties.

Omeprazole.

Reduced gastric acidity during omeprazole use may alter absorption of drugs whose absorption is pH-dependent. Concomitant use of omeprazole with nelfinavir and atazanavir reduces their plasma concentrations. Concomitant use of omeprazole with nelfinavir is contraindicated. Administration of omeprazole 40 mg once daily reduces nelfinavir levels by an average of 40% and its pharmacologically active metabolite M8 by 75–90%. Another possible mechanism of interaction involves CYP2C19.

Concomitant use of omeprazole and atazanavir is not recommended. When omeprazole 40 mg once daily is used concomitantly with atazanavir 300 mg/ritonavir 100 mg in healthy volunteers, atazanavir exposure is reduced by 75%. Increasing the atazanavir dose to 400 mg does not compensate for this effect of omeprazole. When omeprazole 20 mg once daily is used concomitantly with atazanavir 400 mg/ritonavir 100 mg in healthy volunteers, atazanavir exposure is reduced by approximately 30%.

Increased serum levels of other antiretroviral agents such as saquinavir have been reported. There are also other antiretroviral drugs whose serum levels remain unchanged when used concomitantly with omeprazole.

Concomitant use of omeprazole 20 mg once daily with digoxin in healthy volunteers increases digoxin bioavailability by 10%. Although digoxin toxicity has not been reported in such cases, caution should be exercised when using omeprazole at high doses with digoxin in elderly patients.

In a crossover clinical study, concomitant use of clopidogrel (loading dose 300 mg, then 75 mg daily) with omeprazole (80 mg taken simultaneously) for 5 days reduced the effect of clopidogrel’s active metabolite by 46% (first day) and 42% (second day). Platelet aggregation was reduced by 47% at 24 hours and by 30% on day 5. In another clinical study, it was shown that administering clopidogrel and omeprazole at different times does not prevent this interaction, which is likely due to omeprazole-induced inhibition of CYP2C19.

Omeprazole use significantly reduces absorption of posaconazole, erlotinib, ketoconazole, and itraconazole, potentially reducing the clinical efficacy of these drugs. Concomitant use of the drug with posaconazole and erlotinib should be avoided.

Omeprazole inhibits CYP2C19, the main enzyme responsible for omeprazole metabolism. Thus, metabolism of concomitant drugs metabolized by CYP2C19, such as diazepam, phenytoin, warfarin (R-warfarin), or other vitamin K antagonists and cilostazol, may be slowed. Monitoring is recommended for patients taking phenytoin; dose reduction of phenytoin may also be necessary. However, concomitant use of 20 mg omeprazole daily did not alter blood phenytoin concentrations in patients on long-term therapy. Monitoring of INR is recommended in patients taking warfarin or other vitamin K antagonists; dose reduction of warfarin (or another vitamin K antagonist) may be needed. Nevertheless, concomitant use of 20 mg omeprazole daily did not alter coagulation time in patients on long-term warfarin therapy. Omeprazole is also partially metabolized by CYP3A4 but does not inhibit this enzyme. Therefore, omeprazole does not affect the metabolism of drugs metabolized by CYP3A4, such as cyclosporine, lidocaine, quinidine, estradiol, erythromycin, and budesonide. Increased methotrexate levels have been reported in some patients when taken concomitantly with proton pump inhibitors. In cases requiring high-dose methotrexate, temporary discontinuation of omeprazole should be considered.

Concomitant use of omeprazole with tacrolimus may lead to increased serum concentrations of tacrolimus. Monitoring of plasma tacrolimus levels is recommended at the beginning or after completion of omeprazole treatment.

Concomitant use of omeprazole with inhibitors of CYP2C19 and CYP3A4 (e.g., clarithromycin and voriconazole) may lead to increased omeprazole serum levels due to reduced metabolism. Concomitant use of voriconazole and omeprazole results in a doubling of omeprazole's effects. Since this increase in omeprazole levels is generally acceptable, dose adjustment is usually not required, except in patients with severe hepatic impairment or during long-term treatment.

Drugs that induce CYP2C19, CYP3A4, or both enzymes (such as rifampicin, St. John’s wort) may lead to decreased omeprazole serum levels by accelerating its metabolism.

Other active substances.

Amoxicillin: omeprazole causes significant and prolonged inhibition of gastric acid secretion. Concomitant administration of amoxicillin and omeprazole may impair antibiotic absorption, leading to reduced bioavailability.

Iron: omeprazole intake leads to significant and prolonged inhibition of gastric acid secretion, which may result in reduced iron absorption in the gastrointestinal tract.

Carbamazepine: it has been reported that after a single dose of carbamazepine, omeprazole increased its half-life, increased the area under the concentration-time curve (AUC), and decreased carbamazepine clearance.

Cyanocobalamin: omeprazole may reduce absorption of vitamin B12 when administered orally.

Cyclosporine: the effect of omeprazole on cyclosporine concentrations is not fully established. Controlled studies have not shown significant changes or reductions in plasma cyclosporine concentrations. Cases of both increased and decreased cyclosporine levels have been reported. Therefore, when treating a patient concomitantly with cyclosporine and omeprazole, cyclosporine plasma levels should be monitored.

Disulfiram: concomitant use with omeprazole may lead to increased disulfiram concentrations in serum, with manifestations of disulfiram toxicity such as confusion, disorientation, and changes in mental status.

Grapefruit juice: concomitant intake of grapefruit juice and omeprazole 20 mg reduces cytochrome P450 3A4-mediated formation of omeprazole sulfone but does not inhibit cytochrome P450 2C19-mediated formation of 5-hydroxyomeprazole. The clinical significance of this interaction is not established.

Cranberry juice: concomitant intake with omeprazole causes significant reduction in gastric juice pH. Regular consumption of cranberry juice during treatment with proton pump inhibitors may reduce their efficacy. Occasional consumption of cranberry juice is unlikely to have a clinical impact on gastric juice acidity, but caution is recommended. It is currently unknown whether dietary supplements containing cranberry extracts have the same effect on gastric juice acidity, but caution is advised.

Absorption of omeprazole may be delayed by food intake; therefore, the drug should be administered on an empty stomach.

Clopidogrel: clopidogrel inhibits the metabolism of omeprazole in individuals identified as rapid metabolizers of cytochrome P450 2C19 (CYP2C19).

Unknown interaction mechanisms.

Concomitant administration of omeprazole with saquinavir/ritonavir resulted in approximately 70% increase in saquinavir plasma concentrations, which was associated with good tolerability in HIV-infected patients.

Special precautions for use.

Antacid or antisecretory drugs, when used concomitantly with domperidone, should be taken after meals, but they should not be taken simultaneously with domperidone. Patients who continue to experience postprandial discomfort and require ongoing domperidone treatment for more than 2 weeks should consult a physician. Patients in whom nausea and vomiting persist for more than 48 hours should seek medical advice.

In studies investigating interaction with oral ketoconazole, QT interval prolongation has been observed. Although the clinical significance of this finding is not fully established, alternative treatment should be considered if antifungal therapy with ketoconazole is indicated (see section "Interaction with other medicinal products and other forms of interaction").

Domperidone should be used with caution in patients with risk factors for QT interval prolongation, including hypokalemia, severe hypomagnesemia, organic heart disease, and in patients with mild hepatic and/or renal impairment.

Renal impairment. Acute tubulointerstitial nephritis [ATIN] has been observed in patients treated with omeprazole (the active ingredient in the medicinal product OMEZ D®) (see section "Side effects"). ATIN may occur at any time during therapy and may progress to renal failure. If ATIN is suspected, the drug should be discontinued and appropriate treatment initiated immediately.

The elimination half-life of domperidone is prolonged in severe renal impairment. With prolonged use, the dosing frequency of domperidone should be reduced to once or twice daily, depending on the severity of the impairment. Dose reduction may also be necessary.

If peptic ulcer is present or suspected, or if any of the following symptoms occur—significant unexplained weight loss, vomiting, dysphagia, hematemesis, or melena—a malignant process should be ruled out, as omeprazole treatment may mask symptoms and delay diagnosis.

If a patient has known intolerance to certain sugars, medical advice should be sought before taking this medicinal product.

The product contains lactose and sucrose; therefore, it should not be administered to patients with lactose intolerance, galactosemia, glucose-galactose malabsorption, fructose intolerance, or sucrose-isomaltase deficiency.

Domperidone may cause an increase in prolactin levels, leading to galactorrhea in women and gynecomastia in men.

Hypertensive crisis may occur in patients with pheochromocytoma when treated with domperidone.

Patients should be informed that domperidone is not recommended for use in motion sickness.

Concomitant use with apomorphine. Domperidone is contraindicated for concomitant use with medicinal products that prolong the QT interval, particularly apomorphine, except when the benefit outweighs the risk, and only if strict adherence to the warnings provided in the apomorphine product information is maintained.

Cardiovascular effects. Domperidone has been associated with QT interval prolongation on ECG. During post-marketing surveillance, very rare cases of QT prolongation and ventricular fibrillation/torsades de pointes have been reported in patients taking domperidone. These reports included patients with other predisposing risk factors, electrolyte disturbances, and concomitant therapies that may have contributed.

According to ICH-E14 guidelines, a thorough QT interval study was conducted in healthy subjects. The QT interval prolongation observed with domperidone at the recommended dosing regimens (10 or 20 mg four times daily) was not considered clinically significant.

Due to the increased risk of ventricular arrhythmia, domperidone is contraindicated in patients with prolonged cardiac conduction intervals, particularly QTc, those with significant electrolyte imbalances (hypokalemia, hyperkalemia, hypomagnesemia), bradycardia, or underlying heart conditions such as congestive heart failure. Electrolyte imbalances (hypokalemia, hyperkalemia, hypomagnesemia) and bradycardia are known to increase the proarrhythmic risk.

If signs or symptoms suggestive of cardiac arrhythmia occur, domperidone should be discontinued immediately and the patient should seek medical advice without delay.

The following information should be considered regarding the risk of cardiovascular complications associated with domperidone-containing medicinal products:

• Some epidemiological studies have indicated that domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death;
• The risk of serious ventricular arrhythmias or sudden cardiac death may be higher in patients over 60 years of age or when oral doses exceed 30 mg per day.

Domperidone should be prescribed to adults and children at the lowest effective dose.

The benefit-risk balance of domperidone remains favorable.

Concomitant use of atazanavir with proton pump inhibitors is not recommended. If a combination of atazanavir with a proton pump inhibitor cannot be avoided, close clinical monitoring (e.g., viral load) is recommended, along with increasing the atazanavir dose to 400 mg with 100 mg ritonavir; the omeprazole dose should not exceed 20 mg.

Reduced gastric acid secretion, resulting from proton pump inhibitors or other acid-inhibiting agents, leads to increased bacterial load in the gastrointestinal tract, thereby slightly increasing the risk of intestinal infections caused by bacteria such as Salmonella and Campylobacter.

Omeprazole is an inhibitor of CYP2C19. Potential interactions with drugs metabolized by CYP2C19, such as clopidogrel, should be considered at the initiation or discontinuation of omeprazole therapy. The clinical significance of this interaction remains unclear. As a precautionary measure, concomitant use of omeprazole and clopidogrel should be avoided.

During treatment with antisecretory agents, plasma gastrin concentration increases due to reduced hydrochloric acid secretion. Reduced acid secretion also increases chromogranin A (CgA) levels. Elevated CgA levels may interfere with diagnostic tests for neuroendocrine tumors. To prevent such interference, proton pump inhibitor therapy should be discontinued at least 5 days before measuring CgA levels.

Omeprazole may reduce the absorption of cyanocobalamin. This should be considered during long-term treatment in patients with low vitamin B12 levels or impaired vitamin B12 absorption from the gastrointestinal tract.

Omeprazole, like other acid-inhibiting agents, may reduce vitamin B12 (cyanocobalamin) absorption due to hypo- or achlorhydria. This should be considered when treating patients with vitamin B12 deficiency or at risk of reduced vitamin B12 absorption during long-term therapy. In some cases, monitoring plasma vitamin B12 levels may be advisable.

The use of proton pump inhibitors, particularly at high doses and for prolonged periods (>1 year), may slightly increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or in the presence of other identified risk factors. Observational studies suggest that proton pump inhibitors may increase fracture risk by 10–40%.

In some cases, this is associated with other patient-related risk factors. Patients at risk of osteoporosis should receive appropriate treatment and adequate intake of vitamin D and calcium.

The use of proton pump inhibitors may be associated with an increased risk of Clostridium difficile-associated diarrhea.

In patients taking proton pump inhibitors, including omeprazole, for at least 3 months, clinically significant hypomagnesemia may occur (in most cases, patients had been taking the drug for about 1 year). Hypomagnesemia may present with serious symptoms such as fatigue, muscle spasms, delirium, dizziness, and ventricular arrhythmias. However, symptoms may be masked in some cases, delaying timely recognition. In most patients, symptoms resolve and magnesium levels normalize after magnesium supplementation and discontinuation of proton pump inhibitors.

In patients requiring long-term proton pump inhibitor therapy and in those concomitantly taking digoxin or other drugs that may cause hypomagnesemia (e.g., diuretics), serum magnesium levels should be checked before starting treatment and periodically during therapy.

In some cases, treatment of chronic conditions in children may require longer-term use of the drug, although this is not recommended.

Omeprazole may cause serious skin reactions, including redness, blistering, and rash (see section "Side effects"). If an allergic reaction occurs, the drug should be discontinued and immediate medical attention sought.

The use of proton pump inhibitors has occasionally been associated with the development of subacute cutaneous lupus erythematosus. If skin manifestations appear, particularly in sun-exposed areas and accompanied by arthralgia, immediate medical consultation is required, and discontinuation of omeprazole should be considered. A history of subacute cutaneous lupus erythematosus following proton pump inhibitor use may increase the risk of recurrence with other proton pump inhibitors.

Use during pregnancy or breastfeeding.

The drug should not be used in pregnant women. If the drug must be prescribed, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery.

Particular caution is required when driving vehicles and/or operating potentially hazardous machinery during treatment with this drug.

Method of administration and dosage.

Capsules should be taken whole, without opening or chewing, swallowed with a glass of water.

The recommended dose and duration of treatment depend on the course of the disease and are determined individually by a physician. The average recommended dose for adults and children aged 12 years and older is 1 capsule 2–3 times daily, 30 minutes before meals.

The daily dose must not exceed 30 mg calculated as domperidone (3 capsules). Unless otherwise prescribed by a physician, Omez D® should generally not be used for longer than one week.

Children.

The drug is indicated for treatment of children aged 12 years and older with body weight of at least 35 kg.

Overdose.

Overdose caused by domperidone.

Symptoms: agitation, impaired consciousness, seizures, disorientation, drowsiness, extrapyramidal reactions.

Treatment: gastric lavage, administration of activated charcoal, anticholinergic agents to counteract extrapyramidal disorders. In case of extrapyramidal reactions, anticholinergic drugs and agents used in the treatment of parkinsonism should be administered.

Overdose caused by omeprazole.

Symptoms: dry mouth, nausea, vomiting, dizziness, profuse sweating, abdominal pain, flatulence, diarrhea, flushing, headache, blurred vision, tachycardia, apathy, depression, drowsiness, confusion. All symptoms are transient. Elimination rate remains unchanged regardless of dose (first-order kinetics).

Treatment – symptomatic. There is no specific antidote. A significant portion of omeprazole is protein-bound in plasma; therefore, hemodialysis is ineffective.

Adverse Reactions

When dosage and duration recommendations are followed, domperidone is generally well tolerated, and adverse events occur infrequently.

The adverse reactions listed below are classified by organ systems and by frequency of occurrence: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and those with unknown frequency.

Immune system disorders.
Rare: angioedema; hypersensitivity reactions including anaphylaxis, anaphylactic shock; urticaria, bronchospasm, abdominal swelling.
Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis.

Skin and subcutaneous tissue disorders.
Uncommon: rash, pruritus, dermatitis, urticaria.
Rare: alopecia, photosensitization, purpura and/or petechiae (sometimes recurring upon re-exposure to the drug), skin inflammation, dry skin, hyperhidrosis.
Very rare: erythema multiforme, subacute cutaneous lupus erythematosus, angioedema.
Frequency not known: skin redness, blisters.

Psychiatric disorders.
Uncommon: anxiety.
Rare: agitation, confusion, depression.
Very rare: aggression, hallucinations, nervousness, irritability, decreased or absent libido.

Nervous system disorders.
Very rare: headache, dizziness, paresthesia, somnolence, taste disturbances, loss of consciousness, general weakness, insomnia, lethargy, anxiety, paresthesia, agitation, reversible confusion, aggressiveness, depression, nervousness, tremor, apathy, hallucinations, hemifacial dysesthesia.
Frequency not known: seizures, extrapyramidal disorders, irritability, agitation, akathisia, systemic vertigo.

Cardiac and cardiovascular disorders.
Very rare: ventricular arrhythmias, peripheral edema, palpitations, disturbances in heart rate and rhythm.
Frequency not known: QT interval prolongation, ventricular arrhythmias of the "torsade de pointes" type, sudden cardiac death, chest pain or angina, tachycardia, bradycardia, increased blood pressure, peripheral edema.

Eye disorders.
Rare: blurred vision.
Frequency not known: oculogyric crisis.

Ear and labyrinth disorders.
Tinnitus.

Respiratory system disorders.
Rare: bronchospasm.

Gastrointestinal disorders.
Common: abdominal pain, constipation, flatulence.
Rare: gastrointestinal disturbances including abdominal pain, regurgitation of acidic gastric contents, changes in appetite, nausea, heartburn, constipation.
Very rare: dry mouth, transient intestinal spasms, diarrhea, stomatitis, gastrointestinal candidiasis, loss of appetite, taste distortion.
Frequency not known: intestinal colic, altered taste, vomiting, microscopic colitis, pancreatitis (sometimes with fatal outcome), change in stool color, atrophy of the tongue mucosa, thirst. Gastric fundic gland polyps have been diagnosed occasionally during omeprazole treatment. These polyps are benign and may regress after discontinuation of treatment. Gastric and duodenal carcinoids have been reported in patients with Zollinger-Ellison syndrome during prolonged omeprazole therapy. These changes are considered to be manifestations of the underlying disease, which is known to be associated with such tumors.

Musculoskeletal and connective tissue disorders.
Rare: arthralgia, myalgia.
Very rare: muscle weakness.
Frequency not known: leg pain, fractures of the femur, wrist, or spine.

Hepatobiliary disorders.
Rare: elevated liver enzymes, hepatitis with or without jaundice.
Very rare: liver failure, encephalopathy in patients with pre-existing liver disease.

Renal and urinary disorders.
Rare: tubulointerstitial nephritis (sometimes recurring upon re-exposure to the drug, with possible progression to renal failure), urinary tract infection, microcylindruria, elevated serum creatinine, proteinuria, hematuria, glucosuria, testicular pain.
Very rare: urinary retention, dysuria, frequent urination.

Reproductive system and breast disorders.
Rare: galactorrhea, breast enlargement/gynecomastia, breast tenderness, nipple discharge, breast pain, amenorrhea, elevated prolactin levels, irregular menstrual cycle.

Metabolic and nutritional disorders.
Rare: hyponatremia, elevated prolactin levels.
Very rare: hypomagnesemia, which may lead to hypokalemia; severe hypomagnesemia, which may result in hypocalcemia.

Blood and lymphatic system disorders.
Rare: leukopenia, thrombocytopenia.
Very rare: agranulocytosis (sometimes with fatal outcomes), pancytopenia, neutropenia, anemia, leukocytosis, hemolytic anemia.

Laboratory findings:
Very rare: increased ALT, AST, and cholesterol levels.
Rare: increased serum prolactin levels.
Very rare: abnormal liver function test results.

Since the pituitary gland lies outside the blood-brain barrier, domperidone may cause an increase in prolactin levels. In isolated cases, such hyperprolactinemia may lead to neuroendocrine adverse effects such as galactorrhea, gynecomastia, and amenorrhea.

Other disorders.
Rare: asthenia, malaise, peripheral edema.
Rare: increased sweating, elevated body temperature, impotence.
Frequency not known: conjunctivitis, stomatitis, lethargy.

During the post-marketing period, no differences in the safety profile of domperidone use between adults and children have been observed, except for extrapyramidal disorders and other central nervous system-related events such as seizures and agitation, which were observed predominantly in children.

Shelf life. 2 years.

Storage conditions.
Store in a dry, light-protected, and child-inaccessible place at a temperature not exceeding 25 °C.

Packaging.
10 capsules per strip, 3 strips per cardboard box.

Prescription status.
Prescription only.

Manufacturer.
Torrent Pharmaceuticals Ltd, India.

Manufacturer's name and address.
Indrad Plant, Near Indrad Village, Taluka Kadi, District Mehsana, Gujarat 382 721, India.

Marketing Authorization Holder.
Dr. Reddy’s Laboratories Ltd, India.