Limzer

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LIMZER (LIMZER)

Composition:

Active substances: 1 capsule contains omeprazole 20 mg, domperidone 30 mg;

Excipients: neutral micropellets*, hypromellose, talc, methacrylate copolymer dispersion, sodium hydroxide, colloidal anhydrous silicon dioxide, ethylcellulose, titanium dioxide (E 171), triacetin, glyceryl monostearate, polysorbates, magnesium stearate, hypromellose phthalate, dibutyl sebacate, iron oxide yellow (E 172), iron oxide red (E 172);

Capsule shell: gelatin, methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), Ponceau 4R (E 124), Quinoline Yellow FCF (E 110), titanium dioxide (E 171);

*Neutral micropellets: sucrose, corn starch, povidone, hypromellose.

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules size "3" with orange body and red cap, containing a mixture of white or almost white pellets and brown or yellowish-brown pellets, spherical or oval in shape.

Pharmacotherapeutic group.
Agents for treatment of acid-related disorders. ATC code A02.

Pharmacological Properties.

Pharmacodynamics.

A combined medicinal product, whose action is determined by the components contained in its composition.

Omeprazole belongs to anti-ulcer agents that inhibit basal and stimulated secretion of hydrochloric acid in the parietal cells of the stomach due to specific action on H⁺-K⁺-ATPase (proton pump). The antisecretory effect of omeprazole develops rapidly within the first hour and persists throughout 24 hours. Due to its high lipophilicity, omeprazole easily penetrates into gastric parietal cells, accumulates there, and exerts a cytoprotective effect. The inhibitory effect increases during the first 4 days of administration. Omeprazole does not affect gastrointestinal motility.

Domperidone blocks peripheral dopamine receptors, eliminates the inhibitory effect of dopamine on the motor function of the gastrointestinal tract, and enhances gastric evacuatory and motor activity. It exerts antiemetic action, relieves hiccups, and alleviates nausea. It poorly penetrates the blood-brain barrier and therefore has virtually no effect on dopamine receptors in the central nervous system.

Pharmacokinetics.

Not studied.

Clinical characteristics.

Indications.

Functional dyspepsia, reflux esophagitis, delayed gastric emptying, and gastroparesis.

Contraindications.

Limzer is contraindicated:

• in patients with known hypersensitivity to the drug or to any of the excipients;
• in patients with diagnosed prolactin-secreting pituitary tumor (prolactinoma);
• in patients with severe or moderate hepatic and/or renal impairment (see section "Special precautions");
• in patients with known prolongation of cardiac conduction intervals, particularly QTc;
• in patients with significant electrolyte imbalances or underlying heart diseases such as congestive heart failure (see section "Special precautions");
• in patients with hepatic insufficiency;
• when stimulation of gastric motility may be dangerous, e.g., gastrointestinal hemorrhage, mechanical obstruction, or perforation;
• concomitant use with ketoconazole, erythromycin, or other potent inhibitors of CYP3A4 is contraindicated;
• concomitant use with medicinal products that prolong the QT interval, such as fluconazole, erythromycin, itraconazole, oral ketoconazole, posaconazole, ritonavir, saquinavir, telaprevir, voriconazole, clarithromycin, amiodarone, telithromycin, except for apomorphine (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Antacid preparations delay and reduce the absorption of Limzer; therefore, they should not be administered earlier than 2 hours after taking Limzer.

Omeprazole.

Suppression of gastric acid secretion during treatment with omeprazole and other drugs from the PPI group may reduce or increase the absorption of medicinal products whose absorption is pH-dependent. As with other agents that reduce intragastric acidity, the absorption of drugs such as ketoconazole, itraconazole, and erlotinib may be decreased, whereas the absorption of drugs such as digoxin may be increased during omeprazole treatment.

Omeprazole inhibits CYP2C19 – the main enzyme responsible for omeprazole metabolism. Thus, the metabolism of concomitant drugs metabolized by CYP2C19, such as diazepam, phenytoin, warfarin (R-warfarin), propranolol, prednisolone, theophylline, other vitamin K antagonists, and cilostazol, may be slowed. Monitoring of patients taking phenytoin is recommended; dose reduction of phenytoin may be necessary. 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 required.

Omeprazole increases the maximum concentration (Cmax) and area under the concentration-time curve (AUC) of cilostazol and its active metabolites.

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.

It has been reported that concomitant use of omeprazole increases serum levels of tacrolimus.

Elevated methotrexate levels have been reported in some patients when co-administered with proton pump inhibitors. If high-dose methotrexate is required, temporary discontinuation of omeprazole should be considered.

Omeprazole has been observed to interact with certain antiretroviral agents. The clinical significance and mechanism of such interaction are not always known. Increased gastric pH during omeprazole use may alter the absorption of antiretroviral drugs. Another possible mechanism of interaction involves CYP2C19. When certain antiretroviral agents such as atazanavir and nelfinavir were used concomitantly with omeprazole, reduced serum levels of these agents were observed. Therefore, concomitant use of omeprazole with atazanavir and nelfinavir is not recommended. 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.

Since omeprazole is metabolized by CYP2C19 and CYP3A4, drugs that inhibit CYP2C19, CYP3A4, or both enzymes (such as clarithromycin and voriconazole) may lead to increased omeprazole serum levels by slowing its metabolism. Drugs that induce CYP2C19, CYP3A4, or both enzymes (such as rifampicin) may lead to decreased omeprazole serum levels by accelerating its metabolism.

Domperidone.

Anticholinergic drugs may counteract the antidyspeptic effect of Limzer. The risk of QT interval prolongation increases due to pharmacodynamic and/or pharmacokinetic interactions.

Antacid and antisecretory drugs should not be taken simultaneously with Limzer, as they reduce its bioavailability after oral administration (see section "Special precautions").

Domperidone is predominantly metabolized via CYP3A4. In vitro studies have shown that concomitant use of drugs that strongly inhibit this enzyme may lead to increased plasma levels of domperidone.

Clinically significant QT interval changes 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.

Concomitant use of the following QTc-prolonging drugs is contraindicated:

• Class IA antiarrhythmic agents (e.g., disopyramide, quinidine, hydroquinidine);
• Class III antiarrhythmic agents (e.g., amiodarone, dofetilide, dronedarone, ibutilide, sotalol);
• certain neuroleptic agents (e.g., haloperidol, pimozide, sertindole);
• certain antidepressants (e.g., citalopram, escitalopram);
• certain antibiotics (e.g., levofloxacin, moxifloxacin, erythromycin, spiramycin);
• certain antifungal agents (e.g., pentamidine);
• certain antimalarial agents (e.g., halofantrine, lumefantrine);
• certain gastrointestinal agents (e.g., cisapride, dolasetron, prucalopride);
• certain antihistamines (e.g., mequitazine, mizolastine);
• certain oncology drugs (e.g., toremifene, vandetanib, vincamine);
• certain other drugs (e.g., bepridil, methadone, difemalane).

Examples of potent CYP3A4 inhibitors with which Limzer should not be used:

• azole antifungal agents 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*;
• amprepitant;
• nefazodone;
• telithromycin*;
• apomorphine, except when benefit outweighs risk, and only under strict adherence to recommended precautionary measures for concomitant use. Refer to the medical instructions for the medicinal product containing apomorphine as the active substance.

* 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 interval 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.

The above list is representative but not exhaustive.

Limzer may be combined with:

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

In specific in vivo pharmacodynamic/pharmacokinetic interaction studies, concomitant oral administration of ketoconazole or erythromycin in healthy volunteers confirmed that these drugs significantly inhibit the presystemic metabolism of domperidone mediated by CYP3A4. When 10 mg domperidone was administered orally four times daily concomitantly with 200 mg ketoconazole orally twice daily, QTc interval prolongation averaged 9.8 msec during the observation period; individual values ranged from 1.2 to 17.5 msec. When 10 mg domperidone four times daily was administered concomitantly with 500 mg erythromycin orally three times daily, QTc interval was prolonged on average by 9.9 msec, with individual values ranging from 1.6 to 14.3 msec. Steady-state Cmax and AUC values of domperidone increased approximately threefold in each of these interaction studies. The contribution of elevated plasma concentrations of domperidone to the observed QTc effect is unknown. In these studies, during monotherapy with domperidone (10 mg orally four times daily), QTc interval was prolonged on average by 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while administration of ketoconazole alone (200 mg twice daily) or erythromycin alone (500 mg three times daily) resulted in QTc interval increases of 3.8 and 4.9 msec, respectively, during the observation period.

Theoretically, since Limzer exerts a prokinetic effect on the stomach, it may affect the absorption of concomitantly administered oral drugs, particularly prolonged-release formulations or enteric-coated preparations. However, in patients already stabilized on digoxin or paracetamol, concomitant administration of domperidone did not affect blood levels of these drugs.

Special precautions for use.

Before starting and after completing therapy with Limzer, an endoscopic examination should be performed to exclude undiagnosed malignant conditions, as treatment with the drug may mask symptoms and delay correct diagnosis of malignancy. Significant unexplained weight loss, vomiting, dysphagia, hematemesis, or melena may be signs of a malignant process.

Patients with chronic liver disease require regular monitoring (no less than once every 2 weeks) of liver enzymes via blood laboratory tests. If any quantitative or qualitative changes in these parameters occur, Limzer must be discontinued immediately.

Patients with hypersensitivity or intolerance to gluten should not take this medicinal product, as maize starch is included among the excipients.

The product contains sucrose. This medicinal product should not be used in patients with rare hereditary conditions such as fructose intolerance, sucrase-isomaltase deficiency, or glucose-galactose malabsorption.

Limzer is not recommended in patients with vertigo.

Limzer should be used with caution in elderly patients or in patients with existing heart disease or a history of cardiac disorders.

Cardiovascular effects. Domperidone has been associated with QT interval prolongation on ECG. Very rare cases of QT prolongation and ventricular fibrillation/flutter have been reported in patients taking domperidone. These reports included patients with other non-modifiable risk factors, electrolyte disturbances, and concomitant therapies that could act as contributing factors.

According to ICH-E14 guidelines, a thorough QT study was conducted in healthy volunteers. The QT interval prolongation observed in the study with domperidone administered at the recommended dosage regimens (10 or 20 mg four times daily) was not considered to be of clinical significance.

Use with apomorphine: Domperidone is contraindicated for concomitant use with drugs that prolong the QT interval, including apomorphine, except when the benefit outweighs the risk, and only under strict adherence to the recommended precautionary measures for concomitant use specified in the apomorphine product information. Refer to the product information for the medicinal product containing apomorphine.

Warnings: Domperidone should be used with caution in patients with mild hepatic and/or renal impairment.

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

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

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

Antacid or antisecretory agents should not be taken simultaneously with oral formulations of Limzer, as they reduce the oral bioavailability of domperidone (see section "Interaction with other medicinal products and other forms of interaction"). When used concomitantly, Limzer should be taken before meals, and antacid or antisecretory agents should be taken after meals.

Acute tubulointerstitial nephritis (ATIN) has been reported in patients taking omeprazole and may occur at any time during omeprazole therapy (see section "Adverse reactions"). Acute tubulointerstitial nephritis may progress to renal failure.

If ATIN is suspected, omeprazole should be discontinued and appropriate treatment initiated immediately.

Use with ketoconazole: In interaction studies with oral ketoconazole, QT interval prolongation was 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").

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

• Some epidemiological studies have shown 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 aged 60 years or older, or when oral doses exceeding 30 mg per day are used. Therefore, Limzer should be used with caution in elderly patients. Patients aged 60 years or older should consult their physician before taking Limzer.
• Domperidone should be prescribed to adults and children at the lowest effective dose.

The benefit-risk balance of domperidone remains favorable.

Use during pregnancy or breastfeeding.

The medicinal product is contraindicated during pregnancy and breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

During treatment with this medicinal product, caution should be exercised when driving or operating machinery.

Dosage and Administration.

Capsules should be taken whole, without breaking or chewing. The recommended dosage and duration of treatment depend on the course of the disease and are determined individually by a physician. The average recommended dose is 1 capsule once daily, 10–15 minutes before a meal, taken with a glass of water.

Dosing in elderly patients and patients with renal insufficiency.

An individual approach to dose determination is required; however, in many cases, dose adjustment is not necessary.

The duration of treatment is determined by the physician depending on the nature and course of the disease, and usually lasts 4–8 weeks.

Children.

The drug is not intended for use in children.

Overdose.

Symptoms: agitation, impaired consciousness, seizures, disorientation, apathy, headache, drowsiness, extrapyramidal reactions, vomiting, nausea, flatulence, diarrhea, tachycardia.

Treatment. There is no specific antidote. In case of overdose, gastric lavage and administration of activated charcoal are recommended, along with close monitoring of the patient and supportive, symptomatic therapy.

Adverse Reactions.

Omeprazole.

Blood and lymphatic system disorders: leukopenia, thrombocytopenia, agranulocytosis, pancytopenia.

Immune system disorders: hypersensitivity reactions such as fever, angioedema, anaphylaxis, anaphylactic reactions/shock.

Metabolism and nutrition disorders: hyponatremia, hypomagnesemia.

Psychiatric disorders: insomnia, agitation, aggression, confusion, depression, hallucinations.

Nervous system disorders: headache, dizziness, paresthesia, somnolence, taste alteration.

Eye disorders: blurred vision.

Ear and labyrinth disorders: vertigo.

Respiratory system disorders: bronchospasm.

Gastrointestinal disorders: abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting, dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis.

Hepatobiliary disorders: increased liver enzymes, hepatitis with or without jaundice, hepatic failure, encephalopathy in patients with pre-existing liver disease.

Skin and subcutaneous tissue disorders: dermatitis, pruritus, rash, urticaria, alopecia, photosensitivity, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN).

Musculoskeletal and connective tissue disorders: arthralgia, myalgia, muscle weakness.

Renal and urinary disorders: interstitial nephritis, tubulointerstitial nephritis (with possible progression to renal failure).

Reproductive system disorders: gynecomastia.

General disorders: malaise, increased sweating, peripheral edema.

Domperidone.

Immune system disorders: allergic reactions, including anaphylaxis, anaphylactic shock, hypersensitivity.

Endocrine disorders: increased prolactin levels.

Psychiatric disorders: nervousness, irritability, agitation, excitement, depression, anxiety, decreased or absent libido.

Nervous system disorders: dry mouth, insomnia, dizziness, thirst, convulsions, lethargy, headache, somnolence, akathisia, extrapyramidal disorders.

Cardiac disorders: edema, palpitations, disturbances in heart rate and rhythm, QT interval prolongation (frequency unknown), serious ventricular arrhythmias, ventricular arrhythmias of the torsade de pointes type, sudden cardiac death.

Gastrointestinal disorders: gastrointestinal disturbances including abdominal pain, regurgitation, vomiting, appetite changes, nausea, heartburn, constipation; dry mouth, transient intestinal spasms, diarrhea.

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, angioedema.

Reproductive system disorders: galactorrhea, breast enlargement/gynecomastia, breast tenderness, nipple discharge, amenorrhea, breast swelling, breast pain, lactation disorders, irregular menstrual cycle.

Musculoskeletal disorders: leg pain.

Renal disorders: urinary retention, dysuria, frequent urination.

General disorders: asthenia.

Eye disorders: oculogyric crises.

Other: conjunctivitis, stomatitis.

Laboratory abnormalities: increased ALT, AST, and cholesterol levels; deviations from normal liver function test results, increased blood prolactin levels.

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

During the post-marketing period in adults and children, adverse events have been reported, apart from extrapyramidal disorders related to the central nervous system, which were observed predominantly in children.

Shelf life.

2.5 years.

Storage conditions.

Store in a dry, protected from light place at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 capsules in a strip; 3 or 10 strips in a cardboard box;

14 capsules in a strip; 1 strip in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Inventia HealthCare Ltd, India.

Manufacturer's address and location of business activity.

F1-F1/1-F75/1, Edisenel Ambernath, M.I.D.C., Ambernath (East), 421506, District Thane, Maharashtra State, India.