Instructions for Limzer capsules strip No. 30
Composition
active ingredients: 1 capsule contains omeprazole 20 mg, domperidone 30 mg;
excipients: neutral micropellets*, hypromellose, talc, methacrylate copolymer dispersion, sodium hydroxide, colloidal anhydrous silica, ethylcellulose, titanium dioxide (E 171), triacetin, glycerol monostearate, polysorbates, magnesium stearate, hypromellose phthalate, dibutyl sebacate, iron oxide yellow (E 172), iron oxide red (E 172);
capsule shell: gelatin, methyl parahydroxybenzoate (E 218), propyl parahydroxybenzoate (E 216), ponceau 4 R (E 124), sunset yellow FCF (E 110), titanium dioxide (E 171);
*neutral micropellets: sucrose, corn starch, povidone, hypromellose.
Dosage form
Capsules.
Main physicochemical properties: hard gelatin capsules size "3" with an orange body and a red cap, containing a mixture of: white or almost white pellets and brown or yellowish-brown pellets, spherical or oval in shape.
Pharmacotherapeutic group
Drugs for the treatment of acid-dependent conditions. ATC code A02.
Pharmacological properties
Pharmacodynamics
A combined medicinal product, the effect of which is due to the components that make up its composition.
Omeprazole belongs to antiulcer drugs that inhibit basal and stimulated secretion of hydrochloric acid in the parietal cells of the stomach due to a specific effect on H+-K+- ATPase (proton pump). The antisecretory effect after taking omeprazole develops very quickly within the first hour and persists throughout the day. Omeprazole, due to its high lipophilicity, easily penetrates the parietal cells of the stomach, concentrates in them and has a cytoprotective effect. The inhibitory effect increases in the first 4 days of administration. Omeprazole does not affect the motility of the gastrointestinal tract.
Domperidone blocks peripheral dopamine receptors, eliminates the inhibitory effect of dopamine on the motor function of the digestive tract and increases the evacuation and motor activity of the stomach. It has an antiemetic effect, soothes hiccups and eliminates nausea. It penetrates poorly through the blood-brain barrier, has practically no effect on dopamine receptors in the brain.
Pharmacokinetics
Not studied.
Indication
Functional dyspepsia, reflux esophagitis, delayed gastric emptying, and gastroparesis.
Contraindication
Limzer is contraindicated:
patients with established hypersensitivity to the drug or to excipients;
patients with a prolactin-secreting pituitary tumor (prolactinoma);
patients with severe or moderate liver and/or kidney dysfunction (see section "Special warnings and precautions for use");
patients with known prolongation of cardiac conduction intervals, in particular QTc;
patients with significant electrolyte imbalances or underlying heart disease, such as congestive heart failure (see section "Special warnings and precautions for use");
patients with liver failure;
if stimulation of gastric motor function may be dangerous, for example, gastrointestinal bleeding, mechanical obstruction or perforation;
Concomitant use of ketoconazole, erythromycin, or other potent CYP3A4 inhibitors is contraindicated;
Concomitant use of drugs that prolong the QT interval, such as fluconazole, erythromycin, itraconazole, oral ketoconazole, posaconazole, ritonavir, saquinavir, telaprevir, voriconazole, clarithromycin, amiodarone, telithromycin is contraindicated (see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other types of interactions”).
Interaction with other medicinal products and other types of interactions
Antacids slow down and reduce the absorption of Limzer, so they should be used no earlier than 2 hours after taking it.
Omeprazole.
The inhibition of gastric acid secretion during treatment with omeprazole and other PPIs may reduce or increase the absorption of drugs whose absorption depends on gastric pH. As with other drugs that reduce intragastric acidity, the absorption of drugs such as ketoconazole, itraconazole and erlotinib may be reduced, while the absorption of drugs such as digoxin may be increased during treatment with omeprazole.
Omeprazole inhibits CYP2C19, the main omeprazole-metabolizing enzyme. Therefore, the metabolism of concomitant drugs also metabolized by CYP2C19, diazepam, phenytoin, warfarin (R-warfarin), propranolol, prednisolone, theophylline, other vitamin K antagonists and cilostazol may be slowed. Monitoring of patients taking phenytoin is recommended. A reduction in the dose of phenytoin may be necessary. Monitoring of MHC is recommended in patients taking warfarin or other vitamin K antagonists; a reduction in the dose of warfarin (or other vitamin K antagonist) may be necessary.
Omeprazole is also partially metabolized by CYP3A4, but does not inhibit this enzyme. Thus, omeprazole does not affect the metabolism of drugs metabolized by CYP3A4, such as cyclosporine, lidocaine, quinidine, estradiol, erythromycin, and budesonide.
Concomitant use of omeprazole has been reported to increase serum levels of tacrolimus.
Increased methotrexate levels have been reported in some patients when co-administered with proton pump inhibitors. If high doses of methotrexate are necessary, temporary withdrawal of omeprazole should be considered.
Omeprazole has been reported to interact with some antiretroviral agents. The clinical significance and mechanism of this interaction are not always known. The increase in gastric pH during omeprazole use may alter the absorption of antiretroviral agents. Another possible mechanism of interaction is via CYP 2C19. In the case of some antiretroviral agents, such as atazanavir and nelfinavir, decreased serum levels have been reported when co-administered with omeprazole. Therefore, concomitant use of omeprazole and agents such as atazanavir and nelfinavir is not recommended. Increased serum levels of other antiretroviral agents, such as saquinavir, have been reported. There are also other antiretroviral agents whose serum levels have remained unchanged when co-administered 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 serum levels of omeprazole by slowing its metabolism. Drugs that induce CYP2C19, CYP3A4, or both enzymes (such as rifampicin) may lead to decreased serum levels of omeprazole by accelerating its metabolism.
Domperidone.
Anticholinergic drugs may neutralize the antidyspeptic effect of Limzer. Due to pharmacodynamic and/or pharmacokinetic interactions, the risk of QT prolongation is increased.
Antacids and antisecretory drugs should not be taken simultaneously with Limzer, as they reduce its bioavailability after oral administration (see section “Special instructions”).
Domperidone is metabolized primarily by CYP3A4. In vitro studies have shown that concomitant use of drugs that significantly inhibit this enzyme may lead to increased plasma levels of domperidone.
Clinically significant changes in the QT interval have been observed when domperidone was used concomitantly with potent CYP3A4 inhibitors that can prolong the QT interval. Therefore, the concomitant use of domperidone with certain drugs is contraindicated (see section “Contraindications”).
Concomitant use of the following drugs with domperidone is contraindicated.
All drugs that prolong the QT interval:
Class IA antiarrhythmic drugs (e.g., disopyramide, quinidine, hydroquinidine);
Class III antiarrhythmic drugs (e.g. amiodarone, dofetilide, dronedarone, ibutilide, sotalol);
some neuroleptic drugs (e.g. haloperidol, pimozide, sertindole);
some antidepressants (e.g. citalopram, escitalopram);
certain antibiotics (e.g., levofloxacin, moxifloxacin, erythromycin, spiramycin);
some antifungal drugs (e.g. pentamidine);
certain antimalarial drugs (e.g., halofantrine, lumefantrine);
certain gastrointestinal medications (e.g., cisapride, dolasetron, prucalopride);
some antihistamines (e.g. mecitazine, mizolastine);
some drugs used in cancer (e.g. toremifene, vandetanib, vincamine);
some other drugs (e.g. bepridil, methadone, diphemanil).
Examples of strong CYP3A4 inhibitors with which Limzer is not recommended:
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 antagonists such as diltiazem and verapamil;
amiodarone*;
amrepitant;
nefazodone;
telithromycin*.
* prolong the QTc interval.
The simultaneous use of the following substances requires caution.
Use with caution with drugs that cause bradycardia and hypokalemia, as well as 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 with caution when used concomitantly with potent CYP3A4 inhibitors that have not been shown to prolong the QT interval, 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 can be combined with:
neuroleptics, the effect of which it enhances;
In separate in vivo pharmacodynamic/pharmacokinetic interaction studies with concomitant oral administration of ketoconazole or erythromycin in healthy volunteers, it was confirmed that these drugs significantly inhibit the CYP3A4-mediated first-pass metabolism of domperidone. With concomitant administration of 10 mg domperidone orally 4 times a day and 200 mg ketoconazole orally 2 times a day, a prolongation of the QTc interval by an average of 9.8 msec was observed during the observation period; individual values ranged from 1.2 to 17.5 msec. With concomitant administration of 10 mg domperidone 4 times a day and 500 mg erythromycin orally 3 times a day, the QTc interval was prolonged by an average of 9.9 msec during the observation period, with the range of individual values ranging from 1.6 to 14.3 msec. The steady-state Cmax and AUC of domperidone increased approximately threefold in each of these interaction studies. The contribution of the increased plasma concentrations of domperidone to the observed effect on QTc is unknown. In these studies, domperidone monotherapy (10 mg orally 4 times a day) prolonged the QTc interval by an average of 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while the use of ketoconazole (200 mg twice a day) or erythromycin (500 mg three times a day) alone resulted in an increase in the QTc interval during the observation period of 3.8 and 4.9 msec, respectively.
Theoretically, since Limzer has a prokinetic effect on the stomach, this could affect the absorption of concomitant oral medications, particularly extended-release or enteric-coated formulations. However, in patients already stabilized on digoxin or paracetamol, concomitant use of domperidone did not affect the blood levels of these medications.
Application features
Before starting and after completing therapy with Limzer, an endoscopic examination should be performed to exclude cases of undiagnosed malignancy, since treatment with the drug may mask symptoms and delay the correct diagnosis of malignancy. Significant unexplained weight loss, vomiting, dysphagia, haematemesis or melena may be signs of malignancy.
Patients with chronic liver disease should have regular (at least once every 2 weeks) laboratory blood tests for liver enzymes. In case of any quantitative or qualitative changes in these parameters, Limzer should be discontinued immediately.
Patients with hypersensitivity or intolerance to gluten should not take this medicine, as the excipients include corn starch.
This medicine contains sucrose. Patients with rare hereditary problems of fructose intolerance, sucrase-isomaltose insufficiency, or glucose-galactose malabsorption should not take this medicine.
Limzer is not recommended for swaying.
Limzer should be used with caution in elderly patients or in patients with existing heart disease or a history of heart disease.
Cardiovascular effects. Domperidone has been associated with prolongation of the QT interval on the ECG. Very rare cases of QT prolongation and ventricular flutter/fibrillation have been reported in patients taking domperidone. These reports included patients with other predisposing risk factors, electrolyte disturbances and concomitant medications that may have been contributing factors.
A study was conducted in healthy volunteers in accordance with ICH-E14 guidelines to investigate the QT interval. The QT prolongation observed in the study with domperidone, at the recommended dosage regimen at the usual therapeutic doses (10 or 20 mg 4 times a day), is not clinically relevant.
Caution: Domperidone should be used with caution in patients with mild hepatic and/or renal impairment.
Due to the increased risk of ventricular arrhythmia, Limzer is contraindicated in patients with prolongation of cardiac conduction intervals, particularly QTc, in patients with significant electrolyte imbalance (hypokalemia, hyperkalemia, hypomagnesemia) or bradycardia, or in patients with underlying cardiac disease such as congestive heart failure. Electrolyte imbalance (hypokalemia, hyperkalemia, hypomagnesemia) and bradycardia are known to be conditions that increase proarrhythmic risk.
If signs or symptoms that may be associated with cardiac arrhythmia appear, Limzer should be discontinued and the patient should consult a physician immediately.
Renal impairment. 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 daily, depending on the severity of the impairment. A dose reduction may also be required.
Acute tubulointerstitial nephritis (ATIN) has been reported in patients taking omeprazole and may occur at any time during omeprazole therapy (see section 4.8). Acute tubulointerstitial nephritis may progress to renal failure.
If GTIN is suspected, omeprazole should be discontinued and appropriate treatment should be initiated immediately.
Use with ketoconazole: In interaction studies with oral ketoconazole, prolongation of the QT interval was observed. Although the significance of this study is not clearly established, alternative treatment should be considered if antifungal therapy with ketoconazole is indicated (see section 4.5).
The following information should be considered regarding the risk of cardiovascular complications caused by medicines 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 over 60 years of age or with oral doses of the drug greater than 30 mg per day. Therefore, Limzer should be used with caution in elderly patients. Patients over 60 years of age should consult a doctor before taking Limzer.
Domperidone should be prescribed to adults and children at the lowest effective dose.
The risk-benefit ratio of domperidone remains favorable.
Use during pregnancy or breastfeeding
The drug is contraindicated during pregnancy or breastfeeding.
Ability to influence reaction speed when driving vehicles or other mechanisms
During treatment with the drug, caution should be exercised when driving or operating other machinery.
Method of administration and doses
Capsules are taken orally whole, without breaking or chewing. The recommended dose and course of treatment depend on the course of the disease and are set by the doctor individually. The average recommended dose is 1 capsule once a day 10-15 minutes before meals, washed down with a glass of water.
Dosages for elderly patients and patients with renal insufficiency.
An individual approach to dose determination is necessary, but in many cases dose adjustment is not necessary.
The course of treatment is determined by the doctor depending on the nature and course of the disease, and usually lasts 4-8 weeks.
Children
The drug is not used in children.
Overdose
Symptoms: agitation, impaired consciousness, convulsions, disorientation, apathy, headache, drowsiness and extrapyramidal reactions, vomiting, nausea, flatulence, diarrhea, tachycardia.
Treatment: There is no specific antidote, but in case of overdose, gastric lavage and administration of activated charcoal are recommended, as well as close monitoring of the patient and supportive and symptomatic therapy.
Side effects
Omeprazole.
From the blood and lymphatic system: leukopenia, thrombocytopenia, agranulocytosis, pancytopenia.
Immune system disorders: hypersensitivity reactions such as fever, angioedema, anaphylaxis, anaphylactic reactions/shock.
Metabolic: hyponatremia, hypomagnesemia.
On the part of the psyche: insomnia, agitation, aggression, confusion, depression, hallucinations.
From the nervous system: headache, dizziness, paresthesia, drowsiness, change in taste.
On the part of the organs of vision: blurred vision.
From the organs of hearing and balance: vertigo.
Respiratory system: bronchospasm.
On the part of the digestive tract: abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting, dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis.
Hepatobiliary system: 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 system: arthralgia, myalgia, muscle weakness.
Renal and urinary disorders: interstitial nephritis, tubulointerstitial nephritis (with possible progression to renal failure).
From the reproductive system: gynecomastia.
General disorders: malaise, increased sweating, peripheral edema.
Domperidone.
On the part of the immune system: allergic reactions, including anaphylaxis, anaphylactic shock, hypersensitivity.
On the part of the endocrine system: increased prolactin levels.
On the part of the psyche: nervousness, irritability, agitation, excitement, depression, anxiety, decreased or absent libido.
Nervous system: dry mouth, insomnia, dizziness, thirst, convulsions, lethargy, headache, drowsiness, akathisia, extrapyramidal disorders.
On the part of the digestive tract: gastrointestinal disorders, including abdominal pain, regurgitation, vomiting, change in appetite, nausea, heartburn, constipation; dry mouth, short-term intestinal spasms, diarrhea.
Skin and subcutaneous tissue disorders: itching, rash, urticaria, angioedema.
Reproductive system: galactorrhea, breast enlargement/gynecomastia, breast tenderness, breast discharge, amenorrhea, breast swelling, breast pain, lactation disorder, irregular menstrual cycle.
Musculoskeletal system: leg pain.
From the urinary system: urinary retention, dysuria, frequent urination.
General disorders: asthenia.
On the part of the organs of vision: oculogyric crises.
Others: conjunctivitis, stomatitis.
Changes in laboratory parameters: increased levels of ALT, AST and cholesterol; abnormal liver function tests, increased levels of prolactin in the blood.
Since the pituitary gland is located outside the blood-brain barrier, domperidone may cause an increase in prolactin levels. In rare cases, this hyperprolactinemia may lead to neuroendocrine side effects such as galactorrhea, gynecomastia, and amenorrhea.
During post-marketing use of the drug in adults and children, no adverse reactions were observed, except for extrapyramidal disorders related to the central nervous system, which were observed mainly in children.
Expiration date
2.5 years.
Storage conditions
Store in a dry place, protected from light, 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.
Vacation category
According to the recipe.
Producer
Inventia Healthcare Ltd.
Location of the manufacturer and address of its place of business
F1-F1/1, Ambernath Extension, M.I.D.C., Ambernath (East), 421506, Thane District, Maharashtra, India.
