for medical use
active substance: domperidone;
1 mL of suspension contains domperidone 1 mg;
excipients: saccharose, polysorbate 80, colloidal silicon dioxide anhydrous, carboxymethylcellulose sodium, sodium chloride, propylene glycol, glycerol, methyl parahydroxybenzoate (Е 218), propyl parahydroxybenzoate (Е 216), Ponseau 4R (Е 124), strawberry flavor, purified water.
Pharmaceutical form. Oral suspension.
Basic physical and chemical properties:pink suspension with a characteristic odor.
Peristalsis stimulants (propulsive agents). ATC code А03F А03.
Domperidone is a dopamine antagonist with antiemetic properties. Domperidone slightly penetrates the blood-brain barrier. The use of domperidone is rarely accompanied by extrapyramidal side effects, especially in adults, but Domperidone stimulates production of prolactin from the pituitary gland. His antiemetic effect is possibly due to a combination of peripheral (gastrokinetic) action and antagonism to dopamine receptors in the chemoreceptor trigger zone, which is outside the blood-brain barrier in the back area (area postrema). Studies in animals, as well as low concentrations that were determined in the brain indicate a predominantly peripheral effect of domperidone on dopamine receptors.
Studies in humans have shown that when used orally domperidone increases pressure in the lower esophagus, improves antroduodenal motility and accelerates gastric release.
Domperidone has no effect in gastric secretion.
Domperidone is rapidly absorbed after oral administration in fasting state; the maximum plasma concentration is reached approximately after 30-60 minutes. Low absolute bioavailability of oral domperidone (about 15 %) is due to extensive first-pass metabolism in the intestinal wall and in the liver. Tough in healthy individuals bioavailability of domperidone is increased when taking it in fed state, patients with complaints of the gastrointestinal tract should take domperidone 15-30 minutes before meal. Gastric hypoacidity reduces absorption of domperidone. When the drug is taken orally after meal, its maximum absorption is somewhat decelerated and the area under the curve (AUC) is somewhat increased.
When taken orally, domperidone is not accumulated and does not induce its metabolism; the maximum plasma level after 90 minutes (21 ng/ml) after a two-week oral administration of 30 mg per day was approximately the same as after receiving the first dose (18 ng/ml). 91-93% of domperidone are bound to the plasma proteins. Studies of domperidone distribution conducted in animals using the radiolabeled drug have shown its significant distribution in the tissues, but low concentration in the brain. In animals, small amounts of the drug to penetrate through the placenta.
Domperidone is rapidly and extensively metabolized in the liver by hydroxylation and N-dealkylation. The studies of metabolism in vivo with a diagnostic inhibitor have shown that CYP3A4 is the main form of cytochrome P450, taking part in N-dealkylation, and CYP3A4, CYP1A2 and CYP2E1take part in aromatic hydroxylation of domperidone.
Excretion with the urine and feces is 31 and 665 of the oral dose, respectively. Excretion of the unchanged drug is a small percent (10% with the feces and about 1% with the urine). Plasma half-life after a single oral dose is 7-9 hours in healthy volunteers, but is prolonged in patients with severe liver failure.
For relief of symptoms of nausea and vomiting that last less than 48 hours.
Domrid® is contraindicated:
- for patients with known hypersensitivity to the drug or its excipients;
- for patients with prolactin-secretory pituitary tumor (prolactinoma);
- for patients with moderate to severe hepatic/renal function impairment (see section “Administration details”);
- for patients with known prolongation of cardiac conduction intervals, particularly QTs, patients with significant electrolyte imbalance with such background cardiac diseases as congestive heart failure (see section “Administration details”);
- for patients with hepatic failure;
- if stimulation of motor function of the stomach may be dangerous, for instance in case of gastro-intestinal hemorrhage, mechanical obstruction or perforation;
- concomitant use of ketoconazole, erythromycin or other potent CYP3A4 inhibitors is contraindicated;
- concomitant use of drugs that prolong QT interval, such as fluconazole, erythromycin, itraconazole, oral ketoconazole, posaconazole, ritonavir, saquinavir, telaprevir, voriconazole, clarithromycin, amiodarone, telithromycin and others (see sections “Administration details” and “Interaction with other medicinal products and other types of interaction”).
Interaction with other medicinal products and other types of interaction.
Anticholinergic drugs may neutralize the antidyspeptic effect of domperidone. The risk of QT-interval prolongation is increased due to the pharmacodynamic and/or pharmacokinetic interaction.
Do not take antacids and antisecretory drugs concomitantly with domperidone since they decrease its bioavailability after oral administration (see section “Administration details”).
Domperidone is metabolized mainly by CYP3A4. According to the data of in vitro studies and in humans, concomitant use of drugs that significantly inhibit this enzyme may cause the increase in the plasma level of domperidone.
When using domperidone concomitantly with potent CYP3A4 inhibitors able to prolong QT interval, clinically significant changes in QT interval have been observed. Therefore, the 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 QT interval:
anti-arrhythmics class IA (e.g., disopyramide, quinidine, hydroquinidine);
anti-arrhythmics class III (e.g., amiodarone, dofetilide, dronedarone, ibutilide, sotalol);
certain neuroleptics ( 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 (in particular halofantrine, lumefantrine);
certain gastro-intestinal medicines (e.g., cisapride, dolasetron, prucalopride);
certain antihistamines (e.g., mequitazine, mizolastine);
certain medicines used in cancer (e.g., toremifene, vandetanib);
certain other medicines (e.g., bepridil, methadone, diphemanil).
With the concomitant use of oral ketoconazole or erythromycin in vivo, it has been confirmed that these drugs significantly inhibit domperidone's CYP3A4 mediated presystemic metabolism. With the concomitant use of oral domperidone 10 mg 4 times daily and oral ketoconazole 200 mg 2 times daily, mean QTc over the observation period was prolonged by 9.9 msec, with changes at individual time points ranging from 1.2 to 17.5 msec. With the concomitant use of domperidone 10mg 4 times daily and oral erythromycin 500mg 3 times daily, mean QTc over the observation period was prolonged by 9.9 msec, with changes at individual time points ranging from 1.6 to 14.3 msec. Cmax and the AUC of domperidone at steady state were increased approximately three-fold in each of these interaction studies. The impact of the increased plasma concentrations of domperidone on the observed effect on QTc is unknown. In these studies in case of domperidone monotherapy (10 mg given orally 4 times daily) QTc interval increased on average by 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while ketoconazole monotherapy (200 mg 2 times daily) and erythromycin monotherapy (500mg 3 times daily) led to increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.
Due to pharmacodynamic and/or pharmacokinetic interactions, the risk of occurrence of QT-interval prolongation is increased.
Examples of potent CYP3A4 inhibitors, which are not recommended for concomitant use with Domrid® is not recommended:
azole antifungals, such as fluconazole*, itraconazole, ketoconazole*, and voriconazole*;
macrolide antibiotics, such as clarithromycin* and erythromycin*;
HIV-protease inhibitors, such as amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir and saquinavir;
calcium antagonists, such as diltiazem and verapamil;
*- prolong QTc interval.
Concomitant use of the following substances requires caution.
Caution should be exercised with bradycardia and hypokalemia-inducing drugs, as well as with the following macrolides involved in QT-interval prolongation: azithromycin and roxithromycin (clarithromycin is contra-indicated as it is a potent CYP3A4 inhibitor).
Caution should be exercised when using domperidone concomitantly with potent CYP3A4 inhibitors that o not cause QT-interval prolongation, such as indinavir, and the patients should be closely monitored for signs or symptoms of adverse reactions.
The above list is representative, but not exhaustive.
Domrid® may be combined with:
-neuroleptics, whose effect it increases;
-dopaminergic agonists (bromocriptine, L-dopa), the adverse effects of which, such as indigestion, nausea, vomiting, it inhibits without neutralizing its main properties.
Since domperidone has prokinetic effect in the stomach, theoretically this may have effect on absorption of concomitantly used oral preparations, particularly on the sustained release or enteric formulations. However, in patients whose condition has stabilized on the background of using digoxin or paracetamol, concomitant use of domperidone had no effect on the blood levels of these preparations.
Domrid®is not recommended for use in motion sickness.
Domrid® should be used with caution in elderly patients or in patients with the present cardiac diseases or with the history of cardiac diseases.
Cardiovascular effects. Domperidone was associated with QT-interval prolongation on the ECG. During the postmarketing study, very rare cases of QT prolongation and ventricular fibrillation have been observed in patients taking domperidone. These reports included information about patients with other confounding risk factors, electrolyte disturbances and concomitant treatment, which may have been contributing factors. QT-interval prolongation observed in healthy individuals using domperidone in accordance with the recommended dosage regimen in usual therapeutic doses (10 or 20 mg 4 times a day) had no clinical significance.
Caution. Domperidone should be used with caution in patients with mild hepatic and/or renal impairment.
Due to the increased risk of ventricular arrhythmia, Domrid®is not recommended for use in patients with prolonged cardiac conduction intervals, in particular QTc, patients with significant electrolyte imbalance (hypokalemia, hyperkalemia, hypomagnesemia) or bradycardia, or patients with background cardiac diseases, such as congestive heart failure. It is known that electrolyte imbalance (hypokalemia, hyperkalemia, hypomagnesemia) and bradycardia are the conditions that increase proarrhythmogenic risk.
In case of signs and symptoms that may be associated with cardiac arrhythmia, the use of the drug Domrid® should be stopped, and the patient should seek medical attention immediately.
Impaired renal function. The half-life period of domperidone in severe renal dysfunction is prolonged. In case of long-term administration, the dosage frequency of domperidone should be reduced to one or two times per day depending on the severity of the disorder. In addition, dose reduction might be required.
Antacids or antisecretory drugs should not be taken concomitantly with the drug Domrid®, since they decrease oral bioavailability of domperidone (see section “Interaction with other medicinal products and other types of interaction”). As a part of a combined therapy, the drug Domrid® should be taken before meal, and antacids or antisecretory drugs should be taken after meal.
Use with ketoconazole. In the interaction studies with oral form of ketoconazole, QT-interval prolongation has been marked. Though the significance of this study has not been clearly determined, alternative treatment should be chosen is antifungal therapy with ketoconazole is indicated (see section “Interaction with other medicinal products and other types of interaction”).
Note the following information regarding the risk of complications of cardiovascular diseases caused by 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 and more or at oral doses over 30 mg per day. Domrid® should therefore be used with caution in elderly patients. Patients aged 60 years and more should consult their physician before taking the drug Domrid®.
Domperidone should be prescribed to adults and children at the lowest effective dose.
The risk/benefit ratio of using domperidone remains favorable.
If you have known intolerance to some sugars, consult your physician before taking this medicinal product since the drug contains sucrose. The drug contains Ponseau 4R which may cause allergic reactions, asthmatic attacks, especially in patients with hypersensitivity to acetylsalicylic acid. Methyl parahydroxybenzoate and propyl parahydroxybenzoate that are contained in the drug may cause allergic reactions (probably delayed).
Use during pregnancy and lactation.
The post-marketing data on the use of domperidone in pregnant women are limited. Therefore, Domrid® during pregnancy should only be used during pregnancy when, according to the doctor, the anticipated therapeutic benefit for the mother outweighs the potential risk to the fetus.
The amount of domperidone that may penetrate to the organism of the infant through the breast milk is extremely low. The maximum relative dose for the infants (%) is evaluated at the level of approximately 0.1 % of the mother’s dose adjusted for body weight. It is unknown whether it is harmful for the infant, therefore, the mothers taking Domrid® should refrain from breast-feeding.Occurrence of adverse effects, in particular cardiac effects cannot be excluded after exposure via breast milk. Caution should be exercised in case of QTc prolongation risk factors in breast-fed infants.
Effects on ability to drive and use machines.
Taking into account the adverse reactions of the nervous system, patients should be careful when driving or using other mechanisms.
Posology and method of administration.
It is recommended to take Domrid® before meal. If the drug is taken after meal, absorption of the drug is somewhat delayed.
Duration of treatment should not exceed 1 week.
Adults and children aged 12 and more weighing more than 35 kg: 10 mg (10 ml of suspension) up to 3 times per day.
The maximum daily dose is 30 mg (30 ml of suspension).
Children aged less than 12, and children aged more than 12 weighing less than 35 kg: 0.25 mg (0.25 ml of suspension)/kg of bodyweight up to 3 times per day.
The maximum daily dose is 0.75 mg (0.75 ml of suspension)/kg of bodyweight.
Note that the measuring spoon is for measuring 2.5 or 5 ml of suspension. To measure less than 1 ml of suspension, use a 2 ml plastic single use syringe without a needle.
Domperidone should be used in children at the lowest effective dose.
Caution should be exercised when prescribing the drug to neonates and premature infants.
When using in neonates, especially in premature infants and breast-fed infants, the prescribed dose should be carefully calculated. Extrapyramidal disorders may occur if the recommended dose is exceeded.
Symptoms. The symptoms of overdose may be agitation, impaired consciousness, seizures, drowsiness, disorientation and extrapyramidal reactions, especially in children.
Treatment. There is no specific antidote to domperidone, but in case of significant overdose, gastric lavage is recommended within 1 hour after the intake of the drug, and usage of activated charcoal, as well as careful observation of the patient and supportive therapy. Anticholinergic drugs for the treatment of Parkinson's disease may be effective to control extrapyramidal reactions.
On condition of compliance with the recommendation on dosage and duration of therapy, domperidone is usually well tolerated, and the adverse events occur rarely.
Immune system: allergic reactions, including anaphylaxis, anaphylactic shock, hypersensitivity.
Endocrine system: prolactin levels increase.
Psychiatric disorders: anxiety, irritability, agitation, depression, anxiety, decreased or absent libido.
Nervous system: extrapyramidal disorders, insomnia, dizziness, thirst, muscle cramps, weakness, headache, somnolence, akathisia.
Cardiovascular system: edema, palpitation sensation, impaired rate and rhythm of heart contractions, lengthening the interval QT (frequency unknown), severe ventricular arrhythmia, ventricular arrhythmias of the type “torsade de pointes”), sudden cardiac death.
Gastrointestinal tract: dry mouth, intermittent intestinal cramps, diarrhea, gastrointestinal disorders, including abdominal pain, regurgitation, change of appetite, nausea, heartburn, constipation.
Organs of vision: oculogyric crisis.
Skin and subcutaneous tissue: pruritus, rash, urticaria, angioedema.
Reproductive system and mammary glands: galactorrhea, breast enlargement / gynecomastia, breast sensitivity, discharge from the breasts, amenorrhea, breast swelling, pain in the breast, impaired lactation, irregular menstrual cycle.
Musculoskeletal system and connective tissue: pain in the legs.
Urinary system: urinary retention, dysuria, frequent urination.
General disorders: asthenia.
Other: conjunctivitis, stomatitis.
Changes in in laboratory parameters: abnormal liver function tests, increased ALT, AST and cholesterol, increased prolactin levels.
Since the pituitary gland is outside the blood-brain barrier, domperidone may cause increase in prolactin levels. In rare cases, this hyperprolactinemia may lead to neuro-endocrine side effects such as galactorrhea, gynecomastia and amenorrhea.
During the postmarketing use of the drug, no differences in the safety profiles of the drug in adults and children were noted except for extrapyramidal disorders and other phenomena, convulsions and agitation associated with the central nervous system, observed mainly in children.
Shelf-life. 3 years.
Store in the original package at the temperature not more than 25oC.
Keep out of reach of children.
Store the drug no longer than 4 weeks after the first opening of the bottle.
60 ml of 100 ml are in bottles, or 30 ml are in a jar. Each bottle or jar is in a carton package together with a measuring spoon.
Conditions of supply.
KUSUM PHARM LLC.
Ukraine, 40020, Sumy region, Sumy, Skryabina Str., 54.
Date of last revision.
1 mL of suspension contains Domperidone 1 mg; Peristalsis stimulanst (propulsive agents).
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