D2-dopamine receptor antagonists
Nausilium®Nausilium® Registration Certificate Number UA/1680/01/01
Adults. Nausea and vomiting, epigastric feeling of repletion, pain in the upper abdominal region, heartburn with reflux of stomach content to the mouth or without it.
Children. Symptomatic relief of nausea and vomiting.
for medical use of the medicinal product
Active substance: domperidone;
1 tablet contains domperidone maleate equal to 10 mg of domperidone;
Inactive substances: lactose, monohydrate; corn starch; povidone K30; microcrystalline cellulose; sodium lauryl sulfate; magnesium stearate; anhydrous colloidal silicone dioxide.
Pharmaceutical form. Tablets.
Basic physical and chemical properties: white to almost white round biconvex tablets.
Pharmacotherapeutic group. Agents used in functional gastrointestinal disorders. Peristalsis stimulants. ATC code A03F A03.
Domperidone is a dopamine antagonist with antiemetic properties. Domperidone crosses the blood-brain barrier to a little extent. Administration of domperidone is rarely associated with extrapyramidal adverse reactions, especially in adults; however, domperidone stimulates pituitary prolactin secretion. Its antiemetic activity might be attributed to the combination of peripheral (gastrokinetic) action and antagonism to dopamine receptors in chemoreceptor trigger zone (CTZ), which is located in the area postrema of the medulla oblongata. Animal studies and low concentrations determined in the brain, demonstrate predominantly peripheral domperidone effect on dopamine receptors.
Studies in humans demonstrated that oral intake of domperidone increases the pressure in the lower esophagus, improves the antroduodenal motility and accelerates bowel movements. Domperidone has no effect on gastric secretion.
Domperidone is rapidly absorbed after the oral intake on an empty stomach, its maximum blood plasma concentrations are achieved approximately in 30-60 minutes. The low absolute bioavailability of oral domperidone (approximately 15%) is attributed to extensive first-pass metabolism in intestinal wall and in liver. Although in healthy patients, domperidone bioavailability increases after eating, patients with gastrointestinal problems should administer domperidone 15-30 minutes before meals. Reduced gastric acidity leads to a decreased domperidone absorption. The bioavailability at the oral intake of the drug decreases if cimetidine or sodium bicarbonate were administered before. At the oral intake of the drug after meals, its maximum absorption is slightly decreased, and the area under curve (AUC) is slightly increased.
At the oral intake, domepridone does not accumulate and does not induce its own metabolism; its maximum blood plasma concentrations in 90 minutes (21 ng/ml) after the 2-week oral administration of 30 mg per day were almost the same as after the administration of the first dose (18 ng/ml). Domperidone binds to blood plasma proteins by 91-93%. The studies of domperidone distribution, which have been conducted in animals with the drug marked with radioactive isotope, have demonstrated its significant distribution in tissues, but low concentration in brain. In animals, small amounts of the drug cross the placenta.
Domperidone is rapidly and extensively metabolized in liver by means of hydroxylation and N-dealkylation. Studies of metabolism in vitro with a diagnostic inhibitor, demonstrated that CYP3A4 is the main form of cytochrome P450, involved in N-dealkylation, and CYP3A4, CYP1A2, AND CYP2E1 are involved in aromatic domperidone hydroxylation.
Excretion in urine and faeces makes 31% and 66% of the oral dose, respectively. The unchanged drug excretion is not significant (10% in faeces and approximately 1% in urine). The blood plasma elimination half-life after the intake of a single dose is 7-9 hours in healthy volunteers, and is prolonged in patients with renal insufficiency.
To relieve the symptoms of nausea and vomiting that last less than 48 hours.
Nausilium is contraindicated:
- - in patients with determined increased sensitivity to the drug or inactive substances;
- - in patients with pituitary tumor (prolactinoma);
- - in patients with impaired renal and/or liver function;
- - in patients with determined prolongation of the QT interval, which causes cardiac diseases and disorders;
- - in patients with liver failure.
Nausilium should not be used, if the stimulation of gastrointestinal motility function can be dangerous, for example, in case of gastrointestinal haemorrhage, mechanical bowel obstruction, or perforation.
Concomitant use of ketoconazole, erythromycin, or other potent inhibitors of CYP3A4, drugs that prolong the QT interval, e.g. fluconazole, erythromycin, itraconazole, peroral ketoconazole, posakonazole, ritonavir, saquinavir, telaprevir, vorikonazole, clarythromycin, amiodarone, telithromycin (see sections “Precautions for use” and “Interaction with other medicinal products and other forms of interaction”).
Interaction with other medicinal products and other forms of interaction.
Anticholinergic drugs can neutralize the antidyspeptic activity of Nausilium.
Antacid and antisecretory drugs should not be administered concomitantly with Nausilium, because they decrease its bioavailability after the oral intake.
Domperidone is mainly metabolized by CYP3A4. According to the studies in vitro, concomitant administration of the drugs that significantly inhibit this enzyme, might lead to the increase of domperidone level in blood plasma.
In some studies of pharmacokinetic and phrmacodynamic interaction in vivo at concomitant oral administration of ketoconazole or erythromycin in healthy volunteers, it was confirmed that these drugs significantly inhibit the presystemic metabolism of domperidone, indirectly caused by CYP3A4. At concomitant oral use of domperidone 10 mg 4 times a day and ketoconazole 200 mg 2 times a day, during the monitoring period, the prolongation of a QTc interval by 9.8 msec was observed; and some values fluctuated from 1.2 to 17.5 msec. At concomitant use ofdomperidone 10 mg 4 times a day and erythromycin 500 mg 3 times a day, the QTc interval during the monitoring period was prolonged by 9.9. msec on average, the interval of some values was from 1.6 to 14.3 msec. The equivalent domperidone values Cmax and AUC increased approximately 3-fold in each of these interaction studies. The contribution of increased domperidone plasma concentrations to the observatory effect of QTc is unknown. In these studies when domperidone was used as monotherapy (oral intake of 10 mg 4 times a day), the average prolongation of the QTc interval was 1.6 msec (studies of ketoconazole) and 2.5 msec (studies of erythromycin), while administration of ketoconazole alone (200 mg 2 times a day) or erythromycin (500 mg 3 times a day) led to the prolongation of the QT intervalduring the monitoring period by 3.8 and 4.9 msec, respectively.
Theoretically, Nausilium’sgastricprokineticeffect might influence theabsorptionofperoralagentsthatareadministeredconcomitantly, particularly, theprolonged-releaseandenterosolublepharmaceuticalforms. However, in patients whose state has stabilized due to the administration of digoxin or paracetamol, concomitant administration of domperidone had no influence on the blood levels of these drugs.
Examples of potent CYP3A4 inhibitors, which are not recommended to use with Nausilium:
- - azole antifungal agents, such as fluconazole*, itraconazole, ketoconazole*, and voriconazole*;
- - macrolide antibiotics, such as clarythromycin*, and erythromycin*;
- - HIV protease inhibitors, such as amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir, and saquinavir;
- - calcium antagonist, such as diltiazem, and verapamil;
- - amiodaron*;
- - amrepitant;
- - nefazodone;
- - telithromycin*.
*prolong QTc. .
Nausilium can be combined with:
- - neuroleptics, which activity it does not enhance;
- - dofaminergic agonists (bromcriptine, L-dopa) which peripheral adverse reactions, such as digestive disorders, nausea, vomiting, are inhibited without neutralizing their main effect
Possible interactions with other medicinal agents
The main metabolic pathway of domperidone is through CYP3A4. The studies in vitro and in humans demonstrate that concomitant use of the drugs that significantly inhibit this enzyme might lead to an increase of blood plasma domperidone levels. Concomitant administration of domperidone and potent inhibitors of CYP3A4, which might cause prologation of the QT interval, is contraindicated (see section “Adverse reactions”).
Domperidone is to be used with great caution concomitantly with potent inhibitors of CYP3A4, which does not prolong the QT interval, e.g. indinavir; and patients should be closely monitored for the signs or symptoms of adverse reactions.
Domperidone and the drugs that prolong the QT interval should be co-administered with great caution; and the patients should be closely monitored for the signs or symptoms of adverse cardiovascular reactions. Such drugs, for example, are:
- - antiarrythmic agents class IA;
- - antiarrythmic agents class ІІІ;
- - some neuroleptic agents;
- - some antidepressants;
- - some antibiotics;
- - some antifungal agents;
- - some antimalarial agents;
- - some gastro-intestinal agents;
- - some agents administered at oncological diseases;
- - some other agents.
The abovementioned list is representative, yet, not exhaustive.
Precautions for use.
Patients who suffer from nausea and vomiting that persist longer than 48 hours should consult a doctor. Nausilium is not recommended for motion sickness.
The following information regarding the risk of development of cardiovascular diseases complications, caused by the drugs that contain domperidone, should be considered:
Nausilium should be administered in elderly patients or in patients with a history of a heart disease with great caution.
Some epidemiological studies demonstrated that domperidone might be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death. These studies show that the risk of serious ventricular arrhythmias or sudden cardiac death can be higher in patients older than 60 years or at peroral intake of the drug doses of more than 30 mg per day. That is why Naisilium is to be used with caution in elderly patients. Patients older than 60 years should consult a doctor before use.
In case any signs or symptoms associated with cardiac arrhythmia occur, treatment with domperidone should be discontinued and the patient should consult a doctor.
Antacid or antisecretory drugs should not be co-administered with Naisilium, as they lower the peroral bioavailability of domperidone (see section “Interaction with other medicinal agents and other forms of interaction”). At concomitant administration, Nausilium should be taken before meals, and antacid or antisecretory drugs – after meals.
Co-administration with ketoconazole
The studies of the interaction with peroral form of ketoconazole showed the prolongation of the QT interval. Although the significance of this study has not been clearly determined, it is advisable to opt for an alternative treatment, if antifungal therapy with ketoconazole is prescribed (see section “Interaction with other medicinal products and other forms of interaction”).
Due to the increased risk of ventricular arrhythmias, Nausilium is not recommended to use in patients with prolonged QTc interval, in patients with significant imbalance of electrolytes (hypokalemia, hyperkalemia, hypomagnesemia) or bradycardia; or in patients with pre-existing heart diseases, e.g. congestive heart failure. It is known that electrolyte imbalance (hypokalemia, hyperkalemia, hypomagnesemia) and bradycardia are states that increase the proarrythmogenic risk.
Domperidone should be used with caution in patients with the risk factors for QT interval prolongation, including hypokalemia, severe hypomagnesemia, organic heart diseases, concomitant administration of the drugs that prolong QT interval.
Domperidone should be prescribed to adults and children in the lowest effective dose.
The domperidone risk-benefit ratio remains profitable.
Naisilium tablets contain lactose, so the drug should not be used in patients with galactose intolerance, lactase insufficiency, and glucose/galactose malabsorption syndrome.
Warning for patients with diabetes:
1 tablet contains less than 0.01 of carbohydrate exchanges.
Use during pregnancy and lactation.
There are limited data on the use of domperidone in pregnant women. Therefore, Nausilium during pregnancy should only be prescribed when the doctor expects the positive outcome for the mother to outweigh the potential risk for the fetus.
The studies showed that domperidone enters breast milk. The amount of domperidone that can get into the baby’s organism is little. The maximum relative dose for new-borns (%) is assessed as about 0.1% of the mother’s dose adjusted for body weight.
It is unknown if it is harmful for new-borns, therefore, mothers who administer Nausilium, should refrain from breastfeeding.
Effects on reaction rates while driving vehicles or operating other machinery.
Considering the CNS adverse events, patients should be careful while driving vehicles or operating other machinery.
Routes of administration and dosage.
Nausilium is advised to be administered before meals. The absorption of the drug is somewhat slowed down, if it is administered after meals. The duration of the treatment should not exceed 1 week.
For relieving the symptoms of nausea and vomiting.
Adults and children over 16 years old: 1 tablet (10 mg 3 times a day)
The maximum daily dose is 3 tablets (30 mg)
The maximum duration of the treatment – 48 hours without consulting a doctor.
The drug can be used for treating children aged over 16 years.
Domperidone is prescribed for children in the lowest effective dose.
Symptoms: the overdose symptoms might include agitation, impaired consciousness, seizures, disorientation, drowsiness and extrapyramidal reactions.
Treatment. There is no specific antidote to domperidone, but in case of significant overdose, gastric lavage within 1 hour after the intake, use of activated charcoal, close monitoring and supporting therapy are recommended. Anticholinergic agents, drugs for treatment of Parkinson’s disease might be effective for controlling extrapyramidal reactions.
If the recommendations for dosage and duration of the treatment are followed, domperidone is usually well-tolerated, and adverse reactions rarely occur.
Adverse reactions that were observed at the use of domperidone preparations in clinical practice, are distributed according to the organ systems, and the frequency of their occurrence is the following: very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon (≥ 1/1000 to <1/100); rare (≥ 1/10000 to <1/1000); very rare (<1/10000), including isolated data.
Immune system disorders: very rare – allergic reactions, including anaphylaxis, anaphylactic shock, hypersensitivity.
Endocrine system disorders: rare – increase of prolactin level.
Mental disorders: very rare – nervousness, annoyance, agitation, depression, anxiety, decrease or loss of libido.
Nervous system disorders: very rare – insomnia, dizziness, thirst, seizures, headache, migraine, drowsiness, akathisia, extrapyramidal disorders.
Cardiovascular system disorders: very rare – oedema, palpitation, irregular heartbeat and abnormal heart rhythms, QT interval prolongation (frequency is unknown) severe ventricular arrhythmias, oedema, arterial hypertension, sudden cardiac death.
Gastrointestinal tract disorders: rare – gastrointestinal disorders, including abdominal pain, regurgitation, appetite loss, nausea, pyrosis, constipation; very rare – dry mouth, short-term intestinal spasms, abdominal spasms, eructation, diarrhoea.
Eyesight disorders: of unknown frequency – oculogyric crisis.
Skin and subcutaneous tissues disorders: very rare – itching, rash; of unknown frequency – urticaria, angioneurotic oedema.
Reproductive system and breasts disorders: rare – galactorrhea, increase of breasts/gynecomastia, sensitivity of breasts, nipple discharge, breast pain, lactation impairment, irregular menstruations.
Musculoskeletal system and connective tissue disorders: rare – pain in legs.
Urinary system disorders: very rare – urinary retention, dysuria, often and painful urination.
General disorders: rare – asthenia.
Other: conjunctivitis, stomatitis, calf muscles seizures, increased sweating, fever.
Changes in laboratory tests: very rare – increase in ALT and AST levels, cholesterol levels; uncommon – functional liver tests aberrations; rare – increased blood prolactin levels.
As pituitary is outside the blood-brain barrier, domperidone might cause an increase in prolactine levels. In single cases, such hyperprolactinemia might lead to neuroendocrine adverse reactions, such as galactorrhea, gynecomastia, and amenorrhea.
During the post-marketing use of the drug, no differences in the safety profile of adults and children were observed, except for pyramidal disorders and other events, seizures and excitement, connected to the CNS, and mainly observed in children.
Storage life. 3 years
Storage conditions. Keep at temperature not exceeding 30 °С in the original package. Keep out of reach of children.
Package. 10 tablets in a blister, 1 or 3 blisters in a box.
Terms of dispensing. Without prescription.
Flamingo Pharmaceuticals Ltd.
Manufacturer’s registered address.
Е-28, Opp. Fire Brigade, MIDC, Taloja, Dist. Raigad, Maharashtra, IN-410 208, India.
Flamingo Pharmaceuticals Lts.
Applicant’s registered address:
7/1, Corporate Park, Sion Trombay Road, Chembur, Mumbai – 400 071, India.
Date of last review. 05.12.14.