INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NАUSILIUM (NAUSILIUM)

Composition:

Active substance: domperidone;

1 tablet contains domperidonum maleate equivalent to domperidone 10 mg;

Excipients: lactose monohydrate; corn starch; povidone K-30; microcrystalline cellulose; sodium lauryl sulfate; magnesium stearate; colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, biconvex tablets of white or almost white color.

Pharmacotherapeutic group. Agents used for functional gastrointestinal disorders. Prokinetic agents. ATC code A03F A03.

Pharmacological properties.

Pharmacodynamics.

Domperidone is a dopamine antagonist with antiemetic properties. Domperidone penetrates the blood-brain barrier to a minimal extent. The use of domperidone is very rarely associated with extrapyramidal side effects, particularly in adults, but domperidone stimulates prolactin release from the pituitary gland. Its antiemetic effect is likely due to a combination of peripheral (gastrokinetic) action and antagonism of dopamine receptors in the chemoreceptor trigger zone located outside the blood-brain barrier in the posterior region (area postrema). Animal studies, as well as low brain concentrations detected, indicate that domperidone acts predominantly on peripheral dopamine receptors.

Studies in humans have shown that oral administration of domperidone increases lower esophageal sphincter pressure, improves antroduodenal motility, and accelerates gastric emptying. Domperidone does not affect gastric secretion.

Effect on QT/QTc interval and cardiac electrophysiology.

According to ICH-E14 international guidelines, a thorough QT interval study was conducted in healthy volunteers. This was a double-blind, placebo-controlled study using recommended and supratherapeutic doses (10 and 20 mg administered four times daily). When 20 mg of domperidone was administered four times daily, QT interval prolongation was observed, with changes ranging from 3.4 to 5.9 ms throughout the observation period, but this did not exceed 10 ms. The QT prolongation observed in this study with domperidone administered at the recommended dosage is not considered clinically significant.

This lack of clinical significance is supported by pharmacokinetic parameters and QTc interval data obtained from two earlier studies involving 5-day treatment with 20 mg and 40 mg of domperidone four times daily. ECGs were recorded before the study, on day 5 approximately 1 hour (around tmax) after the morning dose, and after 3 days. In both studies, no difference in QTc was observed between active treatment and placebo. Therefore, it is considered that administration of domperidone at doses of 80 mg and 160 mg daily did not have a clinically significant effect on QTc in healthy volunteers.

Pharmacokinetics.

Absorption.

Domperidone is rapidly absorbed after oral administration on an empty stomach, with peak plasma concentration (Cmax) reached within approximately 60 minutes. Cmax and AUC values of domperidone increased proportionally with doses ranging from 10 to 20 mg. A 2–3-fold accumulation of domperidone (AUC) was observed after repeated administration four times daily (every 5 hours) over 4 days. The low absolute oral bioavailability of domperidone (approximately 15%) is due to extensive first-pass metabolism in the intestinal wall and liver. Although domperidone bioavailability increases when administered after food in healthy volunteers, patients with gastrointestinal symptoms should take domperidone 15–30 minutes before meals. Reduced gastric acidity decreases domperidone absorption. Oral bioavailability is reduced when co-administered with cimetidine and sodium bicarbonate. Oral administration after food slightly delays peak absorption and slightly increases AUC.

Distribution.

After oral administration, domperidone does not accumulate and does not induce its own metabolism; the maximum plasma level at 90 minutes (21 ng/mL) after two weeks of oral administration at 30 mg daily was nearly the same as after the first dose (18 ng/mL). Domperidone is 91–93% bound to plasma proteins. Animal distribution studies using radiolabeled domperidone showed extensive tissue distribution but low brain concentrations. In animals, small amounts of the drug cross the placenta.

Metabolism.

Domperidone is rapidly and extensively metabolized in the liver via hydroxylation and N-dealkylation. In vitro metabolism studies using diagnostic inhibitors have shown that CYP3A4 is the primary cytochrome P450 isoform involved in N-dealkylation, while CYP3A4, CYP1A2, and CYP2E1 are involved in aromatic hydroxylation of domperidone.

Excretion.

Excretion via urine and feces accounts for 31% and 66% of the oral dose, respectively. Elimination of unchanged drug accounts for a small percentage (10% in feces and approximately 1% in urine). The elimination half-life in plasma after a single dose is 7–9 hours in healthy volunteers, but is prolonged in patients with severe renal impairment.

Special patient populations.

Hepatic impairment.

In patients with moderate hepatic impairment (Child-Pugh score 7–9, class B according to Child-Pugh classification), AUC and Cmax of domperidone were 2.9 and 1.5 times higher, respectively, than in healthy volunteers. The free fraction increased by 25%, and the terminal elimination half-life was prolonged from 15 to 23 hours. In patients with mild hepatic impairment, exposure was slightly lower than in healthy volunteers with respect to Cmax and AUC, without changes in protein binding or terminal elimination half-life. The use of domperidone in patients with severe hepatic impairment has not been studied. Domperidone is contraindicated in patients with moderate to severe hepatic impairment (see section "Contraindications").

Renal impairment.

In patients with severe renal impairment (serum creatinine clearance < 30 mL/min/1.73 m²), the elimination half-life of domperidone is prolonged from 7.4 to 20.8 hours, but plasma drug concentrations are lower than in patients with normal renal function. Since only a very small amount of the drug (approximately 1%) is excreted unchanged by the kidneys, dose adjustment is unlikely to be required after single-dose administration in patients with renal impairment. However, with repeated administration, the dosing frequency should be reduced to 1–2 times daily depending on the severity of impairment, and dose reduction may also be necessary.

Clinical characteristics.

Indications.

For relief of symptoms of nausea and vomiting.

Contraindications.

Nausiclum is contraindicated:

in patients with known hypersensitivity to the drug or to excipients;
in patients with established prolactin-secreting pituitary tumor (prolactinoma);
in patients with severe or moderate hepatic and/or renal impairment (see section "Pharmacokinetic properties", "Special precautions");
in patients with known prolongation of cardiac conduction intervals, particularly QTc, in patients with significant electrolyte imbalances or underlying cardiac 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. in 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 (except apomorphine), such as fluconazole, erythromycin, itraconazole, oral ketoconazole, posaconazole, ritonavir, saquinavir, telaprevir, voriconazole, clarithromycin, amiodarone, telithromycin, is contraindicated (see sections "Interaction with other medicinal products and other forms of interaction", "Special precautions").

Interaction with other medicinal products and other forms of interaction.

Anticholinergic drugs may counteract the anti-dyspeptic effect of Nausiclum. Due to pharmacodynamic and/or pharmacokinetic interactions, the risk of QT interval prolongation increases.

Antacids and antisecretory agents should not be taken simultaneously with Nausiclum, 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 significantly 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 with levodopa. Although dose adjustment of levodopa is not considered necessary, increased plasma concentrations of domperidone (up to 30–40%) have been observed when administered concomitantly with levodopa.

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

All medicinal products that prolong the QT interval (risk of "torsade de pointes"):

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., fluconazole, pentamidine);
some antimalarials (e.g., halofantrine, lumefantrine);
some gastrointestinal agents (e.g., cisapride, dolasetron, prucalopride);
some antihistamines (e.g., mizolastine, mequitazine);
some oncology drugs (e.g., toremifene, vandetanib, vinca alkaloids);
some other drugs (e.g., bepridil, methadone, diphenylamine).
apomorphine, except when the benefit of concomitant use outweighs the risks, and under strict adherence to recommended precautionary measures for concomitant use (see the apomorphine product information, section "Contraindications").

Examples of strong CYP3A4 inhibitors with which Nausiclum use is contraindicated:

azole antifungals such as fluconazole*, itraconazole, ketoconazole*, posaconazole and voriconazole*;
macrolide antibiotics such as clarithromycin* and erythromycin*;
protease inhibitors * (e.g., ritonavir, saquinavir, telaprevir);
HIV protease inhibitors such as amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir and saquinavir;
calcium channel blockers such as diltiazem and verapamil;
amiodarone*;
aprepitant;
nefazodone;
telithromycin*.

* prolong QTc interval.

Concomitant use of the following substances requires caution.

Domperidone should be used cautiously with drugs causing bradycardia and hypokalemia, as well as with macrolides that may cause QT interval prolongation: azithromycin and roxithromycin (clarithromycin is contraindicated as it is a potent CYP3A4 inhibitor).

Domperidone should also be used cautiously with potent CYP3A4 inhibitors that do not cause QT prolongation, such as indinavir. Close monitoring for signs or symptoms of adverse reactions is required.

The above list is representative but not exhaustive.

Nausiclum may be combined with:

neuroleptics, whose effects it potentiates;
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 pharmacokinetic/pharmacodynamic 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 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 domperidone plasma concentrations to the observed QTc effect is unknown. In these studies, monotherapy with domperidone (10 mg orally four times daily) prolonged QTc interval by 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), respectively, while administration of ketoconazole alone (200 mg twice daily) or erythromycin alone (500 mg three times daily) resulted in QTc prolongation of 3.8 and 4.9 msec, respectively, during the observation period.

Theoretically, since Nausiclum 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.

Nausicilium is not recommended for use in motion sickness.

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

Cardiovascular effects.

Domperidone has been associated with QT interval prolongation on ECG. In post-marketing surveillance, very rare cases of QT prolongation and ventricular flutter/fibrillation have been reported in patients taking domperidone. These reports included information on patients with other adverse risk factors, electrolyte disturbances, and concomitant therapies that could be contributing factors (see section "Adverse reactions").

According to ICH-E14 guidance, a thorough QT study was conducted in healthy volunteers. The QT interval prolongation observed in the study with domperidone administered at the recommended dosing regimen and usual therapeutic doses (10 or 20 mg four times daily) is not considered to be of clinical significance.

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

If signs or symptoms suggestive of cardiac arrhythmia occur, treatment with domperidone should be discontinued and medical advice should be sought immediately.

Patients should promptly report any cardiac symptoms.

Warnings.

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

Renal function impairment.

The elimination half-life of domperidone is prolonged in severe renal impairment. With long-term 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.

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

Use with apomorphine.

Domperidone is contraindicated for concomitant use with medicinal products that prolong the QT interval, including apomorphine, except when the benefit of concomitant use with apomorphine outweighs the risk, and only if strict adherence to the precautions described in the apomorphine product information is ensured.

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

Some epidemiological studies have shown that domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death (see section "Adverse reactions").
The risk of serious ventricular arrhythmias or sudden cardiac death may be higher in patients aged 60 years or older, in patients receiving oral doses exceeding 30 mg per day, and in patients taking concomitant medicinal products that prolong the QT interval or CYP3A4 inhibitors. Therefore, Nausicilium should be used with caution in elderly patients. Patients aged 60 years or older should consult a physician before taking the medicine.
Domperidone should be prescribed to adults and children at the lowest effective dose.

The benefit-risk ratio of domperidone remains favorable.

Warning for diabetic patients: 1 tablet contains less than 0.01 carbohydrate exchange units.

Excipients.

Nausicilium tablets contain lactose and therefore should not be used in patients with lactose intolerance, galactosemia, or glucose/galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy

Data on post-marketing use of domperidone in pregnant women are limited. Therefore, Nausicilium should be prescribed during pregnancy only if, in the opinion of the physician, the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding

The amount of domperidone that may pass into the infant via breast milk is very low. The maximum relative infant dose (%) is estimated at approximately 0.1% of the maternal dose adjusted for body weight. It is unknown whether it may harm the infant; therefore, mothers taking Nausicilium should avoid breastfeeding. The decision to discontinue breastfeeding or to discontinue domperidone therapy should be made after considering the benefits of breastfeeding for the child and the benefits of therapy for the mother. Caution should be exercised if risk factors for QTc interval prolongation are present in breastfed infants. After exposure due to passage of the drug into breast milk, adverse effects, particularly cardiovascular effects, cannot be excluded.

Ability to affect reaction speed when driving vehicles or operating machinery.

Dizziness and somnolence have been reported after administration of domperidone. Therefore, patients should be advised to refrain from driving vehicles, operating machinery, or engaging in other activities requiring concentration and coordination until they know how the medicine affects them.

Method of Administration and Dosage

The medication should be used at the lowest effective dose for the shortest duration necessary to relieve nausea and vomiting symptoms.

Adults and children aged 12 years and older with body weight of at least 35 kg

One tablet (10 mg) three times daily.

Maximum daily dose – 3 tablets (30 mg per day).

It is recommended to take Nausilium before meals. Drug absorption is slightly delayed when taken after food. The patient should take the medication according to the recommended dosing schedule. If a dose is missed, the next dose should be taken according to the prescribed schedule. The dose should not be doubled to make up for a missed dose. Treatment duration should not exceed 1 week.

Adults aged > 60 years

Patients aged 60 years and older should consult a physician before taking the medication.

Renal Impairment

Since the elimination half-life of domperidone is prolonged in patients with severe renal impairment, the dosing frequency of domperidone should be reduced to once or twice daily, depending on the severity of impairment; dose reduction may also be required. Patients with severe renal impairment should be monitored regularly (see section "Pharmacological Properties").

Hepatic Impairment

Domperidone is contraindicated in patients with moderate (7–9 Child-Pugh points) or severe (> 9 Child-Pugh points) hepatic impairment (see section "Contraindications"). Dose adjustment is not required in patients with mild hepatic impairment (5–6 Child-Pugh points) (see section "Pharmacological Properties").

Children

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

Domperidone should be prescribed to children at the lowest effective dose for the shortest possible duration.

Overdose

Symptoms

Overdose has been reported primarily in infants and children.

Symptoms of overdose may include agitation, altered consciousness, seizures, disorientation, drowsiness, and extrapyramidal reactions.

Treatment

There is no specific antidote for domperidone. However, in cases of significant overdose, gastric lavage within 1 hour after drug intake and administration of activated charcoal are recommended, along with close patient monitoring and supportive therapy. ECG monitoring should be performed due to the potential for QT interval prolongation. Anticholinergic drugs and medications used in Parkinson's disease may be effective in controlling extrapyramidal reactions.

Adverse reactions.

The safety of domperidone was evaluated during clinical trials and post-marketing use. A total of 1275 patients with dyspepsia, gastroesophageal reflux disease, irritable bowel syndrome, nausea and vomiting, or other related conditions participated in double-blind, placebo-controlled clinical studies. All patients were at least 15 years of age and received at least one dose of the drug. The mean total daily dose was 30 mg (range from 10 to 80 mg), and the median duration of exposure was 28 days (range from 1 to 28 days). Patients with diabetic gastroparesis or symptoms induced by chemotherapy or Parkinsonism were not included in the studies.

Assessment of the frequency of adverse reactions: very common (≥ 1/10); common (≥ 1/100, <1/10); uncommon (≥ 1/1000, <1/100); rare (≥ 1/10,000, <1/1000); very rare (<1/10,000), including isolated reports; frequency not known (cannot be estimated from the available data).

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

Immune system disorders: frequency not known – allergic reactions, including anaphylaxis, anaphylactic shock, hypersensitivity.

Endocrine system disorders: rare – increased prolactin levels.

Psychiatric disorders: uncommon – decreased or absent libido, irritability, agitation, nervousness; very rare – depression, anxiety.

Nervous system disorders: uncommon – headache, drowsiness, dizziness, extrapyramidal disorders; very rare – insomnia, thirst, lethargy, akathisia; frequency not known – convulsions, restless legs syndrome (exacerbation of restless legs syndrome in patients with Parkinson's disease).

Cardiac disorders: very rare – edema, palpitations, disturbances in heart rate and rhythm, serious ventricular arrhythmias; frequency not known – QT interval prolongation, ventricular arrhythmias of the torsade de pointes type, sudden cardiac death.

Gastrointestinal disorders: common – dry mouth; uncommon – diarrhea; rare – gastrointestinal disorders including abdominal pain, regurgitation, appetite changes, nausea, heartburn, constipation; very rare – transient intestinal spasms.

Skin and subcutaneous tissue disorders: uncommon – rash, pruritus, urticaria; frequency not known – angioneurotic edema.

Reproductive system and breast disorders: rare – breast enlargement, galactorrhea, breast swelling, lactation disorders, irregular menstrual cycle; uncommon – galactorrhea, breast pain, breast tenderness; frequency not known – gynecomastia, amenorrhea.

Musculoskeletal and connective tissue disorders: rare – leg pain.

Renal and urinary disorders: very rare – dysuria, frequent urination; frequency not known – urinary retention.

General disorders: uncommon – asthenia.

Eye disorders: frequency not known – oculogyric crisis.

Other: conjunctivitis, stomatitis.

Laboratory test abnormalities: very rare – increased levels of ALT, AST, and cholesterol; frequency not known – liver function test abnormalities, increased serum prolactin levels.

In 45 studies where domperidone was used at higher doses, for longer durations, and for additional indications including diabetic gastroparesis, the frequency of adverse reactions (except dry mouth) was significantly higher. This was particularly evident in pharmacologically predictable cases related to elevated prolactin levels.

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.

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

Reporting of adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach and sight of children.

Packaging. 10 tablets per blister, 1 or 3 blisters per cardboard pack.

Prescription status. Over-the-counter (without prescription).

Manufacturer.

Flamingo Pharmaceuticals Ltd.

Manufacturer's address and place of business.

E-28, Opp. Fire Brigade, M.I.D.C., Talegaon, Raigad District, Maharashtra, IN-410 208, India.

Marketing Authorization Holder.

Ananta Medikare Ltd.

Address of the Marketing Authorization Holder.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.