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Nausilium®

Nausilium®

Indications

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.

Registration Certificate Number UA/1680/01/01

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INSTRUCTION

for medical use of the medicinal product

 

NAUSILIUM

 

Composition:

active substance: domperidone;

1 tablet contains domperidone maleate equivalent to domperidone 10 mg;

excipients: lactose monohydrate; maize starch; povidone K-30; microcrystalline cellulose; sodium lauryl sulphate; magnesium stearate; colloidal silica anhydrous.

 

Pharmaceutical form. Tablet.

Basic physical and chemical properties: a white or almost white round biconvex tablet.

 

Pharmacotherapeutic group. Propulsives, ATC code A03F A03

 

Pharmacological properties.

Pharmacodynamics.

Domperidone is a dopamine antagonist with anti-emetic properties, Domperidone does not readily cross the blood-brain barrier. In domperidone users, especially in adults, extrapyramidal side effects are very rare, but domperidone promotes the release of prolactin from the pituitary. Its anti-emetic effect may be due to a combination of peripheral (gastrokinetic) effects and antagonism of dopamine receptors in the chemoreceptor trigger zone, which lies outside the blood-brain barrier in the area postrema. Animal studies, together with the low concentrations found in the brain, indicate a predominantly peripheral effect of domperidone on dopamine receptors.

Studies in man have shown oral domperidone to increase lower oesophageal pressure, improve antroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion.

Effect on QT/QTc interval and cardiac electrophysiology.

In accordance with ICH-E14 guidelines, a thorough QT study was performed in healthy subjects. This study was a double, placebo-controlled study using the recommended and over-therapeutic doses (10 and 20 mg, administered 4 times daily). At simultaneous reception of 20 mg of domperidone 4 times a day QT prolongation was reported. The changes varied from 3.4 to 5.9 msec during all period of supervision, but this parameter did not exceed 10 msec. No clinically relevant QTc effect were observed in this study when domperidone was administered as per the recommended dosing.

This lack of clinical significance is confirmed by pharmacokinetic parameters and QTc interval data obtained from two previous studies that included 5-day treatment with 20 mg and 40 mg domperidone 4 times daily. An ECG was recorded before the study, on Day 5 (approximately tmax) one hour after the morning dose and 3 days later. In both studies, there was no difference between QTc after active treatment and placebo. Therefore, domperidone 80 and 160 mg daily were not considered to have a clinically relevant effect on QTc in healthy volunteers.

Pharmacokinetics.

Absorption.

Domperidone is rapidly absorbed after oral administration with peak plasma concentrations occurring at approximately 1 hr after dosing.

The low absolute bioavailability of oral domperidone (approximately 15%) is due to an extensive first-pass metabolism in the gut wall and liver. Although domperidone's bioavailability is enhanced in normal subjects when taken after a meal, patients with gastrointestinal complaints should take domperidone 15-30 minutes before a meal. Reduced gastric acidity impairs the absorption of domperidone. The time of peak absorption is slightly delayed when the oral drug is taken after a meal.

Distribution.

Oral domperidone does not appear to accumulate or induce its own metabolism; a peak plasma level after 90 minutes (21 ng/ml) after two weeks oral administration of 30 mg per day was almost the same as that (18 ng/ml) after the first dose. Domperidone is 91-93% bound to plasma proteins. Distribution studies with radiolabelled drug in animals have shown wide tissue distribution, but low brain concentration. Small amounts of drug crossed the placenta in animals.

Metabolism.

Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation. In vitro metabolism experiments with diagnostic inhibitors revealed that CYP3A4 is a major form of cytochrome P-450 involved in the N-dealkylation of domperidone, whereas CYP3A4, CYP1A2 and CYP2E1 are involved in domperidone aromatic hydroxylation.

Excretion.

Urinary and faecal excretions amount to 31 and 66% of the oral dose respectively. The proportion of the drug excreted unchanged is small (10% of faecal excretion and approximately 1% of urinary excretion). The plasma half- life after a single oral dose is 7-9 hours in healthy subjects but is prolonged in patients with severe renal insufficiency.

Special population.

Hepatic impairment.

In subjects with moderate hepatic impairment (Pugh score 7 to 9, Child-Pugh rating B), the AUC and Cmax of domperidone is 2.9- and 1.5- fold higher, respectively, than in healthy subjects. The unbound fraction is increased by 25%, and the terminal elimination half-life is prolonged from 15 to 23 hours. Subjects with mild hepatic impairment have a somewhat lower systemic exposure than healthy subjects based on Cmax and AUC, with no change in protein binding or terminal half-life. Subjects with severe hepatic impairment were not studied. Domperidone is contraindicated in patients with moderate or severe hepatic impairment (see section "Contraindications").

Renal impairment.

In subjects with severe renal insufficiency (creatinine clearance > 6 mg/100 ml, i.e. > 0.6 mmol/L) the elimination half-life of domperidone is increased from 7.4 to 20.8 hours, but plasma drug levels are lower than in healthy volunteers. Very little unchanged drug (approximately 1%) is excreted via the kidneys (see section "Method of administration and dosage").

 

 

 

Clinical particulars.

Indications.

The drug is indicated for the relief of nausea and vomiting symptoms.

 

Contraindications.

Nausilium is contraindicated in the following situations:

  • - in patients with known hypersensitivity to domperidone or any of the excipients;
  • - in patients with prolactin-releasing pituitary tumour (prolactinoma);
  • - in patients with moderate or severe hepatic impairment (see section "Pharmacokinetics",

"Precautions for use");

  • - in patients who have known existing prolongation of cardiac conduction intervals, particularly

QTc, patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure (see section "Precautions for use");

  • - in patients with hepatic insufficiency;
  • - when stimulation of gastric motility could be harmful e.g. in patients gastro-intestinal

haemorrhage, mechanical obstruction or perforation;

  • - co-administration with ketoconazole, erythromycin or other potent CYP3A4 inhibitors;
  • - co-administration with QT prolonging drugs, such as fluconazole, erythromycin, itraconazole, oral ketoconazole, posaconazole, ritonavir, saquinavir, telaprevir, voriconazole, clarithromycin, amiodarone, telithromycin (see sections “Interaction with other medicinal products and other forms of interaction”, “Precautions for use”).

 

Interaction with other medicinal products and other forms of interaction.

Anticholinergic drugs can neutralize the antidyspeptic effect of Nausilium. Increased risk of occurrence of QT-interval prolongation, due to pharmacodynamic and/or pharmacokinetic interactions.

Antacids and antisecretory drugs should not be taken concomitantly with Nausilium, as they reduce its bioavailability after oral administration (see section "Precautions for use").

The main metabolic pathway of domperidone is through CYP3A4. In vitro data suggest that the concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of domperidone.

When domperidone was co-administered with potent CYP3A4 inhibitors capable for QT-interval prolongation, clinically significant changes in QT interval were observed. Therefore, concomitant use of domperidone with certain drugs is contraindicated (see section "Contraindications").

Concomitant use of the following substances is contraindicated.

QTc-prolonging medicinal products:

  • - anti-arrhythmics class IA (e.g., disopyramide, hydroquinidine, quinidine);
  • - anti-arrhythmics class III (e.g., amiodarone, dofetilide, dronedarone, ibutilide, sotalol);
  • - certain antipsychotics (e.g., haloperidol, pimozide, sertindole);
  • - certain antidepressants (e.g., citalopram, escitalopram);
  • - certain antibiotics (e.g., erythromycin, levofloxacin, moxifloxacin, spiramycin);
  • - certain antifungal agents (e.g., pentamidine);
  • - certain antimalarial agents (in particular halofantrine, lumefantrine);
  • - certain gastro-intestinal medicines (e.g., cisapride, dolasetron, prucalopride);
  • - certain antihistaminics (e.g., mequitazine, mizolastine);
  • - certain medicines used in cancer (e.g., toremifene, vandetanib, vincamine);
  • - certain other medicines (e.g., bepridil, diphemanil, methadone).

Potent CYP3A4 inhibitors:

  • - azole antifungal drugs 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 QTc interval.

Concomitant use of the following substances requires caution in use.

Domperidone should be used with caution in combination with bradycardia and hypokalaemia-inducing drugs, as well as with the following macrolides involved in QT-interval prolongation: azithromycin and roxithromycin (clarithromycin is contraindicated as it is a potent CYP3A4 inhibitor).

Domperidone should be used with caution in combination with potent CYP3A4 inhibitors that did not cause QT prolongation, such as indinavir. Patients should be closely monitored for signs or symptoms of adverse reactions..

The above list of substances is representative and not exhaustive.

Nausilium can be combined with:

  • - neuroleptics, the effect of which it enhances;
  • - dopaminergic agonists (bromocriptine, L-dopa), the undesirable peripheral effects of which, such as indigestion, nausea and vomiting, domperidone suppresses without neutralizing the basic properties.

Separate in vivo pharmacokinetic/pharmacodynamic interaction studies with oral ketoconazole or oral erythromycin in healthy subjects confirmed a marked inhibition of domperidone's CYP3A4 mediated first pass metabolism by these drugs. With the combination of oral domperidone 10 mg four times daily and ketoconazole 200 mg twice daily, a mean QTc prolongation of 9.8 msec was seen over the observation period, with changes at individual time points ranging from 1.2 to 17.5 msec. With the combination of domperidone 10 mg four times daily and oral erythromycin 500 mg three 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. Both the Cmax and AUC of domperidone at steady state were increased approximately three-fold in each of these interaction studies. The contribution of increased plasma concentrations of domperidone to the observed effect on QTc is unknown. In these studies domperidone monotherapy at 10 mg given orally four times daily resulted in increases in mean QTc of 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while Ketoconazole monotherapy (200 mg twice daily) or erythromycin (500mg three times daily) led to increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.

Since Nausilium has a prokinetic effect on the stomach, it may theoretically affect the absorption of oral drugs used concomitantly, in particular prolonged-release or intestinal-soluble dosage forms. However, in patients whose condition had already stabilized with digoxin or paracetamol, concomitant use of domperidone did not affect the level of these drugs in the blood.

 

Precautions for use.

Nausilium is not recommended for motion sickness.

Nausilium should be used with caution in elderly patients or patients with pre-existing heart disease or a history of heart disease.

Cardiovascular effects.

Domperidone has been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking domperidone. These reports included patients with confounding risk factors, electrolyte abnormalities and concomitant treatment which may have been contributing factors.

According to the ICH-E14 guideline, a careful QT interval study was conducted in healthy volunteers. The QT prolongation observed in the study with domperidone, according to the recommended dosing regimen at the usual therapeutic doses (10 or 20 mg 4 times a day), has no clinical significance.

Warnings.

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

Domperidone is contraindicated in patients with known existing prolongation of cardiac conduction intervals, particularly QTc, in patients with significant electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia), or bradycardia, or in patient with underlying cardiac diseases such as congestive heart failure due to increased risk of ventricular arrhythmia. Electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia) or bradycardia are known to be conditions increasing the proarrythmic risk.

Treatment with domperidone should be stopped if signs or symptoms occur that may be associated with cardiac arrhythmia, and the patient should consult their physician.

Renal impairment.

The elimination half-life of domperidone is prolonged in severe renal impairment. For repeated administration, the dosing frequency of domperidone should be reduced to once or twice daily depending on the severity of the impairment. The dose may also need to be reduced.

Antacids or antisecretory drugs should not be taken concomitantly with Nausilium, as they reduce the oral bioavailability of domperidone (see section “Interaction with other medicinal products and other forms of interaction”). When co-administered, Nausilium should be taken before a meal, and antacids or antisecretory drugs should be taken after a meal.

Use with ketoconazole.

QT prolongation has been reported in interactions with oral ketoconazole. Although the value of this study is not clearly established. An alternative treatment should be chosen if antifungal ketoconazole therapy is indicated (see section “Interaction with other medicinal products and other forms of interaction”).

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

The following information on a risk of cardiovascular complications due to domperidone-containing medicines should be considered:

  • Epidemiological studies showed that domperidone was associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death.
  • A higher risk of serious ventricular arrhythmias or sudden cardiac death was observed in patients older than 60 years or those taking daily doses greater than 30 mg, Therefore, Nausilium should be used with caution in elderly patients. Patients over 60 years of age should consult a physician before taking the drug.
  • Domperidone should be used at the lowest effective dose in adults and children.

The risk-benefit balance of domperidone remains favourable.

Warnings for patients with diabetes: 1 tablet contains less than 0.01 carbohydrate metabolism units.

 

Pregnancy and lactation.

There are limited post-marketing data on the use of domperidone in pregnant women. Therefore, Nausilium should only be used during pregnancy when the expected beneficial effect for the mother outweighs the potential risk to the foetus in the opinion of the physician.

A very small amount of domperidone is excreted in human milk. The maximum relative dose for infants (%) is estimated at about 0.1% of the maternal weight-adjusted dose. It is not known whether it harms the baby, so mothers taking Nausilium should refrain from breastfeeding. Caution should be exercised in case of QTc prolongation risk factor in breast-fed infants. Occurrence of adverse effects, in particular cardiac effects cannot be excluded after exposure via breast milk.

 

Effects on ability to drive and use machines.

Dizziness and drowsiness were observed after domperidone administration. Therefore, patients should be advised to refrain from driving, operating machinery or other activities requiring concentration and coordination until patients have understood how the drug affects them.

 

Method of administration and dosage.

The drug is indicated for the relief of nausea and vomiting symptoms.

Adults and children over 12 years of age and those weighing 35 kg or more

1 tablet (10 mg) 3 times a day.

The maximum daily dose is 3 tablets (30 mg per day).

It is recommended to take Nausilium before a meal. Absorption of the drug is delayed if taken after a meal. The duration of treatment should not exceed 1 week.

Adults> 60 years old

Patients over 60 years of age should consult a physician before taking the drug.

Renal impairment

Since the elimination half-life of domperidone is prolonged in severe renal impairment, on repeated administration, the dosing frequency of Domperidone tablets should be reduced to once or twice daily depending on the severity of the impairment, and the dose may need to be reduced. Such patients on prolonged therapy should be reviewed regularly (see section "Pharmacological properties").

Hepatic impairment

Domperidone is contraindicated in moderate (7-9 points on Child–Pugh score) or severe (> 9 points on Child–Pugh score) hepatic impairment (see section "Contraindications"). Dose adjustment in mild hepatic impairment (5-6 points on Child–Pugh score) is not needed (see section "Pharmacological properties").

 

Children.

The drug is used to treat children over 12 years of age and those weighing at least 35 kg.

Domperidone should be given to children in the lowest effective dose for the shortest period of time.

 

Overdose.

Symptoms.

Symptoms of overdose may include agitation, altered consciousness, convulsions, disorientation, somnolence and extrapyramidal reactions.  

Treatment.

There is no specific antidote to domperidone, but in the event of overdose, gastric lavage is recommended within 1 hour after administration of the drug and the use of activated charcoal, and close monitoring of the patient and maintenance therapy as well. Anticholinergic, anti-parkinson drugs may be helpful in controlling the extrapyramidal reactions.

 

Adverse reactions.

The following frequencies of adverse reactions are applied: very common (≥ 1/10); common (≥ 1/100, <1/10); uncommon (≥ 1/1.000, < 1/100); rare (≥ 1/10.000, < 1/1.000); very rare (< 1/10.000), including isolated data; frequency unknown (cannot be estimated from the available data).

If the dosage and duration of treatment are followed, domperidone is usually well tolerated and side effects are uncommon.

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

Endocrine system disorders: rare – increase in prolactin levels.

Psychiatric disorders: very rare – nervousness, irritability, agitation, depression, anxiety, low or loss of libido.

Nervous system disorders: very rare – insomnia, dizziness, thirst, convulsions, lethargy, headache, drowsiness, akathisia, extrapyramidal disorders.

Cardiovascular disorders: very rare – oedema, palpitations, abnormal heart rhythm, QT prolongation (frequency unknown), severe ventricular arrhythmias, torsade de pointes, sudden cardiac death.

Gastrointestinal disorders: rare – gastrointestinal disorders, including abdominal pain, regurgitation, loss of appetite, nausea, heartburn, constipation; very rare – dry mouth, short-term intestinal cramps, diarrhea.

Skin and subcutaneous tissue disorders: very rare – itching, rash; not known – urticaria, angioneurotic oedema.

Reproductive system and breast disorders: rare – galactorrhea, breast enlargement/gynecomastia, breast tenderness, mammary secretions, amenorrhea, breast oedema, breast pain, lactation disorders, irregular menstrual cycle.

Musculoskeletal and connective tissue: rare – leg pain.

Renal and urinary disorders: very rare – urinary retention, dysuria, frequent urination.

General disorders: rare – asthenia.

Eye disorders: not known – oculogyric crisis.

Other: conjunctivitis, stomatitis.

Investigations: very rare – increase in ALT, AST and cholesterol; uncommon – liver function test abnormal; rare – blood prolactin increased.

Since the pituitary gland is outside the blood-brain barrier, domperidone may cause an increase in prolactin levels. In isolated cases, such hyperprolactinaemia may lead to neuroendocrine side effects such as galactorrhea, gynecomastia and amenorrhea.

In the post-marketing period, there were no differences in the safety profile of the drug in adults and children, except for extrapyramidal disorders and other phenomena, seizures and excitement associated with the central nervous system, which were observed mainly in children.

 

Shelf life. 3 years.

 

Storage conditions.

Store in the original package at a temperature not exceeding 30 °С.

Keep out of the reach of children.

 

Packaging.  10 tablets in a blister. 1 or 3 blisters in a carton.

 

Terms of dispensing. No prescription.

 

Manufacturer.

Flamingo Pharmaceuticals Ltd.

 

Manufacturer’s registered address

Е-28, Opp. Fire Brigade, M.I.D.C., Taloja, Dist. Raigad, Maharashtra, IN-410208, India

 

Applicant.

Flamingo Pharmaceuticals Ltd.

 

Applicant’s registered address.

7/1, Corporate Park, Sion-Trombay Road, Chembur, Mumbai - 400071, India.

 

Applicant’s registered address.

30.08.2019.