MOTILIUM - PACKAGE LEAFLET - LEAFLETS

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Motilium - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Domperidone

Motilium 10 mg film-coated tablets

Motilium package inserts are available for pack sizes:

Motilium 10 mg film-coated tablets
Motilium 1 mg / ml oral suspension

Why is Motilium used? What is it for?

This medicine is used in adults and children to treat nausea and vomiting (feeling sick).

See the section "How to take MOTILIUM" to see which formulations are to be used in adults and children.

Contraindications When Motilium should not be used

Do not take MOTILIUM if:

you are allergic (hypersensitive) to domperidone or any of the other ingredients of MOTILIUM
have stomach bleeding or habitually experience severe abdominal pain or persistent black stools
have intestinal obstructions or perforations
have tumors of the pituitary gland with prolactin release (prolactinomas).
have moderate or severe liver disease
the "ECG (electrocardiogram) detects a heart disorder called" prolongation of the "QT interval"
you have or have ever had a condition where your heart is unable to pump blood around your body as it should (a condition called heart failure).
have a disorder that causes you to have a low level of potassium or magnesium or a high level of potassium in your blood.
you are taking certain medicines (see 'Taking other medicines').

Precautions for use What you need to know before taking Motilium

Before taking this drug contact your doctor if:

suffer from liver problems (hepatic impairment or insufficiency) (see "Do not use MOTILIUM")
suffer from kidney problems (renal impairment or failure). Talk to your doctor for advice in case of prolonged treatment as you may need to take a lower dose of this drug or take this drug less often and your doctor may want to see you regularly.

Domperidone may be associated with an increased risk of heart rhythm disturbances and cardiac arrest. The risk may be more likely in people over the age of 60 or taking doses greater than 30 mg per day. The risk also increases when domperidone is given together with other drugs. Tell your doctor or pharmacist if you are taking medicines to treat infections (fungal infections or bacterial infections) and / or if you have heart problems or AIDS / HIV (see section "Other medicines and MOTILIUM").

MOTILIUM should be used at the lowest effective dose in adults and children.

While taking MOTILIUM, contact your doctor if you notice heart rhythm disturbances such as palpitations, breathing difficulties, fainting. In this case, treatment with MOTILIUM should be stopped.

Interactions Which drugs or foods can modify the effect of Motilium

Do not take MOTILIUM if you are taking medicines to treat:

fungal infections, for example pentamidine or azole antifungals, especially itraconazole oral ketoconazole, fluconazole posaconazole or voriconazole
bacterial infections, especially erythromycin, clarithromycin, telithromycin, levofloxacin, moxifloxacin, spiramycin (these drugs are antibiotics)
heart problems or high blood pressure (e.g. amiodarone, dronedarone, ibutilide, disopyramide, dofetilide, sotalol, hydroquinidine, quinidine)
psychosis (e.g. haloperidol, pimozide, sertindole)
depression (e.g. citalopram, escitalopram)
gastrointestinal disorders (e.g. cisapride, dolasetron, prucalopride)
allergy (e.g. mechitazine, mizolastine)
malaria (especially halofantrine, lumefantrine)
AIDS / HIV eg ritonavir, saquinavir or telaprevir (these are protease inhibitors)
tumors (e.g. toremifene, vandetanib, vincamine)

Do not take MOTILIUM if you are taking other medicines (eg bepridil, dihfemanile, methadone).

Tell your doctor or pharmacist if you are taking any medications to treat infections, heart conditions or AIDS / HIV.

It is important to ask your doctor or pharmacist if MOTILIUM is safe for you while taking other medicines, including non-prescription medicines.

MOTILIUM with food and drink

Take MOTILIUM before meals. If taken after meals, the absorption of the medicine is somewhat slowed down.

Warnings It is important to know that:

Pregnancy

It is not known whether the use of MOTILIUM during pregnancy is harmful.

If you are pregnant or think you are pregnant, tell your doctor before taking MOTILIUM.

Feeding time

Small amounts of domperidone have been detected in breast milk. MOTILIUM can cause side effects on the heart of the breastfed baby. MOTILIUM should only be used during breastfeeding if your doctor deems it strictly necessary. Ask your doctor for advice before taking this drug.

Driving and using machines

MOTILIUM does not affect the ability to drive or use machines.

Important information about some MOTILIUM components

MOTILIUM oral suspension contains less than 1 mmol sodium, therefore it can be considered sodium-free.
MOTILIUM oral suspension contains sorbitol (E420). Sorbitol can have mild laxative effects. If you have been told that you have an "intolerance to some sugars, consult your doctor before taking this medicine
MOTILIUM oral suspension also contains methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216). These substances can cause allergic reactions (even delayed) and, in exceptional cases, bronchospasm.

Dose, Method and Time of Administration How to use Motilium: Posology

Follow these instructions strictly, unless your doctor has given you different instructions.

Take MOTILIUM before meals because if taken after meals, the absorption of the medicine is somewhat slowed down.

Duration of treatment:

Symptoms usually resolve within 3-4 days of taking this medicine. Do not take MOTILIUM for more than 7 days without consulting your doctor.

Adults and adolescents 12 years of age or older and weighing 35 kg or more

A measuring cap is provided with this medicine. This measuring cup has three lines: 2.5ml, 5ml and 10ml (for example you will have 10ml of oral suspension when the measuring cup is filled to the top line).
Measure the necessary quantity with the special measuring cup.
Make sure the arrow on the measuring cup points upwards.
Do not dilute MOTILIUM and do not mix it with other liquids.
The usual dose is 10 ml (oral suspension containing domperidone 1 mg / ml) up to three times a day. Do not take more than 30ml per day (this is equivalent to 3 scoops filled to the top line).
Clean the measuring cup after use.

Newborns, infants, children under 12 years of age and adolescents with a body weight of less than 35 kg

Your doctor will explain to you exactly how much medicine to give to your child and how often.
Give MOTILIUM to your child using the measuring cup provided with the medicine.
In children the dose depends on body weight The usual dose is 0.25 mg / kg. This dose can be administered up to three times per day for a maximum total dose of 0.75 mg / kg per day. For example, for a child weighing 10 kg, the dose of each administration is 2.5 mg and can be given up to three times per day for a maximum total dosage of 7.5 mg per day.
Give the dose a maximum of 3 times a day at least 4-6 hours apart, if possible before meals / breastfeeding. Do not give the drug more than 3 times in a 24 hour period.

Gently shake the contents of the bottle to avoid foaming.

How to open the bottle

Using the measuring cup

POUR THE SUSPENSION INTO THE "HOLLOW INDICATED BY THE ARROW ON THE MEASUREMENT" (as described in the drawing)

The holes on the measuring cup allow the suspension to come out if it is mistakenly poured from the opposite side to that indicated by the arrow.

Overdose What to do if you have taken too much Motilium

If you take more MOTILIUM than you should

If you have taken too much MOTILIUM, contact your doctor, pharmacist or nearest poison center immediately, particularly if a child has taken too much. In the event of an overdose, symptomatic treatment should be given.

Electrocardiogram monitoring should be done, given the possibility of a heart problem called "prolongation of the" QT interval ".

Information for the physician: close medical surveillance of the subject, gastric lavage, use of activated charcoal and supportive therapy are recommended. Parkinson's anticholinergic drugs may be useful in the control of extrapyramidal disorders.

If you forget to take MOTILIUM

Take the medicine as soon as you remember. If it is almost time for your next dose, wait until your next dose and then continue as normal. Do not take a double dose to make up for a forgotten dose.

Side Effects What are the side effects of Motilium

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Uncommon (may affect up to 1 in 100 people):

Involuntary movements of the face or arms or legs, excessive shaking, excessive stiffness or muscle spasm

Not known (frequency cannot be estimated from the available data):

Convulsions
A type of reaction that can occur soon after administration and is characterized by a rash, itching, shortness of breath and / or swelling of the face
A severe hypersensitivity reaction which can occur soon after administration and is characterized by hives, itching, flushing, fainting, and among other possible symptoms, difficulty breathing
Cardiovascular system disorders: heart rhythm disturbances (rapid or irregular heart rhythm); in the presence of such complaints, you should stop treatment immediately. Domperidone may be associated with an increased risk of heart rhythm disturbances and cardiac arrest. This risk may be more likely in patients over 60 years of age or taking doses greater than 30 mg per day. Domperidone should be used at the lowest effective dosage in adults and children.

Stop treatment with MOTILIUM and contact your doctor immediately if any of the side effects described above occur.

Other side effects that have occurred with MOTILIUM are listed below:

Common (may affect up to 1 in 10 people):

Dry mouth

Uncommon (may affect up to 1 in 100 people):

Anxiety
Agitation
Nervousness
Loss or reduction of libido
Headache
Drowsiness
Diarrhea
Rash
Itching
Urticaria
Painful or sore breasts
Breast milk secretions
General feeling of weakness

Not known (frequency cannot be estimated from the available data):

Upward movement of the eyes
Interruption of the menstrual cycle in women
Enlarged breasts in men
Inability to urinate
Changes in some laboratory tests.

Some patients who have used MOTILIUM for conditions and dosages requiring medical surveillance have experienced the following side effects: Restlessness; breast swelling or enlargement, abnormal secretions from the breasts, irregular menstrual cycle in women, difficulty in breastfeeding, depression, hypersensitivity.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on safety. of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.
Do not use MOTILIUM after the expiry date shown on the label. The expiry date "EXP." Refers to the last day of that month, the first two numbers indicate the month, the following the year.
MOTILIUM oral suspension should not be used more than 3 months after first opening the bottle.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Composition and pharmaceutical form

What MOTILIUM contains

The active ingredient is domperidone.

The other ingredients are:

non-crystallizable liquid sorbitol, microcrystalline cellulose, sodium carboxymethylcellulose, methyl hydroxybenzoate (E218), propyl hydroxybenzoate (E216), sodium saccharin, polysorbate 20, sodium hydroxide and purified water.

Description of MOTILIUM appearance and contents of the package

MOTILIUM 1 mg / ml oral suspension - 200 ml bottle.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Motilium can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the primary packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER CIO 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

MOTILIUM

▼ Medicinal product subject to additional monitoring. This will allow the rapid identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains 10 mg domperidone.

The oral suspension contains domperidone 1 mg per ml.

Excipients with known effect

Film-coated tablets: lactose monohydrate

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablets.

Slightly creamy white tablets, circular tablets e

biconvex.

Oral suspension.

Homogeneous white suspension.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Motilium is indicated for relieving the symptoms of nausea and vomiting.

04.2 Posology and method of administration

Motilium should be used at the lowest effective dose for the shortest duration necessary to control nausea and vomiting.

Oral intake of Motilium before meals is recommended. If taken after meals, the absorption of the drug is somewhat slower.

Patients should try to take each dose at the correct time. If a dose is missed, it should be missed and the usual dosing schedule should be resumed. A double dose should not be taken to make up for a forgotten dose.

As a rule, the maximum treatment duration should not exceed one week.

Adults and adolescents (12 years of age or older and 35 kg or more weight)

Tablets

One 10 mg tablet up to three times a day for a maximum dose of 30 mg per day.

Oral suspension

10 ml (of 1 mg / ml oral suspension) up to 3 times per day for a maximum dosage of 30 ml per day.

Newborns, infants, children (less than 12 years of age) and adolescents weighing less than 35 kg

Oral suspension

The dose is 0.25 mg / kg for each administration. This dose should be administered at least 4-6 hours apart up to three times a day without exceeding the total dosage of 0.75 mg / kg per day. For example, for a child weighing 10 kg, the dose is 2.5 mg for each administration and can be administered three times a day without exceeding the total dosage of 7.5 mg per day.

Oral Domperidone should be taken before meals / breastfeeding. When taken after meals, absorption of the drug is somewhat delayed.

Tablets

Due to the need for precision in dosing, the tablets are not suitable for use in children and adolescents weighing less than 35 kg. The use of the oral suspension is recommended in these patients.

Hepatic impairment

Motilium is contraindicated in moderate or severe hepatic impairment (see section 4.3). However, no dosage adjustment is required in case of mild hepatic impairment (see section 5.2).

Renal impairment

Since the elimination half-life of domperidone is prolonged in the presence of severe renal impairment, the dosing frequency of Motilium should be reduced to once or twice daily depending on the severity of the impairment in case of repeated administration and may need to be reduced. the dosage.

04.3 Contraindications

Motilium is contraindicated in the following situations:

• known hypersensitivity to the active substance or to any of the excipients.

• prolactin-releasing pituitary tumors (prolactinomas).

• in cases where stimulation of gastric motility may be harmful, for example in patients with gastrointestinal bleeding, mechanical obstruction or perforation.

• in patients with moderate or severe hepatic impairment (see section 5.2)

• in patients with known prolongation of cardiac conduction intervals, particularly the QTc interval, in patients with significant electrolyte disturbances and pre-existing heart disease, eg congestive heart failure (see section 4.4).

• concomitant administration of all drugs that prolong the QT interval (see section 4.5).

• concomitant administration of potent CYP3A4 inhibitors (regardless of their effects on QT interval prolongation) (see section 4.5).

04.4 Special warnings and appropriate precautions for use

Renal impairment

The elimination half-life of domperidone is prolonged in severe renal insufficiency. In case of repeated administration, the dosing frequency of Motilium should be reduced to once or twice daily depending on the severity of the impairment. In addition, it may be necessary to reduce the dosage.

Cardiovascular effects

Domperidone has been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, very rare cases of QT interval prolongation and torsades de pointes have been found in patients taking domperidone. These cases included patients with confounding risk factors, electrolyte disturbances and concomitant treatment which may have been contributing factors. (see section 4.8).

Epidemiological studies have shown that domperidone was associated with an increased risk of severe ventricular arrhythmias or sudden cardiac death (see section 4.8). An increased risk has been observed in patients over 60 years of age, in patients taking daily doses greater than 30 mg and in patients taking concomitant QT-prolonging drugs or CYP3A4 inhibitors.

Domperidone should be used at the lowest effective dose in adults and children.

Domperidone is contraindicated in patients with known existing prolongation of cardiac conduction intervals, particularly the QTc interval, in patients with significant electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia), or bradycardia, or in patients with pre-existing heart disease such as insufficiency congestive heart disease due to the increased risk of ventricular arrhythmia (see section 4.3) Electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia) or bradycardia are known to be conditions that increase proarrhythmic risk.

Domperidone treatment should be discontinued in the presence of signs or symptoms associated with cardiac arrhythmia and patients should consult their physician.

Patients should be advised to promptly report any cardiac symptoms.

Pediatric population

Although neurological side effects are rare (see section 4.8), the risk of neurological side effects is higher in young children as metabolic functions and the blood-brain barrier are not fully developed during the first months of life. Therefore it is recommended that the dose be accurately determined in neonates, infants and children (see section 4.2).

Overdose can cause extrapyramidal symptoms in children, but other causes need to be considered.

Precautions for use

The film-coated tablets contain lactose and may be unsuitable for patients with lactose intolerance, galactosemia or glucose / galactose malabsorption.

The oral suspension contains sorbitol and may not be suitable for patients with

intolerance to sorbitol.

04.5 Interactions with other medicinal products and other forms of interaction

When antacid or antisecretory medications are used concomitantly, they should not be taken simultaneously with oral formulations of Motilium (domperidone based), for example they should be taken after meals and not before meals.

Domperidone is predominantly metabolised via the CYP3A4 enzyme system. Data from in vitro studies suggest that concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of domperidone.

Increased risk of QT interval prolongation occurring due to pharmacodynamic and / or pharmacokinetic interactions.

Concomitant intake of the following substances is contraindicated

Medicines that prolong the QTc interval (risk of torsades de pointes)

• class IA anti-arrhythmics (eg disopyramide, hydroquinidine, quinidine)

• class III anti-arrhythmics (eg amiodarone, dofetilide, dronedarone, ibutilide, sotalol)

• some antipsychotics (eg haloperidol, pimozide, sertindole)

• some antidepressants (eg citalopram, escitalopram)

• some antibiotics (for example erythromycin, levofloxacin, moxifloxacin, spiramycin)

• some antifungal agents (eg fluconazole, pentamidine)

• some antimalarial agents (in particular halofantrine, lumefantrine)

• some gastrointestinal medications (eg cisapride, dolasetron, prucalopride)

• some antihistamines (eg mechitazine, mizolastine)

• some drugs used in the treatment of cancers (for example toremifene, vandetanib, vincamine)

• some other medicines (eg bepridil, dihemanyl, methadone) (see section 4.3).

Potent CYP3A4 inhibitors (regardless of their QT-prolonging effects), for example:

• protease inhibitors (eg ritonavir, saquinavir, telaprevir)

• systemic azole antifungals (eg itraconazole, ketoconazole, posaconazole, voriconazole)

• some macrolide antibiotics (for example clarithromycin and telithromycin)

(see section 4.3).

Concomitant use of the following substances is not recommended

• Moderate inhibitors of CYP3A4, eg diltiazem, verapamil and some macrolides.

The concomitant intake of the following substances requires caution in use

Caution should be exercised with drugs that induce bradycardia and hypokalaemia, as well as with the following macrolides involved in prolongation of the QT interval: azithromycin and roxithromycin (clarithromycin is contraindicated as it is a potent inhibitor of CYP3A4).

The above list of substances is indicative and not exhaustive.

04.6 Pregnancy and lactation

Pregnancy

There are few post-marketing data on the use of domperidone in pregnant women. A study in rats showed reproductive toxicity at a high dose, toxic to the mother. The potential risk to humans is unknown.

Therefore, Motilium should only be used in pregnancy if justified by the expected therapeutic benefits.

Breastfeeding

Domperidone is excreted in human milk and breastfed infants receive less than 0.1% of the dose adjusted for maternal weight. The occurrence of adverse effects, particularly cardiac effects, cannot be excluded after exposure via breast milk. In this case, a decision must be made whether to discontinue breastfeeding or to discontinue / discontinue domperidone therapy by evaluating the benefits. of breastfeeding for the infant and the benefits of therapy for the mother. Caution should be exercised in case of risk factors that prolong the QTc interval in breastfed infants.

04.7 Effects on ability to drive and use machines

Motilium has no or negligible influence on the ability to drive and use machines.

04.8 Undesirable effects

The safety of domperidone was evaluated in 1,275 patients with dyspepsia, gastro-oesophageal reflux disease (GERD), irritable bowel syndrome (IBS), nausea and vomiting or other related conditions in 31 double-blind, controlled clinical trials. placebo. All patients were at least 15 years old and received at least one dose of Motilium (based on domperidone). The mean total daily dose was 30 mg (range 10 to 80 mg) and the mean duration of exposure was been 28 days (intervals 1 to 28 days). Studies in diabetic gastroparesis or symptoms secondary to chemotherapy or parkinsonism were excluded.

The following definitions and frequencies apply: very common (≥1 / 10), common (≥1 / 100,

System and organ classification Adverse drug reaction Frequency common Uncommon Not known Disorders of the immune system Anaphylactic reaction (includes anaphylactic shock) Psychiatric disorders Loss of libido Anxiety Agitation Nervousness Nervous system disorders Drowsiness Convulsions Headache Extrapyramidal disorders Eye disorders Oculogyric crisis Cardiac pathologies Ventricular arrhythmias Prolongation of the QTc interval Twists toe Sudden cardiac death (see section 4.4) Gastrointestinal disorders Dry mouth Diarrhea Skin and subcutaneous tissue disorders Rash Angioedema Itching Urticaria Renal and urinary disorders Urinary retention Diseases of the reproductive system and breast Galattorea Gynecomastia Breast pain Amenorrhea Breast tenderness General disorders and administration site conditions Asthenia Diagnostic tests Abnormal liver function test results Increased levels of prolactin in the blood

In 45 clinical trials where domperidone was used at higher doses, for longer duration and for indications including diabetic gastroparesis, the frequency of adverse events (except dry mouth) was significantly higher. This was particularly evident for pharmacologically predictable events related to increased prolactin levels. In addition to the reactions listed above, akathisia, breast discharge, breast enlargement, breast swelling, depression, hypersensitivity, breast disorders have also been reported. "breastfeeding and irregular menstrual cycle.

Extrapyramidal disorders occur mainly in infants and very young children.

Other central nervous system undesirable effects such as convulsions and agitation are reported mainly in infants and children.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicine is important as it allows for continuous monitoring of the benefit / risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. address http://www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose

Symptoms

Cases of overdose have mainly been reported in infants and children. Symptoms of overdose may include agitation, impaired consciousness, seizures, disorientation, somnolence and extrapyramidal manifestations.

Treatment

There is no specific antidote for domperidone. In the event of an overdose, standard symptomatic treatment should be given immediately. ECG monitoring should be performed because of the possibility of QT interval prolongation. Gastric lavage and the use of activated charcoal may be helpful. Close medical surveillance and supportive therapy is recommended. Anticholinergic and anti-parkinson drugs may be useful in the control of extrapyramidal disorders.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Prokinetics, ATC Code: A03FA03

Domperidone is a dopamine antagonist with antiemetic properties. Domperidone does not easily cross the blood brain barrier. In patients treated with domperidone, especially in adults, extrapyramidal side effects are very rare, but domperidone promotes the release of prolactin from the pituitary. The antiemetic effect of domperidone may result from the combination of peripheral (gastrokinetic) effects and antagonism. of dopaminergic receptors in the "chemoreceptor trigger zone". , located in the postrema area, outside the blood brain barrier. Studies in animals, together with the low concentrations found in the brain, indicate a predominantly peripheral effect of domperidone on dopaminergic receptors. Studies in humans have shown that oral domperidone increases lower esophageal sphincter pressure, improves anthroduodenal motility and accelerates gastric emptying. It has no effect on gastric secretion.

A thorough QT interval study was performed in accordance with ICH guidelines "." E14. This study included a placebo, an active comparator and a positive control and was conducted in healthy subjects with a domperidone dosage of up to 80 mg. per day in doses of 10 or 20 mg administered 4 times a day. This study identified a maximum difference in corrected QT interval (QTc) between domperidone and placebo, mean LS (Least Squares) in change from baseline, of 3.4 msec for 20 mg of domperidone administered 4 times daily on Day 4. The two-way confidence interval of 90% (1.0 to 5.9 msec) did not exceed 10 msec. QTc interval when domperidone was administered at a dose up to 80 mg / day (e.g. more than twice the maximum recommended dose).

However, two previous drug interaction studies have shown evidence of QTc interval prolongation when domperidone was given as monotherapy (10 mg 4 times a day). The maximum time-matched mean difference in Fridericia corrected QT interval (QTcF) between domperidone and placebo was 5.4 msec (95% CI: -1.7 to 12.4) and 7.5, respectively. msec (95% CI: 0.6 to 14.4).

05.2 Pharmacokinetic properties

Absorption

Domperidone is rapidly absorbed following oral administration, with peak plasma concentrations recorded approximately 1 hour after administration. Domperidone Cmax and AUC values increased proportionally with dose over the range of 10 mg to 20 mg. A 2- or 3-fold accumulation of domperidone AUC has been observed with repeated doses of domperidone four times daily (every 5 hours) for 4 days.

Although the bioavailability of domperidone is increased in normal subjects when taken after a meal, patients with gastrointestinal disorders should take domperidone 15-30 minutes before a meal. The reduction of gastric acidity alters the absorption of domperidone. Oral bioavailability is reduced by prior concomitant administration of cimetidine and sodium bicarbonate.

Distribution

Domperidone is 91-93% bound to plasma proteins.

Distribution studies, performed with radiolabelled drug in animals, showed "wide tissue distribution but low brain concentrations. Small amounts of the drug cross the placenta in rats."

Metabolism

Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation.

Metabolism Studies in vitro with diagnostic inhibitors indicate that CYP3A4 is the form of cytochrome P-450 most involved in the N-dealkylation of domperidone, while CYP3A4, CYP1A2 and CYP2E1 are involved in the aromatic hydroxylation of domperidone.

Excretion

Urinary and faecal excretion amount to 31% and 66% of the oral dose, respectively. The proportion of unchanged drug excreted 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 volunteers but is prolonged in patients with severe renal insufficiency.

Hepatic impairment

In subjects with moderate hepatic impairment (Pugh score 7 to 9, Child-Pugh classification B), the AUC and C of domperidone are 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 slightly lower systemic exposure than healthy subjects based on Cmax and AUC values, without no changes in protein binding or terminal half-life. Subjects with severe hepatic impairment have not been studied. Motilium is contraindicated in patients with moderate or severe hepatic impairment (see section 4.3).

Renal impairment

In subjects with severe renal impairment (creatinine clearance 2) the elimination half-life of domperidone increased from 7.4 to 20.8 hours but plasma drug levels were lower than in healthy volunteers.

As a very small amount of unchanged drug is excreted (approximately 1%) via the kidneys, it is unlikely that the dose of a single administration will need to be adjusted in patients with renal impairment.

However, in case of repeated administration, the frequency of doses should be reduced to once or twice daily depending on the severity of the disorder and the dosage may need to be reduced.

Pediatric population

No pharmacokinetic data are available in the pediatric population.

05.3 Preclinical safety data

Electrophysiological studies in vitro And in vivo indicate a moderate overall risk of QTc interval prolongation in humans for domperidone. In experiments in vitro on isolated cells transfected with hERG and on isolated myocytes from guinea pigs, exposure ratios ranged from 26 to 47 times, based on IC50 values that inhibit IKr ion channel currents versus free plasma concentrations in humans after administration of the maximum daily dose of 10 mg administered 3 times daily. The safety margins for prolonging the duration of action potential in in vitro experiments on isolated cardiac tissues were 45 times higher than the free plasma concentrations in humans at the maximum dose. daily (10 mg administered 3 times a day). The safety margins in proarrhythmic models in vitro (isolated Langendorff perfused heart) were 9 to 45 times higher than the free plasma concentrations in humans at the maximum daily dose (10 mg administered 3 times a day). In models in vivo no effect levels for prolonged corrected QT interval (QTc) in dogs and induction of arrhythmias in a rabbit model sensitized for torsades de pointes were more than 22-fold and 435-fold, respectively, above the free plasma concentrations in "man at the maximum daily dose (10 mg administered 3 times a day). In the anesthetized guinea pig model, following slow intravenous infusions, there was no effect on the corrected QT interval (QTc) at total plasma concentrations of 45," 4 ng / ml, which is 3 times higher than the total plasma levels in humans at the maximum daily dose (10 mg administered 3 times a day). The relevance of this latest study to humans following exposure to domperidone administered orally is uncertain.

In the presence of inhibition of metabolism by CYP3A4 the free plasma concentrations of domperidone can triple.

At a high maternal toxic dosage (more than 40 times the recommended human dose) teratogenic effects were seen in the rat. No teratogenicity was observed in mice and rabbits.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Motilium 10 mg film-coated tablets

Lactose monohydrate, corn starch, microcrystalline cellulose, pregelatinized potato starch, povidone K90, magnesium stearate, hydrogenated cottonseed oil, sodium lauryl sulfate.

Coating: hypromellose, sodium lauryl sulfate.

Motilium 1 mg / ml oral suspension

Non-crystallizable liquid sorbitol, microcrystalline cellulose, carboxymethylcellulose, methylhydroxybenzoate (E218), propylhydroxybenzoate (E216), sodium saccharin, polysorbate 20, sodium hydroxide, purified water.