Change relates to the implementation of the PRAC recommendations following the outcome of the domperidone PSUSA (PSUSA/00001158/201611). These recommendations include updating Sections 4.3, 4.4, and 4.5 of the Summary of Product Characteristics in order to facilitate the safe use of domperidone together with apomorphine in the specific population of patients suffering of Parkinson's disease, and to update the Package leaflet accordingly.

Section 4.5 Added text "Co-administration with levodopa
Although no dosage adjustment of levodopa is deemed necessary, an increase (maximum of 30% - 40%) of plasma concentration has been observed when domperidone was taken concomitantly with levodopa."

Section 4.7 Replaced "Motilium has no, or negligible, influence on the ability to drive and use machines" with "Dizziness and somnolence have been observed following use of domperidone (see section 4.8). Therefore, patients should be advised not to drive or use machinery or engage in other activities requiring mental alertness and coordination until they have established how Motilium affects them"

Section 4.8 Included "Dizziness" and "Restless leg syndrome" in the table, along with "^{*exacerbation of restless legs syndrome in patients with Parkinson’s disease} " following the table.

Section 10 Replaced dat ewith "April 2016"

SECTION 4.1

FROM

Adults
The relief of the symptoms of nausea and vomiting, epigastric sense of fullness, upper abdominal discomfort and regurgitation of gastric contents.
Children
The relief of the symptoms of nausea and vomiting.

TO

Motilium is indicated forthe relief of the symptoms of nausea and vomiting.

SECTION 4.2

FROM

It is recommended to take oral Motilium before meals. If taken after meals, absorption of the drug is somewhat delayed.
The initial duration of treatment is four weeks. Patients should be re-evaluated after four weeks and the need for continued treatment re-assessed. Therapy should not exceed 14 days of continuous treatment without medical consultation.
See section 4.4 for further information.

Adults and adolescents (over 12 years and weighting35 kg or more)
10 ml to 20 ml of oral suspension (containing domperidone 1 mg per ml) three to four times per day with a maximum daily dose of 80 ml.
Infants and Children under 12 years of age and weighing less than 35kg
0.25-0.5 mg/kg three to four times per day with a maximum daily dose of 2.4 mg/kg (but do not exceed 80 mg per day).
Hepatic Impairment
Motilium is contraindicated in moderate or severe hepatic impairment (see section 4.3). Dose modification in mild hepatic impairment is however not needed (see section 5.2).
Renal Impairment
Since the elimination half-life of domperidone is prolonged in severe renal impairment, on repeated administration, the dosing frequency of Motilium 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 sections 4.4 and 5.2)

TO

Motilium should be used at the lowest effective dose for the shortest duration necessary to control nausea and vomiting
It is recommended to take oral Motilium before meals. If taken after meals, absorption of the drug is somewhat delayed.
Patients should try to take each dose at the scheduled time. If a scheduled dose is missed, the missed dose should be omitted and the usual dosing schedule resumed. The dose should not be doubled to make up for a missed dose.

Usually, the maximum treatment duration should not exceed one week.
Adults and adolescents (12 years of age and older and weighting35 kg or more)
10 ml (of 1mg/ml oral suspension) up to three times per day with a maximum dose of 30 ml per day.
Neonates, infants, children (less than 12 years of age) and adolescents weighing less than 35 kg
The dose is 0.25mg/kg per intake. This should be given at least 4-6 hours apart up to three times per day not to exceed a maximum of 0.75 mg/kg per day . For example, for a child weighing 10 kg, the dose is 2.5 mg per intake and this can be given up to three times per day not to exceed a total amount of 7.5 mg per day.

Motilium Oral Suspension should be taken before meals/feeding. If taken after meals, absorption of the drug is somewhat delayed

Hepatic Impairment
Motilium is contraindicated in moderate or severe hepatic impairment (see section 4.3). Dose modification in mild hepatic impairment is however not needed (see section 5.2).
Renal Impairment
Since the elimination half-life of domperidone is prolonged in severe renal impairment, on repeated administration, the dosing frequency of Motilium should be reduced to once or twice daily depending on the severity of the impairment, and the dose may need to be reduced.

SECTION 4.3

FROM

Motilium is contraindicated in the following situations:
 known hypersensitivity to domperidone or any of the excipients
 prolactin-releasing pituitary tumour (prolactinoma).
Motilium should not be used
• when stimulation of the gastric motility could be harmful, e.g. in patients with gastro-intestinal haemorrhage, mechanical obstruction or perforation.
• In patients with moderate or severe hepatic impairment (see section 5.2).

TO

Motilium is contraindicated in the following situations:
 known hypersensitivity to domperidone or any of the excipients
 prolactin-releasing pituitary tumour (prolactinoma).
• when stimulation of the gastric motility could be harmful, e.g. in patients with gastro-intestinal haemorrhage, mechanical obstruction or perforation.
• In patients with moderate or severe hepatic impairment (see section 5.2).
• 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 4.4)
• co administration with QT prolonging drugs (see section 4.5)
• co administration with potent CYP3A4 inhibitors (regardless of their QT prolonging effects) (see section 4.5).

SECTION 4.4

FROM

Precautions for use
The suppositories contain butylated hydroxyanisole which can irritate eyes, skin and the lining of the mouth and nose (mucous membranes).
Use during lactation
The total amount of domperidone excreted in human breast milk is expected to be less than 7μg per day at the highest recommended dosing regimen. It is not known whether this is harmful to the newborn. Therefore Motilium is not recommended in breast-feeding women.
Use in infants
Although neurological side effects are rare (see "Undesirable effects" section), the risk of neurological side effects is higher in young children since metabolic functions and the blood-brain barrier are not fully developed in the first months of life.
Overdosing may cause extrapyramidal symptoms in children, but other causes should be taken into consideration.
Renal impairment
Since the elimination half-life of domperidone is prolonged in severe renal impairment, , on repeated administration, the dosing frequency of Motilium 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 5.2).
Use with potent CYP3A4 inhibitors
Co-administration with oral ketoconazole, erythromycin or other potent CYP3A4 inhibitors that prolong the QTc interval should be avoided (see section 4.5).

Cardiovascular effects:
Some epidemiological studies showed that domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death (see section 4.8). The risk may be higher in patients older than 60 years or with daily doses more than 30 mg. Domperidone should be used at the lowest effective dose in adults and children.

Use of domperidone and other drugs which prolong QTc intervals requires that caution be exercised in patients who have existing prolongation of cardiac conduction intervals, particularly QTc, and patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure.

TO


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

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 (see section 4.8).

Epidemiological studies showed that domperidone was associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death (see section 4.8). A higher risk was observed in patients older than 60 years, patients taking daily doses greater than 30 mg, and patients concurrently taking 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 QTc, in patients with significant electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia), or bradycardia, or in patients with underlying cardiac diseases such as congestive heart failure due to increased risk of ventricular arrhythmia (see section 4.3). 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 patients should consult their physician.

Patients should be advised to promptly report any cardiac symptoms.

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

Overdosing may cause extrapyramidal disorders in children, but other causes should be taken into consideration.
Precautions for use
The suppositories contain butylated hydroxyanisole which can irritate eyes, skin and the lining of the mouth and nose (mucous membranes).

SECTION 4.5

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.
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. 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) and erythromycin monotherapy (500 mg three times daily) led to increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.

TO

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

Concomitant use of the the following substances is contraindicated
QTc prolonging medicinal products (risk of torsades de points)
• 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., fluconazole, 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)
(see section 4.3).
Potent CYP3A4 inhibitors (regardless of their QT prolonging effects), i.e.,:
• protease inhibitors (e.g. ritonavir, saquinaver, telaprevir)
• systemic azole antifungals (e.g. itraconazole, ketoconazole, posaconazole, voriconazole)
• certain macrolide antibiotics (e.g., clarithromycin, telithromycin)
(see section 4.3).

Concomitant use of the following substances is not recommended
• Moderate CYP3A4 inhibitors i.e., diltiazem, verapamil and some macrolides.

Concomitant use of the following substances requires caution with use
Caution 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).

The above list of substances is representative and not exhaustive.


SECTION 4.6

FROM

There are limited post-marketing data on the use of domperidone in pregnant women. A study in rats has shown reproductive toxicity at a high, maternally toxic dose. The potential risk for humans is unknown. Therefore, Motilium should only be used during pregnancy when justified by the anticipated therapeutic benefit.
The drug is excreted in breast milk of lactating rats (mostly as metabolites: peak concentration of 40 and 800 ng/ml after oral and i.v. administration of 2.5 mg/kg respectively). Domperidone concentrations in breast milk of lactating women are 10 to 50% of the corresponding plasma concentrations and expected not to exceed 10 ng/ml. The total amount of domperidone excreted in human breast milk is expected to be less than 7 micrograms per day at the highest recommended dosing regimen. It is not known whether this is harmful to the newborn. Therefore Motilium is not recommended in breast-feeding women.

TO


Pregnancy
There are limited post-marketing data on the use of domperidone in pregnant women. A study in rats has shown reproductive toxicity at a high, maternally toxic dose. The potential risk for humans is unknown. Therefore, Motilium should only be used during pregnancy when justified by the anticipated therapeutic benefit.
Breast feeding
Domperidone is excreted in human milk and breast fed infants receive less than 0.1% of the maternal weight adjusted dose. Occurrence of adverse effects, in particular cardiac effects cannot be excluded after exposure via breast milk. A decision should be made whether to discontinue breast feeding or to discontinue/abstain from domperidone therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Caution should be exercised in case of QTc prolongation risk factors in breast fed infants.

SECTION 4.8

FROM
The safety of Motilium was evaluated in 1275 patients with dyspepsia, gastro-oesophageal reflux disorder (GERD), Irritable Bowel Syndrome (IBS), nausea and vomiting or other related conditions in 31 double-blind, placebo-controlled studies. All patients were at least 15 years old and received at least one dose of Motilium (domperidone base). The median total daily dose was 30 mg (range 10 to 80 mg), and median duration of exposure was 28 days (range 1 to 28 days). Studies in diabetic gastroparesis or symptoms secondary to chemotherapy or parkinsonism were excluded.

The following terms and frequencies are applied: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), and very rare (<1/10,000). Where frequency can not be estimated from clinical trials data, it is recorded as “Not known”.

System Organ Class Adverse Drug Reaction
Frequency
Common Uncommon
Psychiatric disorders Loss of libido
Anxiety

Nervous system disorders Somnolence
Headache
Gastrointestinal disorders Dry mouth Diarrhoea
Skin and subcutaneous tissue disorder Rash
Pruritus
Reproductive system and breast disorders Galactorrhoea
Breast pain
Breast tenderness
General disorders and administration site conditions Asthenia

In 45 studies where domperidone was used at higher dosages, for longer duration and for additional indications including diabetic gastroparesis, the frequency of adverse events (apart from dry mouth) was considerably higher. This was particularly evident for pharmacologically predictable events related to increased prolactin. In addition to the reactions listed above, akathisia, breast discharge, breast enlargement, breast swelling, depression, hypersensitivity, lactation disorder, and irregular menstruation were also noted.

Postmarketing experience

In addition to the adverse effects reported during clinical studies and listed above, the following adverse drug reactions have been reported.

Immune system disorders
Not known Anaphylactic reaction (including anaphylactic shock)

Psychiatric disorders
Not known Agitation, nervousness

Nervous system disorders
Not known
Convulsion, extrapyramidal disorder
Eye disorders
Not known Oculogyric crisis

Cardiac disorders (see section 4.4)
Not Known Ventricular arrhythmias, sudden cardiac death, QTc prolongation

Skin and subcutaneous tissue disorders
Not known Urticaria, angioedema


Renal and urinary disorders
Not known Urinary retention

Reproductive system and breast disorders
Not known Gynaecomastia, amenorrhoea

Investigations
Not known
Liver function test abnormal, blood prolactin increased



Extrapyramidal disorder occurs primarily in neonates and infants.
Other central nervous system-related effects of convulsion, agitation, and somnolence also are very rare and primarily reported in infants and children.

TO
The safety of domperidone was evaluated in clinical trials and in post marketing experience. The clinical trials included1,275 patients with dyspepsia, gastro-oesophageal reflux disorder (GERD), Irritable Bowel Syndrome (IBS), nausea and vomiting or other related conditions in 31 double-blind, placebo-controlled studies. All patients were at least 15 years old and received at least one dose of Motilium (domperidone base). The median total daily dose was 30 mg (range 10 to 80 mg), and median duration of exposure was 28 days (range 1 to 28 days). Studies in diabetic gastroparesis or symptoms secondary to chemotherapy or parkinsonism were excluded.

The following terms and frequencies are applied: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), and very rare (<1/10,000). Where frequency can not be estimated from clinical trials data, it is recorded as “Not known”.
System Organ Class Adverse Drug Reaction
Frequency
Common Uncommon Not known
Immune system disorders Anaphylactic reaction (including anaphylactic shock)
Psychiatric disorders Loss of libido
Anxiety
Agitation
Nervousness
Nervous system disorders Somnolence
Headache
Extrapyramidal disorder Convulsion

Eye disorders Oculogyric crisis
Cardiac disorders Ventricular arrhythmias
QTc prolongation
Torsade de Pointes
Sudden cardiac death
(see section 4.4)
Gastrointestinal disorders Dry mouth Diarrhoea
Skin and subcutaneous tissue disorder Rash
Pruritus
Urticaria Angioedema
Renal and urinary disorders Urinary retention
Reproductive system and breast disorders Galactorrhoea
Breast pain
Breast tenderness Gynaecomastia
Amenorrhoea
General disorders and administration site conditions Asthenia
Investigations Liver function test abnormal
Blood prolactin increased

In 45clinical studies where domperidone was used at higher dosages, for longer duration and for additional indications including diabetic gastroparesis, the frequency of adverse events (apart from dry mouth) was considerably higher. This was particularly evident for pharmacologically predictable events related to increased prolactin. In addition to the reactions listed above, akathisia, breast discharge, breast enlargement, breast swelling, depression, hypersensitivity, lactation disorder, and irregular menstruation were also noted.

Extrapyramidal disorder occurs primarily in neonates and infants.
Other central nervous system-related effects of convulsion, agitation, and somnolence also are very rare and primarily reported in infants and children.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail:medsafety@hpra.ie.


SECTION 4.9

FROM

Symptoms
Overdose has been reported primarily in infants and children. Symptoms of overdose may include agitation, altered consciousness, convulsion, disorientation, somnolence and extrapyramidal reactions.
Treatment
There is no specific antidote to domperidone, but in the event of overdose, gastric lavage, as well as the administration of activated charcoal, may be useful. Close medical supervision and supportive therapy is recommended.
Anticholinergic, anti-parkinson drugs may be helpful in controlling the extrapyramidal reactions.

TO

Symptoms
Overdose has been reported primarily in infants and children. Symptoms of overdose may include agitation, altered consciousness, convulsion, disorientation, somnolence and extrapyramidal reactions.
Treatment
There is no specific antidote to domperidone. , In the event of overdose, standard symptomatic treatment should be given immediately. ECG monitoring should be undertaken, because of the possibility of QTc interval prolongation Gastric lavage, as well as the administration of activated charcoal, may be useful. Close medical supervision and supportive therapy is recommended.
Anticholinergic, anti-parkinson drugs may be helpful in controlling the extrapyramidal disorders.


SECTION 5.1

FROM

Pharmacotherapeutic group: Propulsives, ATC code: A03F A 03
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.

TO

Pharmacotherapeutic group: Propulsives, ATC code: A03F A 03
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 disordersare 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.
In accordance with ICH E14 guidelines, a thorough QT study was performed. This study included a placebo, an active comparator and a positive control and was conducted in healthy subjects with up to 80 mg per day (10 or 20 mg administered four times a day) of domperidone. This study found a maximal difference of QTc between domperidone and placebo in LS means in the change from baseline of 3.4 msec for 20 mg domperidone administered four times a day on Day 4. The 2 sided 90% CI (1.0 to 5.9 msec) did not exceed 10 msec. No clinically relevant QTc effects were observed in this study when domperidone was administered at up to 80 mg/day (i.e., more than twice the maximum recommended dosing).

However, two previous drug drug interaction studies showed some evidence of QTc prolongation when domperidone was given as monotherapy (10 mg administered four times a day). The largest time matched mean difference of QTcF between domperidone and placebo was 5.4 msec (95% CI: 1.7 to 12.4) and 7.5 msec (95% CI: 0.6 to 14.4), respectively.

SECTION 5.2

FROM

Absorption
In fasting subjects, domperidone is rapidly absorbed after oral administration, with peak plasma concentrations at 30 to 60 minutes. 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 gastro-intestinal complaints should take domperidone 15-30 minutes before a meal. Reduced gastric acidity impairs the absorption of domperidone. Oral bioavailability is decreased by prior concomitant administration of cimetidine and sodium bicarbonate. The time of peak absorption is slightly delayed and the AUC somewhat increased when the oral drug is taken after a meal.
The bioavailability of a 60mg suppository after single or repeated dosing is approximately 65% of 80mg of oral tablets, given over 24 hours. After rectal administration of 60 mg domperidone suppositories, mean domperidone plasma concentrations between 20 and 40 ng/ml are maintained from approximately 0.5 to 5 hours after single- and multiple-dose administration. Following single-dose administration, mean peak plasma levels of 60 mg suppositories are88% of that of two 10mg oral tablets but, the mean dose normalized rectal bioavailability relative to oral tablets is 64%. Following multiple-dose administration, peak plasma levels and dose-normalized bioavailability of 60 mg suppositories administered every 12 hours are 63% and 66%, respectively, of two 10 mg oral tablets administered every 6 hours.
Distribution
Oral domperidone does not appear to accumulate or induce its own metabolism; a peak plasma level after 90 minutes of 21 ng/ml after two weeks oral administration of 30 mg per day was almost the same as that of 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 cross the placenta in rats.
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.
Hepatic impairment (see Section 4.3)
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.
Renal impairment
In subjects with severe renal insufficiency (serum creatinine > 6 mg/100 ml, i.e. > 0.6 mmol/L) the half-life of domperidone is increased from 7.4 to 20.8 hours, but plasma drug levels are lower than in subjects with normal renal function. Very little unchanged drug (approximately 1%) is excreted via the kidneys (see section 4.4).

Paediatric population
No pharmacokinetic data are available in the paediatric population.


TO


Absorption
Domperidone is rapidly absorbed after oral administration, with peak plasma concentrations occurring at approximately 1 hr after dosing. The Cmax and AUC values of domperidone increased proportionally with dose in the 10 mg to 20 mg dose range. A 2 to 3 fold accumulation of domperidone AUC was observed with repeated four times daily (every 5 hr) dosing of domperidone for 4 days.
Although domperidone’s bioavailability is enhanced in normal subjects when taken after a meal, patients with gastro-intestinal complaints should take domperidone 15-30 minutes before a meal. Reduced gastric acidity impairs the absorption of domperidone. Oral bioavailability is decreased by prior concomitant administration of cimetidine and sodium bicarbonate. Based on the Cmax resulting from administering multiple twice daily doses of 60 mg suppository, a 30 mg suppository given twice daily is expected to provide peak plasma levels similar to those of a 10 mg oral dose administered four times a day.
Distribution
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 cross the placenta in rats.
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.

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. 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 < 30ml/min/1.73m2), ) the elimination half-life of domperidone was increased from 7.4 to 20.8 hours, but plasma drug levels were lower than in healthy volunteers.Since very little unchanged drug (approximately 1%) is excreted via the kidneys, it is unlikely that the dose of a single administration needs to be adjusted in patients with renal impairment. However, on repeated administration, the dosing frequency should be reduced to once or twice daily depending on the severity of the impairment, and the dose may need to be reduced.

Paediatric population
No pharmacokinetic data are available in the paediatric population.

SECTION 5.3

FROM

Electrophysiological in vitro and in vivo studies indicate an overall moderate risk of domperidone to prolong the QT interval in humans. In in vitro experiments on isolated cells transfected with HERG and on isolated guinea pig myocytes, exposure ratios ranged between 5- and 30-fold based on IC50 values inhibiting currents through IKr ion channels in comparison to the free plasma concentrations in humans after administration of the maximum daily dose of 20 mg (q.i.d.). Exposure margins for prolongation of action potential duration in in vitro experiments on isolated cardiac tissues exceeded the free plasma concentrations in humans at maximum daily dose (20mg q.i.d.) by 17-fold. However, safety margins in in vitro pro-arrhythmic models (isolated Langendorff perfused heart) and in in vivo models (dog, guinea pig, rabbits sensitised for torsades de points) exceeded the free plasma concentrations in humans at maximum daily dose (20mg q.i.d.) by more than 17-fold. In the presence of inhibition of the metabolism via CYP3A4 free plasma concentrations of domperidone can rise up to 10- fold.
At a high, maternally toxic dose (more than 40 times the recommended human dose), teratogenic effects were seen in the rat. No teratogenicity was observed in mice and rabbits.

TO


Electrophysiological in vitro and in vivo studies indicate an overall moderate risk of domperidone to prolong the QTc interval in humans. In in vitro experiments on isolated cells transfected with hERG and on isolated guinea pig myocytes, exposure ratios ranged between 26 to 47 fold, based on IC50 values inhibiting currents through IKr ion channels in comparison to the free plasma concentrations in humans after administration of the maximum daily dose of 10 mg administered three times a day. Safety margins for prolongation of action potential duration in in vitro experiments on isolated cardiac tissues exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered three times a day) by 45 fold. Safety margins in in vitro pro arrhythmic models (isolated Langendorff perfused heart) exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered three times a day) by 9 up to 45 fold. In in vivo models, the no effect levels for QTc prolongation in dogs and induction of arrhythmias in a rabbit model sensitised for torsade de points exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered three times a day) by more than 22 fold and 435 fold, respectively. In the anesthetised guinea pig model following slow intravenous infusions, there were no effects on QTc at total plasma concentrations of 45.4 ng/ml, which are 3 fold higher than the total plasma levels in humans at maximum daily dose (10 mg administered three times a day). The relevance of the latter study for humans following exposure to orally administered domperidone is uncertain.

In the presence of inhibition of the metabolism via CYP3A4, free plasma concentrations of domperidone can rise up to 3 fold. E
At a high, maternally toxic dose (more than 40 times the recommended human dose), teratogenic effects were seen in the rat. No teratogenicity was observed in mice and rabbits.


SECTION 6.6

FROM

6.6 Instruction for Use and Handling

TO

6.6 Special precautions for disposal and other handling


SECTION 10

Updated to March 2015

Section 4.2:

 

Added:

 

Therapy should not exceed 14 days of continuous treatment without medical consultation.

 

‘under 12 years of age and weighing  less than 35kg’ after ‘Infants and Children’

 

Hepatic Impairment

Motilium is contraindicated in moderate or severe hepatic impairment (see section 4.3).  Dose modification in mild hepatic impairment is however not needed (see section 5.2).

Renal Impairment

Since the elimination half-life of domperidone is prolonged in severe renal impairment, on repeated administration, the dosing frequency of Motilium 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 sections 4.4 and 5.2)

 

Section 4.3:

 

Added:

 

In patients with moderate or severe hepatic impairment (see section 5.2).

 

Section 4.4:

 

Removed from ‘Use in infants’ section:

 

Therefore it is recommended that the dose be determined accurately and followed strictly in neonates, infants, toddlers and small children.

 

 ‘Use in liver’ section deleted.

 

Use in kidney disorders’ section changed to:

 

Renal impairment

 Since the elimination half-life of domperidone is prolonged in severe renal impairment,, on repeated administration, the dosing frequency of Motilium should be reduced to once or twice daily, depending on the severity of the impairment, and the dose may need to be reduced. Patients on prolonged therapy should be reviewed regularly (see section 5.2).

 

Added:

 

Cardiovascular effects:

Some epidemiological studies showed that domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death (see section 4.8). The risk may be higher in patients older than 60 years or with  daily doses more than 30 mg. Domperidone should be used at the lowest effective dose in adults and children.

 

Use of domperidone and other drugs which prolong QTc intervals requires that caution be exercised in patients who have existing prolongation of cardiac conduction intervals, particularly QTc, and patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure.

 

 

Section 4.5:

 

Added:

 

When antacids or antisecretory drugs are used concomitantly, they should not be taken simultaneously with oral formulations of Motilium (domperidone base), i.e., they should be taken after meals and not before meals.

 

Section 4.8

 

Complete new section:

 

The safety of Motilium was evaluated in 1275 patients with dyspepsia, gastro-oesophageal reflux disorder (GERD), Irritable Bowel Syndrome (IBS), nausea and vomiting or other related conditions in 31 double-blind, placebo-controlled studies. All patients were at least 15 years old and received at least one dose of Motilium (domperidone base).  The median total daily dose was 30 mg (range 10 to 80 mg), and median duration of exposure was 28 days (range 1 to 28 days).  Studies in diabetic gastroparesis or symptoms secondary to chemotherapy or parkinsonism were excluded.

 

The following terms and frequencies are applied: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), and very rare (<1/10,000).  Where frequency can not be estimated from clinical trials data, it is recorded as “Not known”.

 

System Organ Class	Adverse Drug Reaction Frequency
	Common	Uncommon
Psychiatric disorders		Loss of libido Anxiety
Nervous system disorders		Somnolence Headache
Gastrointestinal disorders	Dry mouth	Diarrhoea
Skin and subcutaneous tissue disorder		Rash Pruritus
Reproductive system and breast disorders		Galactorrhoea Breast pain Breast tenderness
General disorders and administration site conditions		Asthenia

 

In 45 studies where domperidone was used at higher dosages, for longer duration and for additional indications including diabetic gastroparesis, the frequency of adverse events (apart from dry mouth) was considerably higher. This was particularly evident for pharmacologically predictable events related to increased prolactin.  In addition to the reactions listed above, akathisia, breast discharge, breast enlargement, breast swelling, depression,  hypersensitivity, lactation disorder, and irregular menstruation were also noted.

 

Postmarketing experience

 

In addition to the adverse effects reported during clinical studies and listed above, the following adverse drug reactions have been reported. 

 

Immune system disorders
Not known	Anaphylactic reaction (including anaphylactic shock)
Psychiatric disorders
Not known	Agitation, nervousness
Nervous system disorders
Not known	Convulsion, extrapyramidal disorder
Eye disorders
Not known	Oculogyric crisis
Cardiac disorders (see section 4.4)
Not Known	Ventricular arrhythmias, sudden cardiac death, QTc prolongation
Skin and subcutaneous tissue disorders
Not known	Urticaria, angioedema
Renal and urinary disorders
Not known              Urinary retention
Reproductive system and breast disorders
Not known	Gynaecomastia, amenorrhoea
Investigations
Not known	Liver function test abnormal, blood prolactin increased

 

Extrapyramidal disorder occurs primarily in neonates and infants.

Other central nervous system related effects of convulsion, agitation and somnolence also are very rare and primarily reported in infants and children.

 

Section 5.2:

 

Added:

 

Under ‘Absorption’:

 

The bioavailability of a 60 mg suppository after single or repeated dosing is approximately 65% of 80 mg of oral tablets, given over 24 hours. After rectal administration of 60 mg domperidone suppositories, mean domperidone plasma concentrations between 20 and 40 ng/ml are maintained from approximately 0.5 to 5 hours after single- and multiple-dose administration. Following single-dose administration, mean peak plasma levels of 60 mg suppositories 88% of that of two oral tablets, but the mean dose normalized rectal bioavailability relative to oral bioavailability is 64%.   Following multiple-dose administration, peak plasma levels and dose-normalized bioavailability of 60 mg suppositories administered every 12 hours are 63% and 66%, respectively, of two 10 mg oral tablets administered every 6 hours.

 

Added:

 

Hepatic impairment (see section 4.3)

In subjects with moderate hepatic impairment (Pugh score 7 to 9, Child-Pugh rating B), the AUC and C_max 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 C_max and AUC, with  no change in protein binding or terminal half-life. Subjects with severe hepatic impairment were not studied.

 

Renal impairment

In subjects with severe renal insufficiency (serum creatinine > 6 mg/100 ml, i.e. > 0.6 mmol/L) the half-life of domperidone is increased from 7.4 to 20.8 hours, but plasma drug levels are lower than in subjects with normal renal function. Very little unchanged drug (approximately 1%) is excreted via the kidneys (see section 4.4).

 

Paediatric population

No pharmacokinetic data are available in the paediatric population.

Section 4.4: Detail added on possible neurological side effects in use in infants
Section 4.8: More undesirable effects added
Section 4.9 More detail on overdose symptoms

Section 7 - New MAH - McNeil Healthcare (Ireland) Ltd.
Section 10 - December 2009

X

Change to section 7 – Marketing Authorisation Holder

Change to MAH address

X	Change to section 9 – Date of Renewal of Authorisation	Changed in line with schedule
X	Change to section 10 – Date of revision of text	August 2008

Change to section 6.3 – Shelf Life	Reduced from 5 years to 3 years
Change to section 6.6 –  Instructions for use, handling and disposal	Extra information

Change to section 4.4 – Special Warnings and Precautions for Use	Use with CYP3A4 inhibitors
Change to section 4.5 –Interaction with other medicinal products and other forms of interaction	Domperidone use with Ketoconazole
Change to section 4.8 – Undesirable effects	Cardiac disorders
Change to section 5.3 - Preclinical Safety Data	Extra information
Change to section 10 – Date of revision of text	May 2008