PRODUCT NAME

MOTILIUM (domperidone base)

DOSAGE FORMS AND STRENGTHS

One film-coated tablet contains 10 mg domperidone.
The oral suspension contains 1 mg domperidone per mL.

For excipients, see List of Excipients.

CLINICAL INFORMATION
Indications
1. The dyspeptic symptom complex that is often associated with delayed gastric emptying,
gastro-esophageal reflux and esophagitis:
 epigastric sense of fullness, early satiety, feeling of abdominal distension, upper
abdominal pain;
 bloating, eructation, flatulence;
 nausea and vomiting;
 heartburn with or without regurgitations of gastric contents in the mouth.
2. Nausea and vomiting of functional, organic, infectious or dietary origin.
3. Nausea and vomiting induced by:
 radiotherapy or drug therapy
 dopamine agonists (such as L-dopa and bromocriptine) used in the treatment of
Parkinson's disease.

Dosage and Administration

It is recommended to take oral MOTILIUM 15-30 minutes before meals. If taken after meals,
absorption of the drug is somewhat delayed.

Adults and adolescents ≥ 12 years of age and weighing ≥ 35 kg

The dose of MOTILIUM® should be the lowest effective dose for the individual situation
(typically 30mg/day) and can be increased if necessary to a maximum daily oral dose of 40mg.

Usually, the maximum treatment duration should not exceed one week for the treatment of acute
nausea and vomiting. If nausea and vomiting persists for longer than one week, patients should
consult their physician. For other indications, the initial duration of treatment is up to four weeks.
If treatment exceeds four weeks, patients should be re-evaluated and the need for continued
treatment reassessed.

Formulation (domperidone per Dosage Maximum dose

unit) per day
Film-coated tablets (10 mg/tablet) 1 tablet three to four times 40 mg (4x10mg
per day tablet)
Oral suspension (1 mg/ml) 10 mL three to four times 40 mg (40 mL of
per day 1mg/mL oral
suspension)
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Doses above 30mg/day should be used with caution due to potential risk of arrhythmias
associated with the higher doses.

Infants and children < 12 years of age and weighing < 35 kg

The efficacy of MOTILIUM® has not been established in infants and children < 12 years of age
and weighing < 35 kg (see Clinical Studies).

Use in renal insufficiency

Since the elimination half-life of domperidone is prolonged in severe renal impairment (serum
creatinine > 6mg/100mL, i.e. > 0.6mmol/L, 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 with severe renal impairment should be reviewed regularly (see
Pharmacokinetic Properties).

Hepatic impairment
MOTILIUM® is contraindicated for patients with moderate (Child-Pugh 7 to 9) or severe (Child-
Pugh >9) hepatic impairment (see Contraindications). Dose adjustment is not required for
patients with mild (Child-Pugh 5 to 6) hepatic impairment (see Pharmacokinetic Properties).

Contraindications
MOTILIUM is contraindicated in the following situations:
 Known hypersensitivity to domperidone or any of the excipients
 Prolactin-releasing pituitary tumour (prolactinoma)
 Co-administration with QT-prolonging drugs (see Interactions)
 Co-administration with potent CYP3A4 inhibitors (see Interactions)
 In patients who have known existing prolongation of cardiac conduction of intervals,
particularly QTc, patients with significant electrolyte disturbances or underlying cardiac
diseases such as congestive heart failure (see Warnings and Precautions)
 Whenever stimulation of gastric motility might be dangerous, e.g. in the presence of
gastro-intestinal haemorrhage, mechanical obstruction or perforation
 In patients with moderate or severe hepatic impairment (see Pharmacokinetic
Properties)

Warnings and Precautions

Cardiac effects
Epidemiological studies showed that domperidone may be associated with an increased risk of
serious ventricular arrhythmias or sudden cardiac death (see Adverse Reactions). Those studies
suggest this increased risk may be higher in patients older than 60 years or in patients taking oral
doses greater than 30 mg per day. Therefore, MOTILIUM® should be used with caution in older
patients. Domperidone should be used at the lowest effective dose in adults.

Patients older than 60 years of age should consult their physician before taking MOTILIUM®.

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Due to increased risk of ventricular arrhythmia, MOTILIUM® 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.
Electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia) and bradycardia are
known to be conditions increasing the proarrhythmic risk.

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

Chronic administration of domperidone is not recommended.

Use with Antacids or antisecretory agents

Antacids or antisecretory agents should not be taken simultaneously with oral formulations of
MOTILIUM as they lower the oral bioavailability of domperidone. When used concomitantly,
MOTILIUM should be taken before meals and antacids or antisecretory agents after meals.
Dosing with these agents should be separated from dosing with MOTILIUM by at least 2 hours.

Excipients
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 be unsuitable for patients with sorbitol
intolerance.

Interactions
The main metabolic pathway of domperidone is through CYP3A4. In vitro and human data show
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 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 anti-psychotics (e.g., haloperidol, pimozide, sertindole)
 certain anti-depressants (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)
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  certain medicines used in cancer (e.g., toremifene, vandetanib, vincamine)
 certain other medicines (e.g., bepridil, diphemanil, methadone) (see Contraindications)

Potent CYP3A4 inhibitors (regardless of their QT prolonging effects), i.e.:

 protease inhibitors
 systemic azole antifungals
 some macrolides (erythromycin, clarithromycin, telithromycin) (see Contraindications)

Concomitant use of the following substances is not recommended

Moderate CYP3A4 inhibitors i.e. diltiazem, verapamil and some macrolides (see
Contraindications)

Concomitant use of the following substances requires caution in 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.

Concomitant administration of anticholinergic drugs (e.g., dextromethorphan, diphenhydramine)

may antagonize the anti-dyspeptic effect of MOTILIUM®.

Theoretically, since MOTILIUM has gastro-kinetic effects, it could influence the absorption of
concomitantly orally administered drugs, particularly those with sustained release or enteric
coated formulations. However, in patients already stabilized on digoxin or paracetamol,
concomitant administration of domperidone did not influence the blood levels of these drugs.

MOTILIUM may also be given with:

 neuroleptics, the action of which it does not potentiate,
 dopaminergic agonists (bromocriptine, L-dopa), whose unwanted peripheral effects such
as digestive disorders, nausea and vomiting it suppresses without counteracting their
central properties.

Pregnancy and Breast-feeding

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
The amount of domperidone that could be ingested by an infant through breast milk is low. The
maximal relative infant dose (%) is estimated to be about 0.1% of the maternal weight-adjusted
dosage. It is not known whether this is harmful to the newborn. Therefore, breast-feeding is not
recommended for women who are taking MOTILIUM.
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Effects on Ability to Drive and Use Machines
Dizziness and somnolence have been observed following use of domperidone (see Adverse
Reactions). 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.

Adverse Reactions
Throughout this section, adverse reactions are presented. Adverse reactions are adverse events
that were considered to be reasonably associated with the use of domperidone based on the
comprehensive assessment of the available adverse event information. A causal relationship with
domperidone usually cannot be reliably established in individual cases. Further, because clinical
trials are conducted under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug
and may not reflect the rates observed in clinical practice.

Clinical Trial Data

The safety of MOTILIUM was evaluated in 1221 patients with gastroparesis, dyspepsia, gastro-
esophageal reflux disorder (GERD), or other related conditions in 45 clinical trials included in
the safety database. All patients were 15 years old and received at least one dose of oral
MOTILIUM (domperidone base). Slightly fewer than one-half (553/1221) of patients were
diabetic. The median total daily dose was 80 mg (range 10 to 160 mg), with 230 patients
receiving a dose greater than 80 mg. Median duration of exposure was 56 days (range 1 to 2248
days).

Adverse reactions reported by ≥1% of patients treated with domperidone in these 45 clinical
trials are shown in Table 1.

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 Table 1. Adverse Reactions Reported by ≥ 1% of Domperidone-Treated
Patients in 45 Clinical Trials
System/Organ Class Domperidone (n=1221)
Adverse Reaction %
Psychiatric Disorders
Depression 2.5
Anxiety 1.6
Libido Decreased/Loss of Libido 1.5
Nervous System Disorders
Headache 5.6
Somnolence 2.5
Akathisia 1.0
Gastrointestinal Disorders
Diarrhoea 5.2
Skin and Subcutaneous Tissue Disorders
Rash 2.8
Pruritus 1.7
Reproductive System and Breast Disorders
Breast Enlargement/Gynaecomastia 5.3
Breast Tenderness 4.4
Galactorrhoea 3.3
Amenorrhoea 2.9
Breast Pain 2.3
Menstruation Irregular 2.0
Lactation Disorder 1.6
General Disorders and Administration Site Conditions
Asthenia 1.9

Adverse reactions that occurred in <1% of Domperidone-treated patients in the 45 clinical trials
(n=1221) are listed below in Table 2.

Table 2. Adverse Reactions Reported by <1% of Domperidone-Treated

Patients in 45 Clinical Trials
System/Organ Class Domperidone (n=1221)
Adverse Reaction %
Immune System Disorders
Hypersensitivity 0.2
Skin and Subcutaneous Tissue Disorders
Urticaria 0.7
Reproductive System and Breast Disorders
Breast Discharge 0.8
Breast Swelling 0.5

The following adverse reaction has been reported with over-the-counter use: dry mouth.

Postmarketing
In addition to the adverse reactions reported during clinical studies and listed above, the
following adverse reactions have been reported during postmarketing experience (Table 3). In
the table, the frequencies are provided according to the following convention:

Very common ≥1/10

Common ≥1/100 and < 1/10
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 Uncommon ≥ 1/ 1,000 and < 1/100
Rare ≥1/10,000 and < 1/1,000
Very rare <1/10,000, including isolated reports.

In Table 3, adverse reactions are presented by frequency category based on spontaneous

reporting rates.

Table 3. Adverse Reactions Identified During Postmarketing Experience with

Domperidone by Frequency Category Estimated from Spontaneous
Reporting Rates

Immune System Disorders

Very rare Anaphylactic Reaction (including Anaphylactic Shock)

Psychiatric Disorders
Very rare Agitation, Nervousness

Nervous System Disorders

Very rare Dizziness, Extrapyramidal Disorder, Convulsion

Cardiac Disorders
Very rare Sudden Cardiac Death*, Serious Ventricular
Arrhythmias*(see Warnings and Precautions)

Skin and Subcutaneous Tissue Disorders

Very rare Angioedema

Renal and Urinary Disorders

Very rare Urinary Retention

Investigations
Very rare Liver Function Test Abnormal, Blood Prolactin Increased
*Based on epidemiology data

Pediatric population
In postmarketing experience, there were no differences in the safety profile of adults and
children.

As the hypophysis is outside the blood brain barrier, domperidone may cause an increase in
prolactin levels. In rare cases this hyperprolactinaemia may lead to neuro-endocrinological side
effects such as galactorrhoea, gynaecomastia and amenorrhoea.

Overdose
Symptoms and signs
Overdose has been reported primarily in infants and children. Symptoms of overdose may
include agitation, altered consciousness, convulsion, disorientation, somnolence and
extrapyramidal reactions.

Treatment

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There is no specific antidote to domperidone. Close medical supervision and supportive therapy
is recommended. Anticholinergic or anti-Parkinson drugs may be helpful in controlling the
extrapyramidal reactions.

It is advisable to contact a poison control center to obtain the latest recommendations for the
management of an overdose.

PHARMACOLOGICAL PROPERTIES
Pharmacodynamic Properties
Pharmacotherapeutic group: Propulsives, ATC code: A03FA03

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 included a placebo, active comparator and positive control and was
conducted using recommended and supra-therapeutic doses (10 and 20 mg administered 4 times
a day). This study found a maximal difference was QTc between domperidone and placebo in
LS-means in the change from baseline of 3.4 msec for 20 mg domperidone administered 4 times
a day on Day 4, and the 2-sided 90% CI (1.0 - 5.9 msec) did not exceed 10 msec. The QT
prolongation observed in this study when domperidone was administered according to the
recommended dosing regimen is not clinically relevant.

Clinical Studies
Infants and children ≤ 12 years of age
A multicenter, double blind, randomized, placebo controlled, parallel group, prospective study
was conducted to evaluate the safety and efficacy of domperidone in 292 children with acute
gastroenteritis aged 6 months to 12 years (median age 7 years). In addition to oral rehydration
treatment (ORT), randomized subjects received domperidone oral suspension at 0.25 mg/kg (up
to a maximum of 30 mg domperidone/day), or placebo, 3 times a day, for up to 7 days. This
study did not achieve the primary objective, which was to demonstrate that domperidone
suspension plus ORT is more effective than placebo plus ORT at reducing the percentage of
subjects with no vomiting episodes during the first 48 hours after the first treatment
administration.

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Pharmacokinetic Properties
Absorption
In fasting subjects, domperidone is rapidly absorbed after oral administration, with peak plasma
concentrations occurring at approximately 60 minutes after dosing. The key pharmacokinetic
parameters after a single or multiple doses (administered 4 times a day) of 10mg domperidone
base tablets to healthy subjects are presented in the table below. The C max and AUC values of
domperidone increased proportionally with dose in the 10mg to 20mg dose range.

Key Domperidone Pharmacokinetic Parameters After a Single or Multiple Doses (administered

4 times a day) of 10 mg Domperidone Base Tablets to Healthy Subjects
PK parameter Domperidone 10 mg administered four times a day
Mean Day 1 Day 4
n 40 40
Cmin, ng/mL NA 5.26 (CV: 31.1%)
Cmax, ng/mL 11.6 (CV: 50.8%) 17.3 (CV: 35.4%)
tmax, ha 1.02 (range: 0.52 - 5.02) 1.02 (range: 0.50 - 4.03)
AUC5h, ng.h/mL 20.4 (CV: 34.4%) 47.8 (CV: 30.5%)
a
median (range)
Source: Study DOM-DYP-1001

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 base. Oral bioavailability of domperidone base 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.

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 fecal 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 Populations
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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 (see
Contraindications).

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 Dosage and Administration).

NON-CLINICAL INFORMATION
At a high, maternally toxic dose of 200mg/kg/day, teratogenic effects (organ abnormalities such
as anophthalmia, microphthalmia and displacement of the subclavian artery) were seen in the rat.
The clinical significance of these findings is unknown. No teratogenicity was observed in mice
and rabbits.

Electrophysiological in vitro and in vivo studies have shown that domperidone, at high
concentrations, may prolong the QTc interval.

In juvenile rats, a no observed adverse effect level of 10mg/kg was observed following 30 days
of once daily repeat intraperitoneal dosing. Single introperitoneal or intravenous doses showed
similar LD50 values (mean range 53-76mg/kg) in both juvenile and adult rats.

PHARMACEUTICAL INFORMATION
List of Excipients
Film coated tablets
Hydrogenated cottonseed oil, hypromellose, lactose monohydrate, magnesium stearate, maize
starch, microcrystalline cellulose, polyvidone, pregelatinized potato starch sodium lauryl
sulphate (formulation F42).

Oral suspension
Methyl-parahydroxybenzoate, microcrystalline cellulose and sodiumcarboxy-methylcellulose,
polysorbate, propyl-parahydroxybenzoate, purified water, sodium hydroxide, sodium saccharin,
sorbitol liquid non-crystallising(formulation F45).

Incompatibilities
None known.

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Shelf Life
Refer to Outer Carton

Storage Conditions
Keep out of reach of children.
Store between 15 and 30°C.

Instructions for Use and Handling

Oral suspension
Mix the contents of the bottle completely using a
gentle tilting motion to avoid the formation of
foam.

Directions for opening the bottle

Fig. 1: The bottle comes with a childproof cap,
and should be opened as follows:
- Push the plastic screw cap down while
turning it counter clockwise.
- Remove the unscrewed cap.

Directions for using the measuring cup

A measuring cup is supplied with the
MOTILIUM® oral solution. Use the measuring
cup just as it sits on the bottle. Make sure that
the side with the graduations (the side that holds
less) is uppermost; that is the side you have to
fill. When the arrow on the side points up, the
correct side is uppermost.

BATCH RELEASER
Janssen Pharmaceutica NV
Turnhoutseweg 30
B-2340 Beerse, Belgium

Janssen-Cilag
Domaine de Maigremont
27100 Val de Reuil
France

PRODUCT REGISTRANT
Johnson & Johnson Pte Ltd
2 Science Park Drive
#07-13, Ascent
11
Singapore Science Park 1
Singapore 118222

DATE OF REVISION OF THE TEXT

24 April 2018 (CCDS 24 Jan 2018)

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