Domperidone is indicated for the relief of the symptoms of nausea and vomiting.

Domperidone should be used at the lowest effective dose for the shortest duration necessary to
control nausea and vomiting.
It is recommended to take oral domperidone 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 weighing 35 kg or more)
10 ml (of oral suspension containing domperidone 1mg per ml) up to three times per day with a
maximum daily dose of 30 ml per day.
Oral domperidone should be taken before meals/feeding. If taken after meals absorption of the
drug is somewhat delayed.
Hepatic Impairment
Domperidone 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 domperidone 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)

Domperidone 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 gastrointestinal 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. • Co-administration with QT-prolonging drugs. • Co-administration with potent CYP3A4 inhibitors (regardless of their QT prolonging effects).

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 adolescents 12 years of
age and older.
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.

Renal impairment
The elimination half-life of domperidone is prolonged in severe renal impairment. For repeated
administration, the dosing frequency of domperidone should be reduced to once or twice daily
depending on the severity of the impairment, and the dose may need to be reduced. Such patients
on prolonged therapy should be reviewed regularly (see section 5.2).
Excipients
The oral suspension contains sorbitol (E420). Patients with rare hereditary problems of fructose
intolerance should not take this medicine. The oral suspension includes propylhydroxybenzoate
(E216) and methylhydroxybenzoate (E218) which may cause allergic reactions (possibly
delayed).

Antacids or antisecretory agents should not be taken simultaneously with oral formulations of
domperidone as they lower the oral bioavailability of domperidone. Domperidone should be
taken before meals and antacids or antisecretory agents after meals.
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 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)
• 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
• systemic azole antifungals
• some macrolides (erythromycin, 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. (see section 4.3)
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 contra-indicated as it is a potent CYP3A4 inhibitor).
The above list of substances is representative and not exhaustive.
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 10mg four times daily and ketoconazole 200mg 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
10mg four times daily and oral erythromycin 500mg 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 10mg 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
(200mg twice daily) led to increases in QTc of 3.8 and 4.9 msec, respectively, over the
observation period.

 

Pregnancy:
There are limited post-marketing data on the use of domperidone in pregnant women. Studies in
animals have shown reproductive toxicity at maternally toxic doses (see section 5.3).
Domperidone 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.

Fertility
There are no data on the effects of domperidone on human fertility.

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

 

Tabulated list of adverse reactions
The safety of domperidone was evaluated in clinical trials and in postmarketing experience. The
clinical trials included 1275 patients with dyspepsia, gastro-oesophageal reflux disorder
(GORD), 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 domperidone (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 (≥1/1,000 to <1/100); rare
(≥1/10,000 to <1/1,000); 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	Convulsion Extrapyramidal disorder
Eye disorders			Oculogyric crisis
Cardiac disorders (see section 4.4)			Ventricular arrhythmias Sudden cardiac death QTc prolongation Torsade de Pointes
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 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.

To reports any side effect(s):
• Saudi Arabia
-The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npcG
• Other GCC States:
− Please contact the relevant competent authority.

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

Pharmacotherapeutic group: Propulsives, ATC code: A03FA03
Mechanism of action
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 oesophaegeal 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 4 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 4 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 administered as monotherapy (10 mg 4 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.

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.
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.
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.
Biotransformation
Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and Ndealkylation.
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. Domperidone is
contraindicated in patients with moderate or severe hepatic impairment (see section 4.3).
Renal impairment
In subjects with severe renal insufficiency (creatinine clearance <30ml/min/1.73m2) the
elimination half-life of domperidone is increased from 7.4 to 20.8 hours, but plasma drug levels
are lower than in healthy volunteers. 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 insufficiency.
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.

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 26-
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 3 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 3 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 3 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 sensitized for torsade de pointes exceeded the free plasma
concentrations in humans at maximum daily dose (10 mg administered 3 times a day) by more
than 22-fold and 435-fold, respectively. In the anesthetized 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 3 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.
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.

Sucrose
Polysorbate 80
Xanthan Gum
Sodium Sacchrain
Sorbitol 70 % solution
Methylparaben
Propylparaben
Avicel RC 591
Banana Flavour
Purified water

Not applicable.

24 month

Do not store above 30 °C. Advice to be used within 3 month of bottle opening.

Immediate Container: Amber coloured glass bottles 200 ml.
Secondary Container: Carton label & PIL

No special requirements.