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XOMOLIX 2.5MG/ML SOLUTION FOR INJECTION

Active substance(s): DROPERIDOL

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Xomolix 2.5 mg/ml solution for injection

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each millilitre of the solution contains 2.5 mg droperidol.
Excipient: sodium < 23 mg per ml.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Solution for injection.
Clear colourless solution, free from visible particles.
The pH of droperidol solution for injection is 3.0 – 3.8 and has an osmolarity
of approximately 300 milliosmol /kg water.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications
 Prevention and treatment of post-operative nausea and vomiting (PONV) in adults and, as


second line, in children (2 to 11 years) and adolescents (12 to 18 years).
Prevention of nausea and vomiting induced by morphine and derivatives during postoperative patient controlled analgesia (PCA) in adults.

Certain precautions are required when administering droperidol: see sections 4.2, 4.3,
and 4.4.
4.2

Posology and method of administration

Posology

For intravenous use.
Prevention and treatment of post-operative nausea and vomiting (PONV).
Adults: 0.625 mg to 1.25 mg (0.25 to 0.5 ml).
Elderly (over 65 years): 0.625 mg (0.25 ml)
Renal/hepatic impairment: 0.625 mg (0.25 ml)
Paediatric population
Children (2 to 11 years) and adolescents (12 to 18 years): 10 to 50 microgram/kg (up to a
maximum of 1.25 mg).
Children (below the age of 2 years): not recommended.

Administration of droperidol is recommended 30 minutes before the anticipated end
of surgery. Repeat doses may be given every 6 hours as required.

The dosage should be adapted to each individual case. The factors to be considered
here include age, body weight, use of other medicinal products, type of anaesthesia
and surgical procedure.
Prevention of nausea and vomiting induced by morphine and derivatives during post-operative
patient controlled analgesia (PCA).
Adults: 15 to 50 micrograms droperidol per mg of morphine, up to a maximum daily dose of
5 mg droperidol.
Elderly (over 65 years), renal and hepatic impairment: no data in PCA available.
Paediatric population
Children (2 to 11 years) and adolescents (12 to 18 years): not indicated in PCA.
Continuous pulse oximetry should be performed in patients with identified or suspected risk
of ventricular arrhythmia and should continue for 30 minutes following single i.v.
administration.
For instructions on dilution of the product before administration, see section 6.6.
See also sections 4.3, 4.4 and 5.1.

4.3

Contraindications

Droperidol is contraindicated in patients with:
Hypersensitivity to droperidol or to any of the excipients;
Hypersensitivity to butyrophenones;
Known or suspected prolonged QT interval (QTc of > 450 msec in females and
> 440 msec in males). This includes patients with congenitally long QT interval, patients
who have a family history of congenital QT prolongation and those treated with medicinal
products known to prolong the QT interval (see section 4.5);
 Hypokalaemia or hypomagnesaemia;
 Bradycardia (< 55 heartbeats per minute);
 Known concomitant treatment leading to bradycardia;
 Phaeochromocytoma;
 Comatose states;
 Parkinson’s Disease;
 Severe depression.





4.4

Special warnings and precautions for use

Central Nervous System

Droperidol may enhance CNS depression produced by other CNS-depressant drugs.
Any patient subjected to anaesthesia and receiving potent CNS depressant medicinal
products or showing symptoms of CNS depression should be monitored closely.
Concomitant use of metoclopramide and other neuroleptics may lead to an increase in
extrapyramidal symptoms and should be avoided (see section 4.5).
Use with caution in patients with epilepsy (or a history of epilepsy) and conditions
predisposing to epilepsy or convulsions.

Cardiovascular

Mild to moderate hypotension and occasionally (reflex) tachycardia have been
observed following the administration of droperidol. This reaction usually subsides
spontaneously. However, should hypotension persist, the possibility of hypovolaemia
should be considered and appropriate fluid replacement administered.
Patients with, or suspected of having, the following risk factors for cardiac arrhythmia
should be carefully evaluated prior to administration of droperidol:
a history of significant cardiac disease including serious ventricular arrhythmia,
second or third degree atrio-ventricular block, sinus node dysfunction,
congestive heart failure, ischemic heart disease and left ventricular hypertrophy;
family history of sudden death;
renal failure (particularly when on chronic dialysis);
significant chronic obstructive pulmonary disease and respiratory failure;
-

risk factors for electrolyte disturbances, as seen in patients taking laxatives,
glucocorticoids, potassium-wasting diuretics, in association with the administration of
insulin in acute settings, or in patients with prolonged vomiting and/or diarrhoea.

Patients at risk for cardiac arrhythmia should have serum electrolytes and creatinine
levels assessed and the presence of QT prolongation excluded prior to administration
of droperidol.
Continuous pulse oximetry should be performed in patients with identified or suspected risk
of ventricular arrhythmia and should continue for 30 minutes following single i.v.
administration.
General

To prevent QT prolongation, caution is necessary when patients are taking medicinal
products likely to induce electrolyte imbalance (hypokalaemia and/or
hypomagnesaemia) e.g. potassium-wasting diuretics, laxatives and glucocorticoids.
Substances inhibiting the activity of cytochrome P450 iso-enzymes (CYP) CYP1A2,
CYP3A4 or both could decrease the rate at which droperidol is metabolised and
prolong its pharmacological action. Hence, caution is advised if droperidol is given
concomitantly with strong CYP1A2 and CYP3A4 inhibitors (see section 4.5).
Patients who have, or are suspected of having, a history of alcohol abuse or recent
high intakes, should be thoroughly assessed before droperidol is administered.
In case of unexplained hyperthermia, it is essential to discontinue treatment, since this
sign may be one of the elements of malignant syndrome reported with neuroleptics.
Cases of venous thromboembolism (VTE) have been reported with antipsychotic
drugs. Since patients treated with antipsychotics often present with acquired risk
factors for VTE, all possible risk factors for VTE should be identified before and
during treatment with Xomolix and preventive measures undertaken.
The dose should be reduced in the elderly and those with impaired renal and hepatic
function (see section 4.2).

This medicinal product contains less than 1 mmol sodium (23 mg) per 1 ml, i.e.
essentially ‘sodium-free’.
4.5

Interaction with other medicinal products and other forms of interaction

Contraindicated for concomitant use

Medicinal products known to cause torsades de pointes through QT prolongation
should not be concomitantly administered with droperidol. Examples include
Examples include:
Class IA antiarrhythmics e.g. quinidine, disopyramide, procainamide
Class III antiarrhythmics e.g. amiodarone, sotalol
macrolide antibiotics e.g. erythromycin, clarithromycin
fluoroquinolone antibiotics e.g. sparfloxacin
antihistamines e.g. astemizole, terfenadine
certain antipsychotic medications e.g. chlorpromazine, haloperidol, pimozide,
thioridazine
anti-malaria agents e.g. chloroquine, halofantrine
cisapride, domperidone, methadone, pentamidine.
Concomitant use of medicinal products that induce extrapyramidal symptoms, e.g.
metoclopramide and other neuroleptics, may lead to an increased incidence of these
symptoms and should therefore be avoided.
Consumption of alcoholic beverages and medicines should be avoided.
Caution is advised for concomitant use

To reduce the risk of QT prolongation, caution is necessary when patients are taking
medicinal products likely to induce electrolyte imbalance (hypokalaemia and/or
hypomagnesaemia) e.g. potassium-wasting diuretics, laxatives and glucocorticoids.
Droperidol may potentiate the action of sedatives (barbiturates, benzodiazepines,
morphine derivatives). The same applies to antihypertensive agents, so that orthostatic
hypotension may ensue.
Like other sedatives, droperidol may potentiate respiratory depression caused by
opioids.
Since droperidol blocks dopamine receptors, it may inhibit the action of dopamine agonists,
such as bromocriptine, lisuride, and of L-dopa.

Substances inhibiting the activity of cytochrome P450 iso-enzymes (CYP) CYP1A2,
CYP3A4 or both could decrease the rate at which droperidol is metabolised and
prolong its pharmacological action. Hence, caution is advised if droperidol is given
concomitantly with CYP1A2 inhibitors (e.g. ciprofloxacin, ticlopidine), CYP3A4
inhibitors (e.g. diltiazem, erythromycin, fluconazole, indinavir, itraconazole,
ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, verapamil) or both (e.g.
cimetidine, mibefradil).
4.6

Fertility, pregnancy and lactation

Fertility

There were no effects on fertility in studies conducted in male and female rats (see section
5.3). The clinical effect of droperidol on fertility has not been established.
Pregnancy
A limited amount of clinical data have shown no increase of malformative risk.
Droperidol has not been shown to be teratogenic in rats. Animal studies are insufficient with
respect to the effects on pregnancy and embryonal/foetal, parturition and postnatal
development.
In newborn babies from mothers under long-term treatment and high doses of neuroleptics,
temporary neurological disturbances of extrapyramidal nature have been described.
In practice, as a precautionary measure, it is preferable not to administer droperidol during
pregnancy. In late pregnancy, if its administration is necessary, monitoring of the newborn’s
neurological functions is recommended.
Breastfeeding
Neuroleptics of the butyrophenone type are known to be excreted in breast milk; treatment
with droperidol should be limited to a single administration. Repeat administration is not
recommended.

4.7
Effects on ability to drive and use machines
Droperidol has major influence on the ability to drive and use machines.
Patients should not drive or operate a machine for 24 hours after droperidol
administration.

4.8

Undesirable effects

The most frequently reported events during clinical experience are incidents of drowsiness
and sedation. In addition, less frequent reports of hypotension, cardiac arrhythmias,
neuroleptic malignant syndrome (NMS) and symptoms associated with NMS, plus movement
disorders, such as dyskinesias, plus incidents of anxiety or agitation have occurred.

System
Organ Class

Blood and
lymphatic
systems
disorders
Immune
system
disorders

Metabolism

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

Not known
(cannot be
estimated
from the
available
data)

Blood
dyscrasias
Anaphylactic
reaction;
Angioneuroti
c oedema;
Hypersensitivity
Inappropriate

and nutrition
disorders

Psychiatric
disorders

Nervous

Anxiety;
Restlessness/
Akathisia;
Drowsiness

system

Confusional
states;
Agitation

Dystonia;
Oculogyratio
n

Extrapyramidal
disorder;
Convulsions;
Tremor

disorders

Cardiac
disorders

Vascular
Hypotension
disorders
Respiratory,
thoracic and
mediastinal
disorders
Skin and
subcutaneous
system
disorders
General
disorders and
administratio
n site
conditions

Tachycardia;
Dizziness

Dysphoria

Cardiac
arrhythmias,
including
ventricular
arrhythmias

anti-diuretic
hormone
secretion
Hallucinatio
ns

Epileptic
fits;
Parkinson’s
disease;
Psychomotor
hyperactivity
; Coma

Cardiac
arrest;
Torsades de
pointes;
Electrogram
QT
prolonged
Syncope
Bronchospasm;
Laryngospas
m

Rash

Neuroleptic
malignant
syndrome
(NMS)

Sudden
death

Symptoms potentially associated with NMS have occasionally been reported i.e. changes in
body temperature, stiffness and fever. An alteration in mental status with confusion or
agitation and altered consciousness, have been seen. Autonomic instability may manifest as
tachycardia, fluctuating blood pressure, excessive sweating/salivation and tremor. In extreme
cases NMS may lead to coma, or renal and/or hepato-biliary problems.

Isolated cases of amenorrhoea, galactorrhoea, gynaecomastia, hyperprolactinaemia,
and oligomenorrhoea have been associated with prolonged exposure in psychiatric
indications.
Cases of venous thromboembolism, including cases of pulmonary embolism and cases
of deep vein thrombosis have been reported with antipsychotic medicinal products frequency unknown.

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 the Yellow Card Scheme, www.mhra.gov.uk/yellowcard.
4.9
Overdose
Symptoms
The manifestations of droperidol overdose are an extension of its pharmacologic
actions.
Symptoms of accidental overdose are psychic indifference with a transition to sleep,
sometimes in association with lowered blood pressure.
At higher doses or in sensitive patients, extrapyramidal disorders may occur
(salivation, abnormal movements, sometimes muscle rigidity). Convulsions may
occur at toxic doses.
Cases of QT-interval prolongation, ventricular arrhythmias and sudden death have
been reported rarely.
Treatment
No specific antidote is known. However, when extrapyramidal reactions occur, an
anticholinergic should be administered.
Patients with droperidol overdose should be closely monitored for signs of QT
interval prolongation.
Factors which predispose to torsades de pointes, e.g. electrolyte disturbances
(especially hypokalaemia or hypomagnesaemia) and bradycardia should be taken into
consideration.
Pronounced hypotension should be treated by boosting circulation volume and taking
other appropriate measures. Clear airways and adequate oxygenation should be
maintained; an oropharyngeal airway or endotracheal tube might be indicated.
If required, the patient should be observed carefully for 24 hours or longer; body
warmth and adequate fluid intake should be maintained.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: application pending. ATC code: application pending.
Droperidol is a butyrophenone neuroleptic. Its pharmacologic profile is characterised mainly
by dopamine-blocking and weak α1-adrenolytic effects. Droperidol is devoid of
anticholinergic and antihistaminic activity.
Droperidol’s inhibitory action on dopaminergic receptors in the chemotrigger zone in the area
postrema, gives it a potent antiemetic effect, especially useful for the prevention and
treatment of postoperative nausea and vomiting and/or induced by opioid analgesics.
At a dose of 0.15 mg/kg, droperidol induces a fall in mean blood pressure (MBP), due to a
decrease in cardiac output in a first phase, and then subsequently due to a decrease in preload. These changes occur independently of any alteration in myocardial contractility or

vascular resistance. Droperidol does not affect myocardial contractility or heart rate, therefore
has no negative inotropic effect. Its weak α1-adrenergic blockade can cause a modest
hypotension and decreased peripheral vascular resistance and may decrease pulmonary
arterial pressure (particularly if it is abnormally high). It may also reduce the incidence of
epinephrine-induced arrhythmia, but it does not prevent other forms of cardiac arrhythmia.

Droperidol has a specific antiarrhythmic effect at a dose of 0.2 mg/kg by an effect on
myocardial contractility (prolongation of the refractory period) and a decrease in
blood pressure.
Two studies (one placebo-controlled and one comparative active treatment-controlled)
performed in the general anaesthesia setting and designed to better identify the QTc
changes associated with postoperative nausea and vomiting treatment by small dose of
droperidol (0.625 and 1.25 mg intravenous, and 0.75 mg intravenous, respectively)
identified a QT interval prolongation at 3-6 min after administration of 0.625 and 1.25
mg droperidol (respectively 15 ± 40 and 22 ± 41 ms), but these changes did not differ
significantly from that seen with saline (12 ± 35 ms). There were no statistically
significant differences amongst the droperidol and saline groups in the number of
patients with greater than 10% prolongation in QTc versus baseline. There was no
evidence of droperidol-induced QTc prolongation after surgery.
No ectopic heartbeats were reported from the electrocardiographic records or 12-lead
recordings during the perioperative period. The comparative active-treatment study
with 0.75 mg intravenous droperidol identified a significant QTc interval prolongation
(maximal of 17 ± 9 ms at the second minute after droperidol injection when compared
with pre-treatment QTc measurement), with the QTc interval significantly lower after
the 90th minute.
5.2

Pharmacokinetic properties

The action of a single intravenous dose commences 2-3 minutes following administration.
The tranquillising and sedative effects tend to persist for 2 to 4 hours, although alertness may
be affected for up to 12 hours.
Distribution
Following intravenous administration, plasma concentrations fall rapidly during the first 15
minutes. Plasma protein binding amounts to 85 – 90 %. The distribution volume is
approximately 1.5 l/kg.
Metabolism
Droperidol is extensively metabolised in the liver, and undergoes oxidation, dealkylation,
demethylation and hydroxylation by cytochrome P450 isoenzymes 1A2 and 3A4, and to a
lesser extent by 2C19. The metabolites are devoid of neuroleptic activity.
Elimination
Elimination occurs mainly through metabolism; 75% is excreted via the kidneys. Only 1% of
the active substance is excreted unchanged with urine, and 11% with faeces. Plasma clearance
is 0.8 (0.4 - 1.8) l/min. The elimination half-life (t½ß) is 134 ± 13 min.

Paediatric Population
In a study of 12 children (age 3.5 to 12 years), the values for distribution volume and
clearance reported were lower than those found in the adult population

(0.58 ± 0.29 l/kg and 4.66 ± 2.28 ml/kg*min respectively) and decrease in parallel.
The elimination half-life (101.5 ± 26.4 min) was similar to that found in adults.
5.3

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies
of repeated dose toxicity, genotoxic or carcinogenic potential, and reproductive
toxicity.
Electrophysiological in vitro and in vivo studies indicate an overall risk of droperidol
to prolong the QT interval in humans.
In humans, the free peak plasma concentration is approximately 4-fold higher to 25fold lower than the droperidol concentrations affecting the endpoints examined in the
different in vitro and in vivo test systems used to assess the impact of this drug on
cardiac repolarisation. Plasma levels fall by about one order of magnitude over the
first twenty minutes after administration.
Environmental Risk Assessment (ERA)
This product is unlikely to represent a risk to the environment following its prescribed
use in patients.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Mannitol
Tartaric acid
Sodium hydroxide (for pH adjustment)
Water for injections.

6.2
Incompatibilities
Incompatible with barbiturates. This medicinal product must not be mixed with other
medicinal products except those mentioned in section 6.6.
6.3
Shelf life
Unopened: 3 years.
After first opening: For immediate use.
Following dilution: Compatibility of droperidol with morphine sulphate in 0.9%
sodium chloride (14 days at room temperature) has been demonstrated in plastic
syringes. From a microbiological point of view, the diluted product should be used
immediately. If not used immediately, in-use storage times and conditions prior to use
are the responsibility of the user and would normally not be longer than 24 hours at 2
to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.
6.4

Special precautions for storage

Store in the original package.
For storage conditions after dilution, and first opening of the medicinal product, see section
6.3.

6.5

Nature and contents of container

Type I amber glass ampoules containing 1 ml solution for injection, in packs of 10 ampoules.

6.6

Special precautions for disposal and other handling
For single use only. Any unused solution should be discarded.
The solution should be inspected visually prior to use. Only clear and
colourless solutions free from visible particles should be used.
For use in PCA: Draw droperidol and morphine into a syringe and make up
the volume with 0.9% sodium chloride for injection.
Any unused product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
ProStrakan Ltd
Galabank Business Park

Galashiels
TD1 1QH
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)

PL 16508/0036

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
27/09/2012

10

DATE OF REVISION OF THE TEXT
08/03/2015

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Source: Medicines and Healthcare Products Regulatory Agency

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