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DACEPTON 5 MG/ML SOLUTION FOR INFUSION

Active substance(s): APOMORPHINE HYDROCHLORIDE HEMIHYDRATE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Dacepton 5 mg/ml solution for infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml contains 5 mg apomorphine hydrochloride hemihydrate
20 ml contain 100 mg apomorphine hydrochloride hemihydrate
Excipient with known effect:
Sodium metabisulphite (E223) 1 mg per ml
Sodium chloride 8 mg per ml
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Solution for infusion
Clear and colourless to slightly yellow solution, free from visible particles
pH of 3.3 – 4.0.
Osmolality: 290 mOsm/kg

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Treatment of motor fluctuations (“on-off” phenomena) in patients with Parkinson's
disease which are not sufficiently controlled by oral anti-Parkinson medication.

4.2

Posology and method of administration
Selection of Patients suitable for Dacepton 5 mg/ml solution for infusion:
Patients selected for treatment with Dacepton 5 mg/ml solution for infusion
should be able to recognise the onset of their ”off” symptoms and be capable
of injecting themselves or else have a responsible carer able to inject for them
when required.

Patients treated with apomorphine will usually need to start domperidone at
least two days prior to initiation of therapy. The domperidone dose should be
titrated to the lowest effective dose and discontinued as soon as possible.
Before the decision to initiate domperidone and apomorphine treatment, risk
factors for QT interval prolongation in the individual patient should be
carefully assessed to ensure that the benefit outweighs the risk (see section
4.4).
Apomorphine should be initiated in the controlled environment of a specialist
clinic. The patient should be supervised by a physician experienced in the
treatment of Parkinson's disease (e.g. neurologist). The patient's treatment with
levodopa, with or without dopamine agonists, should be optimised before
starting treatment with Dacepton 5 mg/ml solution for infusion.
Adults
Method of administration
Dacepton 5 mg/ml solution for infusion is a pre-diluted vial intended for use
without dilution for subcutaneous use and to be administered as a continuous
subcutaneous infusion by minipump and/or syringe-driver (see section 6.6). It
is not intended to be used for intermittent injection.
Apomorphine must not be used via the intravenous route.
Do not use if the solution has turned green. The solution should be inspected
visually prior to use. Only clear, colourless to slightly yellow and particle free
solution should be used.
Posology
Continuous Infusion
Patients who have shown a good “on” period response during the initiation
stage of apomorphine therapy, but whose overall control remains
unsatisfactory using intermittent injections, or who require many and frequent
injections (more than 10 per day), may be commenced on or transferred to
continuous subcutaneous infusion by minipump and/or syringe-driver as
follows:
The choice, of which minipump and / or syringe-driver to use, and the dosage
settings required, will be determined by the physician in accordance with the
particular needs of the patient.
Determination of Threshold Dose

The threshold dose for continuous infusion should be determined as follows:
Continuous infusion is started at a rate of 1 mg apomorphine hydrochloride
hemihydrate (0.2 ml) per hour then increased according to the individual
response each day. Increases in the infusion rate should not exceed 0.5 mg at
intervals of not less than 4 hours. Hourly infusion rates may range between 1
mg and 4 mg (0.2 ml and 0.8 ml), equivalent to 0.014 - 0.06 mg/kg/hour.
Infusions should run for waking hours only. Unless the patient is experiencing
severe night-time problems, 24 hour infusions are not advised. Tolerance to
the therapy does not seem to occur as long as there is an overnight period
without treatment of at least 4 hours. In any event, the infusion site should be
changed every 12 hours.
Patients may need to supplement their continuous infusion with intermittent
bolus boosts, as necessary, and as directed by their physician.
A reduction in dosage of other dopamine agonists may be considered during
continuous infusion.
Establishment of treatment
Alterations in dosage may be made according to the patient's response.
The optimal dosage of apomorphine hydrochloride hemihydrate varies
between individuals but, once established, remains relatively constant for each
patient.
Precautions on continuing treatment
The daily dose of Dacepton 5 mg/ml solution for infusion varies widely
between patients, typically within the range of 3-30 mg.
It is recommended that the total daily dose of apomorphine hydrochloride
hemihydrate should not exceed 100 mg.
In clinical studies it has usually been possible to make some reduction in the
dose of levodopa; this effect varies considerably between patients and needs to
be carefully managed by an experienced physician.
Once treatment has been established, domperidone therapy may be gradually
reduced in some patients but successfully eliminated only in a few, without
any vomiting or hypotension.
Paediatric population

Dacepton 5 mg/ml solution for infusion is contraindicated for children and
adolescents under 18 years of age (see section 4.3).
Elderly
The elderly are well represented in the population of patients with Parkinson's
disease and constitute a high proportion of those studied in clinical trials of
apomorphine. The management of elderly patients treated with apomorphine
has not differed from that of younger patients. However, extra caution is
recommended during initiation of therapy in elderly patients because of the
risk of postural hypotension.
Renal impairment
A dose schedule similar to that recommended for adults, and the elderly, can
be followed for patients with renal impairment (see section 4.4).

4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section
6.1.
In patients with respiratory depression, dementia, psychotic diseases or hepatic
insufficiency.
Apomorphine hydrochloride hemihydrate treatment must not be administered to
patients who have an “on” response to levodopa which is marred by severe dyskinesia
or dystonia.
Dacepton 5 mg/ml solution for infusion is contraindicated for children and
adolescents under 18 years of age.

4.4

Special warnings and precautions for use
Apomorphine hydrochloride hemihydrate should be given with caution to
patients with renal, pulmonary or cardiovascular disease and persons prone to
nausea and vomiting.
Extra caution is recommended during initiation of therapy in elderly and/or
debilitated patients.

Since apomorphine may produce hypotension, even when given with
domperidone pre-treatment, care should be exercised in patients with preexisting cardiac disease or in patients taking vasoactive medicinal products
such as antihypertensives, and especially in patients with pre-existing postural
hypotension.
Since apomorphine, especially at high dose, may have the potential for QT
prolongation, caution should be exercised when treating patients at risk for
torsades de pointes arrhythmia.
When used in combination with domperidone, risk factors in the individual
patient should be carefully assessed. This should be done before treatment
initiation, and during treatment. Important risk factors include serious
underlying heart conditions such as congestive cardiac failure, severe hepatic
impairment or significant electrolyte disturbance. Also medication possibly
affecting electrolyte balance, CYP3A4 metabolism or QT interval should be
assessed. Monitoring for an effect on the QTc interval is advisable. An ECG
should be performed:
- prior to treatment with domperidone
- during the treatment initiation phase
- as clinically indicated thereafter
The patient should be instructed to report possible cardiac symptoms including
palpitations, syncope, or near-syncope. They should also report clinical
changes that could lead to hypokalaemia, such as gastroenteritis or the
initiation of diuretic therapy.
At each medical visit, risk factors should be revisited.
Apomorphine is associated with local subcutaneous effects. These can
sometimes be reduced by the rotation of injection sites or possibly by the use
of ultrasound (if available) in order to avoid areas of nodularity and induration.
Haemolytic anaemia and thrombocytopenia have been reported in patients
treated with apomorphine. Haematology tests should be undertaken at regular
intervals as with levodopa, when given concomitantly with apomorphine.
Caution is advised when combining apomorphine with other medicinal
products, especially those with a narrow therapeutic range (see Section 4.5).
Neuropsychiatric problems co-exist in many patients with advanced
Parkinson's disease. There is evidence that for some patients neuropsychiatric
disturbances may be exacerbated by apomorphine. Special care should be
exercised when apomorphine is used in these patients.

Apomorphine has been associated with somnolence, and episodes of sudden
sleep onset, particularly in patients with Parkinson's disease. Patients must be
informed of this and advised to exercise caution while driving or operating
machines during treatment with apomorphine. Patients who have experienced
somnolence and/or an episode of sudden sleep onset must refrain from driving
or operating machines. Furthermore, a reduction of dosage or termination of
therapy may be considered.
Impulse control disorders
Patients should be regularly monitored for the development of impulse control
disorders. Patients and carers should be made aware that behavioural
symptoms of impulse control disorders including pathological gambling,
increased libido, hypersexuality, compulsive spending or buying, binge eating
and compulsive eating can occur in patients treated with dopamine agonists
including apomorphine. Dose reduction/tapered discontinuation should be
considered if such symptoms develop.
Dacepton 5 mg/ml solution for infusion contains sodium metabisulphite which
may rarely cause severe hypersensitivity reactions and bronchospasm.
Dacepton 5 mg/ml contains 3.4 mg sodium per ml. To be taken into
consideration by patients on a controlled sodium diet.

4.5

Interaction with other medicinal products and other forms of interaction
Patients selected for treatment with apomorphine hydrochloride hemihydrate are
almost certain to be taking concomitant medications for their Parkinson's disease. In
the initial stages of apomorphine hydrochloride hemihydrate therapy, the patient
should be monitored for unusual side-effects or signs of potentiation of effect.
Neuroleptic medicinal products may have an antagonistic effect if used with
apomorphine. There is a potential interaction between clozapine and apomorphine,
however clozapine may also be used to reduce the symptoms of neuropsychiatric
complications.
If neuroleptic medicinal products have to be used in patients with Parkinson's disease
treated by dopamine agonists, a gradual reduction in apomorphine dose may be
considered when administration is by minipump and or syringe-driver (symptoms
suggestive of neuroleptic malignant syndrome have been reported rarely with abrupt
withdrawal of dopaminergic therapy).
The possible effects of apomorphine on the plasma concentrations of other medicinal
products have not been studied. Therefore caution is advised when combining

apomorphine with other medicinal products, especially those with a narrow
therapeutic range.

Antihypertensive and Cardiac Active Medicinal Products
Even when co-administered with domperidone, apomorphine may potentiate the
antihypertensive effects of these medicinal products (see Section 4.4)
It is recommended to avoid the administration of apomorphine with other drugs
known to prolong the QT interval.

4.6

Fertility, pregnancy and lactation
Pregnancy
There is no experience of apomorphine usage in pregnant women.
Animal reproduction studies do not indicate any teratogenic effects, but doses given
to rats which are toxic to the mother can lead to failure to breathe in the newborn. The
potential risk for humans is unknown. See Section 5.3.
Dacepton 5 mg/ml solution for infusion should not be used during pregnancy unless
clearly necessary
Breast-feeding
It is not known whether apomorphine is excreted in breast milk. A decision on
whether to continue/discontinue breastfeeding or to continue/discontinue therapy with
Dacepton 5 mg/ml solution for infusion should be made taking into account the
benefit of breast-feeding to the child and the benefit of Dacepton 5 mg/ml solution for
infusion to the woman.

4.7

Effects on ability to drive and use machines
Apomorphine hydrochloride hemihydrate has minor or moderate influence on the
ability to drive and use machines.
Patients being treated with apomorphine and presenting with somnolence and/or
sudden sleep episodes must be informed to refrain from driving or engaging in
activities (e.g. operating machines) where impaired alertness may put themselves or
others at risk of serious injury or death until such recurrent episodes and somnolence
have resolved (see also section 4.4).

4.8

Undesirable effects
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)

Not known:

(cannot be estimated from the available data)

Blood and
lymphatic system
disorders

Uncommon:
Haemolytic anaemia and thrombocytopenia have
been reported in patients treated with
apomorphine.
Rare:
Eosinophilia has rarely occurred during treatment
with apomorphine hydrochloride hemihydrate.

Immune system
disorders

Rare:

Psychiatric
disorders

Very common:

Due to the presence of sodium metabisulphite,
allergic reactions (including anaphylaxis and
bronchospasm) may occur.
Hallucinations
Common:
Neuropsychiatric disturbances (including transient
mild confusion and visual hallucinations) have
occurred during apomorphine hydrochloride
hemihydrate therapy.
Not known:
Impulse control disorders:
Pathological gambling, increased libido,
hypersexuality, compulsive spending or buying,
binge eating and compulsive eating can occur in
patients treated with dopamine agonists including
apomorphine (see section 4.4).

Nervous system
disorders

Common:
Transient sedation with each dose of apomorphine
hydrochloride hemihydrate at the start of therapy
may occur; this usually resolves over the first few

weeks.
Apomorphine is associated with somnolence.
Dizziness / light-headedness have also been
reported.
Uncommon:
Apomorphine may induce dyskinesias during
“on” periods which can be severe in some cases,
and in a few patients may result in cessation of
therapy.
Apomorphine has been associated with sudden
sleep onset episodes. See section 4.4.
Unknown:
Syncope
Vascular
disorders

Uncommon:

Respiratory,
thoracic and
mediastinal
disorders

Common:

Postural hypotension is seen infrequently and is
usually transient (see section 4.4)
Yawning has been reported during apomorphine
therapy
Uncommon:
Breathing difficulties have been reported.

Gastrointestinal
disorders

Common:

Skin and
subcutaneous
tissue disorders

Uncommon:

General disorders
and administration
site conditions

Very common:

Nausea and vomiting, particularly when
apomorphine treatment is first initiated, usually as
a result of the omission of domperidone (See
section 4.2).
Local and generalised rashes have been reported.

Most patients experience injection site reactions,
particularly with continuous use. These may
include subcutaneous nodules, induration,
erythema, tenderness and panniculitis. Various
other local reactions (such as irritation, itching,
bruising and pain) may also occur.
Uncommon:
Injection site necrosis and ulceration have been
reported
Not Known:

Peripheral oedema has been reported.
Investigations

Uncommon:
Positive Coombs' tests have been reported for
patients receiving apomorphine.

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 at:
www.mhra.gov.uk/yellowcard.

4.9

Overdose
There is little clinical experience of overdose with apomorphine by this route of
administration. Symptoms of overdose may be treated empirically as suggested
below:
Excessive emesis may be treated with domperidone.
Respiratory depression may be treated with naloxone.
Hypotension: appropriate measures should be taken, e.g. raising the foot of the bed.
Bradycardia may be treated with atropine.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Anti-Parkinson drugs, dopamine agonists, ATC code:
N04B C07
Mechanism of action
Apomorphine is a direct stimulant of dopamine receptors and while possessing both
D1 and D2 receptor agonist properties does not share transport or metabolic pathways
with levodopa.

Although in intact experimental animals, administration of apomorphine suppresses
the rate of firing of nigro-striatal cells and in low dose has been found to produce a
reduction in locomotor activity (thought to represent pre-synaptic inhibition of
endogenous dopamine release) its actions on parkinsonian motor disability are likely
to be mediated at post-synaptic receptor sites. This biphasic effect is also seen in
humans.

5.2

Pharmacokinetic properties
After subcutaneous injection of apomorphine its fate can be described by a twocompartment model, with a distribution half-life of 5 (±1.1) minutes and an
elimination half-life of 33 (±3.9) minutes. Clinical response correlates well with
levels of apomorphine in the cerebrospinal fluid; the active substance distribution
being best described by a two-compartment model. Apomorphine is rapidly and
completely absorbed from subcutaneous tissue, correlating with the rapid onset of
clinical effects (4-12 minutes), and that the brief duration of clinical action of the
active substance (about 1 hour) is explained by its rapid clearance. The metabolism of
apomorphine is by glucuronidation and sulphonation to at least ten per cent of the
total; other pathways have not been described.

5.3

Preclinical safety data
Repeat dose subcutaneous toxicity studies reveal no special hazard for humans,
beyond the information included in other sections of the SmPC.
In vitro genotoxicity studies demonstrated mutagenic and clastogenic effects, most
likely due to products formed by oxidation of apomorphine. However, apomorphine
was not genotoxic in the in vivo studies performed.
The effect of apomorphine on reproduction has been investigated in rats.
Apomorphine was not teratogenic in this species, but it was noted that doses which
are toxic to the mother can cause loss of maternal care and failure to breathe in the
newborn.
No carcinogenicity studies have been performed.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Sodium metabisulphite (E223)

Sodium chloride
Hydrochloric acid (for pH-adjustment)
Water for injections

6.2

Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed
with other medicinal products.

6.3

Shelf life
Unopened: 30 months
After opening and filling the drug product in syringes attached with infusion sets:
chemical and physical in-use stability has been demonstrated for 7 days at 25 °C.
From a microbiological point of view, unless the method of opening and further
handling precludes the risk of microbial contamination, the product should be used
immediately. If not used immediately, in-use storage times and conditions are the
responsibility of the user.
Single use only.
Discard any unused contents

6.4

Special precautions for storage
Keep the vials in the outer carton in order to protect from light.
Do not refrigerate or freeze.
For storage conditions after first opening of the medicinal product, see section 6.3.

6.5

Nature and contents of container
Clear glass vials, type I with bromobutyl rubber stopper and a flip-off cap,
containing 20 ml solution for infusion, in packs of 1, 5 or 30 vials.
Bundle packs: 5 x 1, 10 x 1, 30 x 1, 2 x 5 and 6 x 5

Not all pack sizes may be marketed

6.6

Special precautions for disposal
Do not use if the solution has turned green.
The solution should be inspected visually prior to use. Only clear and colourless to
slightly yellow solutions without particles in undamaged containers should be used.
For single use only. Any unused medicinal product or waste material should be
disposed in accordance with local requirements.

Continuous infusion and the use of a minipump and or syringe-driver
The choice of which minipump and or syringe-driver to use, and the dosage settings
required, will be determined by the physician in accordance with the particular needs
of the patient.

7

MARKETING AUTHORISATION HOLDER
EVER Neuro Pharma GmbH
Oberburgau 3
4866 Unterach
Austria

8

MARKETING AUTHORISATION NUMBER(S)
PL 40369/0003

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
20/02/2014

10

DATE OF REVISION OF THE TEXT
12/08/2016

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