SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Dacepton 10 mg/ml Solution for injection or infusion

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

1 ml contains 10 mg apomorphine hydrochloride 5 ml contains 50 mg apomorphine hydrochloride Excipient:

Sodium metabisulphite (E223) 1 mg per ml For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for injection or infusion

The solution is clear and colourless or almost colourless to slightly yellow, practically free from visible particles

pH of 3.0 - 4.0.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

The treatment of disabling motor fluctuations (“on-off’    phenomena) in patients with

Parkinson's disease which persist despite individually titrated treatment with levodopa (with a peripheral decarboxylase inhibitor) and/or other dopamine agonists.

4.2    Posology and method of administration

Selection of Patients suitable for Dacepton 10 mg/ml injections:

Patients selected for treatment with Dacepton 10 mg/ml 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.

It is essential that the patient is established on domperidone, usually 20 mg three times daily, for at least two days prior to initiation of therapy.

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 10 mg/ml.

Adults

Administration

Dacepton 10 mg/ml is for subcutaneous use by intermittent bolus injection. Dacepton 10 mg/ml may also be administered as a continuous subcutaneous infusion by minipump and/or syringe-driver (see section 6.6).

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 and particle free solution should be used.

Determination of the threshold dose

The appropriate dose for each patient is established by incremental dosing schedules. The following schedule is suggested:

1 mg of apomorphine hydrochloride (0.1 ml), that is approximately 15-20 micrograms/kg, may be injected subcutaneously during a hypokinetic or “off’ period and the patient is observed over 30 minutes for a motor response.

If no response, or an inadequate response, is obtained a second dose of 2 mg of apomorphine hydrochloride (0.2 ml) is injected subcutaneously and the patient observed for an adequate response for a further 30 minutes.

The dosage may be increased by incremental injections with at least a forty minute interval between succeeding injections, until a satisfactory motor response is obtained.

Establishment of treatment

Once the appropriate dose is determined, a single subcutaneous injection may be given into the lower abdomen or outer thigh at the first signs of an “off’ episode. It cannot be excluded that absorption may differ with different injection sites within a single individual. Accordingly, the patient should then be observed for the next hour to assess the quality of their response to treatment. Alterations in dosage may be made according to the patient's response.

The optimal dosage of apomorphine hydrochloride varies between individuals but, once established, remains relatively constant for each patient.

Precautions on continuing treatment

The daily dose of Dacepton 10 mg/ml varies widely between patients, typically within the range of 3-30 mg, given as 1-10 injections and sometimes as many as 12 separate injections per day.

It is recommended that the total daily dose of apomorphine hydrochloride should not exceed 100 mg and that individual bolus injections should not exceed 10 mg per hour.

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.

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:

Continuous infusion is started at a rate of 1 mg apomorphine hydrochloride (0.1 ml) per hour then increased according to the individual response. Increases in the infusion rate should not exceed 0.5 mg per hour at intervals of not less than 4 hours. Hourly infusion rates may range between 1 mg and 4 mg (0.1 ml and 0.4 ml), equivalent to 0.015 - 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.

Children and adolescents

Dacepton 10 mg/ml 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 Dacepton 10 mg/ml. The management of elderly patients treated with Dacepton 10 mg/ml 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

In patients with respiratory depression, dementia, psychotic diseases or hepatic insufficiency.

Apomorphine hydrochloride must not be administered to patients who have an “on” response to levodopa which is marred by severe dyskinesia or dystonia.

Dacepton 10 mg/ml should not be administered to patients who have a known hypersensitivity to apomorphine or any excipients of the medicinal product.

Dacepton 10 mg/ml is contraindicated for children and adolescents under 18 years of age.

4.4 Special warnings and precautions for use

Apomorphine hydrochloride 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 pre-existing 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.

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 other dopamine agonists can be associated with sudden sleep onset episodes, 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 must refrain from driving or operating machines. Furthermore, a reduction of dosage or termination of therapy may be considered.

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 10 mg/ml contains sodium metabisulphite which may rarely cause severe allergic reactions and bronchospasm.

This medicinal product contains less than 1 mmol sodium (23 mg) per 10 ml, i.e. essentially ”sodium-free”.

4.5 Interaction with other medicinal products and other forms of interaction

Patients selected for treatment with apomorphine hydrochloride are almost certain to be taking concomitant medications for their Parkinson's disease. In the initial stages of apomorphine hydrochloride 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

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 10 mg/ml should not be used during pregnancy unless clearly necessary

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 10 mg/ml should be made taking into account the benefit of breast-feeding to the child and the benefit of Dacepton 10 mg/ml to the woman.

4.7 Effects on ability to drive and use machines

Apomorphine hydrochloride 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.
Immune system disorders Rare: Due to the presence of sodium metabisulphite, allergic reactions (including anaphylaxis and bronchospasm) may occur.
Psychiatric disorders	Common: Neuropsychiatric disturbances are common in parkinsonian patients. Dacepton 10 mg/ml should be used with special caution in these patients. Neuropsychiatric disturbances (including transient mild confusion and visual hallucinations) have occurred during apomorphine hydrochloride therapy. Not known: 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 (see section 4.4).
Nervous system disorders	Common: Transient sedation with each dose of apomorphine hydrochloride 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.
Vascular disorders	Uncommon: Postural hypotension is seen infrequently and is usually transient (see section 4.4)
Respiratory, thoracic and mediastinal disorders	Common: Yawning has been reported during apomorphine therapy Uncommon: Breathing difficulties have been reported.
Gastrointestinal disorders	Common: Nausea and vomiting, particularly when apomorphine treatment is first initiated, usually as a result of the omission of domperidone (See section 4.2).
Skin and subcutaneous tissue disorders	Uncommon: Local and generalised rashes have been reported.
General disorders and administration site conditions	Very common: 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.

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: Dopamine agonists ATC code: N04B C07

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 two-compartment 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)

Hydrochloric acid (for pH-adjustment)

Sodium hydroxide (for pH-adjustment)

Water for injections

6.2    Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened: 30 months

Once opened, use immediately. Discard any unused contents Shelf-life after dilution (if applicable):

Chemical and physical in-use stability has been demonstrated for up to 24 hours at 15 - 25°C when the product is diluted with sodium chloride 0.9%.

From a microbiological point of view the 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°C to 8°C, unless opening and dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions. Keep the ampoules in the outer carton in order to protect from light.

Do not refrigerate or freeze.

6.5 Nature and contents of container

Clear, colourless type I glass ampoules containing 5 ml solution for injection, in packs of 1, 5 or 10 ampoules.

Bundle packs: 5 x 1, 10 x 1, 2 x 5, 5 x 5, 10 x 5, 3 x 10 and 10 x 10 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 product should be discarded.

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.

Dacepton 10 mg/ml is compatible with sodium chloride solution 0.9 % (9 mg/ml).

7 MARKETING AUTHORISATION HOLDER

EVER Neuro Pharma GmbH Oberburgau 3 866 Unterach Austria

8    MARKETING AUTHORISATION NUMBER(S)

PL 40369/0001

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29/06/2012

10    DATE OF REVISION OF THE TEXT

04/07/2014