SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Apomorphine hydrochloride 5 mg/ml, solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml contains 5 mg apomorphine hydrochloride hemihydrate.

One 20 ml vial contains 100 mg apomorphine hydrochloride hemihydrate. Excipient with known effect: Sodium metabisulfite 1 mg per ml.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for infusion

Clear and practically colourless solution

pH 2.6 - 4.0

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of motor fluctuations ('on-off¹ phenomena) in patients with Parkinson’s disease which are not sufficiently controlled by oral anti-Parkinson medication.

4.2 Posology and method of administration

Posology

Patients Suitable for Apomorphine hydrochloride

Patients selected for treatment with Apomorphine hydrochloride be capable of inserting the needle s.c. themselves or else have a responsible carer able to insert the needle s.c. 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 treatment should be initiated in a controlled environment of a specialist clinic. The treatment should be managed 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 Apomorphine hydrochloride treatment.

Method of administration

Apomorphine hydrochloride 5 mg/ml, solution for infusion, is intended for use without dilution as a continuous subcutaneous infusion by minipump and / or syringe pump (infusion pump).

Apomorphine must not be used via the intravenous route.

Do not use if the solution has turned green. The solution should be visually inspected prior to

use. Only clear and particle free solutions should be used. See Section 6.6.

Continuous Infusion

Patients who have shown a good ‘on period’ response during an initial apomorphine injection, 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 pump as follows:

The choice of which minipump and / or syringe pump to use, and dosage settings required will be determined by the physician in accordance with the particular needs of the patient.

The threshold dose for continuous infusion should be determined as follows:

Continuous infusion is started at a rate of 1 mg apomorphine hydrochloride (0.2 ml) per hour. The dose can thereafter be increased according to the patient’s response during that particular 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 recommended. Tolerance to the therapy does not seem to occur as long as there is an overnight period without treatment of at least 4 hours. The infusion site should be changed every 12 hours.

Where appropriate and as advised by a physician, the continuous infusion may need to be supplemented with intermittent bolus doses.

A reduction in dosage of other dopamine agonists may be considered during continuous infusion treatment.

Establishment of 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, it remains relatively constant for the individual patient.

Precautions on continuing treatment

The daily dose of Apomorphine hydrochloride varies widely between patients, typically within the range of 3-30 mg.

The total daily dose of apomorphine hydrochloride should not exceed 100 mg.

In clinical studies it has usually been possible to make a slight reduction in the dose of levodopa. This varies however considerably between patients and must be carefully managed by an experienced physician.

Once treatment has been established domperidone therapy may be gradually reduced in some patients. Only in a few patients domperidone may be completely discontinued without any vomiting or hypotension as a result.

Paediatric population

Apomorphine hydrochloride 5 mg/ml, solution for infusion, is contra-indicated 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 hydrochloride. The treatment with apomorphine hydrochloride has been the same in elderly and younger patients. Special caution is however recommended during initiation of therapy in elderly patients due to 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.

Respiratory depression, dementia, psychotic diseases or hepatic insufficiency.

Apomorphine hydrochloride treatment must not be administered to patients who develop severe dyskinesia or dystonia as response to levodopa.

Apomorphine hydrochloride must not be given to 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.

Special caution is recommended during initiation of therapy in elderly and/or debilitated patients.

Since apomorphine may produce hypotension, even when given with domperidone, care should be exercised in patients with cardiac disease or in patients taking vasoactive medicinal products such as antihypertensives, and especially in patients with a history of 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 reactions. These may sometimes be reduced by switching injection site or possibly by using ultra-sound (if this is available) on areas with nodularity and induration.

Haemolytic anaemia has been reported in patients treated with levodopa and 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).

Neuropyschiatric 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.

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 and hyper sexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including Apomorphine hydrochloride. Dose reduction/tapered discontinuation should be considered if such symptoms develop.

Apomorphine hydrochloride 5 mg/ml, solution for infusion, contains sodium metabisulfite which may rarely cause severe hypersensitivity reactions and bronchospasm.

This medicinal product contains 3.3 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 are almost certain to be taking concomitant medicinal products for their Parkinson’s disease. In the initial stages of apomorphine hydrochloride therapy the patient should be monitored for unusual undesirable 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.

Clozapine may however also be used to reduce the symptoms of neuropsychiatric complications.

If neuroleptics 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 pump (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.

Reproduction studies in animals do not indicate any teratogenic effect, but in rats, dosages that are toxic to the mother may cause respiratory failure in the newborn offspring. The potential risk for humans is unknown. Apomorphine hydrochloride should therefore be used during pregnancy only when considered absolutely necessary.

Breast-feeding

It is not known whether apomorphine is excreted in breast milk. Decision whether breast-feeding should be continued/ discontinued or if Apomorphine hydrochloride treatment should be continued/discontinued should be taken after consideration of the advantages of breast-feeding the child and the advantages of Apomorphine hydrochloride treatment for the mother.

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 fej/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 metabisulfite, allergic reactions (including anaphylaxis and

bronchospasm) may occur.

Psychiatric disorders

Common

Neuropsychiatric disturbances are common in patients with Parkinson's disease. Apomorphine hydrochloride 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

Pathological gambling, increased libido and hyper sexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including Apomorphine hydrochloride (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 / lightheadedness have also been reported.

Uncommon

Apomorphine may induce dyskinesia 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 treatment.

Uncommon

Breathing difficulties have been reported.

Gastrointestinal disorders

Common

Nausea and vomiting, particularly when apomorphine treatment is first initiated, usually as a result of not using 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

In most patients injection site reactions develop, particularly with continuous use. These may include subcutaneous nodules, induration, erythema, tenderness and panniculitus. A number of other local reactions (such as irritation, pruritus, bruising and pain) may also occur.

Uncommon

Necrosis and ulceration at the injection site have been reported.

Not known

Periferal edema has been reported.

Investigations

Uncommon

Positive Coombs' tests have been reported for patients receiving levodopa and apomorphine.

4.9 Overdose

There is limited clinical experience of overdose with apomorphine by subcutaneous 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: N04BC07

Apomorphine is a direct stimulant of dopamine receptors. Even if it is possessing both D1 and

D2 receptor agonist properties it 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 pharmacokinetics 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. Apomorphine is rapidly and completely absorbed from subcutaneous tissue, correlating with the rapid onset of clinical effects (4-12 minutes). The brief duration of clinical action of apomorphine (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 in vivo studies.

The effect of apomorphine on reproduction has been studied in rats. Apomorphine was not teratogenic in this species, but it was observed that toxic doses to the mother can result in impaired maternal attention and respiratory failure in the newborn offspring.

No carcinogenicity studies have been performed.

6.1 List of excipients

Sodium chloride Sodium metabisulfite (E223) 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

2 years.

Once opened the vial must be used immediately.

From a microbiological point of view, once opened, the product should be used immediately. The product may be kept in the minipump and / or syringe pump and administered during/up to 24 hours without limitation of storage temperature. Other in-use storage times and conditions are the responsibility of the user.

6.4 Special precautions for storage

Keep in the outer carton in order to protect from light.

Do not store above 25 °C.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Vial (type I glass) with bromobutyl rubber stopper and aluminium cap. 1 pack contains 5 vials of 20 ml, stored in a cardboard box.

6.6 Special precautions for disposal

For single use only.

Do not use if the solution has turned green. The solution should be visually inspected prior to

use. Only clear and particle free solutions should be used. See Section 4.2.

After use, vials and syringes and any unused contents should be discarded.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Pharmaceuticals Sales & Development Sweden AB Midskogsgrand 11 115 43 Stockholm Sweden

8    MARKETING AUTHORISATION NUMBER(S)

PL 41183/0001

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/11/2012

10    DATE OF REVISION OF THE TEXT

23/11/2012