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

Selection of patients suitable for APO-go injections:

Patients selected for treatment with APO-go 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 APO-go treatment.

Posology

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 HCl (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 HCl (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 APO-go 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 HCl should not exceed 100mg and that individual bolus injections should not exceed 10 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

APO-go Pen 10 mg/ml Solution for Injection 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 APO-go. The management of elderly patients treated with APO-go 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).

Method of Administration

APO-go Pen 10 mg/ml Solution for Injection is for subcutaneous use by intermittent bolus 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 and particle free solution should be used.

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

Apomorphine HCl treatment must not be administered to patients who have an 'on' response to levodopa which is marred by severe dyskinesia or dystonia.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. APO-go should not be administered to patients who have a known hypersensitivity to apomorphine or any excipients of the medicinal product.

APO-go is contraindicated for children and adolescents under 18 years of age.

Apomorphine HCl 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 anti-hypertensives, 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 to 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 whilst 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 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.

Dopamine dysregulation Syndrome (DDS) is an addictive disorder resulting in excessive use of the product seen in some patients treated with apomorphine. Before initiation of treatment, patients and caregivers should be warned of the potential risk of developing DDS.

APO-go Pen 10 mg/ml Solution for Injection contains sodium bisulphite 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” .

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

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 Drugs

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.

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.

APO-go should not be used during pregnancy unless clearly necessary.

Breastfeeding

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 APO-go should be made taking into account the benefit of breast-feeding to the child and the benefit of APO-go to the woman.

Apomorphine HCl 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 Section 4.4).

“ This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

- The medicine is likely to affect your ability to drive

- Do not drive until you know how the medicine affects you

- It is an offence to drive while under the influence of this medicine

- However, you would not be committing an offence (called 'statutory defence') if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely”

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 HCl.

Immune system disorders

Rare:

Due to the presence of sodium bisulphite, allergic reactions (including anaphylaxis and bronchospasm) may occur.

Psychiatric disorders

Very Common:

Hallucinations

Common:

Neuropsychiatric disturbances (including transient mild confusion and visual hallucinations) have occurred during apomorphine HCl 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).

Aggression, agitation

Nervous system disorders

Common:

Transient sedation with each dose of apomorphine HCl 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).

Not known:

Syncope

Headache

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 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:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance,

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

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.

Pharmatherapeutic group: Dopamine agonists, ATC Classification: 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.

Distribution and Elimination

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 drug distribution being best described by a two- compartment model.

Absorption

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 drug (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.

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.

Environmental Risk Assessment (ERA)

Apomorphine HCl is a well-established active substance and APO-go products have been on the market for 10 years, it is our conclusion that no environmental risk assessment is needed for this active substance.

Sodium bisulphite (E222)

Hydrochloric Acid (37%), concentrated (for pH adjustment )

Water for injections

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

2 years

48 hours after first opening.

Do not store above 25° C.

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

The product should be stored at the same conditions after opening and between withdrawals.

Cartridge.

APO-go Pen 10 mg/ml is a disposable multiple dose pen injector system incorporating a clear glass (type I) cartridge containing a clear solution for injection. The glass cartridge is sealed at one end with a bromobutyl rubber piston, and at the other end with a bromobutyl rubber/aluminium membrane.

Each pen contains 3 ml of solution for injection.

Packs containing 1, 5, or 10 x 3 ml pens in a moulded plastic tray in an outer cardboard carton.

Multipacks containing 25 (5 packs of 5) pens.

Not all pack sizes may be marketed.

APO-go PEN

Do not use if solution has turned green.

Discard each pen no later than 48 hours from first use.

(see attached diagram)

* This pack does NOT contain needles for use with your Pen.

Use pen needles not more than 12.7 mm (½ ” ) in length and not finer than 30G. Pen needles recommended for use with insulin pens are compatible with APO-go^® Pen.

IMPORTANT: Do not pull the red capped dial (see 1) before you have set the dosage (see 'Selecting the correct dose').

Attaching the needle

(a) Before using APO-go Pen you will need some surgical wipes and one needle in its protective cone (see 2).

(b) Take the Pen out of its box and remove the outer sleeve (see 3).

(c) Wipe the membrane of the Pen (see 4) with a surgical wipe.

(d) Peel off the paper from the needle cone (see 2).

(e) It is important to bring the needle to the Pen in a straight line, as shown above. If the needle is presented at an angle it may cause the Pen to leak.

(f) Screw the cone (see 2) clockwise onto the membrane until it is tight. This securely attaches the needle.

(g) Remove the protective cone (see 5), but do not throw it away. Do not remove the needle protector (see 6) at this stage.

(h) Replace the Pen's outer sleeve (see 3).

Selecting the correct dose

(i) Press the red capped dosage dial (see 1) and whilst holding it down, turn the dial clockwise until the arrow points to the dose your doctor chose for you (see 7&8). Release the downward pressure on the red capped dial. The dose is now set and you do not need to redial for subsequent injections.

Important: If you pass your prescribed dose while turning the dial, just continue pressing and turning in the same direction until the arrow points to the dose your doctor chose for you.

Never pull and turn the red capped dosage dial at the same time.

If your dose is 1 mg, start by emptying a 1 mg dose onto a paper tissue and discarding it. This is called 'priming' and is important because it ensures you get a full dose the first time you use your Pen. Then, set the dose you require for injection and inject it in the usual way (see “ Injecting” ). If the first dose required is more than 1 mg, you do not need to prime the Pen.

Injecting

(j) Once you have set the dose, gently pull out the red capped dosage dial as far as it will go. Check the red scale on the plunger (see 9) and inject only if the line that is just visible matches the intended dose.

(k) Using a surgical wipe, clean the area of skin where you plan to inject the medicine and around it.

(l) Remove the Pen's outer sleeve (see 3).

(m) Remove the needle protector (see 6).

(n) Insert the needle (see 10) into the skin as shown by your doctor.

(o) To inject, press the red capped dosage dial (see 1) down as far as it will go, using your thumb if possible. Once the red capped dosage dial is fully depressed, count to three before withdrawing the needle.

(p) Replace the protective cone (see 5) onto the used needle and push gently into place. Once secure, turn the needle anti-clockwise to unscrew it. Keep the needle in its protective cone and discard it in a safe place, such as a “ Sharps” bin or an empty coffee jar.

Preparing for the next injection

(q) Remove the outer sleeve of the Pen and check there is enough apomorphine left in the cartridge for your next injection. If there is, put a new needle in place in the same way as before.

(r) If there is not enough apomorphine left for another injection, prepare another pen.

(s) Finally, replace the outer sleeve of your Pen.