APO-go PEN 10 mg/ml Solution for Injection*

* Abbreviated to APO-go^® Pen in the text

1ml contains 10mg apomorphine hydrochloride

For a full list of excipients see section 6.1

Solution for injection.

Solution is clear and colourless.

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.

APO-go Pen 10 mg/ml Solution for Injection is for subcutaneous use by intermittent bolus injection.

Dosage

Adults

Administration

Selection of patients suitable for APO-go injections:

Determination of the threshold dose.

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

1mg of apomorphine HCl (0.1ml), 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 (0.2ml) 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 3-30mg, 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 10mg.

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.

Children and adolescents:

APO-go Pen 10mg/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.

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).

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

Intermittent apomorphine HCl treatment is not suitable for patients who have an 'on' response to levodopa, which is marred by severe dyskinesia or dystonia.

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 contra-indicated 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 pretreatment, care should be exercised in patients with pre-existing cardiac disease or in patients taking vasoactive medicinal products such as antihypertensives, 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) to areas of nodularity and induration.

APO-go Pen 10mg/ml Solution for Injection contains sodium bisulphite which may rarely cause severe allergic reactions and bronchospasm.

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.

Pathological gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists for Parkinson's disease, including apomorphine.

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 drugs 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 drugs. (See section 4.4).

It is recommended to avoid the administration of apomorphine with other drugs known to prolong the QT interval.

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.

It is not know 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.

Patients being treated with apomorphine and presenting with somnolence 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 unless patients have overcome such experiences of somnolence (see also Section 4.4).

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 metabisulphite, allergic reactions (including anaphylaxis and bronchospasm) may occur.

Psychiatric disorders

Common:

Neuropsychiatric disturbances are common in parkinsonian patients. APO-go should be used with special caution in these patients. Neuropsychiatric disturbances (including transient mild confusion and visual hallucinations) have occurred during apomorphine HCl therapy.

Not known:

Patients treated with dopamine agonists for treatment of Parkinson's disease, including apomorphine, especially at high doses, have been reported as exhibiting signs of pathological gambling, increased libido and hypersexuality; generally reversible upon reduction of the dose or treatment discontinuation.

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.

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.

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.

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. 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.

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.

Store in the original container.

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.

APO-go Pen is available in packs containing 1, 5, or 10 x 3ml pens in a moulded plastic tray in an outer cardboard carton. Each pen contains 3ml of solution for injection. Bundle Packs containing 25 Pens are available in some territories. These bundle packs consist of 5 boxes each containing 5 pens.

Not all pack sizes are 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)

HOW TO USE YOUR APO-go PEN

Read these instructions carefully

DO NOT PULL THE RED DIAL BEFORE YOU HAVE SET THE DOSAGE (See f)

(see attached diagram)

ATTACHING THE NEEDLE

(a) Before using your pen system you will need a surgical wipe and one needle in its protective cone (see 5). Take the pen out of its box and remove the outer sleeve (see 3).

(b) Wipe the membrane (see 4) with the surgical wipe.

(c) Peel off the paper from the needle cone (see 2), and screw the cone clockwise onto the membrane. This will attach needle securely.

PLEASE NOTE

It is important to bring the needle to the Pen in a straight line, as shown. If the needle is presented at an angle it may cause the Pen to leak. This will attach the needle securely.

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

(e) Replace the pen's outer sleeve.

HOW TO SELECT YOUR CORRECT DOSAGE

(see attached diagram)

(f) Press the red dosage dial (see 1) and turn the dial clockwise until the arrow points to your prescribed dosage (see 7,8). Then release downward pressure on the red 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 you arrive at it again. Never pull and turn the red dosage dial at the same time.

If your prescribed dose is 2mg or less, it is necessary to “prime” the pen before injecting the first dose. Do this by emptying the first 2mg dose onto a paper tissue and discard. Then, set the dose you require for injection and inject in the usual way (see below under “INJECTING”). If the first dose required is more than 2mg, then it is not necessary to “prime” the pen.

INJECTING

(see attached diagram)

(g) Pull out the red dosage dial as far as it will go. Check the white scale on the plunger and inject only if the highest number visible corresponds to the intended dose.

(h) Using a surgical wipe, clean the area of skin around the proposed site of injection.

Remove the pen's outer sleeve.

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

(j) Insert the needle into the skin as directed by your doctor.

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

(k) Remove and discard the needle, using the protective cone (see 5). This is done by replacing the protective cone onto the used needle, and pushing it gently into place. Once secure, you can unscrew the needle anti-clockwise. Discard the needle in a safe place.

Important: Each needle can only be used once.

PREPARING FOR THE NEXT INJECTION:

Check that there is enough apomorphine left in the cartridge for the next injection (see 9). If there is, put a new needle in place, following the same procedure as before. (Remember not to throw away the protective cone).

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

Finally, replace the outer sleeve of the pen.

Genus Pharmaceuticals Limited

Park View House

65 London Road

Newbury

Berkshire

RG14 1JN

United Kingdom (IE and UK only)

ITF Hellas S.A.

Areos 103 & Agias Triados 36

17562 Palaio Faliro

Athens

Greece (EL only)

Britannia Pharmaceuticals Limited

41 - 51 Brighton Road

Redhill

Surrey

RH1 6YS

United Kingdom (All other CMS)

PL 06831/0246

PA 1496/2/2

31 March 1999/ 27 July 2009

February 2010