Summary of Product Characteristics

Product Summary

Name of the Medicinal Product
APO-go PFS 5mg/ml Solution for Infusion in Pre-filled Syringe

Qualitative and Quantitative Composition
1ml contains 5mg apomorphine hydrochloride.
Each 10ml pre-filled syringe contains 50mg apomorphine hydrochloride.
For excipients, see Section 6.1

Pharmaceutical Form

Solution for Infusion, pre-filled syringe
Solution is clear and colourless

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.

Posology and Method of Administration
APO-go PFS 5mg/ml Solution for Infusion in Pre-filled Syringe is a pre-diluted pre-filled syringe intended for use as a continuous subcutaneous infusion by minipump and / or syringe-driver.

Apomorphine must not be used via the intravenous route.

Dosage
Adults
Administration
Selection of Patients suitable for APO-go:

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 (see Section 6.6 Instruction for Use/Handling) as follows:-

The threshold dose for continuous infusion should be determined as follows: Continuous infusion is started at a rate of 1 mg apomorphine HCl (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 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.

It is recommended that the total daily dose of apomorphine HCl 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.

Children and adolescents
APO-go PFS 5mg/ml Solution for Infusion in Pre-filled Syringe is contra-indicated for children and adolescents under 18 years of age (see Section 4.3 Contra-indications).

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 Special Warnings and Precautions for Use).

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

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.

Pregnancy and lactation (see Section 4.6 Pregnancy and Lactation).

Special Warnings and Precautions for Use
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, and especially in patients with pre-existing postural hypotension.

APO-go PFS 5 mg/ml Solution for Infusion in Pre-filled Syringe contains sodium metabisulphite which may rarely cause severe allergic reactions and bronchospasm.

Coombs’ positive haemolytic anaemia has been reported rarely in patients treated with levodopa and the incidence in patients taking levodopa and apomorphine is unaltered. Coombs’ positive haemolytic anaemia has not been reported in patients taking apomorphine in association with other therapy. 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 Interactions with other Medicinal Products and Other Forms of Interaction).

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.

Interaction with other Medicinal Products and other forms of Interaction
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.

If neuroleptic medicinal products have to be used in patients with Parkinsons’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 Special Warnings and Precautions for Use).

Pregnancy and Lactation
Animal reproduction studies have not been conducted with apomorphine HCl.

Neither is there any experience of apomorphine usage in pregnant women. Therefore, apomorphine HCl should not be used in women of child-bearing potential.

It is anticipated that apomorphine is excreted in breast milk. Breast-feeding should be avoided during apomorphine HCl therapy.

Undesirable Effects
Very common (>10%):
Local induration and nodules (usually asymptomatic) often develop at subcutaneous sites of injection in most patients, particularly with continuous use. In patients on high doses of apomorphine HCl these may persist and give rise to areas of erythema, tenderness and induration. Panniculitus has been reported from these patients where a skin biopsy has been undertaken. Care should be taken to ensure that areas of ulceration do not become infected. Pruritus may occur at the site of injection.

These local subcutaneous effects can sometimes be reduced by rotation of injection sites or possibly by the use of ultrasound (if available) to areas of nodularity and induration.

Common (1-10%):
Nausea and vomiting, particularly when apomorphine treatment is first initiated, usually as a result of the omission of domperidone (See Section 4.2 Posology and Method of Administration).

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.

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

Uncommon (0.1-1%):
Postural hypotension is seen infrequently and is usually transient (See Section 4.4 Special Warnings and Precautions for Use).

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.

Coombs’ positive haemolytic anaemia has rarely been reported in patients treated with levodopa and apomorphine.

Rare (0.01%-0.1%):
Eosinophilia has rarely occurred during treatment with apomorphine HCl.

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

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.

Pharmacodynamic Properties

Pharmacotherapeutic 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.

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.

There are no data on fertility and embryo-foetal toxicity. No carcinogenicity studies have been performed.

List of Excipients

Nature and Contents of Container

There is no need to dilute APO-go PFS 5mg/ml Solution for Infusion in Pre-filled Syringe prior to use.

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.

APO-go PFS 5mg/ml Solution for Infusion in Pre-filled Syringe is for single use only. Any unused solution 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.

After single use, adaptors and plastic syringes should be discarded and disposed of in a “Sharps” bin.

APO-go PFS 5mg/ml Solution for Infusion in Pre-filled Syringe has been designed for continuous infusion of apomorphine therapy via a syringe driver. It is not intended to be used for intermittent injection.

APO-go PFS 5mg/ml Solution for Infusion in Pre-filled Syringe can be used with suitable pumps/syringe drivers, e.g. APO-go pump or Graseby syringe driver. Detailed explanations will be provided by the Distributor.