Apomorphine 10mg/ml solution for injection

Each ml contains 10mg apomorphine hydrochloride

2ml contains 20mg apomorphine hydrochloride

5ml contains 50mg apomorphine hydrochloride

For excipients, see Section 6.1

Solution for Injection

A clear, colourless to pale yellow solution. .

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.

Apomorphine 10mg/ml solution for injection is for subcutaneous use by intermittent bolus injection. Apomorphine 10mg/ml solution for injection may also be administered as a continuous subcutaneous infusion. Apomorphine 10mg/ml solution for injection may be diluted with sodium chloride solution 0.9% or Water for Injections.

Apomorphine must not be used via the intravenous route.

Dosage

Adults

Administration

Selection of patients suitable for apomorphine 10mg/ml solution for injection

Patients selected for treatment with Apomorphine 10mg/ml solution for injection 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 20mg 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 Apomorphine 10mg/ml solution for injection treatment.

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 to 20 micrograms/kg, may be injected subcutaneously during a hypokinetic or 'off' period and the patient observed over 30 minutes for a motor response.

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

The dosage may be increased by incremental injections with at least a 40 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 apomorphine 10mg/ml solution for injection varies widely between patients, typically within the range of 3mg to 30mg, given as 1 to 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.

Continuous Infusion

Patients who have shown a good 'on' period response during the initiation stage, 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 as follows:

Continuous infusion is started at a rate of 1mg apomorphine HCl (0.1ml) per hour then increased according to the individual response. Increases in the infusion rate should not exceed 0.5mg per hour at intervals of not less than 4 hours. Hourly infusion rates may range between 1mg and 4mg (0.1ml and 0.4ml), equivalent to 0.015 – 0.06mg/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 via the pump system 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

Apomorphine 10mg/ml solution for injection is contraindicated for children and adolescents up to 18 years of age (see section 4.3 Contraindications).

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. The management of elderly patients treated with apomorphine 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 – Special warnings and precautions for use).

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

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

Apomorphine 10mg/ml solution for injection should not be administered to patients who have a known sensitivity to apomorphine or any of the other ingredients of the product.

Apomorphine is contra-indicated in children and adolescents under 18 years of age.

Apomorphine 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.

Apomorphine 10mg/ml solution for injection contains sodium metabisulphite which may rarely cause severe allergic reactions and bronchospasm. It also contains sodium at less than 1mmol (23mg) per ml.

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 – Interaction with other medicinal products and other forms of interaction).

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 are almost certain to be taking concomitant medications for their Parkinson's disease. In the initial stages of apomorphine 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).

Pregnancy

Due to the age of the treated population, the occurrence of pregnancy is improbable. Animal studies are insufficient with respect to the effects on pregnancy, embryo-fetal development, parturition and postnatal development (See section 5.3). The potential risk for humans is unknown.

Caution should be exercised if prescribing apomorphine to pregnant women and women of childbearing age.

Lactation

It is not known whether apomorphine is excreted in breast milk. However, breast-feeding should be avoided during apomorphine therapy.

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 – Special warnings and precautions for use).

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 these may persist and give rise to areas of erythema, tenderness and induration. Panniculitis has been reported from those 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 the use of ultrasound (if available) to areas of nodularity and induration.

Common (1% to 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 at the start of therapy may occur; this usually resolves over the first few weeks.

Apomorphine is associated with somnolence.

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

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

Uncommon (0.1% to 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.

Local and generalised rashes have been reported.

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

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

Breathing difficulties have been reported.

Rare (0.01% to 0.1%)

Eosinophilia has rarely occurred during treatment with apomorphine .

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

Unknown:

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.

There is little clinical experience of overdosage with apomorphine by this route of administration. Symptoms of overdosage 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.

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.

Apomorphine, a potent agonist, has been used in acute and chronic studies of Parkinsonism and other neurological disorders. After subcutaneous injection 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. From the drug absorption, volume of injection, S.C. infusion, and I.V. infusion, it can be concluded that apomorphine is rapidly and completely absorbed from subcutaneous tissue, correlating with the rapid onset of clinical effects (4 to 12 minutes), and that the brief duration of a clinical action of the drug (about 1 hour) is explained by its rapid clearance. The metabolism of apomorphine in humans does not show enantiomer interconversion nor methylation into (iso)apocodeine. Approximately ten per cent of the metabolism is by glucuronidation and sulphonation.

Repeat dose subcutaneous toxicity studies reveal no special hazard for humans, beyond the information included in other sections of the Summary of Product Characteristics.

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.

Sodium metabisulphite

Hydrochloric acid

Sodium hydroxide

Water for Injections

As with all parenteral solutions, incompatibility of addictive medications with the solution must be assessed before addition. In the absence of compatibility studies, this solution must not be mixed with other medicinal products, except sodium chloride 0.9% and Water for Injections.

Unopened: 2 years

Shelf life after first opening the ampoule: Immediate use

Shelf life after dilution: 24 hours

Do not store above 25°C. Keep ampoules in the outer carton.

Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C when the product is diluted with sodium chloride 0.9% injection or Water for Injections. 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 2ºC to 8°C, unless opening and dilution has taken place in controlled and validated aseptic conditions.

Clear, colourless type I glass ampoules containing 2ml solution for injection, supplied in packs of 5 or 10 ampoules.

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

Do not use if the solution has turned green. The solution should be inspected visually prior to use. Only clear, colourless to pale yellow solutions should be used.

For single use only. Any unused solution should be discarded.

Apomorphine 10mg/ml solution for injection is compatible with sodium chloride solution 0.9% and Water for Injections.

Archimedes Pharma UK Limited

250 South Oak Way

GreenPark

Reading

Berkshire

RG2 6UG

UK

PL12406/0024

26 September 2007

26 September 2007

APOINJA-SPC04