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Apomorphine 10mg/ml solution for injection

Last Updated on eMC 10-Jun-2014 View changes  | Archimedes Pharma UK Ltd Contact details

1. Name of the medicinal product

Apomorphine hydrochloride 10 mg/ml solution for injection/infusion

2. Qualitative and quantitative composition

Each ml contains 10mg apomorphine hydrochloride

2ml contains 20mg apomorphine hydrochloride

5ml contains 50mg apomorphine hydrochloride

Excipients with known effect:

Sodium metabisulphite 1 mg/ml

Sodium 0.3 mg/ml (maximum)

For the full list of excipients, see section 6.1

3. Pharmaceutical form

Solution for injection/ infusion

A clear, colourless to pale yellow solution.

pH 3 - 4

4. Clinical particulars
4.1 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.

4.2 Posology and method of administration

Apomorphine hydrochloride is for subcutaneous use by intermittent bolus injection. Apomorphine hydrochloride may also be administered as a continuous subcutaneous infusion by minipump and/or syringe driver. Apomorphine hydrochloride may be diluted with sodium chloride 9 mg/ml (0.9%) solution for injection or Water for Injections.

Apomorphine must not be used via the intravenous route.

Adults

Selection of patients suitable for apomorphine hydrochloride

Patients selected for treatment with Apomorphine hydrochloride 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 hydrochloride (see section 4.5).

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) can be given subcutaneously after at least 40 minutes 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 hydrochloride 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 by minipump and/or syringe-driver 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.

The above volumes are for undiluted apomorphine hydrochloride 10mg/ml. Volumes must be adjusted to allow for dilution undertaken prior to use.

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.

Paediatric population

No data are available

Apomorphine hydrochloride is contraindicated in children and adolescents up to 18 years of age (see section 4.3).

Elderly patients

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.

Patients with 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

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

4.4 Special warnings and precautions for use

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, 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.

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 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.

Apomorphine hydrochloride contains sodium metabisulphite which may rarely cause severe hypersensitivity reactions and bronchospasm. It also contains sodium at less than 1mmol (23mg) per ml, i.e. essentially 'sodium-free'.

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).

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.

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 hydrochloride. Dose reduction/tapered discontinuation should be considered if such symptoms develop.

CAUTION: Apomorphine should not be spilled on clothing or household surfaces and textiles as spillages may turn green.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed

It is recommended to avoid the administration of apomorphine with other drugs known to prolong the QT interval (see section 4.4).

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 (see section 4.4).

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) (see section 4.2).

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of apomorphine in pregnant women.

Animal studies are insufficient with respect to reproductive toxicity

Animal reproduction studies do not indicate any teratrogenic 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).

Apomorphine hydrochloride is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether apomorphine is excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from apomorphine therapy taking into account the benefit of breastfeeding to the child and the benefit of therapy for the woman.

4.7 Effects on ability to drive and use machines

Apomorphine hydrochloride has moderate influence on the ability to drive and use machines.

Patients being treated with apomorphine hydrochloride 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).

4.8 Undesirable effects

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

For the evaluation of adverse effects the following frequency specification will be used:

Very common (≥ 1/10)

Common (≥ 1/1000 to < 1/10)

Uncommon (≥ 1/1000 to <1/100)

Rare (≥ 1/10,000 to <1/1000)

Very rare (< 1/10,000)

Not known (can not be estimated from available data).

System organ class

Frequency

Adverse event

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. Apomorphine 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

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 hydrochloride. (see section 4.4 'Special warnings and precautions for use')

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.

Reporting of suspected 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 the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Dopaminergic agents; dopamine agonists

ATC Code: N04B C07

Mechanism of action

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.

Pharmacodynamic effects

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

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 is by glucurondation and sulphonation to at least ten per cent of the total; other pathways have not been described.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on repeat dose subcutaneous toxicity studies, 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.

No carcinogenicity studies have been 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.

6. Pharmaceutical particulars
6.1 List of excipients

Sodium metabisulphite (E223)

Hydrochloric acid (37%) for pH adjustment

Sodium hydroxide (99%) for pH adjustment

Water for Injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened: 3 years.

After first opening: Immediate use.

After dilution:

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

6.4 Special precautions for storage

Do not store above 25°C. Keep the ampoules in the outer carton, in order to protect from light.

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

6.5 Nature and contents of container

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.

Bundle packs of 25 and 50 ampoules are available in some countries.

The 25 ampoule pack consists of 5 packs each containing 5 ampoules.

The 50 ampoule pack consists of 10 packs each containing 5 ampoules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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.

Apomorphine hydrochloride is compatible with sodium chloride solution 9mg/ml (0.9%) solution for injection and Water for Injections.

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

7. Marketing authorisation holder

Archimedes Pharma UK Limited

250 South Oak Way

Green Park

Reading

Berkshire

RG2 6UG

United Kingdom

8. Marketing authorisation number(s)

PL 12406/0024

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 26 September 2007

Date of latest renewal: 20 November 2013

10. Date of revision of the text

29 April 2014

Company contact details

Archimedes Pharma UK Ltd

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Address

250 South Oak Way, Green Park, Reading, RG2 6UG, UK

Fax

+44 (0)118 931 5056

Medical Information e-mail
Telephone

+44 (0)118 931 5050

Medical Information Direct Line

+44 (0)118 931 5094

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Active ingredients

apomorphine hydrochloride

Legal categories

POM - Prescription Only Medicine

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