- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Excipients with known effect:Sodium metabisulphite 1 mg/mlSodium 0.3 mg/ml (maximum)For the full list of excipients, see section 6.1
Apomorphine must not be used via the intravenous route.
AdultsSelection 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.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 Apomorphine hydrochloride (see section 4.5).
Determination of the threshold doseThe 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 treatmentOnce 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 treatmentThe 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 InfusionPatients 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 populationNo data are available.Apomorphine hydrochloride is contraindicated in children and adolescents up to 18 years of age (see section 4.3).
Elderly patientsThe 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 impairmentA dose schedule similar to that recommended for adults, and the elderly, can be followed for patients with renal impairment (see Section 4.4).
Impulse control disordersPatients 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.
PregnancyThere 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-feedingIt 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.
|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||Very common||Hallucinations|
|Common||Neuropsychiatric disturbances (including transient mild confusion and visual hallucinations) have occurred during apomorphine HCl therapy.|
|Not known||Impulse control disordersPathological 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 reactionsReporting 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.
Mechanism of actionApomorphine 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 effectsAlthough 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.
Kyowa Kirin Ltd
Galabank Business Park, Galashiels, TD1 1QH
+ 44 (0)1896 664 000