APO-go

Apomorphine hydrochloride.

Pre-filled syringe: One ml contains 5mg apomorphine hydrochloride.
Each 10ml pre-filled syringe contains 50mg apomorphine hydrochloride.
Pre-filled pen: Each ml contains 10mg apomorphine hydrochloride.
Excipients/Inactive Ingredients: Pre-filled syringe: Sodium metabisulphite (E223), Hydrochloric acid (37%) (for pH adjustment), Water for injections.
Pre-filled pen: Sodium bisulphite (E222), Concentrated hydrochloric acid (37%) (to adjust pH to 3.0 - 4.0), Water for injection.

Pharmacotherapeutic group: Dopamine agonists. ATC Code: N04B C07.
Pharmacology: Pharmacodynamics: 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.
Pharmacokinetics: 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 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.
Toxicology: Preclinical safety data: Repeat dose subcutaneous toxicity studies reveal no special hazard for humans, beyond the information included in other sections.
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.

Treatment of motor fluctuations ('on-off' phenomena) in patients with Parkinson's disease which are not sufficiently controlled by oral anti-Parkinson medication.

Selection of patients suitable for APO-go: Patients selected for treatment with APO-go 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 Precautions).
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 APO-go treatment.
Children and adolescents: APO-go is contraindicated for children and adolescents under 18 years of age (see 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 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 Precautions).
APO-go pre-filled syringe: Adults: Administration: APO-go PFS 5mg/ml Solution for Infusion in Pre-filled Syringe is a pre-diluted pre-filled syringe intended for use without dilution as a continuous subcutaneous infusion by minipump and / or syringe-driver. It is not intended to be used for intermittent injection.
Apomorphine must not be used via the intravenous route.
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.
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 as follows: 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.
Determination of threshold dose: 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 1mg and 4mg (0.2ml and 0.8ml), 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.
APO-go pre-filled pen: Adults: Administration: APO-go Pen 10mg/ml Solution for Injection is for subcutaneous use by intermittent bolus injection.
Apomorphine must not be used via the intravenous route.
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.
Determination of 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.

There is little clinical experience of overdose with apomorphine by this route of administration. Symptoms of overdose may be treated empirically as suggested as follows: 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.

In patients with respiratory depression, dementia, psychotic diseases or hepatic insufficiency.
Apomorphine HCl treatment must not be administered to 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 of the 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 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.
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.
When used in combination with domperidone, risk factors in the individual patient should be carefully assessed. This should be done before treatment initiation, and during treatment.
Important risk factors include serious underlying heart conditions such as congestive cardiac failure, severe hepatic impairment or significant electrolyte disturbance. Also medication possibly affecting electrolyte balance, CYP3A4 metabolism or QT interval should be assessed. Monitoring for an effect on the QTc interval is advisable.
An ECG should be performed: prior to treatment with domperidone; during the treatment initiation phase; as clinically indicated thereafter.
The patient should be instructed to report possible cardiac symptoms including palpitations, syncope, or near-syncope. They should also report clinical changes that could lead to hypokalaemia, such as gastroenteritis or the initiation of diuretic therapy.
At each medical visit, risk factors should be revisited.
The domperidone dose should be titrated to the lowest effective dose and discontinued as soon as possible.
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) in order to avoid areas of nodularity and induration.
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 Interactions).
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 episodes of sudden sleep onset, 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 and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore a reduction of dosage 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. Dose reduction/tapered discontinuation should be considered if such symptoms develop.
Dopamine dysregulation Syndrome (DDS) is an addictive disorder resulting in excessive use of the product seen in some patients treated with apomorphine. Before initiation of treatment, patients and caregivers should be warned of the potential risk of developing DDS.
Effects on ability to drive and use machines: Apomorphine HCl has minor or moderate influence on the ability to drive and use machines.
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 as previously mentioned).
Pre-filled syringe: APO-go PFS 5mg/ml Solution for Infusion in Pre-filled Syringe contains sodium metabisulphite which may rarely cause severe allergic reactions and bronchospasm.
This medicinal product contains less than 1 mmol sodium (23 mg) per 10 ml, i.e. essentially "sodium-free".
Pre-filled pen: APO-go Pen 10mg/ml Solution for Injection contains sodium bisulphite which may rarely cause severe allergic reactions and bronchospasm.
This medicinal product contains less than 1 mmol sodium (23mg) per 10ml, i.e. essentially "sodium-free".

Pregnancy: 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 to humans is unknown. (See Pharmacology: Toxicology: Preclinical safety data under Actions.)
Apomorphine HCl should not be used during pregnancy unless clearly necessary.
Lactation: It is not known 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 breastfeeding to the child and the benefit of APO-go to the woman.

Very common (≥1/10) (>10%); Common (≥1/100 to <1/10) (1-10%); Uncommon (≥1/1,000 to <1/100) (0.1%-1%); Rare (≥1/10,000 to <1/1,000) (0.01%-0.1%); Very rare (<1/10,000) (<0.01%); Not known (cannot be estimated from the available data).
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 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 (see Precautions).
Aggression, agitation.
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.
Apomorphine has been associated with sudden sleep onset episodes (see Precautions).
Not known: Syncope.
Vascular disorders: Uncommon: Postural hypotension is seen infrequently and is usually transient (see Precautions).
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 Dosage & Administration).
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.

Patients selected for treatment with apomorphine HCl are almost certain to be taking concomitant medicinal products for their Parkinson's disease. In the initial stages of apomorphine HCl therapy, the patient should be monitored for unusual undesirable 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 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 Precautions).
It is recommended to avoid the administration of apomorphine with other drugs known to prolong the QT interval.
Pre-filled syringe: 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).

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Pre-filled syringe: Special precautions for disposal and other handling: APO-go PFS 5mg/ml Solution for Infusion in Pre-filled Syringe is for single use only. Any unused solution should be discarded.
After single use, adaptors and syringes should be discarded and disposed of in a "Sharps" bin.
Pre-filled pen: Instruction for use, handling and disposal: APO-go PEN: Do not use if solution has turned green.
Discard each pen no later than 48 hours from first use.
This pack does NOT contain needles for use with the Pen.
Use pen needles not more than 12mm (½") in length and not finer than 0.33mm (29 G). Pen needles recommended for use with insulin pens are compatible with APO-go Pen.
IMPORTANT: Do not pull the red capped dial before the dosage is set (see Selecting the correct dose as follows).
Attaching the needle: (a) Before using APO-go Pen, some surgical wipes and one needle in its protective cone will be needed.
(b) Take the Pen out of its box and remove the outer sleeve.
(c) Wipe the membrane of the Pen with a surgical wipe.
(d) Peel off the paper from the needle cone.
(e) It is important to bring the needle to the Pen in a straight line. If the needle is presented at an angle, it may cause the Pen to leak.
(f) Screw the cone clockwise onto the membrane until it is tight. This securely attaches the needle.
(g) Remove the protective cone, but do not throw it away. Do not remove the needle protector at this stage.
(h) Replace the Pen's outer sleeve.
Selecting the correct dose: (i) Press the red capped dosage dial and, whilst holding it down, turn the dial clockwise until the arrow points to the dose the doctor chose. Release the downward pressure on the red capped dial. The dose is now set and there is no need to redial for subsequent injections.
Important: If the prescribed dose is passed while turning the dial, just continue pressing and turning in the same direction until the arrow points to the dose the doctor chose.
Never pull and turn the red capped dosage dial at the same time.
If the dose is 1 mg, start by emptying a 1-mg dose onto a paper tissue and discarding it. This is called 'priming' and is important because it ensures a full dose is administered the first time the Pen is used. Then, set the dose required for injection and inject it in the usual way (see Injecting as follows). If the first dose required is more than 1 mg, there is no need to prime the Pen.
Injecting: (j) Once the dose is set, gently pull out the red capped dosage dial as far as it will go. Check the red scale on the plunger and inject only if the line that is just visible matches the intended dose.
(k) Using a surgical wipe, clean the area of skin where the medicine is planned to be injected and the area around it.
(l) Remove the Pen's outer sleeve.
(m) Remove the needle protector.
(n) Insert the needle into the skin as shown by the doctor.
(o) To inject, press the red capped dosage dial down as far as it will go, using the thumb if possible. Once the red capped dosage dial is fully depressed, count to three before withdrawing the needle.
(p) Replace the protective cone onto the used needle and push gently into place. Once secure, turn the needle anti-clockwise to unscrew it.
Keep the needle in its protective cone and discard it in a safe place, such as a "Sharps" bin or an empty coffee jar.
Preparing for the next injection: (q) Remove the outer sleeve of the Pen and check if there is enough apomorphine left in the cartridge for the next injection. If there is, put a new needle in place in the same way as before.
(r) If there is not enough apomorphine left for another injection, prepare another pen.
(s) Finally, replace the outer sleeve of the Pen.

Do not store above 25°C.
Pre-filled syringe: Keep the pre-filled syringe in the outer carton in order to protect from light.
Pre-filled pen: Keep the container in the outer carton to protect from light.
The product should be stored at the same conditions after opening and between withdrawals.
Shelf life: 2 years.
Pre-filled syringe: Once opened, the pre-filled syringe should be used immediately.
Single use only. Any unused solution should be discarded.
Pre-filled pen: 48 hours after first opening.

Antiparkinsonian Drugs

N04BC07 - apomorphine ; Belongs to the class of dopamine agonist. Used in the management of Parkinson's disease.

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