APO-go POD 5 mg/ml solution for infusion in cartridge

APO-go POD is indicated in adults.

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 POD:

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, may be transferred to continuous subcutaneous infusion by minipump. Patients who have frequent 'off' periods not controlled by oral/transdermal medication may also be commenced on continuous subcutaneous infusion by minipump without prior use of intermittent injections.

Patients selected for treatment with APO-go POD should be capable of setting up an infusion system themselves or else have a responsible carer able to set up an infusion system 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 whenever 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 clinic. During the titration phase of apomorphine the patient should be supervised by a trained healthcare professional 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 POD treatment.

Posology

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 (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 - 1.0 mg/hr per day. Once there is adequate control of motor symptoms, the infusion rate can remain stable and will usually range between 2 mg/hr and 8 mg/hr (0.4 ml and 1.6 ml). Infusions should run for waking hours only. 24 hour infusions are not advised, unless the patient is experiencing severe night-time problems (as directed by their physician). Please note that the recommended total daily dose should not exceed 100 mg.

Patients may use a cartridge for up to 48 hours as long as a new infusion line and a different site for infusion is used every 24 hours.

Patients may need to supplement their continuous infusion with intermittent bolus boosts, as necessary, and as directed by their physician (but not exceeding the 100 mg maximum daily dose).

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 24 hours.

Establishment of treatment

Alterations in dosage may be made according to the patient's response. The optimal dosage of apomorphine varies between individuals but, once established, remains relatively constant for each patient.

Precautions on continuing treatment

In clinical studies it has usually been possible to make some reduction in the dose of levodopa and other anti-Parkinson medications; 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 and discontinued altogether whenever possible.

Paediatric population

APO-go POD is contraindicated for children and adolescents under 18 years of age (see Section 4.3).

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. 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).

Method of Administration

APO-go POD is for subcutaneous use.

APO-go POD is a pre-diluted solution intended for use without dilution as a continuous subcutaneous infusion by minipump. APO-go POD is designed to be used with a pump (Crono APO-go III Infusion Pump or the Crono PAR4 20 Infusion Pump) and the Crono Bell Sleeve. These are CE marked medical devices.

A summary of the instructions for setting up the infusion can be found in Section 6.6.

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.

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

Apomorphine treatment must not be administered to patients who have an 'on' response to levodopa which is marred by severe dyskinesia or dystonia.

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1.

The concomitant use of apomorphine with drugs of the 5HT₃ antagonist class is contraindicated (including, for example, ondansetron, granisetron, dolasetron, palonosetron and alosetron), see Section 4.5.

APO-go POD is contraindicated for 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.

Since apomorphine, especially at high doses, 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.

Apomorphine is associated with local subcutaneous effects. These can sometimes be reduced by the rotation and massage of injection sites and good skin hygiene.

Haemolytic anaemia and thrombocytopenia have been reported in patients treated with apomorphine. Haematology tests, as recommended with levodopa, should be undertaken at regular intervals.

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 episodes of sudden sleep onset, particularly in patients with Parkinson's disease. Patients must be informed of this and advised to exercise caution whilst 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.

APO-go POD contains sodium metabisulfite which may rarely cause severe hypersensitivity reactions and bronchospasm.

This medicine contains less than 1 mmol sodium (23 mg) per 20 ml cartridge, that is to say essentially 'sodium-free'.

Patients selected for treatment with apomorphine are almost certain to be taking concomitant medicinal products for their Parkinson's disease. In the initial stages of apomorphine 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.

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 (symptoms suggestive of neuroleptic malignant syndrome have been reported rarely with abrupt withdrawal of dopaminergic therapy).

Based on reports of severe hypotension and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of apomorphine with drugs of the 5HT₃ antagonist class is contraindicated (including, for example, ondansetron, granisetron, dolasetron, palonosetron and alosetron) (see Section 4.3).

Antiemetics with anti-dopaminergic actions (for example, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide, levopromazine and droperidol) have the potential to worsen the symptoms in patients with Parkinson's disease and should be avoided. In addition, use of these anti-emetics could increase the risk of QT prolongation, hypotension and torsade de pointes arrhythmias.

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).

It is recommended to avoid the administration of apomorphine with other drugs known to prolong the QT interval.

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. See Section 5.3.

APO-go POD should not be used during pregnancy unless clearly necessary and, if used, the risk of depressed respiration in newborns warrants close monitoring immediately following delivery.

Breast-feeding

It is not known whether apomorphine is excreted in human breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with APO-go POD should be made taking into account the benefit of breast-feeding to the child and the benefit of APO-go POD to the woman.

Fertility

There is no data on the effects of APO-go POD on fertility.

Apomorphine 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 also Section 4.4).

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

- The medicine is likely to affect your ability to drive

- Do not drive until you know how the medicine affects you

- It is an offence to drive while under the influence of this medicine

- However, you would not be committing an offence (called 'statutory defence') if:

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

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

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.

Pharmacotherapeutic group: Anti-Parkinson drugs, Dopamine agonists.

ATC Code: 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.

The efficacy and safety of apomorphine continuous subcutaneous infusion was evaluated in a randomised, placebo controlled, 12 week double blind study in patients with Parkinson's disease with motor symptoms not adequately controlled on oral/transdermal medication. Patients who entered the double blind phase (DBP) of the study were invited to re-consent to take part in an open label phase (OLP) for up to a further 52 weeks. A total of 107 patients were randomised at the start of the DBP and 84 patients went on to the OLP.

In both phases, patients began infusions with 1 mg/hour with rate increases of 0.5-1.0 mg/hr per day until either a maximum of 8 mg/hr or control of motor symptoms, whichever came first. Other antiparkinsonian drugs could be gradually discontinued in the first 4 weeks of treatment. In the DBP, each patient received a starting dose of apomorphine or placebo as subcutaneous infusion of 1 mg/hour during the first day of titration (Visit 3, Day 1). The hourly flow rate was adjusted by increasing daily by 0.5-1.0 mg/hour during Visit 3 (5-10 days as inpatient or outpatient) and up to Visit 6 (Week 4) of double blind treatment, to an expected steady state infusion rate of 3-8 mg/hour for 14-18 hours per day, depending on individual tolerability and efficacy.

The primary efficacy endpoint was the least squares mean change in 'off' hours per day recorded in patient diaries comparing Day 0 and Week 12 in the modified intent to treat (mITT) population (n=105, 53 apomorphine and 52 placebo) using a mixed effects model for repeated measures (MMRM). The analysis of 'off' time showed a statistically significant reduction in 'off' time for patients treated with apomorphine compared to placebo (p=0.0047), (Table 1).

These data were supported by secondary endpoints in the DBP and in the mITT population of change in daily 'on' time without troublesome dyskinesia and Patient's Global Impression of Change (PGI-C), tested hierarchically. The PGI-C scale ranges from 1 (very much improved) to 7 (very much worse). The least squares mean change in daily 'on' time without troublesome dyskinesia showed a statistically significant increase for patients taking apomorphine compared to placebo (p=0.0022) (Table 1) and the PGI-C score was statistically significantly higher at Week 12 for apomorphine compared to placebo (p<0.0001) (Table 2).

Table 1: Summary of efficacy results from DBP of study comparing continuous subcutaneous infusion of apomorphine vs placebo

Table 2: Number of patients by PGI-C score (DBP)

Eighty-four patients entered the OLP, 40 from the apomorphine group and 44 from the placebo group, and all received apomorphine starting the day after the DBP Week 12 visit, titrated again from 1 mg/hour to a maximum of 8 mg/hour or when motor symptoms were controlled, whichever came first. Results are summarised in Table 3 and show that patients who had been treated with apomorphine in DBP continued to experience a response for up to 52 weeks in the OLP and patients who had received placebo in the DBP (apomorphine naïve) responded to apomorphine and maintained a response for up to 52 weeks. The OLP was not powered for statistical analysis of these results.

Table 3: Summary of efficacy results in open label phase

The European Medicines Agency has waived the obligation to submit the results of studies with APO-go POD 5 mg/ml solution for infusion in cartridge in all subsets of the paediatric population in Parkinson's disease (see Section 4.2 for information on paediatric use).

Absorption

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 active substance (about 1 hour) is explained by its rapid clearance.

Distribution

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.

Biotransformation

The metabolism of apomorphine is extensive and complex and involves enzymatic and non-enzymatic degradation pathways. Hepatic metabolism by glucuronidation and sulphonation occurs to at least ten per cent of the total. Extrahepatic metabolism involves intravascular oxidation, methylation and enteric sulfation.

Elimination

After subcutaneous injection of apomorphine, its fate can be described by a two- compartment model, with a distribution half-life of 5 (±1.1) min and an elimination half-life of 33 (±3.9) minutes.

Linearity/non-linearity

Apomorphine exhibits linear pharmacokinetics.

Pharmacokinetic/pharmacodynamic relationships

Clinical response correlates well with levels of apomorphine in the cerebrospinal fluid; the active substance distribution being best described by a two-compartment model.

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

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.

Carcinogenicity studies have been conducted in mice (short term) and rats (lifetime). Both studies demonstrated skin inflammatory changes at sites of repeated injection with the incidence of skin adenomas being increased at the highest dose administered. There was a higher incidence of testicular Leydig cell tumours in rats although the mechanism by which this occurs is not believed to be relevant in humans.

Environmental Risk Assessment (ERA)

Apomorphine is a well-established active substance. Apomorphine is unlikely to represent a risk to the environment following its prescribed use in patients.

Sodium metabisulfite (E223)

Hydrochloric acid, concentrated (for pH adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

2 years.

Once opened, APO-go POD should be used immediately.

Any unused solution should be discarded after 48 hours and a new cartridge used.

For storage conditions after first opening of this medicinal product, see Section 6.3.

Do not store above 30°C.

A 20 ml Type I, clear glass siliconized cartridge with a chlorobutyl rubber stopper, aluminium seal (with purple flip-off cap) and siliconized chlorobutyl rubber plunger.

Each pack contains 5 cartridges containing 20 ml solution in a cardboard tray, inside an outer cardboard carton.

The CronoBell Sleeve is supplied separately in blister packs containing 5 CronoBell Sleeves.

Bundle packs of 25 and 50 cartridges are available:

- The 25 cartridge bundle packs consist of 5 packs, each containing 5 cartridges.

- The 50 cartridge bundle packs consist of 10 packs, each containing 5 cartridges.

Not all pack sizes may be marketed.

Any unused solution should be discarded after 48 hours.

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.

After use, the infusion line, CronoBell Sleeve and cartridge should be discarded and disposed of in a 'Sharps' bin.

How to set up the infusion with APO-go POD:

Wash and dry your hands before handling any infusion equipment.

Make sure you have a 'Sharps' bin and these items before you begin:

- 1 x Infusion line

- 1 x CronoBell Sleeve

- 1 x Cartridge

- 1 x Pump (Crono APO-go III Infusion Pump or Crono PAR4 20 Infusion Pump) with collar attachment

- Tray

A box of single use sterile Luer caps may also be provided.

Please note that there are three different scenarios on how to use and change the cartridge and are shown in the steps below.

Instructions for using the cartridge for one day

Please follow the steps below if using the cartridge for one day, without changing the cartridge during the day:

Instructions for using the same cartridge over 2 days

Please use the following steps if using the cartridge up to a maximum of 48 hours:

Instructions for changing the cartridge during the day

If you are using the cartridge for more than one day, it may be necessary to use a new cartridge when the old one finishes. Please use the following steps when changing the cartridge during the day:

Note: Different infusion lines require different insertion techniques. The choice of needle will be determined by the physician.

User guides for the pump and CronoBell Sleeve are provided for the healthcare professional, refer to these for details on how to set up APO-go POD for continuous infusion and additional bolus dosing.

There are differences in the pump used to administer this product and some other apomorphine products on the market. Therefore, if the patient switches from or to a different product, re-training under the supervision of a healthcare professional is required.

After use, the infusion line, CronoBell Sleeve and cartridge should be discarded and disposed of in a 'Sharps' bin. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.