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Trenkwalder et al: Parkinsonism & Related Disorders Review article

Expert Consensus Group Report on the use of apomorphine in the

treatment of Parkinson’s disease – clinical practice recommendations

Authors: Claudia Trenkwaldera*, K. Ray Chaudhurib, Pedro J. García Ruizc, Peter

LeWittd, Regina Katzenschlagere, Friederike Sixel-Döringf, Tove Henrikseng, Ángel

Sesarh and Werner Poewei on behalf of an Expert Consensus Group for the Use of

Apomorphine in Parkinson’s Disease†

aCentre of Parkinsonism and Movement Disorders, Paracelsus-Elena Hospital, Kassel,

Germany; Department of Neurosurgery, University Medicine, Goettingen, Germany

bNational Parkinson Foundation Centre of Excellence, Kings College Hospital, Denmark

Hill Campus, London, UK

cMovement Disorders Unit, Department of Neurology, Fundacion Jimenez Diaz, Madrid,

Spain

dWayne State University School of Medicine, Parkinson's Disease and Movement

Disorders Program, Henry Ford West Bloomfield Hospital, West Bloomfield, Michigan,

USA

eDepartment of Neurology and Karl Landsteiner Institute for Neuroimmunological and

Neurodegenerative Disorders, Danube Hospital, Vienna, Austria

fParacelsus-Elena-Klinik, Centre of Parkinsonism and Movement Disorders, Kassel;

Department of Neurology, Philipps-University, Marburg, Germany

gMovement Disorder Clinic, Bispebjerg Hospital, Copenhagen, Denmark

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hDepartment of Neurology, Hospital Clínico Universitario, Santiago de Compostela,

Spain

iDepartment of Neurology, University of Innsbruck, Austria

†Contributors to the Expert Consensus Group:

Mary Baker, President, European Brain Council Brussels, Belgium

Andres Ceballos-Baumann, Department of Neurology, Neurologisches Krankenhaus

München, Munich, Germany

Günther Deuschl, Christian-Albrechts-University Kiel, Germany

Sophie Drapier, Centre Hospitalier Universitaire de Rennes, France

Georg Ebersbach, Movement Disorders Clinic, Beelitz-Heilstatten, Germany

Andrew Evans, Royal Melbourne Hospital, Melbourne, Australia

Hubert Fernandez, Center for Neurological Restoration, Cleveland Clinic, Cleveland,

Ohio, USA

Stuart Isaacson, Florida International University, Herbert Wertheim College School of

Medicine, Miami, Florida, USA

Andrew Lees, UCL Institute of Neurology, London, UK

Simon Lewis, Parkinson’s Disease Research Clinic at the Brain and Mind Research

Institute, University of Sydney, Australia

Juan Carlos Martínez Castrillo, Department of Neurology, Hospital Universitario Ramón

y Cajal, Madrid, Spain

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Pablo Martinez-Martin, National Center for Epidemiology and CIBERNED, Carlos III

Institute of Health, Madrid, Spain

Per Odin, Department of Neurology, Lund University Hospital, Lund, Sweden

John O’Sullivan, Royal Brisbane Clinical School, School of Medicine, University of

Queensland, Brisbane, Australia

Georgios Tagaris, Department of Neurology, Georgios Gennimatas General Hospital of

Athens, Greece

Teus Van Laar, Department of Neurology, University Medical Center, Groningen, The

Netherlands

Karoline Wenzel, Medical University of Graz, Graz, Austria

*Corresponding author: Professor Claudia Trenkwalder

Address for correspondence: Paracelsus-Elena Hospital, Centre of Parkinsonism and

Movement Disorders, Klinikstr. 16, DE-34128 Kassel, Germany

Email: [email protected]

Tel: +49-561-6009-200

Fax: +49-561-6009-126

Search term: Parkinson’s disease/Parkinsonism [165]

Key words: Parkinson’s disease; treatment; clinical practice; apomorphine injection;

apomorphine pump

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mailto:[email protected]


Author contributions: All authors participated in the Expert Consensus Group

Meetings and contributed to manuscript preparation. All contributors participated

in the Expert Consensus Group Meetings and reviewed and approved the

manuscript.

Acknowledgments including sources of support

The Expert Consensus Group was convened and their advisory meetings supported by

Britannia Pharmaceuticals Ltd. Editorial assistance was provided by Dr Karen

Wolstencroft, Helen Lawn Associates, supported by Britannia Pharmaceuticals Ltd.

Abstract

Extensive published evidence supports the use of subcutaneously-administered

apomorphine as an effective therapy for Parkinson´s disease (PD) but to date no

consensus recommendations have been available to guide healthcare professionals in

the optimal application of apomorphine therapy in clinical practice. This document

outlines best-practice recommendations for selecting appropriate candidates for

apomorphine intermittent injection (the pen-injection formulation) or apomorphine

continuous infusion (the pump formulation), for initiating patients onto therapy and for

managing their ongoing treatment.

Apomorphine is a suitable therapeutic option for PD patients who experience

troublesome ‘off’ periods despite optimized treatment with oral PD medications. Due to

its speed of onset, apomorphine injection is particularly suited to those patients requiring

rapid, reliable relief of both unpredictable and predictable ‘off’ periods, those who require

reliable and fast relief when anticipating an ‘off’, those with levodopa absorption or

gastric emptying problems resulting in delayed or failed ‘on’, or for rapid relief of early

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morning dystonia or akinesia. Apomorphine infusion1 is suited for patients whose ‘off’

periods can no longer be adequately controlled by standard oral PD treatment or for

those in whom rescue doses of apomorphine injection are effective but either needed

too frequently (more than 4–6 times per day), or are associated with increasing

dyskinesia. In addition to treating motor fluctuations, there is evidence that apomorphine

infusion may be effective for the management of specific non-motor symptoms of PD

associated with ‘off’ periods. Apomorphine infusion is less invasive than other non-oral

treatment options for advancing disease, intrajejunal levodopa infusion and deep-brain

stimulation.

Introduction

Clinical experience in treating Parkinson’s disease (PD) with apomorphine goes back to

1951 when limited experimentation with this drug showed its potential for relief of

parkinsonian symptomatology [1]. For the past three decades, clinical practice in Europe

and elsewhere has adopted the use of apomorphine for both intermittent and continuous

subcutaneous administration. Although an extensive clinical literature has described the

various applications and outcomes from apomorphine therapy in PD, and Level 1

evidence from randomized, placebo-controlled studies is available for the injection

formulation, a consensus view has not evolved to summarize best practices. To address

this unmet need, an international group of specialists was convened to discuss and

develop recommendations for how to use apomorphine in PD therapeutics. This article

summarizes a consensus of views regarding clinical practice recommendations for using

apomorphine in PD. It is intended for those clinicians who may be unfamiliar with

apomorphine and who might be prescribing the product for the first time, who have not

1 Apomorphine infusion has not received marketing authorization in the USA.

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had the opportunity to judge its effectiveness, or who are continuing to prescribe

apomorphine after specialized centers have initiated this therapy.

Development of these clinical practice recommendations

An international group of specialists with extensive personal experience in treating PD

patients with apomorphine was invited by Britannia Pharmaceuticals Ltd., the

manufacturer of apomorphine injection and infusion, to participate in one or both of two

Advisory Board Meetings, supported by the company, to share their practical experience

of using the product. The aim of the meetings was to develop guidance for neurologists,

general practitioners (GPs) and other healthcare professionals on the optimal clinical

use of apomorphine. The first meeting was held in October 2012 and the second in May

2013 and they involved 26 advisors from 13 countries. All meeting participants were

included in the consensus group. The outcome of the two Advisory Board Meetings led

to a consensus of views on best clinical practice recommendations for subcutaneous

apomorphine in PD and included key findings from a questionnaire that panel members

completed in advance of the second meeting to provide their experience and perception

of treatment practices with apomorphine. In analyzing responses to the 26 completed

questionnaires, ‘consensus’ was considered to be achieved when ≥80% of the advisors

were in agreement. A summary of the questions and response is summarized in

Appendix 1. Due to the number of advisors involved, editorial assistance was provided

by a medical writer, supported by Britannia Pharmaceuticals Ltd, to develop the article

summarizing their consensus views and to obtain advisor input and agreement on the

clinical practice recommendations. All advisors reviewed and input into the manuscript at

all stages.

Initial treatment of Parkinson’s disease

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The overall goals of symptomatic treatment for PD are to provide control of the

symptoms of the disease while minimizing the adverse effects of medication. This

includes late complications such as motor fluctuations and dyskinesia. The most

effective initial treatment for PD is levodopa. Oral and transdermal dopaminergic

agonists (DA) can also achieve dopaminergic benefits and they can delay the

development of motor complications when administered as monotherapy or in

combination with the smallest dose of levodopa required for motor control in early PD.

Once motor fluctuations have developed, therapeutic approaches include increasing

levodopa doses or shortening the intervals between intakes, adding inhibitors of

catechol-O-methyl transferase (COMT) and MAO-B to block the degradation of levodopa

and dopamine, or adding a DA in patients who are not already receiving an agonist,

unless there are contraindications.

However, a sizable proportion of patients remain inadequately controlled despite a range

of oral (or transdermal) treatment options, with gaps in drug effects (switching ‘off’) as

well as involuntary movements (dyskinesias, including dystonia) [2-4].The problem

may be enhanced by alterations in gastric emptying, which is often compromised

as PD progresses; this can limit drug absorption and the reliability of levodopa

efficacy during the day [5, 6]. Difficulty swallowing is sometimes a problem for PD

patients and may interfere with a patient’s ability to adhere to an oral medication

regimen [7].

Beyond standard oral/transdermal therapies

For PD patients experiencing motor complications (including motor fluctuations and

dyskinesias) that cannot be adequately managed by adjustment of oral medications,

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there are a number of options. These include neurosurgical intervention with deep brain

stimulation (DBS) of the subthalamic nucleus or globus pallidus, continuous enteral

infusion of a levodopa/carbidopa intestinal gel (LCIG), and continuous subcutaneous

infusion of apomorphine.

DBS can be very effective for patients who are not well controlled or, or who cannot

tolerate, maximal dopamine replacement therapy [8, 9]. However, it involves invasive

stereotactic brain surgery which has relatively few but potentially serious risks, and it is

therefore generally discouraged in patients of advanced age and those with

neuropsychiatric features such as cognitive decline or severe depression. It is, however,

generally a one-time procedure that aims to improve motor control over the long term

while also enabling patients to reduce their intake of oral medication.

LCIG is a chronic treatment option that involves minor surgery to establish a route of

infusion directly into the jejunum by means of a percutaneous endoscopic jejunostomy

(PEJ) tube. It has proved effective in symptomatic control of advanced PD [10].

Maintaining the PEJ tube in place is sometimes problematic. Local infections can

develop at the site of tube insertion. Complications at the site of skin entry of the tube

may require further surgical interventions. More severe infections such as peritonitis are

rare but potentially life-threatening. Other risks of LCIG that need further investigations

are weight loss, possibly due to malabsorption, and a possible association with axonal

peripheral neuropathy, the mechanism of which is poorly understood. Neuropsychiatric

problems, however, are minimal and usually well controlled.

Apomorphine is a highly potent DA selectively acting at both D1 and D2 dopamine

receptors. It differs substantially in its pharmacological profile from the 26 other DAs that

have been used (experimentally or in clinical practice) to treat PD [11]. Apomorphine

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was, in fact, the first DA used to treat PD [1], long before its dopaminergic properties

were understood and prior to the development of levodopa. In a number of published

clinical trials, apomorphine was shown to achieve anti-parkinsonian efficacy comparable

to that of orally-administered levodopa [12].

Apomorphine in the treatment of Parkinson’s disease

Apomorphine has poor oral bioavailability and due to extensive first pass metabolism,

high doses need to be given to elicit a clinical effect which early studies reported could

cause nephrotoxicity. As a result, apomorphine is given by the subcutaneous route,

either intermittently as an injection or as a continuous infusion. Studies of renal function

in animals chronically treated with subcutaneous apomorphine did not find any evidence

of renal toxicity using this route of administration [13].

Intermittent injections are useful for patients who experience refractory ‘off’ periods due

to a marked delay in the onset of clinical benefit from oral medication. It can also be

used as a rescue from an ‘off’ state, such as when a PD patient wants to become mobile

as soon as possible after awakening. Intermittent apomorphine injection is

recommended as a rescue treatment for those patients experiencing significant episodes

of wearing off. Apomorphine injection has a rapid onset of effect (typically within 4–12

minutes) with a rapid clearance half-life and a mean duration of anti-parkinsonian action

lasting about 45–60 minutes [14]. The most widely used formulations of the drug are

solutions of apomorphine hydrochloride in cartridges containing 10 or 20 mg/ml and a

multi-dose penject is available in some countries.

Administering apomorphine as an infusion is an option when continuous dopaminergic

stimulation is desirable. The dose can be adjusted to optimal effect for continuous

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delivery over a period ranging from 12–24 (usually 16) hours of the day. Apomorphine is

delivered via a subcutaneous catheter connected to a small portable pump, typically

worn on a waist belt or around the neck. The indications for continuous infusion typically

involve unpredictable or prolonged ‘off’ periods, motor fluctuations, or dyskinesias.

The subcutaneous administration of apomorphine is generally well tolerated. However,

skin nodules at the site of drug infusions are a common and sometimes bothersome

complication and typically develop over time. Strategies to minimize the occurrence and

to manage skin reactions are discussed later in this manuscript.

A range of double-blind, randomized, placebo-controlled clinical studies have

demonstrated that intermittent apomorphine injection is a rapid and effective acute

treatment for motor fluctuations in PD paients [15-19]. In the case of continuous

apomorphine infusion, no randomized, double-blind, placebo-controlled studies have

been published to date; however, a limited number of randomized controlled trials as

well as data from smaller open-label and observational studies undertaken over several

decades have confirmed its efficacy in controlling motor fluctuations, reducing ‘off’ time

and improving dyskinesias in PD patients; these findings have been summarized in a

recent review [20].

Clinical practice recommendations for the use of apomorphine in the treatment of PD,

including the selection of suitable candidates for intermittent apomorphine injection

(penject) or continuous apomorphine infusion (by pump) are outlined below.

Recommendations for initiating patients with apomorphine infusion therapy are also

discussed and illustrated with examples of real-life patient cases, as well as suggestions

for optimizing apomorphine treatment and managing adverse events.

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The panel stressed that the decision to use apomorphine should be based on a patient’s

symptoms and their disability as a result of motor complications that have become

refractory to adaptations of oral/transdermal treatment rather than on the perceived

stage of PD. However, there are currently still barriers for clinicians or patients to

commence apomorphine therapy.

Suitable candidates for intermittent apomorphine injection (pen)

The advisors agreed that suitable patients for intermittent apomorphine injection

(penject) are those with motor and non-motor fluctuations inadequately controlled by oral

treatments. Examples include patients with unpredictable ‘off’ periods, patients who

require reliable and fast relief when anticipating an ‘off’, such as in certain social

situations or when outside their home, those with levodopa absorption or gastric

emptying problems resulting in delayed or failed ‘on’, or for rapid relief of early morning

dystonia or akinesia.

There are two important aspects to apomorphine treatment: the speed of drug effect

onset after intermittent apomorphine injection, making it desirable for the patient who

has a predictable but delayed response to levodopa of 15–30 minutes or longer; and the

reliability of its effect at recovering an ‘on’ state (as compared to the effects of oral

dosing with levodopa). Finally the short half-life of apomorphine induces a response of

about 45–60 minutes, which does not generally interfere with the basal drug regimen,

but fills the gaps in motor functioning.

On account of its unique speed of onset, apomorphine is particularly suited to those

patients requiring rapid, reliable relief of both unpredictable and predictable ‘off’ periods,

provided the patient or a caregiver can perform the injection at these times. Off

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symptoms that may improve include off-related dystonia, freezing, and non-motor

symptoms, including pain. Early morning ‘off’ states such as those involving painful

dystonia are particularly suited to apomorphine injection. Some PD patients can

experience a warning that they are about to switch ‘off’. If an under-medicated state is

unacceptable to a patient’s lifestyle, apomorphine injection can provide rapid and reliable

relief of parkinsonian signs and symptoms. Intermittent apomorphine injection also

provides an option for reliable control of parkinsonism when absorption of oral levodopa

is impaired (as, for example, shortly after ingestion of a meal or when gastrointestinal

illness prevents use of the oral route for PD medication).

The consensus reached regarding the reasons for considering treatment with

intermittent apomorphine injection (penject) are summarized in Figure 1.

Suitable candidates for continuous apomorphine infusion (pump)

In determining the profile of suitable candidates for changing to treatment with

subcutaneous apomorphine infusion (pump), the consensus was that this option should

be chosen when ‘off’ periods can no longer be adequately controlled by oral treatment,

or when rescue doses of apomorphine injection are effective but either needed too

frequently (for example, more than 4–6 times per day), or are associated with increasing

dyskinesia. This does not mean that all patients should be initiated on apomorphine

injection first; in fact in most centers, the majority of patients who start apomorphine

pump have not used apomorphine injection previously. The short-half-life of

apomorphine is also an advantage when given as a continuous infusion, because each

change in infusion rate will quickly result in a change of effect.

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A potential benefit of subcutaneous apomorphine infusion was recognized to be the

management of peak-dose dyskinesias. Continuous infusion (usually applied during the

waking day) can achieve a continuous ‘on’ state, which may alter the motor response of

the basal ganglia in such a way that dyskinesia may improve. While this is often

observed in clinical practice and has been repeatedly reported in open, uncontrolled

studies [21-24], no randomized, controlled studies have been performed to date that

confirm the effect of apomorphine infusion on dyskinesias definitively. Improvement in

dyskinesia usually requires a concomitant reduction in levodopa dose and may be

delayed by weeks after starting apomorphine pump therapy.

In addition to treating motor fluctuations, there is accumulating evidence (from non-

randomized studies) that treatment of PD patients with apomorphine infusion is of

benefit for the management of specific non-motor symptoms of PD associated with ‘off’

periods. These problems include ‘off’ pain, mood disturbances and slowness of thinking

[25, 26].

Apomorphine infusion may fulfill the needs of patients for whom enteral LCIG infusion or

DBS are contraindicated for medical reasons, or when these invasive interventions are

not desired by the patient. Unlike DBS, advanced age or the presence of

neuropsychiatric features (e.g. mild hallucinations, moderate cognitive impairment) are

not absolute contraindications to treatment with apomorphine. While hallucinations may

occur or worsen as an adverse effect of apomorphine infusion, the treatment has been

found to be well tolerated in some patients experiencing visual hallucinations and

paranoid ideations [27, 28], and one study reported a reduction in hallucinations in

patients receiving apomorphine infusion as they were able to reduce their oral PD

medication [28]. A study comparing DBS with apomorphine infusion in 25 patients with

advanced PD followed-up for 5 years demonstrated a worsening of Neuropsychiatric

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Inventory (NPI) scores in the DBS group that was not observed in the apomorphine

group [29]. Better neuropsychological performance in apomorphine-treated patients

compared with those treated with DBS has also been shown in other studies [30, 31].

As the least invasive of the advanced treatment options, apomorphine infusion can be

tried as first-line therapy in patients who require treatment escalation before more

invasive procedures (LCIG/DBS) are applied.

Use of the apomorphine pump can also simplify the treatment of PD by providing a

convenient alternative to complex oral dosing regimens which are known to impact on

adherence to therapy [32, 33]. It can also potentially minimize drug–drug interactions

that might arise from taking multiple oral medications [34], or may be used temporarily

when oral intake or absorption is limited for surgical or other reasons.

The consensus regarding the reasons for considering treatment with continuous

apomorphine infusion (pump) are summarized in Figure 1.

Starting patients on continuous apomorphine infusion (pump)

With regard to how a patient should be started on treatment with subcutaneous

apomorphine infusion (pump), the consensus was that a patient experiencing problems

with current PD therapy should be referred to a specialist neurologist (or, where

appropriate, to a geriatrician specializing in PD) who can prescribe apomorphine after

evaluating treatment goals, comorbidities, and the use of other medications.

Good clinical practice would include prior evaluations of the patient to include ECG (to

exclude prolonged QT duration, tachy- and brady-arrhythmias, atrial fibrillation, and

premature ventricular contractions), and exclusion of pre-existing hemolytic anemia.

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How apomorphine therapy should be initiated is shown for the inpatient setting in Figure

2. In many countries, it is not necessary to hospitalize patients for initiation of

apomorphine infusion.

Examples of real patient cases provided by members of the advisory group to help

illustrate best practice in the initiation of apomorphine infusion (pump) in a range of

patient types. are listed in Appendix 2.

Adherence to and optimization of apomorphine therapy

The consensus was that continuous apomorphine pump therapy is recommended due to

its persisting efficacy and tolerability. There is some suggestion – although no firm

evidence – from clinical studies that infusion of apomorphine for the full 24-hour period

may potentially lead to the development of tolerance in some patients and a reduction in

response but that this is rapidly reversible [35-37]. In such cases it is recommended that

the infusion period is reduced. Availability of ongoing support from healthcare

professionals, caregivers and/or spouses/partners is required (including the availability

for ‘troubleshooting’ strategies if difficulties should arise). It was stressed that

commitment and motivation on the part of the patient, clinician, caregiver, and

spouse/partner are generally vital to successful therapy, as are adequate education,

background information and hands-on training (including learning and managing the

expectations of patients receiving this treatment). In many countries the manufacturer of

apomorphine provides an information service to assist neurologists with experience in

the management of motor complications in PD to start using apomorphine infusion.

When to switch from or to stop apomorphine therapy

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The consensus was that many patients are likely to have apomorphine treatment

stopped for the wrong reasons. The view of the panel was that a transient or reversible

adverse event is generally not a valid reason for stopping treatment. The significance of

adverse events differs between patients and their individual circumstances need to be

taken into account when making treatment decisions. The additional demands and

discomfort associated with injection or infusion compared to oral therapy may influence

compliance with apomorphine and tolerability of adverse effects. Depending on the

needs of the individual patient, it may not be necessary to discontinue apomorphine

treatment for mild-to-moderate skin nodules, for dyskinesias (if due to concomitant oral

medication, as these can often be managed ), for non-hemolytic anemia, for mild, non-

threatening hallucinations/illusions, for orthostatic hypotension (which may have another

cause and which has several treatment options), or for perceived lack of efficacy (which

might be attributable to suboptimal dosing). In fact, a common reason for a perceived

inadequate response to apomorphine infusion may be an insufficient infusion rate to

achieve a meaningful improvement after a short observation period (unpublished

observation).

Confirming these views, the questionnaire completed by the expert panel established

that treatment with apomorphine should be continued if possible in the following

situations:

Dyskinesia occurring in combination with oral medication

Perceived lack of efficacy

If mild skin nodules occur, especially those that can be controlled with treatment

(see below)

Mild cognitive impairment

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Mild orthostatic hypotension

Managing adverse events

Effective management of adverse events is the key to long-term treatment with

apomorphine. The experts discussed the frequency and severity of a number of adverse

events and concluded that local reactions occurring with apomorphine infusion, such as

minimal to moderate nodule formation at the infusion site, are readily managed with

conventional methods. These include:

Rotation of the choice of infusion sites

Use of Teflon® needles

Adjusting delivery through the skin to an optimal angle (i.e. 45–90 degrees)

Maintaining good skin hygiene and using emollients at the infusion site

Choosing a lower concentration, e.g. 5 mg per ml; lower concentrations have

been used successfully

Massaging the infusion site (using a spiky rubber massage ball or vibrating

device)

Applying ultrasound treatment

Use of silicone gel dressings

These techniques are recommended on the basis of clinical experience; none have been

proven by means of formal clinical studies, with the exception of ultrasound, which has

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been shown to be effective for the treatment of skin nodules making the treated area

suitable for further injections [38].

The advisors noted that postural hypotension is relatively infrequent, generally mild, and

generally can be managed with non-pharmacological measures such as increased fluid

and salt intake, raised bed ends at night, slow changes of position, compression

stockings etc, or by adding specific drugs such as mineralocorticoids or midodrine.

Neuropsychiatric adverse events, such as confusion, are usually mild and infrequent but

in approximately 10% of cases can be severe. Impulse control disorders may occur as

with any other DA. Punding, the display of stereotyped, repetitive behaviours, may

become problematic and dopamine dysregulation syndrome has been observed.

Nausea is not a common or severe adverse effect of apomorphine infusion (even though

acute injections of apomorphine have had medical use in the past specifically to induce

emesis). Nausea can generally be controlled with domperidone pre-treatment in the

majority of cases (or trimethobenzamide as an alternative in countries where

domperidone is not available [39]). In March 2014, due to concerns about possible QT

prolongation, the European Medicines Agency issued updated treatment advice for

domperidone. While it may continue to be use for the relief of symptoms of nausea and

vomiting, doses should be reduced to no more than 10 mg up to three times daily and it

should not normally be used for longer than one week

(http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/

Domperidone_31/

Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/

WC500162559.pdf).

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http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Domperidone_31/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500162559.pdf




Hemolytic anemia although a potentially severe idiosyncratic adverse outcome, is rare,

occurring in less than 1% of cases. Eosinophilic syndrome is also uncommon but can

very rarely present severe manifestations, including damage to heart and lung tissue,

requiring the drug to be stopped.

Summary and conclusions

This Expert Consensus Group was convened in order to develop clinical practice

recommendations on the use of apomorphine in PD for doctors and healthcare

professionals, in particular those unfamiliar with when and how to make best use of this

therapy.

The advisors recommended that apomorphine treatment, either with intermittent

apomorphine injection (penject) or continuous apomorphine infusion (pump), is suitable

for PD patients with troublesome ‘off’ periods despite optimized oral or transdermal

treatment. After consideration of the full range of non-oral/transdermal therapy options

(apomorphine, DBS, LCIG) clinicians should select apomorphine therapy based on a

patient’s symptoms and potential contraindications for alternative options, as well as the

patient’s preference.

It was recognized from extensive clinical experience over 25 years that apomorphine

can provide rapid (given as a ‘rescue therapy’) and consistent (given as a continuous

infusion) relief from the symptoms of PD. Although it requires subcutaneous

administration, its mode of delivery is less invasive than other therapies often considered

for managing the same stage of disease, namely DBS or LCIG, and is easily and

immediately reversed either when adverse events occur or at the patient’s request.

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Its availability in two formulations – intermittent injection and continuous infusion –

means that apomorphine can be used for a variety of clinical problems. Apomorphine

injection is indicated for patients with both motor and non-motor ‘off’ periods in need of

rapid symptom relief, whereas apomorphine continuous infusion is an option to manage

motor fluctuations that have become refractory to any changes in the oral or transdermal

treatment, e.g. due to dyskinesia or due to intolerable non-motor ‘off’ symptoms or

unpredictability of ‘offs’. This includes the group of patients who respond well to

apomorphine injections but subjectively require too many daily injections.

Figures and Tables

Figure 1: Consensus: Reasons for considering treatment with intermittent apomorphine

injection (pen) and continuous apomorphine infusion (pump).

Figure 2: Consensus: Recommendations for apomorphine infusion (pump) initiation in

the inpatient setting (for outpatients the same protocol should be used but with different

timings).

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Figure 1: Consensus: Reasons for considering treatment with intermittent apomorphine

injection (pen) and continuous apomorphine infusion (pump).

Apomorphine is suitable for PD patients with troublesome ‘OFF’ periods

despite optimized treatment

PEN

Anticipated rescue when required during motor and non-motor off periods

When absorption of oral levodopa is impaired or the patient has gastric emptying problems (gastroparesis)

To treat delayed ‘on’

To treat early-morning motor problems (akinesia and dystonia)

PUMP

Patient considers that rescue doses required too frequently

Dyskinesias limit further therapy optimisation

Non-motor symptoms associated with ‘off’ periods

Simplify complex PD dosing regimens to improve convenience and compliance with therapy

As an alternative to surgical therapy or LCIG if these are contraindicated or because of patient preference

Absorption or gastric emptying of oral levodopa are impaired

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Figure 2: Consensus: Recommendations for apomorphine infusion (pump) initiation in the

inpatient setting (for outpatients the same protocol should be used but with different timings).

APOMORPHINE INFUSION (PUMP) INITIATION Commence 10 mg domperidone tds 1 day before apomorphine initiation then continue for

3–7 days in total. [NOTE: In countries where domperidone is not available , trimethobenzamide treatment tds for 3 days prior to and during apomorphine therapy is recommended as an alternative].

Either:

1. Use apomorphine challenge 1 or 1.5 mg per hour initially increased by 1 or 1.5 mg per hour (minimum interval: 40 minutes) until the minimum effective dose is achieved or adverse effects occur, to determine the range of expected required hourly flow rate and tolerability, or

2. More commonly today, treatment is commenced directly, at a starting dose of apomorphine 0.5 or 1 mg per hour on first day.

Duration of infusion cycle for initiation is waking time, i.e. approximately 16 hours.

Usual dosage 4–7 mg per hour.

Optimal dosage is the dose that leads to sufficient and satisfactory control of motor fluctuations and dyskinesias without, or with minimal, side effects.

The hourly flow rate is up-titrated depending on efficacy and tolerability. T is usually done at increments of 0.5 mg or 1 mg per hour every day during the initial in-patient stay and more slowly afterwards, for instance at weekly intervals.

Oral dopamine agonists are usually discontinued gradually during the up-titration phase of apomorphine. Depending on the dose of the oral dopamine agonist, this usually means that no oral dopamine agonist remains by the time of discharge from the hospital or within 5–7 days. If the dose is low, the oral dopamine agonist may be discontinued on the day of initiating apomorphine. Rapid discontinuation carries a risk of dopamine agonist withdrawal syndrome.

Other antiparkinsonian drugs (MAO-B inhibitors, COMT inhibitors, amantadine, anticholinergics) are subsequently discontinued in a gradual manner, usually within the first days.

Levodopa is usually reduced after the dopamine agonist but may be reduced atthe same time, particularly if dyskinesias are present. If dyskinesias are present, the aim is reduce levodopa substantially or to discontinue it entirely. This may take several weeks or up to a few months.

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