South East London

Kent PDNS Team

Best Practice Guidelines 2013.

This booklet has been produced following an educational grant from Britannia Pharmaceuticals Ltd.

South East London & Kent PD Nurse Specialist Team

This well-established and nationally respected nursing team is comprised of experienced Parkinson’ Disease Nurse Specialist (PDNS) who work in the region. They are employed by a variety of NHS Trusts in Primary, Secondary and Tertiary care. They work in a collaborative manner to provide high quality, equitable care for people with Parkinson’s disease.

These best practice guidelines have been developed by the team to support the use of Apomorphine in this region and are used in conjunction with local Clinical Commissioning Group (CCG) shared care guidelines.

This document is supported by the following Trusts and Consultants:

King’s College Hospital Foundation Trust:

Prof K RayChaudhuri, Dr C Clough, Dr M Samuel. Anne Martin PDNS

Maidstone & Tunbridge Wells NHS Trust:

Dr R Hadden, Dr C Thom, Dr N Khan

Dr G Saldanha, Dr C Lloyd, Dr P Tsang, Dr P Reynolds.

Dartford & Gravesham NHS Trust:

Dr S Delamont, Dr E Fenandes, Dr M Toth.

Medway Maritime NHS Foundation Trust:

Dr S Chong, Dr C Ellis,

QueenElizabethHospital NHS Trust:

Dr M Rose, Dr E Silber, Dr D Lorsardi

Bromley NHS Trust:

Dr Peter Brex, Dr J Quirk, Dr F Norwood, Dr B Kessel

East Kent NHS Trust:

Dr N. Munro, Dr M. Samuel, Dr A Heller, Dr J Hawkins,

Dr M Jenkinson

Oxleas NHS Foundation Trust:

Dr T Britton, Dr D Martino, Dr G Cocco.

UniversityHospital Lewisham NHS Trust:

Prof K RayChaudhuri

Other Health Professionals are welcome to use any part of this document,

but must acknowledge it as the work of the SE London & Kent PDNS Team.

Any comments or suggestions as to how these guidelines can be improved are always welcome; please contact your local PDNS, who is -

The first edition of this document was adapted from UCL Hospitals NHS Trust’s publication of the ‘Treatment of Parkinson’s Disease (PD) with Apomorphine, Shared Care Guidelines’ by kind permission from Dr A Lees and Kirsten Turner.

The South East London & Kent PDNS Team has reviewed this document to reflect the changes in commissioning and service delivery. It is intended to be a source of information and guidance to all health professionals sharing care directly with Kings College Hospital NHS Foundation Trust and regional hospitals via this established nursing team. It aims to identify the lines of communication between primary, secondary and tertiary care and to explain the responsibilities of all those involved in the different aspects and stages of this treatment, providing a smooth and seamless transition between primary, secondary and tertiary care. It promotes best practice in the care of people receiving Apomorphine.

This document is for guidance only. Responsibility for implementing any of the recommendations for each patient remains with the supervising healthcare professional.

These best practice guidelines provide information on the use of Apomorphine in patients with PD who display one or more of the following symptoms; predictable or unpredictable ‘ON – OFF’ motor fluctuations, disabling biphasic or peak dose dyskinesia (unresponsive to therapies such as levodopa, dopamine agonists and enzyme inhibitors), and dystonia.

Apomorphine is available as either an intermittent subcutaneous injection, via a prefilled pen, or by continuous subcutaneous infusion, during waking hours (or in some individuals over 24 hours), using the Crono APO-go ambulatory pump.

Apomorphine is a dopamine agonist with NO opiate or addictive properties. Clinical effect is poor when taken orally because it undergoes extensive first pass metabolism to an inactive metabolite.

Following a single subcutaneous dose, Apomorphine has an onset of action of between 5 to 15 minutes, with duration of action of approximately 1 hour. Intermittent injections are used for rapid relief from acute motor deficits (or “off-periods”). Continuous subcutaneous infusion is recommended for those patients who require exposure to apomorphine for prolonged periods throughout the day.

  1. To provide general practitioners and primary care teams with information on the use of Apomorphine therapy in the treatment of idiopathic Parkinson’s disease.
  1. To provide a framework for co-operation and understanding between the primary care team and the hospital, so that Apomorphine and other anti-Parkinsonism therapy can be monitored and adjusted according to patients’ needs.
  1. To establish clear lines of communication between general practitioners, community pharmacists, district nurses other members of the multidisciplinary primary care team and the hospital team

Disabling motor fluctuations and dyskinesia are a common complication of drug treatment of idiopathic Parkinson’s disease. Figures indicate that 45-50% patients develop troublesome dyskinesias approximately 5 years after treatment with Levodopa. Affected patients develop unpleasant ‘off’ period phenomena such as dystonia, depression, pain, sleep dysfunction, bladder dysfunction and swallowing difficulties. Several open studies have shown that Apomorphine significantly reduces and sometimes reverses these off period phenomena.

Many patients experience peak dose, interdose or biphasic dyskinesia, which can be equally, or more disabling than an ‘OFF’ period. Over many years of experience, we have been able to reduce, and in some cases, eliminate disabling dyskinesias by carefully reducing oral anti-parkinsonian medication and introducing Apomorphine therapy. Drug regimes often become complicated and confusing. Apomorphine can reduce the amount of oral dopaminergic drugs taken by many patients and so reduce anxiety and risks associated with polypharmacy.

The rapid and reliable response to Apomorphine can be an advantage when oral doses of Levodopa, combined with other dopaminergic drugs, become progressively less effective and less predictable. The aim of treatment is to optimise the delicate balance between an effective response and minimal side effects, promoting patient independence and reducing carer burden.

More than 50% of Parkinsonian patients experience fluctuations in motor response after five years of levodopa (L-dopa) treatment or combined therapy (Lees AJ, 1986). The most common side effect of L-dopa therapy is 'end of dose deterioration', ‘ON-OFF’ phenomena and peak dose or biphasic dyskinesias. Optimising treatment is difficult and complex for many patients – these complications are often referred to as the ‘Complex phase’ of Parkinson’s disease.

Initially, the ‘wearing off’ effect is predictable and occurs at the latter part of the dosing interval. As the disease progresses, ‘wearing off’ becomes less predictable and can render someone immobile in a matter of minutes.

The ‘ON-OFF’ phenomena is best described as a sudden and immobilising episode which can transform a mobile person into a rigid, frozen and dependant one within a few moments. The intensity and duration of these episodes are unpredictable and cannot always be accurately related to the timing of oral medication. Off episodes may also affect cognition, mood and communication.

Initiation of Apomorphine therapy occurs mid to late disease and should be supported by centres with experience in the management of complex Parkinson’s disease (Parkinson’s disease National clinical guideline for diagnosis and management in primary and secondary care.) The South East London and Kent Region have a team of Parkinson’s disease Nurse Specialists who are experienced in all aspects of Parkinson’s disease management. Therefore, where a PDNS is in post, people requiring Apomorphine therapy have access to local services, thus admission to tertiary Hospital may not be necessary.

The Apomorphine dose regime is individually titrated according to the patient’s symptom management. This may range from 1-5 intermittent subcutaneous injections daily. Continuous infusion dose may range from 50 to 100mg daily. In rare cases, doses of up to 250 mg daily have been used.

The specialist team provides the patient with information and advice, supported by written and audio information if required, explaining the treatment and use of equipment. Only when the patient and their family are satisfied with the process and the Primary care team have been made aware of their funding obligation, will the treatment proceed. Successful Apomorphine therapy is initiated and maintained in the primary care setting by sharing the responsibilities for care between primary and secondary care. After a successful challenge, the initiation, titration and adjustment of oral therapy will be the managed by the PDNS following discussion with the Consultant and in accordance with the clinical management plan.

The primary care team accepts responsibility for the on going prescribing of Apomorphine and will continue to act as the primary contact for general health care. The PDNS provides training, support and advice for General Practitioners, community pharmacists and District Nurses and the patient and family. It is recommended that D/Ns receive training in the use of the Crono APO-go pump.

Apomorphine is a colourless aqueous solution for injection, containing 10mg per ml of apomorphine hydrochloride.

Available:Apomorphine Pre-filled syringe 5mg/ml (each syringe contains 10ml of pre-diluted solution ready for use. 10ml solution contains 50mg apomorphine).

Apomorphine 10mg/ml 2ml and 5ml Ampoules (these require dilution 50/50 with 0.9% saline for injection prior to use)

Apomorphine Pre-filled multiple dose Pen 10mg/ml (each pen contains 30mg apomorphine in 3ml)

Crono APO-go pumpPre-filled multiple dose pen

Apomorphine has been licensed since 1993 for use in patients with PD and disabling motor fluctuations inadequately controlled by L-dopa or other dopamine agonists. The licence covers intermittent subcutaneous injections and continuous subcutaneous infusions.

Funding arrangements should be agreed with the General Practitioner in advance of arranging a challenge. So if the challenge is sucessful, treatment can be initiated.

The Apomorphine challenge is performed to establish efficacy in a person with diagnosed idiopathic Parkinson’s disease.

  1. To determine whether a patient experiences a positive, safe response to treatment
  2. To observe the patient for potential side effects, such as postural hypotension, confusion

and hallucinations. Such side effects may limit the potential for use.

NICE Guidelines suggest challenge should not be used for differential diagnosis.

Prior to the challenge, Domperidone is commenced to manage the strong, but short-term emetic effects of Apomorphine. The patientcan have the challenge either as an inpatient or as a day case – depending on the local set up and support of a Parkinson’s disease Nurse Specialist. It is necessary that the challenge is performed in a safe, clinical environment with medical support.

Prior to the challenge the GP may be asked to arrange an ECG and bloods- U&Es and FBC, this is to eliminate any undiagnosed cardiac condition may contraindicate the use of Apomorphine.

Procedure

  1. Pre-treat with Domperidone 20 mg tds for 72 hours prior to the challenge. (30mg if PR formulation used.)
  2. The patient should not receive any oral anti-Parkinson medication for a minimum of four to six hours prior to the challenge in order to provoke an ‘OFF’ state. The patient’s mobility should be considered if the challenge is to be performed as a day case.
  3. Using the Unified Parkinson’s Disease Rating Scale (UPDRS) part 3 to assess motor function of patient (‘OFF’) for a base line score. Including base line lying and standing blood pressure and timed walk if possible. Non-motor symptoms should also be recorded.
  4. Administer 1 mg Apomorphine subcutaneously and observe patients motor response 15 and 30 minutes post injection. Repeat baseline measurements.
  5. If no or poor response, give a subsequent dose of 3 mg. Continue to assess and observe.
  6. Increase the dose in incremental steps every 40 minutes thereafter (i.e. 1 mg to 3mg to 5 mg to 7mg. Dependent on patient’s general condition smaller increments can be made) until a response is seen. If at 7 mg no response is seen, then the patient is a non-responder. If some response is observed at 7mg, then the maximum dose of 10mg can be used with caution. Continue with incremental doses of 1 mg to a maximum 10mg until desired response is achieved. Continue assessing the patient and review after the 10mg bolus dose.

A challenge is positive if one or more of the following results are achieved:

  1. An improvement in UPDRS score of 20% of baseline score
  2. More than 25% improvement in walking time
  3. Alleviation of specific symptoms, e.g. pain, dystonia, non-motor presentations such as urinary retention, gastric disturbances, anxiety.

Successful Apomorphine therapy in the community is achieved with effective shared care between primary, secondary and or tertiary centres. Patients, families and healthcare professionals must have access to specialist support.

A full range of educational materials, videos, DVDs and training is available free of charge.

Intermittent subcutaneous injections are used to reverse disabling ‘OFF’ periods in conjunction with oral therapy. These are suitable for patients who experience unpredictable ‘OFF’ periods. ‘OFF’ symptoms can include pain, marked dystonia, freezing and immobility, swallowing and speech problems. Some patients experience a range of non-motor symptoms including depression, gastric and elimination problems.

An individual therapeutic dose is established for each patient. A 10 year review of 161 patients at the Middlesex Hospital showed that once the correct dose has been established it changes very little (Hughes, 1995).

For ease of administration, Apomorphine comes in a pre-filled multiple dose Pen device.

The pen is discrete and easy to use. Patients and carers are trained to use the Pen and administer the injection in the abdominal wall or outer aspects of the upper arms or thighs.

The continuous infusion pump is used when patients demonstrate a good ‘ON’ period response to apomorphine, but whose overall motor control fluctuates between freezing and dyskinesia. Existing patients using in excess of 6 bolus injections per day may benefit from administration by continuous infusion. A continuous infusion allows for adjustment and /or reduction of oral medication (associated with motor fluctuations and dyskinesia) to provide more consistent symptom control.

Experience has found that managing this group of patients on a combination of Apomorphine and oral dopamine agonists, and subsequently reducing or even stopping L-dopa, can dramatically reduce dyskinesia. It is thought a 30% reduction in L-dopa can be made almost immediately once an infusion is commenced.

The Crono APO-go syringe pump has been specifically designed for the purpose of delivering Apomorphine. It permits:

  1. Easy adjustment of the dose rate in small increments
  2. Flow rate accuracy
  3. Accurate bolus doses
  4. It can be used with a 20ml syringe, which means, for most patients, a full days treatment can be given without the need to change syringes. Syringes are supplied free of charge by Britannia Pharmaceuticals and delivered to pharmacist for collection with the Apomorphine prescription.
  5. Neat, compact and lightweight
  6. Time display, so the user knows exactly how much time the infusion will run for
  7. Full alarm/error warning system complying with EU standards
  8. Supplied on a permanent loan basis to the patient, 24-hour help line, provided by Britannia Pharmaceuticals, is available.

District Nurses, patients and carers receive initial training in the use of the pump by their local PDNS (where available) before a patient is established on a continuous infusion of Apomorphine.

The Britannia Pharmaceuticals sales representative can arrange for the Health Care Professional to receive training and training materials.

Pumps no longer required should be returned to Britannia Pharmaceuticals. Contact details and help line number can be found in the back of these shared care guidelines.

Ideally, most patients should become independent of nursing support within a month after initiation of therapy, eliminating the need for continued district nurse visits. However, on occasions, a District Nurse will be required. See appendix. For care plan.

Storage and Stability

Pre-filled syringes (PDFS) containing Apomorphine should be stored at room temperature (at or below 25ºC) and protected from the light. The PFS has an unopened shelf life of 2 years when stored within the recommended conditions.

Apomorphine turns green when exposed to oxygen and stains are difficult to remove. Lemon juice can be effective if used immediately after spillage.

Infusion Crono APO– go Pump Rate Settings

Infusion rates are based on a 50:50 dilution of apomorphine and saline, available ready prepared in a pre-filled syringe.

mg Apomorphine per hour / ml of diluted solution per hr
(Flow rate)
2.0 / 0.4
2.5 / 0.5
3.0 / 0.6
3.5 / 0.7
4.0 / 0.8
4.5 / 0.9
5.0 / 1.00
5.5 / 1.10
6.0 / 1.20
6.5 / 1.30
7.0 / 1.40
7.5 / 1.50
8.0 / 1.60
8.5 / 1.70

Possible side effects are divided into those derived from Apomorphine’s pharmacology and those attributable to the mode of administration, i.e. localised reactions.

Pharmacological Side Effects

Pharmacological / Mode of administration
  • Nausea and vomiting
  • Dyskinesias during ‘ON’ time
  • Neuropsychiatric complications –
Hallucinations, euphoria, increased libido, confusion, personality changes, agitation, restlessness, psychosis, sleep disturbance.
  • Sedation
  • Orthostatic hypotension
  • Light-headedness
  • Haemolytic anaemia
(uncommon 0.1-1%)
  • Eosinophilia
/
  • Nodule formation at injection or infusion site
  • Local infection/abscess
/ulceration/scarring
  • Localised discomfort at injection or infusion site

Where dyskinesia and sedation are experienced, the treatment will be reviewed, adjusted and possibly discontinued. These side effects are more common when apomorphine is administered in conjunction with relatively high levels of oral medication. Drug-induced dyskinesias during ‘ON’ periods can be severe with intermittent injections. In contrast, continuous subcutaneous infusions of Apomorphine as monotherapy can attenuate dyskinesias.

Apomorphine is a strong, short term emetic, and all patients started on Domperidone prior to challenge, will remain on 10-20 mg tds until established on Apomorphine therapy. Domperidone is gradually withdrawn over several weeks on the advice of the PDNS or supervising physician.

Transient, mild confusion and visual hallucinations have occurred; most commonly in patients reporting previous Levodopa (as co-beneldopa or co-careldopa) and/or dopamine agonist induced neuropsychiatric complications. Should these continue to develop, attempts should be made to identify the contributing factor under the direct supervision of the hospital team.

Localised Reactions

  • Nodule formation
  • Redness, irritation and rarely ulceration.