MDS-ES INFUSION COURSE 2020 APOMORPHINE, MANAGEMENT OF ADVERSE EVENTS AND COMPLICATIONS OF APOMORPHINE THERAPY

MDS-ES INFUSION COURSE 2020
APOMORPHINE, MANAGEMENT OF ADVERSE EVENTS AND
    COMPLICATIONS OF APOMORPHINE THERAPY

        Tove Henriksen, MD,
        Movement Disorder Clinic
        University Hospital of Copenhagen

                                            Nymphaea caerula, blue Egyptian water lily
                                                                                         Apomorphine, T. Henriksen, 2020
                                                Royal Botanic Gardens Kew, UK

Apomorphine, T. Henriksen, 2020
APOMORPHINE INFUSION

SIDE EFFECTS

  Dopaminergic effect/systemic effect

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

 Mode of administration

 Technical

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 Long term evaluation of CSAI of 82 PD patients
 Tertiary hospitals in Spain

 Prospective data

 Mean follow up 20 months

 Baseline data compared with last follow up data

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  From 148 adverse events collected:
  93 (62.8%) were mild
  44 (29.7%) moderate
  11 (7.4%) severe but did not lead to treatment dropout.
  No case of HA was reported in these 82 long-term-treated patients.

MOVEMENT DISORDERS 2008

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•   10 years 230 patients with APO (mean age 66.8)
•   As of June 2016, 93 remained on Apo, 137 had stopped.
•   Main indication for APO lack of DBS criteria
•   Average time since APO onset was 40.0 months.
•   In the active group, APO decreased off-state in 4 h
•   Dyskinesia and balance did not worsen.
•   Cognitive decline did not change within the first 15 months.
•   Hallucinations were the same within the first 39 months.
•   The presence of subcutaneous nodules was the most frequent adverse event
•   The main reason for discontinuation was side effects, being psychosis the
•   most common

REASONS FOR DISCONTINUATION, 137 (59,6%)

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ICD BEFORE AND AFTER APO

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STUDY DESIGN

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SIDE EFFECTS

DEALING WITH SIDE EFFECTS, 1
   Nausea, vomiting
     Usually in the starting phase/titration
     Domperidone 20 mg t.i.d.
           EMA may 2014, 10 mg tid, for a maximum of 1 week

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       If present at apomorphine test
           Lower initial dose, slow up titration
   Ortostatic hypotension
     Frequent in PD
     Domperidone
     Critical review of the total medication
           Anti-hypertensive medication, diuretics
       Water repletion (2-2.5 l/day)
       Liberal intake of salt/salt tablets 500 mg t.i.d.
       Ibrufen 200 mg t.i.d.
       Rarely fludrocortison 0.1 mg b.i.d.

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   Small increased risk of serious cardiac adverse drug reactions related to the
    use of domperidone, including QTc prolongation, torsade de pointes, serious
    ventricular arrhythmia and sudden cardiac death.
   A higher risk was observed in patients older than 60 years, adults taking daily
    oral doses of more than 30 mg, and those taking QT prolonging medicines or
    CYP3A4 inhibitors concomitantly
   Domperidone should be used maximum treatment duration should not usually
    exceed one week.
   10 mg orally up to three times daily (maximum dose of 30 mg daily). Adults
    may also be given 30 mg twice daily
   Contraindication: underlying cardiac disease such as congestive heart failure,
    and when coadministered with QT - prolonging medicines or potent CYP3A4
    inhibitors.

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   Prophylactic use of antiemetics was prohibited except in those
    who had been receiving antiemetic treatment before the start
    of study.
   20% of the subjects reported gastrointestinal AEs, including
    nausea and vomiting.
   Some of them required an antiemetic or apomorphine dose
    reduction and disappeared soon after these action taken, but
    none discontinued the study for gastrointestinal AEs,
    suggesting that it is feasible to start apomorphine without pre-
    treatment with antiemetics.

DEALING WITH SIDE EFFECTS, 2

   Sedation
     Rare rapports on sudden sleep attacts, similar to other DA’s

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     Information important
         Driving
         Operating machines, work hazard

   Hemolytic anemia
     Reports of a positive Coomb’s test in both DA’s and l-dopa
     In very rare cases corticosteroids
     A Coomb’s test before starting, and every ½ y
         If positive and associated with anemia:
         Full haematological work up and cessation of Apomorphine

DEALING WITH SIDE EFFECTS, 3

   Neuropsychiatric complications
     Close monitoring

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     Clozapine
     Rivastigmine
     Case: 54 y old patient with familial PD. On amantadin and
      high L-dopa load, already internet addiction prior to
      apomorphine. After risky financial transactions (Struhal et al
      2012):
         Dysregulation Syndrome
         Psychosis

         Depression and paranoia lead to suicide attempt

PSYCHOSIS

    Switching from conventional p.o. dopamin agonist to
     apomorphine infusions reduces confusion, hallucinations,

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     paranoia (Ellis 1997)
    Improvement in mood on BDI when switching to Apomorphine
     infusion (Di Rosa 2003)
    DBS and Apomorphine: motor effect greater in DBS, but NPI
     better in Apomorphine group (De Gaspari 2006, Alegret 2004)
 •    Open label pilot study, fluctuations and severe visual
      hallucinations, apomorphine, NPI-Q improved significantly
      (Van Laar 2010)
      ▫   Due only to reduction in hallucinations
    Cognitive impairment the red flag?

•   Open label pilot study
•   8 ppts with PD, fluctuations and severe visual hallucinations
    ▫   Despite use of anti-psychotics and/or cholineesterase inhibitors in
        7/8
•   Mean apomorphine 5.2 mg/h
•   LEDD did not change significantly
•   NPI-Q improved significantly
    ▫   Due only to reduction in hallucinations
•   NPI-Q distress score improved significantly
•   Mean MMSE and mean FAB unchanged
•   Discontinuation of oral DA                                            Apo
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DOPAMINE DYSREGULATION SYNDROME

   Related to
       Impulse control disorders
       Pathological gambling

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       Kleptomania
       Compulsive sexual behavior
       Binge eating
       Compulsive buying
       Punding
       L-dopa, Apomorphine, oral DA

 Injections worse then infusions to produce DDS (Lees A
  et al 2000)
 Case rapport, woman pen 24/ day, 75 mg apomorphine
  (Tellez C 2006)

There is a trend showing
that the proportion of ICD
is related to the selectivity
for D3 receptors over D2
receptors, with
pramipexole having the
highest association with, or
frequency of ICD.

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32% for pramipexole,
25% for ropinirole,
16% for pergolide,
22% for rotigotine,
10% for apomorphine
6.8% for bromocriptine

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Role of D3 in impulse–control disorder: the proportion of patients with impulse–
control disorder for pramipexole and other agonists correlates with the D3
selectivity, compared to D2, of these drugs. For each molecule of pramipexole that
occupies a D2 receptor to alleviate Parkinson’s disease, there are 66 molecules of
pramipexole that occupy the D3 receptor

DEALING WITH SIDE EFFECTS, 4
 Subcutaneous noduli/infection
 Almost all patients

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 Localized discomfort at infusion site

 Require attention not to result in
     Serious skin infection
     Ulcerations
     Scaring of the skin

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REDUCE RISK OF NODULI

   Educate expert carer (spouse, district nurses) by the outpatient
    clinic as soon as the treatment is started
   Proper hygiene at injection site

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   A new needle/injection line every day
   Rotation of injection site every day
   No reuse of the needle if it falls out
   Ultra sound treatment of the injection sites once or twice a week
    from the start
   A minimum angle of 45° of the needle to avoid injection intra-
    dermal
   Hand massages/massage with a spiky rubber ball of the injected
    areas on a daily basis
   To avoid long term skin problems in general ensure sufficient
    protein intake monitored by weight control on a regular
    basis/dietician.

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   If nodules/panniculitis develops:
   Silicone gel patches placed overnight on injection site

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   Diluting the apomorphine solution from 0.5% to 0.25%.
   Change type of needle, use Teflon (Comfort short, Cleo)
    instead of steel
   Change injection technique
   If this is not helpful, let a specialist nurse monitor the
    procedure used by the patient/carer of placement of
    needle to give a brush up of the right procedure
   If infection occurs:
   Oral antibiotics according to resistance pattern of
    bacteria and if needed, surgical treatment of abscess

SUGGESTIONS TO PREVENT NODULES
   Apomorphine should only be used in centers with
    experience using the treatment, this could include specialist
    nurses and an outpatient setup suited for this specialized
    treatment.
   Expert carer (spouse, district nurses) including education

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    commenced by the outpatient clinic as soon as the
    treatment is started
   Rotation of injection site every day

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TECHNICAL ISSUES
 Clotting of connections
 Arrest of pump

 Leakage at injection site

 Disconnection of/rotation of syringe

 Never leading to cessation

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REASONS FOR STOPPING PUMP TREATMENT,
72 OF 103 PATIENTS

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SIDE EFFECTS RESULTING IN STOPPING TREATMENT

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MAXIMIZE COMPLIANCE
   Perform an apomorphine test
       effect and side effects, give the patient and caregiver an idea of what the
        treatment entails
   Ensure that the clinical problem in question can be expected to be
    alleviated by the treatment
   Convey to patient and caregiver that the treatment is

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       not disease modifying
       involves numerous follow up visits
       can have complications and side effects
   Demonstrate pump, syringe and needle for the patient and caregiver
   Inform about the risk of discoloration of clothing by apomorphine
   Educate the patient, spouse and district nurses/ other professional,
    caregivers in the pump
   Provide patient and caregiver with emergency phone numbers for 24
    h help
   Propose an information source not related to the hospital
       Reliable websites
       Peers from a local Parkinson Association

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THANK YOU FOR YOUR ATTENTION