Levodopa - epgonline.org

ENT416_NURSES LEAVEPIECE.qxd 2/10/06 14:08 Page 1 

Your patients need levodopa but they don’t need pulsatility 

Optimizing 

levodopa therapy: 

a summary for nurses


Parkinson’s disease: a common 

neurological disorder 

• Parkinson’s disease (PD) is a common neurological disease, affecting 

more than four million people worldwide. The incidence rates of PD are 

8–18 per 100,000 person–years, and the prevalence has been estimated 

at 1% in people over 60 years of age 1 

• The symptoms of PD are different for each individual, vary 

in severity and may change over time. The most common 

symptoms are motor and include muscle rigidity, 

resting tremor and slowness of movement 

(bradykinesia). Other motor features include 

loss of balance, a shuffling gait and lack of facial expression 

• Non-motor symptoms, which may precede motor symptoms in the 

development of PD, include depression, pain, fatigue, facial flushing, 

sweating, disordered sleep patterns and abnormal skin sensations such 

as tingling 

• Due to the wide range of symptoms, the treatment of PD is best delivered 

by a multidisciplinary team, including doctors, nurses, physiotherapists 

and pharmacists 

• Recent advances in medications mean that we now have better control 

over the condition than ever before. Optimizing pharmacological therapy 

will improve functionality and quality of life for patients with PD 

Stages of Parkinson’s disease 

EARLY-STAGE: 

• Usually 3–5 years from diagnosis 

• Moderate motor symptoms 

• Excellent response to medication 

• Near-normal functioning 

MID-STAGE: 

• Usually 5–10 years from diagnosis 

• Motor complications (50–70% of patients) vary in severity 

• Difficulty initiating movement and loss of balance 

• Medication is still efficacious 

• Help is needed with normal daily activities 

LATE-STAGE: 

• Usually over 10 years from diagnosis 

• Response to medication is erratic, resulting in severe fluctuations 

• Difficult to control symptoms with medication and side-effects are often more 

challenging than basic symptoms 

• Considerable and frequent need for assistance in daily activities 

[1] de Lau and Breteler. Lancet 2006; 5: 525–35


Parkinson’s disease: the 

challenge of treatment and 

the nurse’s role 

• PD is a complex condition that requires careful monitoring and care from 

a number of different healthcare stecialists which comprise the 

multidisciplinary team 

• As with all neurological conditions, medication for patients with PD must 

be carefully managed to ensure maximum quality of life 

• The nurse, who sees patients in hospital, at clinics and in their own 

homes, is uniquely placed to monitor the effectiveness of changes in 

medication and treatment, and to provide information and education 

Important aspects of the nurse’s role within the 

Parkinson’s healthcare team include… 

• Awareness and treatment of the full range of symptoms seen in PD 

• Helping to maintain contact between the patient and the rest of the 

healthcare team 

• Offering support and reassurance to patients and caregivers 

• Setting reasonable expectations for therapy including the development of 

motor complications and side-effects 

• Initiating and managing change, and evaluating care 

• PD nurses can provide specialist advice to GPs and train other nurses


Levodopa: the most effective 

therapy for Parkinson’s disease 

• As PD is caused by reduced levels of dopamine in the brain, replacing 

dopamine with levodopa (a precursor to dopamine) or mimicking its 

action with dopamine agonists are key approaches to treatment 

• Patients have fewer symptoms and function better with levodopa than 

with other dopaminergic therapies 

Mean change from baseline 

–16 

–14 

–12 

–10 

–8 

–6 

–4 

–2 

0 

Better overall 

function* with 

levodopa vs 

the dopamine 

agonist 

pramipexole 

over 4 year 

follow-up 1 

2 

4 

0 6 12 18 24 30 36 42 48 

Months from randomization 

Levodopa/DDCI Pramipexole 

n=301; 72% of 

pramipexole group 

required open-label 

levodopa with a 

mean total daily 

levodopa dosage 

434 ± 498 mg/day. 

DDCI=dopa-decarboxylase inhibitor 

• The superiority of levodopa to dopamine agonists in patient function 

and side-effects has been repeatedly demonstrated 1–3 

– Patients with levodopa experience better overall function*, activities 

of daily living and motor function compared with those receiving the 

dopamine agonists pramipexole, pergolide and ropinirole 

– Levodopa therapy has a lower incidence of side-effects than dopamine 

agonists. Common side-effects associated with both levodopa and 

dopamine agonists include nausea, vomiting and postural hypotension. 

However, psychiatric symptoms such as hallucinations and psychosis are 

more common with agonists than with levodopa and are particularly prone 

to occur in elderly or patients with cognitive difficulties. Other adverse 

events such as impulse control disorders, edema and fibrosis have been 

associated with dopamine agonist use, although these are relatively rare


• Most side-effects experienced with levodopa can be managed 

conservatively. People who experience nausea and vomiting when 

therapy is first initiated usually find this improves without intervention 

*Improvements in overall function have been based on the Total Unified Parkinson’s Disease Rating 

Scale (UPDRS). The UPDRS score is a standardized measure of patients’ motor abilities, activities 

of daily living and mental abilities. 

[1] Parkinson Study Group. JAMA 2000; 284: 1931–8; [2] Oertel et al. Mov Disord 2006; 21: 

343–53; [3] Rascol et al. N Engl J Med 2000; 342: 1484–91 

Wearing-off is the greatest 

concern patients have with 

traditional levodopa therapy 

Wearing-off occurs when any of the signs or symptoms of PD emerge before 

the next dose of PD medication is due 1 

• Wearing-off is the number one issue patients have with levodopa therapy 2 , 

and can lead to unfounded patient concern 

• Traditional levodopa therapy results in the pulsatile stimulation of 

dopamine receptors, which is associated with the development of motor 

complications such as wearing-off and dyskinesia 

[1] Stacy et al. Mov Disord 2005; 20: 726–33; [2] Lieberman and Vijay. Eur J Neurol 2004; 11: 

S36–182


The typical pattern of wearing-off 

• Wearing-off: 

– Is associated with motor symptoms such as tremor, rigidity and muscle 

cramps, and non-motor symptoms such as anxiety, fatigue and 

slowness of thinking 

– Occurs in up to 40% of patients within 2 years 1 

– Is often detected later than it should be: 

• Patients often take a dose of levodopa just before they see their 

nurse or doctor so their symptoms are well-controlled 

• Doctors often focus on more visible concerns 

• Patients might not link subtle wearing-off symptoms to being 

associated with their PD (e.g. anxiety, pain) 

• Anxiety related to being told of disease progression may prevent 

patients from openly discussing their symptoms with their doctor 

[1] Parkinson Study Group. JAMA 2000; 284: 1931–8


Recognizing the end result of 

pulsatility: wearing-off 

Nearly half of all patients reporting wearing-off are not diagnosed 1 

48% 

Diagnosed by patients 

questionnaire only 

Diagnosed by physician 

questionnaire 

52% 

Questions filled out individually by 300 patients and examining physicians. In some instances, 

wearing-off diagnosed by the physician was also diagnosed by the patient. 

[1] Stacy et al. Mov Disord 2005; 20: 726–33


Asking patients about their 

symptoms will improve 

recognition of wearing-off 

• The wearing-off symptom card lists nine symptoms that commonly occur 

during wearing-off as a result of pulsatile dopaminergic stimulation, 

including tremor, slowness in movement, changes in mood, and anxiety or 

panic attacks 1 

• This was designed to help healthcare workers and patients to rapidly and 

effectively identify wearing-off 

The wearing-off symptom card 

Symptom Experience symptoms Usually improves after 

my next dose 

1. Tremor 

2. Any slowness in movement 

3. Mood changes 

4. Any stiffness 

5. Pain / aching 

6. Reduced dexterity 

7. Cloudy mind / slowness 

of thinking 

8. Anxiety / panic attacks 

9. Muscle cramping 

• It is also good practice to encourage 

patients to keep a diary of their symptoms 

for discussion with their healthcare team 

Nurses, in particular, are well placed to help patients 

identify their wearing-off symptoms 

[1] Stacy et al. Mov Disord 2005; 20: 726–33


Complications of levodopa are 

due to pulsatile delivery 

• Pulsatile delivery of levodopa leading to abnormal variations in blood 

levels is believed to lead to physiological changes that may result in motor 

complications such as wearing-off and dyskinesia 1 

• Improving the way levodopa is given at an early stage may reduce the 

development of motor complications such as wearing-off 

[1] Stocchi. Parkinsonism Relat Disord 2003; 9: S73–81 

However, most therapeutic 

strategies targeting wearing-off 

fail to address pulsatility 

• Steady plasma levels of levodopa may be provided by a constant infusion 

of levodopa; however, its use is cumbersome and impractical 

• Other commonly used methods include increasing the dose of levodopa 

or giving smaller, more frequent doses (fractionation); using controlledrelease 

preparations which have a longer duration of action, or using 

dopamine agonists 

Modifying the dose 

Plasma levels with titrated levodopa/DDCI 1 

Levodopa plasma levels 

(ng/mL) 

4000 

3000 

2000 

1000 

0 

Dose 


• Does nothing to improve the short, 1.5-hour half-life of levodopa


Controlled-release delivery 

Plasma levels with controlled-release 

levodopa/DDCI 2 


(n g/mL ) 

4000 

3000 

2000 

1000 

0 

Full Half Full Half 

Dose 


• Leads to erratic absorption of levodopa 2 

Dopamine agonist supplementation 

Plasma levels with dopamine agonists 


(ng/mL) 

1000 

500 

0 

Levodopa 

Levodopa + DA 

0 4 8 

Hours 

DA=dopamine agonist 

• Does not affect the pharmacokinetics of levodopa 3 

• However, none of these therapeutic strategies affect the pulsatility of 

levodopa, and so do not address the underlying cause of wearing-off 

[1] Nutt. Adv Neurol 1996; 69: 493–6; [2] Olanow et al. Mov Disord 2004; 19: 997–1005; 

[3] Fariello. Drugs 1998; 55 (Suppl 1): 10–6


Stalevo ® : more continuous 

levodopa for less pulsatility 

• Stalevo (levodopa/carbidopa/entacapone) is an enhanced levodopa that 

improves the delivery of dopamine to the brain 

Stalevo provides more consistent delivery 1 

5000 

Levodopa/DDCI + entacapone 

Levodopa/DDCI + placebo 

Levodopa plasma levels (ng/mL) 

4000 

3000 

2000 

1000 

0 

Dose Dose Dose Dose Dose 


18 patients on oral levodopa dosed 3, 4 or 5 times/day had entacapone 200 mg administered with 

each levodopa dose for 4 weeks. Plasma levels were taken over 12 hours before and after addition 

of entacapone. Plasma levels for one patient dosing q3h. 

• In patients with wearing-off, Stalevo 2–8 : 

– Improves overall patient function (represented in the figure opposite by 

UPDRS scores*), activities of daily living (ADL) and motor scores 

versus traditional levodopa 

– Furthermore, Stalevo allows the preservation of function (UPDRS*) 

and levodopa dose for at least the 3 years following initiation. In 

contrast, the use of traditional levodopa and the dopamine agonist 

pramipexole has been shown only to delay the progression of PD 

rather than stabilize it 

– Increases the time that symptoms are well-controlled (‘on’ time) by 

up to 1.7 hours versus baseline 

– Long-term trials indicate that using Stalevo at an early stage confers 

additional sustained benefits in symptom control which are 

maintained for at least 5 years 8 

• Stalevo is well-tolerated, with a favourable side-effect profile


Stalevo improves patient function 2 

Levodopa/DDCI + placebo 

M ean improvement from baseline (% ) 

20 

15 

10 

5 

0 

Stalevo (Levodopa/DDCI + entacapone) 

P


Upgrading to Stalevo ® 

• Patients can be switched directly to an equivalent dose of levodopa if 

they are: 

– Experiencing symptom re-emergence 

– Taking ≤ 800 mg/day levodopa 

– Experiencing no dyskinesia 

• When initiating Stalevo in a patient currently treated with 

levodopa/benserazide, discontinue dosing of levodopa/benserazide the 

previous night and start Stalevo the next morning 

Levodopa/carbidopa Switch Stalevo dose 

50 mg 

50 mg 

100 mg 

100 mg 

+ 150 mg 

150 mg 

Stalevo comes in three convenient dose strengths 

• Each strength has a 4:1 ratio of levodopa to carbidopa, plus 200 mg of 

entacapone 

• The only way to provide dopa-decarboxylase and catechol-Omethyltransferace 

inhibition in a single tablet formulation 

• When initiating Stalevo in a patient currently treated with 

levodopa/benserazide, discontinue dosing of levodopa/benserazide the 

previous night and start Stalevo the next morning

ENT416_NURSES LEAVEPIECE.qxd 2/10/06 14:08 Page 15


Stalevo (levodopa / carbidopa / entacapone) 

PRESCRIBING INFORMATION 

Indications: Stalevo is indicated for the treatment of patients with Parkinson’s disease and end-of-dose motor 

fluctuations not stabilised on levodopa/dopa decarboxylase (DDC) inhibitor treatment. Posology and method 

of administration: Each tablet is to be taken orally either with or without food (see section 5.2). One tablet 

contains one treatment dose and the tablet may only be administered as whole tablets. The optimum daily 

dosage must be determined by careful titration of levodopa in each patient. The daily dose should be preferably 

optimized using one of the three available tablet strengths (50/12.5/200 mg, 100/25/200 mg or 150/37.5/200 mg 

levodopa/carbidopa/entacapone). Patients should be instructed to take only one Stalevo tablet per dose 

administration. Patients receiving less than 70–100 mg carbidopa a day are more likely to experience nausea 

and vomiting. While the experience with total daily dosage greater than 200 mg carbidopa is limited, the 

maximum recommended daily dose of entacapone is 2000 mg and therefore the maximum Stalevo dose is 10 

tablets per day. 

How to transfer patients not currently treated with entacapone to Stalevo: Initiation of Stalevo may be 

considered at corresponding doses to current treatment in some patients with Parkinson’s disease and end-ofdose 

motor fluctuations, who are not stabilised on their current standard release levodopa/DDC inhibitor 

treatment. However, a direct switch from levodopa/DDC inhibitor to Stalevo is not recommended for patients 

who have dyskinesias or whose daily levodopa dose is above 800 mg. In such patients it is advisable to 

introduce entacapone treatment as a separate medication (entacapone tablets) and adjust the levodopa dose if 

necessary, before switching to Stalevo. Entacapone enhances the effects of levodopa. It may therefore be 

necessary, particularly in patients with dyskinesia, to reduce levodopa dosage by 10-30% within the first days 

to first weeks after initiating Stalevo treatment. The daily dose of levodopa can be reduced by extending the 

dosing intervals and/or by reducing the amount of levodopa per dose, according to the clinical condition of the 

patient. Dosage adjustment during the course of the treatment: When more levodopa is required, an increase 

in the frequency of doses and/or the use of an alternative strength of Stalevo should be considered, within the 

dosage recommendations. When less levodopa is required, the total daily dosage of Stalevo should be reduced 

either by decreasing the frequency of administration by extending the time between doses, or by decreasing the 

strength of Stalevo at an administration. If other levodopa products are used concomitantly with a Stalevo tablet, 

the maximum dosage recommendations should be followed. Children and adolescents: Not recommended. 

Elderly: No dosage adjustment required. Mild to moderate hepatic impairment, severe renal impairment 

(including dialysis): Caution advised. Contraindications: Hypersensitivity to active substances or excipients. 

Severe hepatic impairment. Narrow-angle glaucoma. Pheochromocytoma. Concomitant use of non-selective 

monoamine oxidase inhibitors (e.g. phenelzine, tranylcypromine). Concomitant use of a selective MAO-A 

inhibitor and a selective MAO-B inhibitor. Previous history of Neuroleptic Malignant Syndrome (NMS) and/or nontraumatic 

rhabdomyolysis. Warnings and precautions: Not recommended for treatment of drug-induced 

extrapyramidal reactions. Administer with caution to: patients with severe cardiovascular or pulmonary disease, 

bronchial asthma, renal, hepatic or endocrine disease, or history of peptic ulcer disease or of convulsions, or 

past or current psychosis; patients receiving concomitant antipsychotics with dopamine receptor-blocking 

properties, particularly D2 receptor antagonists; patients receiving other medicinal products which may cause 

orthostatic hypotension. In patients with a history of myocardial infarction who have residual atrial nodal, or 

ventricular arrhythmias, monitor cardiac function carefully during initial dosage adjustments. Monitor all patients 

for the development of mental changes, depression with suicidal tendencies, and other serious antisocial 

behaviour. Patients with chronic wide-angle glaucoma may be treated with Stalevo with caution, provided the 

intra-ocular pressure is well controlled and the patient is monitored carefully. 

Caution when driving or operating machines. Doses of other antiparkinsonian treatments may need to be 

adjusted when Stalevo is substituted for a patient currently not treated with entacapone. Rhabdomyolysis 

secondary to severe dyskinesias or NMS has been observed rarely in patients with Parkinson’s disease. 

Therefore, any abrupt dosage reduction or withdrawal of levodopa should be carefully observed, particularly in 

patients who are also receiving neuroleptics. Periodic evaluation of hepatic, haematopoietic, cardiovascular and 

renal function is recommended during extended therapy. Undesirable effects: Levodopa / carbidopa — Most 

common: dyskinesias including choreiform, dystonic and other involuntary movements, nausea. Also mental 

changes, depression, cognitive dysfunction. Less frequently: irregular heart rhythm and/or palpitations, 

orthostatic hypotensive episodes, bradykinetic episodes (the ‘on-off’ phenomenon), anorexia, vomiting, 

dizziness, and somnolence. Entacapone — Most frequently relate to increased dopaminergic activity, or to 

gastrointestinal symptoms. Very common: dyskinesias, nausea and urine discolouration. Common: insomnia, 

hallucination, confusion and paroniria, Parkinsonism aggravated, dizziness, dystonia, hyperkinesias, diarrhoea, 

abdominal pain, dry mouth, constipation, vomiting, fatigue, increased sweating and falls. See SPC for details of 

laboratory abnormalities, uncommon and rare events. Presentations and marketing authorization numbers: 

Stalevo 50mg/12.5mg/200mg, 30 or 100 tablet bottle, MA numbers: EU/1/03/260/002–003. Stalevo 

100mg/25mg/200mg, 30 or 100 tablet bottle, MA numbers: EU/1/03/260/006–007. Stalevo 

150mg/37.5mg/200mg, 30 or 100 tablet bottle, MA numbers: EU/1/03/260/010–011. Marketing authorisation 

holder and manufacturer: Orion Corporation, Orionintie 1, FIN–02200 Espoo, Finland. Full prescribing 

information is available on request. Stalevo is a registered trademark. 

This Parkinson’s leaflet information series is sponsored by an 

unrestricted educational grant from Novartis and Orion Pharma. Item Date: August 2006

Levodopa - epgonline.org

Create successful ePaper yourself

Delete template?

Save as template?