4.9.1 Dopaminergic drugs used in Parkinson's disease

Dopamine receptor agonists

Amantadine
  • Capsules 100mg (£45.54)
  • SolutionSF 50mg in 5ml (£138.99 = 150ml)

Indications

  • Parkinson's disease

Dose

  • Parkinson's disease, 100mg daily increased after one week to 100mg twice daily, usually in conjunction with other treatment; some patients may require higher doses, maximum 400mg daily; elderly 65 years and over, 100mg daily adjusted according to response

Notes

  1. Amantadine has modest antiparkinsonian effects. It improves mild bradykinetic disabilities as well as tremor and rigidity. Unfortunately, only a small proportion of patients derive much benefit from this drug and tolerance to its effects occurs.
  2. May be useful for the control of dyskinesia.
Apomorphine
  • Injection 20mg/2ml, 50mg/5ml
  • APO-go® pen 10mg/ml 3ml pen injector
  • APO-go® PFS 5mg/ml 10ml prefilled syringe

Indications

  • Refractory motor fluctuations in Parkinson's disease ('off' episodes) inadequately controlled by co-beneldopa or co-careldopa or other dopaminergics (for capable and motivated patients under specialist supervision)

Notes

  1. Apomorphine is sometimes helpful in stabilising patients experiencing unpredictable "off" periods with levodopa treatment. It is essential to stabilise patients on domperidone for at least 2 days before starting treatment with apomorphine.
  2. MHRA Drug Safety Alert (April 2016): Patients receiving apomorphine and domperidone require an assessment of cardiac risk factors and ECG monitoring to reduce the risk of serious arrhythmia related to QT-prolongation.
    1. Before starting treatment, carefully consider whether the benefits of concomitant apomorphine and domperidone treatment outweigh the small increased risk of cardiac side effects
    2. Discuss the benefits and risks of apomorphine with patients and carers and advise them to contact their doctor immediately if they develop palpitations or syncopal symptoms during treatment
    3. Check the QT-interval before starting domperidone, during the apomorphine initiation phase and if clinically indicated thereafter (eg if a QT-prolonging or interacting drug is started or if symptoms of cardiac side effects are reported)
    4. Regularly review domperidone treatment to ensure patients take the lowest effective dose for the shortest duration
    5. Advise patients to inform their doctor of any changes that could increase their risk of arrhythmia, such as:
      • symptoms of cardiac or hepatic disorders
      • conditions that could cause electrolyte disturbances (eg, gastroenteritis or starting a diuretic)
      • starting any other medicines

Ergoline

The ergoline dopamine agonists should only be used in exceptional circumstances and after the non-ergoline agonist have been tried.

Fibrotic reactions: Ergot-derived dopamine-receptor agonists, bromocriptine, cabergoline, and pergolide, have been associated with pulmonary, retroperitoneal, and pericardial fibrotic reactions.

Exclude cardiac valvulopathy with echocardiography before starting treatment with these ergot derivatives for Parkinson's disease or chronic endocrine disorders (excludes suppression of lactation); it may also be appropriate to measure the erythrocyte sedimentation rate and serum creatinine and to obtain a chest X-ray. Patients should be monitored for dyspnoea, persistent cough, chest pain, cardiac failure, and abdominal pain or tenderness. If long-term treatment is expected, then lung-function tests may also be helpful. Patients taking cabergoline or pergolide should be regularly monitored for cardiac fibrosis by echocardiography (within 3–6 months of initiating treatment and subsequently at 6–12 month intervals).

Ergot derivatives (bromocriptine, cabergoline and pergolide) act by direct stimulation of surviving dopamine receptors. Although effective, they have no advantages over levodopa. They should be reserved for patients in whom levodopa alone is no longer adequate or who, despite careful titration, cannot tolerate levodopa. They are sometimes useful in reducing "off" periods in ameliorating fluctuations in the later stage of Parkinson's disease.

Excessive daytime sleepiness and sudden onset of sleep can occur with dopaminergic drugs. Patients starting treatment with these drugs should be warned of the possibility of these effects and of the need to exercise caution when driving or operating machinery.

Pergolide
  • Tablet 50 micrograms, 250 micrograms, 1mg (£131.66 = 100 x 1mg)

Indications

  • Alone or as adjunct to co-beneldopa or co-careldopa in Parkinson's disease where dopamine-receptor agonists other than ergot derivative not appropriate

Dose

  • Monotherapy, 50 micrograms at night on day 1, then 50 micrograms twice daily on days 2–4, then increased by 100–250 micrograms daily every 3–4 days to 1.5mg daily in 3 divided doses at day 28; after day 30, further increases every 3–4 days of up to 250 micrograms daily; usual maintenance dose 2.1–2.5mg daily; maximum 3mg daily
  • Adjunctive therapy with levodopa, 50 micrograms daily for 2 days, increased gradually by 100–150 micrograms every 3 days over next 12 days, usually given in 3 divided doses; further increases of 250 micrograms every 3 days; maximum 3mg daily
Pramipexole
  • Tablets 88 micrograms, 180 micrograms, 350 micrograms, 700 micrograms (£32.59 = 350 micrograms three times a day)
  • Pipexus® tablets m/r 260 micrograms, 520 micrograms, 1.05mg, 1.57mg, 2.1mg, 2.62mg, 3.15mg (£64.98 = 1.05mg daily)

Indications

  • Parkinson's disease, used alone or as an adjunct to co-beneldopa or co-careldopa

Dose

  • Parkinson's disease, initially 88 micrograms 3 times daily, dose doubled every 5–7 days if tolerated to 350 micrograms 3 times daily; further increased if necessary by 180 micrograms 3 times daily at weekly intervals; maximum 3.3mg daily in 3 divided doses
  • Modified release: Parkinson's disease (with or without co-beneldopa or co-careldopa), initially 260 micrograms once daily, dose doubled every 5–7 days to 1.05mg once daily; further increased if necessary by 520 micrograms daily at weekly intervals; maximum 3.15mg once daily

Notes

  1. Exercise caution when prescribing, dispensing and administering pramipexole as the packs also express dose as the dihydrochloride and print both doses in milligrams
Ropinirole
  • Tablet 0.25mg, 0.5mg, 1mg, 2mg, 5mg (£3.91= 15mg daily)
  • Starter pack (250 micrograms, 500 micrograms and 1mg tablets) (£40.10)
  • Follow-on pack (500 micrograms, 1mg and 2mg tablets) (£74.40)
  • Ipinnia® XL modified release tablets 2mg, 3mg, 4mg, 6mg, 8mg (£37.90 = 16mg daily)

Indications

  • Parkinson's disease, either used alone or as adjunct to co-beneldopa or co-careldopa

Dose

  • Initially 750 micrograms daily in 3 divided doses, increased by increments of 750 micrograms daily at weekly intervals to 3mg daily in 3 divided doses; further increased by increments of 1.5–3mg daily at weekly intervals according to response; usual range 9–16mg daily in 3 divided doses (but higher doses may be required if used with levodopa); maximum 24mg daily in 3 divided doses
  • Modified release: initial treatment of Parkinson's disease, 2mg once daily for 1 week, then 4mg once daily; increased according to response by 2mg at intervals of at least 1 week up to 8mg once daily; if still no response, increase by 2–4mg at intervals of at least 2 weeks as necessary; maximum 24mg once daily
Rotigotine
  • Patches 2mg/24 hours, 4mg/24 hours, 6mg/24 hours, 8mg/24 hours (£149.93 = 6mg daily)

Indications

  • Parkinson's disease, either used alone or as adjunct to co-beneldopa or co-careldopa

Dose

  • Monotherapy in Parkinson's disease, initially apply '2mg/24 hours' patch, increased in steps of 2 mg/24 hours at weekly intervals if required; maximum 8mg/24 hours
  • Adjunctive therapy with levodopa in Parkinson's disease, initially apply '4mg/24 hours' patch, increased in steps of 2mg/24 hours at weekly intervals if required; maximum 16mg/24 hours

Notes

  1. Consultant initiated
  2. Rotigotine is an option for use as monotherapy in early stage Parkinson's disease or in combination with levodopa over the course of the disease in patients intolerant of entacapone, also for use in patients with swallowing problems or nil by mouth.

Levodopa

Levodopa in combination with a dopa-decarboxylase inhibitor is the treatment of choice for patients disabled by idiopathic Parkinson's disease. It should not be used for neuroleptic-induced Parkinsonism.

Sudden onset of sleep: Excessive daytime sleepiness and sudden onset of sleep can occur with co-careldopa, co-beneldopa, and the dopamine receptor agonists. Patients starting on treatment with these drugs should be warned of the possibility of these effects and of the need to exercise caution when driving or operating machinery. Patients, who have suffered excessive sedation or sudden onset of sleep, should refrain from driving or operating machines, until those effects have stopped.

Levodopa therapy should be initiated with low doses and gradually increased, by small increments, at intervals of 2-3 days. The final dose is usually a compromise between increased mobility and dose-limiting side effects.

Modified release preparations confer no routine benefit over standard preparations, and they are more expensive. They may help with "end-of-dose" deterioration or nocturnal immobility and rigidity. They are not interchangeable, prescribe by brand name.

Co-beneldopa
  • Capsule 62.5mg, 125mg, 250mg (£11.78 = 250mg x 100)
  • Dispersible tablet 62.5mg, 125mg (£10.45 = 125mg x 100)
  • Madopar® CR capsule 125mg (£12.77 = 100 capsules)

Indications

  • Parkinson's disease

Dose (expressed as levodopa)

  • Standard release: initially 50mg 3–4 times daily (100mg 3 times daily in advanced disease), increased by 100mg daily once or twice weekly according to response; usual maintenance dose 400–800mg daily in divided doses
  • Standard release, elderly: initially 50mg once or twice daily, increased by 50mg daily every 3–4 days according to response
  • Modified release: patients not taking levodopa/dopa-decarboxylase inhibitor therapy, initially 1 capsule 3 times daily (maximum initial dose 6 capsules daily)
  • Modified release: patients transferring from immediate-release levodopa/dopa-decarboxylase inhibitor preparations, initially 1 capsule substituted for every 100mg of levodopa and given at same dosage frequency, increased every 2–3 days according to response; average increase of 50% needed over previous levodopa dose and titration may take up to 4 weeks
  • Modified release: supplementary dose of immediate-release may be needed with first morning dose; if response still poor to total daily dose corresponding to 1.2 g levodopa, consider alternative therapy
Co-careldopa
  • Sinemet® tablet 12.5/50mg, 25/100mg, 25/250mg (£18.29 = 100 x 25/250mg)
  • Half Sinemet CR® m/r tablet 25/100 (£11.60 = 60)
  • Sinemet CR® m/r tablet 50/200 (£11.60 = 60)

Indications

  • Parkinson's disease

Dose (expressed as levodopa)

  • Standard release: initially 100mg (with carbidopa 25mg) 3 times daily, increased by 50–100mg (with carbidopa 12.5 or 25mg) daily or on alternate days according to response, up to 800mg (with carbidopa 200mg) daily in divided doses
  • Standard release: alternatively, initially levodopa 50–100mg (with carbidopa 10 or 12.5mg) 3–4 times daily, increased by 50–100mg daily or on alternate days according to response, up to 800mg (with carbidopa 80 or 100mg) daily in divided doses
  • Standard release: alternatively, initially levodopa 125mg (with carbidopa 12.5mg, as ½ tablet of co-careldopa 25/250) 1–2 times daily, increased by 125mg (with carbidopa 12.5mg) daily or on alternate days according to response
  • Modified release: patients not receiving levodopa/dopa-decarboxylase inhibitor therapy, initially, 1 Sinemet® CR tablet twice daily; both dose and interval then adjusted according to response at intervals of not less than 3 days
  • Modified release: patients transferring from immediate-release levodopa/dopa-decarboxylase inhibitor preparations, 1 Sinemet® CR tablet twice daily can be substituted for a daily dose of levodopa 300–400mg in immediate-release Sinemet® tablets (substitute Sinemet® CR to provide approx. 10% more levodopa per day and extend dosing interval by 30–50%); dose and interval then adjusted according to response at intervals of not less than 3 days

Notes

  1. When co-careldopa (10/100) is used, the dose of carbidopa may be insufficient to achieve full inhibition of extracerebral dopa-decarboxylase; co-careldopa 25/100 should therefore be used so that the daily dose of carbidopa is at least 75mg.
With entacapone
Sastravi®
  • Levodopa / Carbidopa / Entacapone tablets (50, 12.5, 200), (75, 18.75, 200), (100, 25, 200), (125, 31.25, 200), (150, 37.5, 200), (175, 43.75, 200), (200, 50, 200) (£34.66 = 100 tablets (all strengths))

Indications

  • For Parkinson's disease and end-of-dose motor fluctuations not adequately controlled with levodopa and dopa-decarboxylase inhibitor treatment

Dose

  • Only 1 tablet to be taken for each dose; maximum 10 tablets daily (50-150mg levodopa), maximum 8 tablets daily (175mg levodopa), maximum 7 tablets daily (200mg levodopa)

Monoamine-oxidase-B inhibitors

Safinamide

The routine commissioning of safinamide is not accepted in Devon for patients with mid-to-late stage fluctuating Parkinson's disease. (see Commissioning Policy for more details).

Selegiline
  • Tablet 5mg, 10mg (£9.02 = 10mg daily)
  • Oral lyophilisates (freeze dried tablets) 1.25mg (£40.28)
  • Syrup 10mg in 5ml (£17.93 = 100ml)

Indications

  • Parkinson's disease, used alone or as adjunct to co-beneldopa or co-careldopa; symptomatic parkinsonism

Dose

  • Initially 5mg in the morning; increasing after 2–4 weeks if tolerated to 10mg in the morning

Notes

  1. 1.25mg oral lyophilisate is equivalent to 10mg tablet
  2. Selegiline is used in severe parkinsonism in conjunction with levodopa to reduce "end-of-dose" deterioration.
Rasagiline
  • Tablets 1mg (£3.15)

Indications

  • Parkinson's disease, used alone or as adjunct to co-beneldopa or co-careldopa

Dose

  • 1mg daily

Notes

  1. Rasagiline has been approved for inclusion in the formulary for use only in patients who have failed or who are intolerant of entacapone.

Catechol-O-methyltransferase inhibitors

Entacapone
  • Tablets 200mg (£5.03 = 30)

Indications

  • Entacapone is licensed for use as an adjunct to co-beneldopa or co-careldopa for patients with Parkinson's disease who experience 'end-of-dose' deterioration and cannot be stabilized on these combinations.

Dose

  • 200mg with each dose of levodopa with dopa-decarboxylase inhibitor; maximum 2g daily

Notes:

  1. It is important than Entacapone and co-beneldopa or co-careldopa are taken together at the same time of day.
Tolcapone
  • Tablets 100mg

Indications

  • Adjunct to co-beneldopa or co-careldopa in Parkinson's disease with 'end-of-dose' motor fluctuations if another inhibitor of peripheral COMT inappropriate (under specialist supervision)

Notes

  1. To be prescribed by a Parkinson's disease specialist only, South Devon Healthcare NHS Foundation Trust
  2. Tolcapone requires specialist monitoring. It should only be used if entacapone fails.
  3. Hepatotoxicity, potentially life-threatening hepatotoxicity including fulminant hepatitis reported rarely, usually in women and during the first 6 months, but late-onset liver injury also reported; test liver function before treatment, and monitor every 2 weeks for first year, every 4 weeks for next 6 months and then every 8 weeks thereafter (restart monitoring schedule if dose increased). Discontinue if abnormal liver function tests or symptoms of liver disorder, do not re-introduce tolcapone once discontinued
  4. Patients should be told how to recognise signs of liver disorder and advised to seek immediate medical attention if symptoms such as anorexia, nausea, vomiting, fatigue, abdominal pain, dark urine, or pruritus develop.

 

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