4.9.1 Dopaminergic drugs used in Parkinson's disease

Levodopa

If PD is suspected all patients regardless of age should be referred to a specialist untreated, for confirmation of the diagnosis and assessment.

When therapy is started the patient will be commenced on the lowest dose and increased slowly in divided doses. The final dose is usually a compromise between increased mobility and dose-limiting side effects.

Treatment should be initiated and modified by a healthcare professional with specialist expertise in Parkinson's disease (or following their advice).

Co-beneldopa

(Combination of levodopa and benserazide)

  • Madopar® capsules 50mg/12.5mg, 100mg/25mg, 200mg/50mg (£11.78 = 200mg/50mg x 100 capsules)
  • Madopar® dispersible tablets 50mg/12.5mg, 100mg/25mg (£10.45 = 100mg/25mg x 100 tablets)
  • Madopar® CR capsule 100mg/25mg (£12.77 = 100 capsules)

Indications

Dose (expressed as levodopa)

  • Standard release:
    • Adults: 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
    • 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)
    • 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
    • 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

Notes

  1. Dispersible tablets may be useful for the first early morning dose, as 'rescue medication' at other times of the day, and in patients who find it difficult to swallow tablets or capsules
Co-careldopa

(Combination of careldopa and levodopa)

  • Tablets 50mg/12.5mg, 100mg/10mg, 100mg/25mg, 250mg/25mg (£8.12 = 100 x 100mg/25mg)
  • Tablets modified-release 100mg/25mg, 200mg/50mg (£11.60 = 60 x 100mg/25mg)

Indications

Dose (expressed as levodopa)

  • Standard release:
    • Adults: 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
    • Alternative regime: 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
  • 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
    • 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. Modified release levodopa preparations are mainly for patients with significant nocturnal hypokinesia
  2. If modified release tablets are required this must be clearly stated on the prescription
  3. When co-careldopa is used, the total daily dose of carbidopa should be at least 70mg. A lower dose may not achieve full inhibition of extra cerebral dopa-decarboxylase with a resultant increase in side effects
With entacapone
Sastravi®

(Combination of levodopa / carbidopa / entacapone)

  • Tablets (50mg/ 12.5mg/ 200mg), (75mg/ 18.75mg/ 200mg), (100mg/ 25mg/ 200mg), (125mg/ 31.25mg/ 200mg), (150mg/ 37.5mg/ 200mg), (175mg/ 43.75mg/ 200mg), (200mg/ 50mg/ 200mg) (£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 strength), maximum 8 tablets daily (175mg levodopa strength), maximum 7 tablets daily (200mg levodopa strength)

Catechol-O-methyltransferase inhibitors (COMTI)

Treatment should be initiated and modified by a healthcare professional with specialist expertise in Parkinson's disease (or following their advice).

Entacapone
  • Tablets 200mg (£4.30 = 30 tablets)

Indications

  • Adjunct to co-beneldopa or co-careldopa in Parkinson's disease with 'end of dose' motor fluctuations (under expert supervision)

Dose

  • 200mg taken with each dose of levodopa product with dopa-decarboxylase inhibitor. Maximum 10 tablets (2g) per day

Notes

  1. The dose should be increased or decreased slowly
  2. It may be necessary to reduce the concurrent levodopa dose by 10-30%
  3. COMTIs may be used appropriately for patients experiencing end-of-dose wearing off effects or other motor fluctuations
Opicapone
  • Tablets 50mg (£93.90 = 30 tablets)

Indications

  • Adjunct to co-beneldopa or co-careldopa in Parkinson's disease with 'end of dose' motor fluctuations (under expert supervision)

Dose

  • 50mg once daily at bedtime, at least one hour before or after levodopa combinations; review after 3 months

Notes

  1. To be used only where entacapone is not tolerated or unsuccessful
  2. Treatment should be initiated and reviewed by specialists. Following a successful 3 month trial, ongoing prescribing may be undertaken in primary care
  3. It may be necessary to reduce the concurrent levodopa dose
  4. The routine commissioning of opicapone is accepted in Devon for the treatment of patients with Parkinson's disease who have not been able to tolerate entacapone (see Commissioning Policy for more details)

The COMTI tolcapone (non-formulary) may be prescribed by specialists working in the Exeter Movement Clinic. Prescribers should be aware of the monitoring schedule required for this drug (see BNF for further details)

Dopamine receptor agonists

Local specialists have indicated that ergot derived dopamine receptor agonists are not routinely used in the treatment of Parkinson's disease. More information on these treatment options can be found in 6.7.1 Bromocriptine and other dopaminergic drugs

Treatment should be initiated and modified by a healthcare professional with specialist expertise in Parkinson's disease (or following their advice).

Patients and their carers should be informed about the risk of impulse control disorders (including pathological gambling, binge eating, and hypersexuality) associated with dopamine-receptor agonists. There is no evidence that ergot- and non-ergot-derived dopamine-receptor agonists differ in their propensity to cause impulse control disorders, so switching between dopamine-receptor agonists to control these side-effects is not recommended. If the patient develops an impulse control disorder, the dopamine-receptor agonist should be withdrawn or the dose reduced until the symptoms resolve.

Apomorphine
  • Injection 10mg/ml (£37.96 = 5 x 2ml ampoules)

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 a very potent dopamine agonist administered subcutaneously by either intermittent injection or continuous infusion. It should only be initiated by a specialist and long-term specialist supervision is advisable throughout treatment. However, once established, patients may safely continue on treatment for many years in the community.
  2. 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.
  3. GPs may also be asked to prescribe apomorphine injection giving sets ("subcutaneous drug delivery accessories"). Specialist services should provide specific details of the required sets and quantities.
  4. MHRA Drug Safety Update (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
Amantadine
  • Capsules 100mg (£40.92 = 56 capsules)

Indications

Dose

  • Adults: 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: 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
Pramipexole
  • Tablets 88 micrograms, 180 micrograms, 700 micrograms (pramipexole base) (£10.75 = 360 micrograms three times daily)
  • Pipexus® tablets modified release 260 micrograms, 520 micrograms, 1.05mg, 1.57mg, 2.1mg, 2.62mg, 3.15mg (£60.65 = 1.05mg daily)

Indications

Dose

  • Standard release:
    • Initially 88 micrograms (base) 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:
    • Initially 260 micrograms (base) 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 may express dose as both the base and the dihydrochloride salt. For equivalence / conversion between base and salt, refer to BNF. Doses above are expressed in terms of pramipexole base
Ropinirole
  • Tablet 0.25mg, 0.5mg, 1mg, 2mg, 5mg (£175.32 = 15mg daily)
  • Ipinnia® XL modified release tablets 2mg, 3mg, 4mg, 6mg, 8mg (£37.90 = 16mg daily)

Indications

Dose

  • Standard release:
    • 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:
    • Initially 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 1mg/24 hours, 2mg/24 hours, 3mg/24 hours, 4mg/24 hours, 6mg/24 hours, 8mg/24 hours (£149.93 = 8mg/24 hours)

Indications

Dose

  • Monotherapy in early-stage Parkinson's disease:
    • Initially apply '2mg/24 hours' patch, increased in steps of 2mg/24 hours at weekly intervals if required; maximum 8mg/24 hours
  • Adjunctive therapy with levodopa with advanced stage Parkinson's disease with motor fluctuations:
    • Initially apply '4mg/24 hours' patch, increased in steps of 2mg/24 hours at weekly intervals if required; maximum 16mg/24 hours

Notes

  1. Transdermal rotigotine should only be prescribed for patients unable to take oral medication or for patients with motor complications who have failed therapy with other dopamine agonists
  2. Patches should be applied to dry, non-irritated skin on torso, thigh or upper arm. Patches should be removed after 24 hours and the replacement patch applied on a different area (avoid using the same area for 14 days)

Monoamine-oxidase-B inhibitors

Treatment should be initiated and modified by a healthcare professional with specialist expertise in Parkinson's disease (or following their advice).

Rasagiline
  • Tablets 1mg (£3.12)

Indications

  • Parkinson's disease, used alone or as adjunct to co-beneldopa or co-careldopa for 'end-of-dose' fluctuations

Dose

  • 1mg daily
Selegiline
  • Tablets 5mg, 10mg (£9.02 = 10mg)

Indications

  • Parkinson's disease, used alone or as adjunct to co-beneldopa or co-careldopa to reduce 'end of dose' deterioration; symptomatic parkinsonism

Dose

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

Notes

  1. Doses may be initiated at 2.5mg to minimise side effects in older patients
  2. Afternoon doses are not advised due to the alerting effects of the drug
  3. Selegiline has a number of drug interactions, particularly with CNS active drugs (refer to BNF)
  4. Sudden withdrawal of selegiline may exacerbate symptoms
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).

 

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