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Co-beneldopa (benserazide and levodopa) oral

Presentation

Oral formulations of levodopa and benserazide

Co-beneldopa is a mixture of benserazide and levodopa in mass proportions corresponding to 1 part benserazide and 4 parts of levodopa.

Drugs List

  • co-beneldopa (benserazide 12.5mg and levodopa 50mg) capsules
  • co-beneldopa (benserazide 12.5mg and levodopa 50mg) dispersible tablet sugar-free
  • co-beneldopa (benserazide 25mg and levodopa 100mg) capsules
  • co-beneldopa (benserazide 25mg and levodopa 100mg) dispersible tablet sugar-free
  • co-beneldopa (benserazide 25mg and levodopa 100mg) modified release capsules
  • co-beneldopa (benserazide 50mg and levodopa 200mg) capsules
  • MADOPAR 125mg capsules
  • MADOPAR 125mg dispersible tablet
  • MADOPAR 250mg capsules
  • MADOPAR 62.5mg capsules
  • MADOPAR 62.5mg dispersible tablet
  • MADOPAR CR 125 capsules
  • Therapeutic Indications

    Uses

    Parkinson's disease (not drug induced)

    Dosage

    Dosage and administration are very variable and must be titrated to the needs of the individual patient.

    Patients with fluctuations related to levodopa plasma concentrations or timings of dose e.g. end of dose deterioration or wearing off effects, are more likely to benefit from modified release co-beneldopa.

    Adults

    Standard release capsules and dispersible tablets

    Patients not previously treated with levodopa:
    The recommended initial dose is one capsule or dispersible tablet of co-beneldopa 12.5/50 mg three or four times daily. If the disease is at an advanced stage, the starting dose should be co-beneldopa 25/100 mg three times daily.

    The daily dosage should then be increased by co-beneldopa 25/100 mg once or twice daily until a full therapeutic effect is obtained or side effects supervene.

    The effective dose usually lies within the range of 4 to 8 capsules or dispersible tablets of co-beneldopa 25/100 mg (400 to 800 mg levodopa) daily in divided doses, most patients requiring no more than 600 mg of levodopa daily.

    Optimal improvement is usually seen in one to three weeks but the full therapeutic effect may not be apparent for some time. It is therefore advisable to allow several weeks to elapse before contemplating dosage increments above the average dosage range. If satisfactory improvement is still not achieved, the dose should be increased with caution. It is rarely necessary to give more than ten capsules or dispersible tablets of co-beneldopa 25/100 mg (1000 mg levodopa) per day.

    Treatment should be continued for at least six months before failure is concluded from the absence of clinical response.

    Patients already receiving levodopa therapy:
    Levodopa alone should be discontinued and co-beneldopa started on the following day. The patient should be initiated on a total of one less co-beneldopa 25/100 mg capsule or dispersible tablet daily than the total number of 500 mg levodopa tablets or capsules previously taken. For example if the patient had previously taken 2 g levodopa daily then he should start on three capsules or dispersible tablets of co-beneldopa 25/100 mg on the following day. Observe the patient for one week then if necessary increase the dosage in the manner described for new patients.

    Patients already receiving other levodopa/decarboxylase inhibitor combinations:
    Previous therapy should be withdrawn for 12 hours. In order to minimise the potential for any effects of levodopa withdrawal, it may be beneficial to discontinue previous therapy at night and institute co-beneldopa therapy the following morning. The initial dose of co-beneldopa should be one capsule or dispersible tablet of co-beneldopa 12.5/50 mg three or four times a day. This dose may then be increased in the manner described for patients not previously treated with levodopa.

    Other anti-parkinsonian drugs may be given with co-beneldopa. Existing treatment with other anti-parkinsonian drugs e.g. anticholinergics or amantadine, should be continued during initiation of co-beneldopa therapy. However as treatment with co-beneldopa proceeds and the therapeutic effect becomes apparent, the dosage of the other drugs may need to be reduced or the drugs gradually withdrawn.

    Modified release capsules

    In patients with nocturnal immobility, positive effects have been reported after gradually increasing the last evening dose to two co-beneldopa modified release capsules on retiring.

    Patients not previously treated with levodopa:
    In patients with mild to moderate disease, the initial recommended dose is one co-beneldopa modified release capsule three times a day.
    Higher doses, in general, of co-beneldopa modified release capsules will be required than with conventional levodopa-decarboxylase inhibitor combinations as a result of the reduced bioavailability.
    The initial dosage should not exceed 600 mg per day of levodopa.

    Some patients may require a supplementary dose of conventional co-beneldopa capsules or dispersible tablets together with the first morning dose of co-beneldopa modified release capsules to compensate for the more gradual onset of the modified release formulation.

    In cases of poor response to co-beneldopa modified release capsules at a total daily doses of co-beneldopa modified release capsules plus any supplementary co-beneldopa corresponding to 1200 mg levodopa, administration of co-beneldopa modified release capsules should be discontinued and alternative therapy considered.

    Patients already receiving levodopa therapy:
    Co-beneldopa modified release capsules should be substituted for the standard levodopa-decarboxylase inhibitor preparation by one capsule co-beneldopa modified release capsule per 100 mg levodopa. For example where a patient previously received daily doses of 200 mg levodopa with decarboxylase inhibitor, then therapy should be initiated with two capsules of co-beneldopa modified release capsules. Therapy should continue with the same frequency of doses as previously.

    With co-beneldopa modified release capsules, on average, a 50% increase in daily levodopa dosage compared with previous therapy has been found to be appropriate. The dosage should be titrated every 2 to 3 days using dosage increments of co-beneldopa modified release capsules and a period of up to 4 weeks should be allowed for optimisation of dosage.

    Patients already on levodopa therapy should be informed that their condition may deteriorate initially until the optimal dosage regimen has been found. Close medical supervision of the patient is advisable during the initial period whilst adjusting the dosage.

    Elderly

    (See Dosage; Adult)

    Additional Dosage Information

    Switching from modified release capsules to dispersible tablets.
    Co-beneldopa dispersible tablets have a higher bioavailability, faster onset of action and shorter duration of action than the modified release capsules. As such, alternative sources suggest a 30% reduction in dose when switching from modified release capsules to dispersible tablets. Adjustments to dose frequency may also be required.

    Contraindications

    Patients under 25 years
    Within 2 weeks of discontinuing MAOIs
    Breastfeeding
    History of malignant melanoma
    Malignant melanoma
    Narrow angle glaucoma
    Pregnancy
    Severe cardiac disorder
    Severe endocrine disease
    Severe hepatic disorder
    Severe psychiatric disorder
    Severe renal disorder

    Precautions and Warnings

    Females of childbearing potential
    General anaesthesia
    Cardiovascular disorder
    Diabetes mellitus
    Endocrine disease
    Hepatic disorder
    History of cardiac arrhythmias
    History of myocardial infarction
    History of peptic ulcer
    History of postural hypotension
    Open angle glaucoma
    Osteomalacia
    Peptic ulcer
    Psychiatric disorder
    Pulmonary disease
    Renal disorder

    Advise patient ability to drive or operate machinery may be impaired
    Advise patient that sudden onset sleep episodes may affect ability to drive
    Some products may contain soya or soya derivative
    Different formulations are not bioequivalent
    Advise patient to take 30 minutes before or 1 hour after meals
    Take at a different time from iron supplement
    Diabetic control may need adjustment
    Exclude pregnancy before issuing each prescription
    Monitor blood glucose closely in patients with diabetes mellitus
    Monitor cardiac function in patients with cardiac disease
    Monitor for melanoma regularly
    Monitor patient for signs and symptoms of depression
    Monitor patients at risk of glaucoma for increases in intraocular pressure
    Monitor patients for impulse control disorders
    Monitor renal, hepatic and haematological parameters
    Review treatment if impulse control disorders symptoms occur
    Advise patient that postural hypotension may occur
    Advise patient that red discolouration of body fluids may occur
    Advise patient to report any new or worsening depression/suicidal ideation
    Dopamine agonists have been associated with pathological gambling
    May affect results of some laboratory tests
    May colour urine red
    Avoid abrupt withdrawal: May cause signs of neuroleptic malignant syndrome
    Discontinue prior to surgery
    Pregnancy confirmed: Discontinue this medication
    Reduce dose or discontinue if sudden onset of sleep during daily activities
    Female: Ensure adequate contraception during treatment
    Advise patient to resume normal activities gradually
    Advise patient/carer about symptoms of impulse control disorders

    Monitor patients for unusual side effects or potentiating effects when given concurrently with other drugs.

    Co-beneldopa may induce dopamine dysregulation syndrome resulting in excessive use of the product.

    If a patient requires a general anaesthesia, the normal co-beneldopa regimen should be continued as close to the surgery as possible, except in the case of halothane. In general anaesthesia with halothane co-beneldopa should be discontinued 12 to 48 hours before surgical intervention as fluctuations in blood pressure and/or arrhythmias may occur in patients on co-beneldopa therapy. Co-beneldopa therapy may be resumed following surgery; the dosage should be increased gradually to the preoperative level.

    If a patient has to undergo surgery when co-beneldopa has not been withdrawn, anaesthesia with halothane should be avoided.

    Co-beneldopa has been reported to induce decreases in blood cell count (e.g. haemolytic anaemia, thrombocytopenia and leukopenia). In a few instances agranulocytosis and pancytopenia have been reported in which the association with co-beneldopa could neither be established, nor be completely ruled out. Therefore, periodical evaluation of blood cell count should be performed during treatment.

    Pregnancy and Lactation

    Pregnancy

    Co-beneldopa is contraindicated during pregnancy and in women of child bearing potential in the absence of adequate contraception.

    The manufacturer does not recommend taking co-beneldopa during pregnancy.

    Lactation

    Co-beneldopa is contraindicated during breastfeeding.

    The manufacturer suggests not breastfeeding whilst taking co-beneldopa. It is unknown if co-beneldopa is expressed in breast milk, therefore the risks like skeletal malformations cannot be excluded.

    Side Effects

    'Unmasking' of psychoses
    Abdominal pain
    Activation of latent Horner's syndrome
    Aggression
    Agitation
    Agranulocytosis
    Allergic reaction
    Alopecia
    Anorexia
    Anxiety
    Ataxia
    Athetosis
    Blepharospasm
    Blurred vision
    Bruxism
    Cardiac arrhythmias
    Chest pain
    Choreiform movement
    Confusion
    Convulsions
    Daytime sedation
    Decrease in mental acuity
    Delusions
    Dementia
    Depression
    Diarrhoea
    Diplopia
    Discolouration of urine
    Dizziness
    Dream abnormalities
    Drowsiness
    Dry mouth
    Dyskinesia
    Dyspepsia
    Dysphagia
    Dyspnoea
    Euphoria
    Exanthema
    False positive Coombs test
    Fine tremor (usually hands)
    Flatulence
    Flushing
    Gamma glutamyl transferase (GGT) increased
    Gastrointestinal bleeding
    Glaucoma (closed angle)
    Haemolytic anaemia
    Hallucinations
    Headache
    Henoch-Schonlein purpura
    Hiccups
    Hoarseness
    Hypersalivation
    Hypersexuality
    Hypertension
    Impulse control disorders
    Increase in alkaline phosphatase
    Increase in blood urea nitrogen
    Increase in serum ALT/AST
    Increased libido
    Increased uric acid level
    Insomnia
    Involuntary movement disorders
    Leucopenia
    Malignant melanoma
    Mild elation
    Muscle cramps
    Nausea
    Neuroleptic malignant syndrome
    Oculogyric crisis
    Oedema
    Orthostatic hypotension
    Paddling foot
    Paraesthesia
    Pathological gambling
    Phlebitis
    Priapism
    Pruritus
    Psychiatric disorders
    Pupillary dilatation
    Rash
    Restless legs
    Somnolence
    Sudden sleep onset episodes
    Sweating
    Syncope
    Taste disturbances
    Temporal disorientation
    Thrombocytopenia
    Tolerance
    Trismus
    Urinary incontinence
    Urinary retention
    Vomiting
    Weight changes

    Effects on Laboratory Tests

    Levodopa may affect the results of laboratory tests for catecholamines, ketone bodies, creatinine, uric acid and glycosuria. The urine test results may give a false positive for ketone bodies. Levodopa therapy has been reported to inhibit the response to protirelin in tests of thyroid function. Coombs' tests may give a false-positive result in patients taking co-beneldopa.

    Overdosage

    It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

    The following number will direct the caller to the relevant local centre (0844) 892 0111

    Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

    Further Information

    Last Full Review Date: August 2014

    Reference Sources

    Summary of Product Characteristics: Madopar CR capsules 125. Roche Products Ltd. Revised December 2020.
    Summary of Product Characteristics: Madopar 200mg/50mg capsules. Roche Products Ltd. Revised March 2020.
    Summary of Product Characteristics: Madopar 100mg/25mg capsules. Roche Products Ltd. Revised March 2020.
    Summary of Product Characteristics: Madopar 50mg/12.5mg capsules. Roche Products Ltd. Revised March 2020.
    Summary of Product Characteristics: Madopar Dispersible tablets. Roche Products Ltd. Revised August 2015.

    NICE Evidence Services Available at: www.nice.org.uk Last accessed: 26 November 2018

    UKMi medicines Q&A October 2018
    How do you convert from co-beneldopa (madopar) prolonged-release capsules to dispersible tablets?
    Available at: www.sps.nhs.uk
    Last accessed: 26 November 2018

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