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Drug Details

Madopar CR Capsules 125

• Drug Class Description
  Anti-Parkinsonian
• Generic Name
  Levodopa and Benserazide
• Presentation
  Prolonged-release capsules, hard. Light blue opaque body and dark green opaque cap imprinted with ROCHE in red.
• Description
  Each capsule contains 100.0mg Levodopa and 25mg Benserazide (as benserazide hydrochloride)
• Indications
  

  Treatment of all stages of Parkinson's disease. Patients with fluctuations related to levodopa plasma concentrations or timing of dose, e.g. end of dose deterioration or wearing-off effects, are more likely to benefit from switching to Madopar CR.

• Adult Dosage
  

  Adults, including the elderly

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

  Madopar CR capsules must always be swallowed whole, preferably with a little water. They may be taken with or without food but antacid preparations should be avoided.

  In patients with nocturnal immobility, positive effects have been reported after gradually increasing the last evening dose to two Madopar CR 100mg/25mg capsules on retiring.

  Patients not currently treated with levodopa

  In patients with mild to moderate disease, the initial recommended dose is one capsule of Madopar CR three times daily with meals. Higher doses, in general, of Madopar CR will be required than with conventional levodopa-decarboxylase inhibitor combinations as a result of the reduced bioavailability. The initial dosages should not exceed 600mg per day of levodopa.

  Some patients may require a supplementary dose of conventional Madopar, or Madopar Dispersible, together with the first morning dose of Madopar CR to compensate for the more gradual onset of the CR formulation.

  In cases of poor response to Madopar CR at total daily doses of Madopar CR plus any supplementary conventional Madopar corresponding to 1200mg levodopa, administration of Madopar CR should be discontinued and alternative therapy considered.

  Patients currently treated with levodopa

  Madopar CR should be substituted for the standard levodopa-decarboxylase inhibitor preparation by one capsule Madopar CR 100mg/25mg per 100mg levodopa. For example, where a patient previously received daily doses of 200mg levodopa with a decarboxylase inhibitor, then therapy should be initiated with two capsules Madopar CR 100mg/25mg. Therapy should continue with the same frequency of doses as previously.

  With Madopar CR, 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 Madopar CR 100mg/25mg 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.

• Child Dosage
  

  Not to be given to patients under 25 years of age: therefore, no dosage recommendations are made for the administration of Madopar CR to children.

• Contra Indications
  

  Madopar must not be given to patients with known hypersensitivity to levodopa or benserazide.

  Madopar is contra-indicated in narrow-angle glaucoma (it may be used in wide-angle glaucoma provided that the intra-ocular pressure remains under control); severe psychoneuroses or psychoses; severe endocrine, renal, hepatic or cardiac disorders.

  It should not be given in conjunction with, or within 2 weeks of withdrawal of, monoamine oxidase (MAO) inhibitors, except selective MAO-B inhibitors (e.g. selegiline) or selective MAO-A inhibitors (e.g. moclobemide).

  It should not be given to patients under 25 years of age.

  It should not be given to pregnant women or to women of childbearing potential in the absence of adequate contraception. If pregnancy occurs in a woman taking Madopar, the drug must be discontinued.

  Suspicion has arisen that levodopa may activate a malignant melanoma. Therefore, Madopar should not be used in persons who have a history of, or who may be suffering from, a malignant melanoma.

• Special Precautions
  

  When other drugs must be given in conjunction with Madopar, the patient should be carefully observed for unusual side-effects or potentiating effects.

  In the event of general anaesthesia being required, Madopar therapy may be continued as long as the patient is able to take fluids and medication by mouth. If therapy is temporarily interrupted, the usual daily dosage may be administered as soon as the patient is able to take oral medication. Whenever therapy has been interrupted for longer periods, dosage should again be adjusted gradually; however, in many cases the patient can rapidly be returned to his previous therapeutic dosage.

  If a patient has to undergo emergency surgery, when Madopar has not been withdrawn, anaesthesia with halothane should be avoided.

  There have been occasional reports of a neuroleptic malignant-like syndrome, involving hyperthermia, on abrupt withdrawal of levodopa preparations. Sudden discontinuation of Madopar, without close supervision, or “drug holidays” should therefore be avoided.

  Pyridoxine (vitamin B₆) may be given with Madopar since the presence of a decarboxylase inhibitor protects against the peripheral levodopa transformation facilitated by pyridoxine.

  Levodopa has been associated with somnolence and episodes of sudden sleep onset. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported very rarely. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with levodopa. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore a reduction of dosage or termination of therapy may be considered.

  Pathological gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists and/or levodopa for Parkinson's disease.

  Care should be taken when using Madopar in the following circumstances: in endocrine, renal, pulmonary or cardiovascular disease, particularly where there is a history of myocardial infarction or arrhythmia; psychiatric disturbances (e.g. depression); hepatic disorder; peptic ulcer; osteomalacia; where sympathomimetic drugs may be required (e.g. bronchial asthma), due to possible potentiation of the cardiovascular effects of levodopa; where antihypertensive drugs are being used, due to possible increased hypotensive action.

  Periodic evaluation of hepatic, haemopoietic, renal and cardiovascular functions is advised.

  Patients who improve on Madopar therapy should be advised to resume normal activities gradually as rapid mobilisation may increase the risk of injury.

  Patients with diabetes should undergo frequent blood sugar tests and the dosage of antidiabetic agents should be adjusted to blood sugar levels.

• Interactions
  

  Ferrous sulphate decreases the maximum plasma concentration and the AUC of levodopa by 30 – 50%. The pharmacokinetic changes observed during co-treatment with ferrous sulphate appeared to be clinically significant in some but not all patients.

  Opioids and drugs which interfere with central amine mechanisms, such as rauwolfia alkaloids (reserpine), tetrabenazine (Nitoman), metoclopramide, phenothiazines, thioxanthenes, butyrophenones, amphetamines and papaverine, should be avoided where possible. If, however, their administration is considered essential, extreme care should be exercised and a close watch kept for any signs of potentiation, antagonism or other interactions and for unusual side-effects. Metoclopramide has been shown to increase the rate of levodopa absorption.

  Combination with other anti-Parkinsonian agents (anticholinergics, amantadine, dopamine agonists) is permissible, though both the desired and undesired effects of treatment may be intensified. It may be necessary to reduce the dosage of Madopar or the other substance. When initiating an adjuvant treatment with a COMT inhibitor, a reduction of the dosage of Madopar may be necessary. Anticholinergics should not be withdrawn abruptly when Madopar therapy is instituted, as levodopa does not begin to take effect for some time.

  There have been rare reports of possible antagonism of levodopa by diazepam. Isolated cases of hypertensive crisis have been reported with concomitant use of tricyclic antidepressants. Madopar must not be given in conjunction with MAO inhibitors.

  Use with antihypertensive agents may increase the hypotensive response, while sympathomimetics may increase the cardiovascular side-effects of levodopa.

  Levodopa may interfere chemically with several diagnostic laboratory tests including those for glucose, ketone bodies, or catecholamines in urine and for glucose or uric acid in blood. 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 Madopar.

  When Madopar CR is given with antacid preparations the bioavailability of levodopa is reduced, in comparison with conventional Madopar.

• Adverse Drug Reactions
  

  Gastro-intestinal:

  − Anorexia, nausea, vomiting, diarrhoea (less commonly than with levodopa) mainly occurring in the early stages of treatment may be controlled by taking Madopar with some food or liquid or increasing the dose slowly.

  − Gastro-intestinal bleeding has been reported with levodopa therapy.

  − Isolated cases of loss or alterations of taste.

  Skin:

  − Rarely allergic reactions such as pruritus and rash.

  Cardiovascular:

  − Occasional reports of cardiac arrhythmias and orthostatic hypotension (less frequently than with levodopa alone). Orthostatic disorders usually improve following dosage reduction.

  Haematological:

  − Rare cases of haemolytic anaemia, transient leucopenia and thrombocytopenia.

  Neuropsychiatric:

  − Psychiatric disturbances are common in Parkinsonian patients, including those treated with levodopa, including mild elation, anxiety, agitation, insomnia, drowsiness, depression, aggression, delusions, hallucinations, temporal disorientation and “unmasking” of psychoses.

  − Levodopa is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes.

  − Patients treated with dopamine agonists and/or levodopa for treatment of Parkinson's disease, especially at high doses, have been reported as exhibiting signs of pathological gambling, increased libido and hypersexuality, generally reversible upon reduction of the dose of treatment discontinuation.

  − Involuntary movements (e.g. choreiform or athetotic, oral dyskinesias, “paddling” foot) are common, particularly on long-term administration. These are usually dose-dependent and may disappear or become tolerable after dose adjustment.

  Laboratory abnormalities:

  − Transient rises in SGOT, SGPT and alkaline phosphatase values have been noted.

  − Increase of gamma-Glutamyltransferase has been reported.

  − Serum uric acid and blood urea nitrogen levels are occasionally increased.

  Others:

  − Flushing and sweating have been reported with levodopa.

  − Urine passed during treatment may be altered in colour; usually red-tinged, this will turn dark on standing. These changes are due to metabolites and are no cause for concern.

  Tolerance to Madopar varies widely between patients and is often related to the rate of dosage increases