1. Name Of The Medicinal Product
Madopar CR 100 mg/25 mg Prolonged Release Hard Capsules
2. Qualitative And Quantitative Composition
Each capsule contains 100.0mg Levodopa and 25mg Benserazide (as benserazide hydrochloride)
For excipients see section 6.1
3. Pharmaceutical Form
Prolonged-release capsules, hard.
Light blue opaque body and dark green opaque cap imprinted with ROCHE in red.
4. Clinical Particulars
4.1 Therapeutic 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.
4.2 Posology And Method Of Administration
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.
Children
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.
4.3 Contraindications
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.
4.4 Special Warnings And Precautions For Use
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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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 (see section 4.3).
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.
4.6 Pregnancy And Lactation
Madopar is contra-indicated in pregnancy and in women of childbearing potential in the absence of adequate contraception.
Since there is evidence of harmful effects in studies in pregnant rabbits and the benserazide component has been found to be associated with skeletal malformations in the rat. If pregnancy occurs in a woman taking Madopar, the drug must be discontinued. Patients taking Madopar should not breast-feed their infants.
4.7 Effects On Ability To Drive And Use Machines
Patients being treated with levodopa and presenting with somnolence and /or sudden sleep episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes and somnolence have resolved (see Section 4.4).
4.8 Undesirable Effects
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.
4.9 Overdose
Symptoms and signs
Symptoms and signs of overdosage are qualitatively similar to the side-effects of Madopar in therapeutic doses but may be of greater severity.
Overdose may lead to cardiovascular side effects (e.g. cardiac arrhythmias), psychiatric disturbances (e.g. confusion and insomnia), gastro-intestinal effects (e.g. nausea and vomiting) and abnormal involuntary movements (see section 4.8).
If a patient has taken an overdose of Madopar CR, occurrence of symptoms and signs may be delayed due to delayed absorption of the active substances from the stomach.
Treatment
Monitor the patient's vital signs and institute supportive measures as indicated by the patient's clinical state. In particular patients may require symptomatic treatment for cardiovascular effects (e.g. antiarrhythmics) or central nervous system effects (e.g. respiratory stimulants, neuroleptics).
In addition, for Madopar CR further absorption should be prevented using an appropriate method.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Madopar is an anti-Parkinsonian agent. Levodopa is the metabolic precursor of dopamine. The latter is severely depleted in the striatum, pallidum and substantia nigra of Parkinsonian patients and it is considered that administration of levodopa raises the level of available dopamine in these centres. However, conversion of levodopa into dopamine by the enzyme dopa decarboxylase also takes place in extracerebral tissues. As a consequence the full therapeutic effect may not be obtained and side-effects occur.
Administration of a peripheral decarboxylase inhibitor, which blocks the extracerebral decarboxylation of levodopa, in conjunction with levodopa has significant advantages; these include reduced gastro-intestinal side-effects, a more rapid response at the initiation of therapy and a simpler dosage regimen. Madopar consists of levodopa and the peripheral decarboxylase inhibitor benserazide in the ratio 4:1 which in clinical trials has been shown to be the most satisfactory combination.
Like every replacement therapy, chronic treatment with Madopar will be necessary.
5.2 Pharmacokinetic Properties
Madopar CR is a controlled-release form which provides more prolonged, but lower, peak plasma concentrations of levodopa than standard Madopar or other conventional formulations of levodopa.
Absorption
The active ingredients of Madopar CR are released slowly in the stomach and the maximum levodopa plasma concentration is reached approximately 3 hours after ingestion. The plasma concentration-time curve for levodopa shows a longer “half-duration” (= time-span when plasma concentrations are equal to or higher than half the maximum concentration) than that of standard Madopar, which indicates pronounced controlled-release properties. Madopar CR bioavailability is approximately 60% that of standard Madopar and is not affected by food. Maximum plasma concentrations of levodopa are not affected by food but occur later (five hours) after postprandial administration. Co-administration of an antacid with Madopar CR reduces the extent of levodopa absorption by 32%.
Distribution
Levodopa crosses the blood-brain barrier by a saturable transport system. It is not bound to plasma proteins. Benserazide does not cross the blood-brain barrier at therapeutic doses. Benserazide is concentrated mainly in the kidneys, lungs, small intestine and liver.
Metabolism
The 2 major routes of metabolism of levodopa are decarboxylation to form dopamine, which in turn is converted to a minor degree to norepinephrine and to a greater extent, to inactive metabolites, and O-methylation, forming 3-O-methyldopa, which has an elimination half-life of approximately 15 hours and accumulates in patients receiving therapeutic doses of Madopar. Decreased peripheral decarboxylation of levodopa when it is administered with benserazide is reflected in higher plasma levels of levodopa and 3-O-methyldopa.
Benserazide is hydroxylated to trihydroxybenzylhydrazine in the intestinal mucosa and the liver. This metabolite is a potent inhibitor of the aromatic amino acid decarboxylase.
Elimination
In the presence of the peripheral decarboxylase inhibitor, benserazide, the elimination half-life of levodopa is approximately 1.5 hours. In elderly patients the elimination half-life is slightly (25%) longer. Clearance of levodopa is 430 ml/min.
Benserazide is almost entirely eliminated by metabolism. The metabolites are mainly excreted in the urine (64%) and to a small extent in faeces (24%).
5.3 Preclinical Safety Data
Not applicable
6. Pharmaceutical Particulars
6.1 List Of Excipients
Capsule contents:
Hypromellose (E464)
Hydrogenated vegetable oil
Calcium phosphate (E341)
Mannitol (E421)
Talc (E553b)
Povidone (E1201)
Magnesium stearate (E572)
Capsule shell:
Gelatin
Indigo carmine (E132)
Titanium dioxide (E171)
Yellow iron oxide (E172)
Printing ink:
Red iron oxide (E172)
6.2 Incompatibilities
Not applicable
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
Do not store above 25°C. Store in the original package. Keep bottle tightly closed.
6.5 Nature And Contents Of Container
Amber glass bottles with polyethylene closure and integrated desiccant containing 100 capsules.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom.
8. Marketing Authorisation Number(S)
PL 00031/0227
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of last renewal: 26 April 2004
10. Date Of Revision Of The Text
April 2009
Madopar is a registered trade mark
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