- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Use during pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Patients not currently treated with levodopaIn 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 600 mg 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 1200 mg levodopa, administration of Madopar CR should be discontinued and alternative therapy considered.
Patients currently treated with levodopaMadopar CR should be substituted for the standard levodopa-decarboxylase inhibitor preparation by one capsule Madopar CR 100 mg/25 mg per 100 mg levodopa. For example, where a patient previously received daily doses of 200 mg levodopa with a decarboxylase inhibitor, then therapy should be initiated with two capsules Madopar CR 100 mg/25 mg. 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 100 mg/25 mg 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.ChildrenNot to be given to patients under 25 years of age: therefore, no dosage recommendations are made for the administration of Madopar CR to children.
Impulse control disordersPatients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments containing levodopa, including Madopar. Review of treatment is recommended if such symptoms develop.
Laboratory testsPeriodical evaluation of hepatic, haemopoietic, renal and cardiovascular function and blood count should be performed during treatment. 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.
Malignant melanomaEpidemiological studies have shown that patients with Parkinson's disease have a higher risk of developing melanoma than the general population (approximately 2-6 fold higher). It is unclear whether the increased risk observed was due to Parkinson's disease, or other factors such as levodopa used to treat Parkinson's disease. Therefore patients and providers are advised to monitor for melanomas on a regular basis when using Madopar for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g. dermatologists).
Pharmacokinetic interactionsCo-administration of the anticholinergic drug trihexyphenidyl with standard dosage form of Madopar reduces the rate, but not the extent, of levodopa absorption. Trihexyphenidyl given concomitantly with Madopar CR formulation does not affect the pharmacokinetics of levodopa. Co-administration of antacids with Madopar CR formulation reduces the extent of levodopa absorption by 32%. Ferrous sulfate decreases the maximum plasma concentration and the AUC of levodopa by 30 50%. The pharmacokinetic changes observed during co-treatment with ferrous sulfate 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 increases the rate of levodopa absorption.Domperidone may increase the bioavailability of levodopa by stimulation of gastric emptying.
Pharmacodynamic interactionsConcomitant administration of antipsychotics with dopamine-receptor blocking properties, particularly D2-receptor antagonists might antagonize the antiparkinsonian effects of Madopar, therefore, should be carried out with caution, and the patient carefully observed for loss of antiparkinsonian effect and worsening of parkinsonian symptoms. Symptomatic orthostatic hypotension occurred when combinations of levodopa and a decarboxylase inhibitor were added to the treatment of patients already receiving antihypertensives. Madopar needs to be introduced cautiously in patients receiving antihypertensive medication. Blood pressure needs to be monitored to allow for potential dosage adjustment of either of the drugs, if required. Concomitant administration of Madopar with sympathomimetics (agents such as epinephrine, norepinephrine, isoproterenol or amphetamine which stimulate the sympathetic nervous system) may potentiate their effects, therefore these combinations are not recommended. Should concomitant administration prove necessary, close surveillance of the cardiovascular system is essential, and the dose of the sympathomimetic agents may need to be reduced. If Madopar is to be administered to patients receiving irreversible non-selective MAO inhibitors, an interval of at least 2 weeks should be allowed between cessation of the MAO inhibitor and the start of Madopar therapy. Otherwise unwanted effects such as hypertensive crises are likely to occur (see 4.3 Contraindications). Selective MAO-B inhibitors, such as selegiline and rasagiline and selective MAO-A inhibitors, such as moclobemide, can be prescribed to patients on levodopa-benserazide. It is recommended to readjust the levodopa dose to the individual patient's needs, in terms of both efficacy and tolerability. Combination of MAO-A and MAO-B inhibitors is equivalent to non-selective MAO inhibition, and hence this combination should not be given concomitantly with Madopar (see 4.3 Contraindications). Combination with other anti-Parkinsonian agents such as anticholinergics, amantadine, selegiline, bromocriptine and dopamine agonists are 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. Levodopa may affect the results of laboratory tests for catecholamines, ketone bodies, creatinine, uric acid and glucose. 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 Madopar. A diminution of effect is observed when the drug is taken with a protein-rich meal.Concomitant administration of antipsychotics with dopamine-receptor blocking properties, particularly D2-receptor antagonists might antagonise the antiparkinsonian effects of levodopa-benserazide. Levodopa may reduce antipsychotic effects of these drugs. These drugs should be co-administered with caution. General anaesthesia with halothane: levodopa-benserazide should be discontinued 12-48 hours before surgical intervention requiring general anaesthesia with halothane as fluctuations in blood pressure and/or arrhythmias may occur. For general anesthesia with other anaesthetics see section 4.4. When Madopar CR is given with antacid preparations the bioavailability of levodopa is reduced, in comparison with conventional Madopar.
|Blood and Lymphatic System Disorder|
|frequency not known||Haemolytic anaemia|
|Metabolic and nutritional disorders|
|frequency not known||Decreased appetite|
|frequency not known||Dopamine dysregulation syndrome|
|Eating disorder symptom|
|Nervous System Disorders|
|frequency not known||Ageusia|
|Dyskinesia (choreiform and athetotic)|
|Fluctuations in therapeutic response|
|On and off phenomenon|
|Sudden onset of sleep|
|frequency not known||Arrhythmia|
|frequency not known||Orthostatic hypotension|
|frequency not known||Nausea|
|Oral mucosa discolouration|
|Liver and Biliary disorders|
|frequency not known||Transaminases increased|
|Alkaline phosphatase increased|
|Skin and subcutaneous tissue disorders|
|frequency not known||Pruritus|
|Musculoskeletal and connective tissue disorders|
|frequency not known||Restless legs syndrome|
|Renal and urinary disorders|
|frequency not known||Blood urea increased|
Impulse Control Disorders:- Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments containing levodopa including Madopar. (see section 4.4).
Nervous System Disorder: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.At later stages of the treatment, dyskinesia (e.g. choreiform or athetotic) may occur. These can usually be eliminated or be made tolerable by a reduction of dosage. With prolonged treatment, fluctuations in therapeutic response may also be encountered.They include freezing episodes, end-of-dose deterioration and the on-off effect. These can usually be eliminated or made tolerable by adjusting the dosage and by giving smaller single doses more frequently. An attempt at increasing the dosage again can subsequently be made in order to intensify the therapeutic effect. Levodopa-benserazide is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes.
Gastrointestinal disorders:− Undesirable gastrointestinal effects, which may occur mainly in the early stages of the treatment, can largely be controlled by taking Madopar with some food or liquid or by increasing the dose slowly. − Gastro-intestinal bleeding has been reported with levodopa therapy. − Isolated cases of loss or alterations of taste.
Vascular Disorders:Orthostatic disorders commonly improve following reduction of the Madopar dosage.
Musculoskeletal and connective tissue disorders:Restless Legs Syndrome: The development of augmentation (time shift of symptoms from the evening/night into the early afternoon and evening before taking the next nightly dose, is the most common adverse effect of dopaminergic long-term treatment.
Others:− Flushing and sweating have been reported with levodopa.
Investigations:Urine may be altered in colour; usually acquiring a red-tinge, which turns dark on standing. These changes are due to metabolites and are no cause for concern. Other body fluids or tissues may also be discoloured or stained including saliva, the tongue, teeth or oral mucosa.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard.
Symptoms and signsSymptoms 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.
TreatmentMonitor 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.
AbsorptionThe 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%.
DistributionLevodopa 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.
MetabolismThe 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.
EliminationIn 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%).
Capsule contents:Hypromellose (E464) Hydrogenated vegetable oil Calcium hydrogen phosphate, anhydrous (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)
Roche Products Limited
Hexagon Place, 6 Falcon Way, Shire Park, Welwyn Garden City, Hertfordshire, AL7 1TW
+44 (0)1707 338 297
+44 (0)1707 384555
+44 (0)1707 366 000
+44 (0)800 328 1629
+44 (0)800 731 5711