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Madopar 50mg/12.5mg Hard Capsules


Each capsule contains 50.0 mg Levodopa and 12.5 mg Benserazide (as
benserazide hydrochloride)
For excipients, see section 6.1


Capsules, hard
Light grey opaque body and a powder blue opaque cap, imprinted with the
name 'Roche' in black ink on both sides.




Therapeutic indications
Parkinsonism - idiopathic post-encephalitic
Previous neurosurgery is not a contra-indication to Madopar.


Posology and method of administration
Dosage and administration are variable and no more than a guide can be given.
Patients not previously treated with levodopa
The recommended initial dose is one capsule or dispersible tablet of Madopar
50mg/12.5mg three or four times daily. If the disease is at an advanced stage,
the starting dose should be one capsule or dispersible tablet of Madopar
100mg/25mg three times daily.
The daily dosage should then be increased by one capsule or dispersible tablet
of Madopar 100mg/25mg, or their equivalent, once or twice weekly until a full
therapeutic effect is obtained, or side-effects supervene.
In some elderly patients, it may suffice to initiate treatment with one capsule
or dispersible tablet of Madopar 50mg/12.5mg once or twice daily, increasing
by one capsule or dispersible tablet every third or fourth day.

The effective dose usually lies within the range of four to eight capsules or
dispersible tablets of Madopar 100mg/25mg (two to four capsules of Madopar
200mg/50mg) daily in divided doses, most patients requiring no more than six
capsules or dispersible tablets of Madopar 100mg/25mg daily.
Optimal improvement is usually seen in one to three weeks but the full
therapeutic effect of Madopar may not be apparent for some time. It is
advisable, therefore, to allow several weeks to elapse before contemplating
dosage increments above the average dose range. If satisfactory improvement
is still not achieved, the dose of Madopar may be increased but with caution. It
is rarely necessary to give more than ten capsules or dispersible tablets of
Madopar 100 mg /25mg (five capsules of Madopar 200mg/50mg) per day.
Treatment should be continued for at least six months before failure is
concluded from the absence of a clinical response.
Madopar 50mg/12.5mg capsules or dispersible tablets may be used to facilitate
adjustment of dosage to the needs of the individual patient. Patients who
experience fluctuations in response may be helped by dividing the dosage into
smaller, more frequent doses with the aid of Madopar 50mg/12.5mg capsules
or dispersible tablets without, however, altering the total daily dose.
Madopar 200mg/50mg capsules are only for maintenance therapy once the
optimal dosage has been determined using Madopar 100mg/25mg capsules or
dispersible tablets.
Patients previously treated with levodopa
The following procedure is recommended: Levodopa alone should be
discontinued and Madopar started on the following day. The patient should be
initiated on a total of one less Madopar 100mg/25mg capsule or dispersible
tablet daily than the total number of 500mg levodopa tablets or capsules
previously taken (for example, if the patient had previously taken 2g levodopa
daily, then he should start on three capsules or dispersible tablets Madopar
100mg/25mg daily on the following day). Observe the patient for one week
and then, if necessary, increase the dosage in the manner described for new
Patients previously treated with other levodopa/decarboxylase inhibitor
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 Madopar therapy the
following morning. The initial Madopar dose should be one capsule or
dispersible tablet of Madopar 50mg/12.5mg three or four times daily. 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 Madopar. Existing treatment
with other anti-Parkinsonian drugs, e.g. anticholinergics or amantadine, should
be continued during initiation of Madopar therapy. However, as treatment with
Madopar proceeds and the therapeutic effect becomes apparent, the dosage of
the other drugs may need to be reduced or the drugs gradually withdrawn.

Although there may be an age-related decrease in tolerance to levodopa in the
elderly, Madopar appears to be well-tolerated and side-effects are generally
not troublesome.
Not to be given to patients under 25 years of age: therefore, no dosage
recommendations are made for the administration of Madopar to children.
Madopar capsules are for oral administration. They should be taken with, or
immediately after, meals.



Madopar must not be given to patients with known hypersensitivity to levodopa or
benserazide or any of the excipients.
Madopar must not be given in conjunction with non-selective monoamine oxidase
(MAO) inhibitors. However, selective MAO-B inhibitors, such as selegiline and
rasagiline or selective MAO-A inhibitors, such as moclobemide, are not
contraindicated. Combination of MAO-A and MAO-B inhibitors is equivalent to nonselective MAO inhibition, and hence this combination should not be given
concomitantly with Madopar (see section 4.5).
Madopar must not be given to patients with decompensated endocrine (e.g.
phaeochromocytoma, hyperthyroidism, Cushing syndrome), renal (except RLS
patients on dialysis) or hepatic function, cardiac disorders (e.g. severe cardiac
arrhythmias and cardiac failure), psychiatric diseases with a psychotic component or
closed angle glaucoma (it may be used in wide-angle glaucoma provided that the
intra-ocular pressure remains under control).
Madopar must not be given to patients less than 25 years old (skeletal development
must be complete).
Madopar must 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 (as advised by the prescribing physician).
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 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.

Hypersensitivity reactions may occur in susceptible individuals.
Regular measurement of intraocular pressure is advisable in patients with open-angle
glaucoma, as levodopa theoretically has the potential to raise intraocular pressure.
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.
Care should be exercised when Madopar is administered to patients with pre-existing
coronary artery disorders, cardiac arrhythmias or cardiac failure (see also section 4.3).
Cardiac function should be monitored with particular care in such patients during the
period of treatment initiation and regularly thereafter throughout treatment.
Close monitoring of patients with risk factors for (e.g. elderly patients, concomitant
antihypertensives or other medication with orthostatic potential) or a history of
orthostatic hypotension is recommended especially at the beginning of treatment or at
dose increases.
Madopar has been reported to induce decreases in blood count (e.g. haemolytic
anaemia, thrombocytopenia and leukopenia). In a few instances agranulocytosis and
pancytopenia have been reported in which the association with Madopar could neither
be established, nor be completely ruled out. Therefore, periodical evaluation of blood
count should be performed during treatment.
Depression can be part of the clinical picture in patients with Parkinson’s disease and
RLS and may also occur in patients treated with Madopar. All patients should be
carefully monitored for psychological changes and depression with or without suicidal
Madopar may induce dopamine dysregulation syndrome resulting in excessive use of
the product. A small subgroup of PD patients suffer from cognitive and behavioural
disturbance that can be directly attributed to taking increasing quantities of medication
against medical advice and well beyond the doses required to treat their motor
If a patient requires a general anaesthetic, the normal Madopar regimen should be
continued as close to the surgery as possible, except in the case of halothane. In general
anaesthesia with halothane Madopar should be discontinued 12 - 48 hours before
surgical intervention as fluctuations in blood pressure and/or arrhythmias may occur in
patients on Madopar therapy. Madopar therapy may be resumed following surgery; the
dosage should be increased gradually to the preoperative level.
If a patient has to undergo emergency surgery, when Madopar has not been withdrawn,
anaesthesia with halothane should be avoided.

Madopar must not be withdrawn abruptly. Abrupt withdrawal of the preparation may
result in a neuroleptic malignant-like syndrome (hyperpyrexia and muscular rigidity,
possibly psychological changes and elevated serum creatinine phosphokinase,
additional signs in severe cases may include myoglobinuria, rhabdomyolysis – and
acute renal failure) which may be life-threatening. Should a combination of such
symptoms and signs occur, the patient should be kept under medical surveillance, if
necessary, hospitalized and rapid and appropriate symptomatic treatment given. This
may include resumption of Madopar therapy after an appropriate evaluation.
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 (see section 4.7).
Impulse control disorders
Patients 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 tests
Periodical evaluation of hepatic, haemopoietic, renal and cardiovascular function and
blood count should be performed during treatment.
Patients with diabetes should undergo frequent blood sugar tests and the dosage of
anti-diabetic agents should be adjusted to blood sugar levels.
Patients who improve on Madopar therapy should be advised to resume normal
activities gradually as rapid mobilisation may increase the risk of injury.
Malignant melanoma
Epidemiological 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).


Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions
Co-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.
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
Pharmacodynamic interactions
Concomitant 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
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 1248 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.

Fertility, pregnancy and lactation
Madopar is contra-indicated in pregnancy and in women of childbearing potential in
the absence of adequate contraception (see section 4.3 and section 5.3).
Since it is not known whether benserazide passes into breast milk, mothers requiring
Madopar treatment should not nurse their infants, since the occurrence of skeletal
malformations in the infants cannot be excluded.

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).


Undesirable effects

The following undesirable effects have been reported (frequency not known, cannot
be estimated from the available data) to occur when levodopa- benserazide is
Frequency categories are as follows:
Very common: ≥1/10;
Common ≥1/100 to <1/10;
Uncommon ≥1/1,000 to <1/100
Rare (≥1/10,000 to <1/1,000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data)
Blood and Lymphatic System Disorder
frequency not known
Haemolytic anaemia
Metabolic and nutritional disorders
frequency not known
Decreased appetite
Psychiatric Disorders
frequency not known
Dopamine dysregulation syndrome
Confusional state
Agitation *
Pathological gambling
Increased libido
Compulsive shopping
Binge eating
Eating disorder symptom
Nervous System Disorders
frequency not known
Dyskinesia (choreiform and athetotic)
Fluctuations in therapeutic response
Freezing phenomenon
End-of-dose deterioration
On and off phenomenon

Sudden onset of sleep
Cardiac disorders
frequency not known
Vascular Disorders
frequency not known
Gastrointestinal disorders
frequency not known

Liver and Biliary disorders
frequency not known

Orthostatic hypotension

Saliva discolouration
Tongue discolouration
Tooth discolouration
Oral mucosa discolouration
Transaminases increased
Alkaline phosphatase increased
Gamma-glutamyltransferase increased

Skin and subcutaneous tissue disorders
frequency not known
Musculoskeletal and connective tissue disorders
frequency not known
Restless legs syndrome
Renal and urinary disorders
frequency not known
Blood urea increased

*These events may occur particularly in elderly patients and in patients with a history of such

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. Levodopabenserazide 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.
− Flushing and sweating have been reported with levodopa.
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 reactions
Reporting 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:

Symptoms and signs
Symptoms and signs of overdose 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).

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).




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 gastrointestinal side-effects, a
more rapid response at the initiation of therapy and a simpler dosage regimen.
Madopar is a combination of levodopa and benserazide in the ratio 4:1 which
in clinical trials has been shown to be the most satisfactory.
Like every replacement therapy, chronic treatment with Madopar will be


Pharmacokinetic properties
Low levels of endogenous levodopa are detectable in pre-dose blood samples.
After oral administration of Madopar, levodopa and benserazide are rapidly
absorbed, mainly in the upper regions of the small intestine and absorption
there is independent of the site. Interaction studies indicate that a higher
proportion of levodopa is absorbed when administered in combination with
benserazide, compared with levodopa administered alone. Maximum plasma
concentrations of levodopa are reached approximately one hour after ingestion
of Madopar. The absolute bioavailability of levodopa from standard Madopar
is approximately 98%.
The maximum plasma concentration of levodopa and the extent of absorption
(AUC) increase proportionally with dose (50 – 200mg levodopa). The peak
levodopa plasma concentration is 30% lower and occurs later when Madopar
is administered after a standard meal. Food intake generally reduces the extent
of levodopa absorption by 15% but this can be variable.
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.

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 0-methylation, forming 3-0methyldopa, 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 3-0methyldopa.
Benserazide is hydroxylated to trihydroxybenzylhydrazine in the intestinal
mucosa and the liver. This metabolite is a potent inhibitor of the aromatic
amino acid decarboxylase.
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 430ml/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%).


Preclinical safety data
See 4.6 Pregnancy and lactation




List of excipients
Capsule contents:
Microcrystalline cellulose (E460)
Povidone K90 (E1201)
Talc (E553b)
Magnesium stearate (E572)
Capsule shell:
Indigo carmine (E132)
Titanium dioxide (E171)
Iron oxide (E172)
Printing Ink:
Black iron oxide (E172)


None known


Shelf life
3 years


Special precautions for storage
Do not store above 25ºC. Store in the original package. Keep bottle tightly


Nature and contents of container
Amber glass bottles with HDPE cap and integral desiccant containing 100


Special precautions for disposal
No special requirements


Roche Products Limited
6 Falcon Way
Shire Park
Welwyn Garden City
United Kingdom


PL 00031/0125





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Source: Medicines and Healthcare Products Regulatory Agency

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