ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Comtess
200 mg film-coated tablets
Each film-coated tablet contains 200 mg entacapone.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
Brownish-orange, oval, biconvex film-coated tablet with "COMT" engraved on one side.
4.
Entacapone
is indicated as an adjunct to
standard preparations of levodopa/benserazide or
levodopa/carbidopa for use in adult patients with Parkinson’s disease and end-of-dose motor
fluctuations, who cannot be stabilised on those combinations.
Entacapone should only be used in combination with levodopa/benserazide or levodopa/carbidopa.
The prescribing information for these levodopa preparations is applicable to their concomitant use with
entacapone.
Posology
One 200 mg tablet is taken with each levodopa/dopa decarboxylase inhibitor dose. The maximum
recommended dose is 200 mg ten times daily, i.e. 2,000 mg of entacapone.
Entacapone enhances the effects of levodopa. Hence, to reduce levodopa-related dopaminergic adverse
reactions, e.g. dyskinesias, nausea, vomiting and hallucinations, it is often
necessary to adjust levodopa
dosage within the first days to first weeks after initiating entacapone
treatment. The daily dose of
levodopa should be reduced by about 10-30% by extending the dosing intervals and/or by reducing the
amount of levodopa per dose, according to the clinical condition of the patient.
If entacapone treatment is discontinued, it is necessary to adjust the dosing of other antiparkinsonian
treatments, especially levodopa, to achieve a sufficient level of control of the parkinsonian symptoms.
Entacapone increases the bioavailability of levodopa from standard levodopa/benserazide preparations
slightly (5-10%) more than from standard levodopa/carbidopa preparations. Hence, patients who are
taking standard levodopa/benserazide preparations may need a larger reduction of levodopa dose when
entacapone is initiated.
Renal impairment:
Renal insufficiency does not affect the pharmacokinetics of entacapone and there is
no need for dose adjustment. However, for patients who are receiving dialysis therapy, a longer dosing
interval may be considered (see section 5.2).
Hepatic impairment
: see section 4.3.
2
Elderly:
No dosage adjustment of entacapone
is required for elderly patients.
Pediatric population:
The safety and efficacy of Comtess in children below age 18 have not been
established. No data are available.
Method of administration
Entacapone
is administered orally and simultaneously with each levodopa/carbidopa or
levodopa/benserazide dose.
Entacapone can be taken with or without food (see section 5.2).
-
Hypersensitivity to the active substance
or to any of the excipients.
-
Hepatic impairment.
-
Phaeochromocytoma.
-
Concomitant use of entacapone and non-selective monoamine oxidase (MAO-A and MAO-B)
inhibitors (e.g. phenelzine, tranylcypromine).
-
Concomitant use of a selective MAO-A inhibitor plus a selective MAO-B inhibitor and entacapone
(see section 4.5).
-
A previous history of neuroleptic malignant syndrome (NMS) and/or non-traumatic
rhabdomyolysis.
Rhabdomyolysis secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS) has been
observed rarely in patients with Parkinson’s disease.
NMS, including rhabdomyolysis and hyperthermia, is characterised by motor symptoms (rigidity,
myoclonus, tremor), mental status changes (e.g. agitation, confusion, coma), hyperthermia, autonomic
dysfunction (tachycardia, labile blood pressure) and elevated serum creatine phosphokinase. In
individual cases, only some of these symptoms and/or findings may be evident.
Neither NMS nor rhabdomyolysis have been reported in association with entacapone treatment from
controlled trials in which entacapone was discontinued abruptly. Since the introduction into the
market, isolated cases of NMS have been reported, especially following abrupt reduction or
discontinuation of entacapone and other concomitant dopaminergic medicinal products. When
considered necessary, withdrawal of entacapone and other dopaminergic treatment should proceed
slowly, and if signs and/or symptoms occur despite a slow withdrawal of entacapone, an increase in
levodopa dosage may be necessary.
Entacapone therapy should be administered cautiously to patients with ischemic heart disease.
Because of its mechanism of action, entacapone
may interfere with the metabolism of medicinal
products containing a catechol group and potentiate their action. Thus, entacapone
should be
administered cautiously to patients being treated with medicinal products metabolised by catechol-O-
methyl transferase (COMT), e.g. rimiterole, isoprenaline, adrenaline, noradrenaline, dopamine,
dobutamine, alpha-methyldopa, and apomorphine (see also section 4.5).
Entacapone is always given as an adjunct to levodopa treatment. Hence, the precautions valid for
levodopa treatment should also be taken into account for entacapone treatment. Entacapone increases
the bioavailability of levodopa from standard levodopa/benserazide preparations 5-10% more than
from standard levodopa/carbidopa preparations. Consequently, adverse dopaminergic reactions may be
more frequent when entacapone is added to levodopa/benserazide treatment (see also section 4.8). To
reduce levodopa-related dopaminergic adverse reactions, it is often necessary to adjust levodopa
3
dosage within the first days to first weeks after initiating entacapone treatment, according to the
clinical condition of the patient (see sections 4.2 and 4.8).
Entacapone may aggravate levodopa-induced orthostatic hypotension. Entacapone should be given
cautiously to patients who are taking other medicinal products which may cause orthostatic
hypotension.
In clinical studies, undesirable dopaminergic effects, e.g. dyskinesia, were more common in patients
who received entacapone and dopamine agonists (such as bromocriptine), selegiline or amantadine
compared to those who received placebo with this combination. The doses of other antiparkinsonian
medicinal products may need to be adjusted when entacapone treatment is initiated.
Entacapone in association with levodopa has been associated with somnolence and episodes of sudden
sleep onset in patients with Parkinson’s disease and caution should therefore be exercised when
driving or operating machines (see also section 4.7).
For patients experiencing diarrhoea, a follow-up of weight is recommended in order to avoid potential
excessive weight decrease. Prolonged or persistent diarrhoea appearing during use of entacapone may
be a sign of colitis. In the event of prolonged or persistent diarrhoea, the drug should be discontinued
and appropriate medical therapy and investigations considered.
Pathological gambling, increased libido and hypersexuality have been reported in Parkinson’s disease
patients treated with dopamine agonists and other dopaminergic treatments such as entacapone in
association with levodopa.
For patients who experience progressive anorexia, asthenia and weight decrease within a relatively
short period of time, a general medical evaluation including liver function should be considered.
No interaction of entacapone with carbidopa has been observed with the recommended treatment
schedule. Pharmacokinetic interaction with benserazide has not been studied.
In single-dose studies in healthy volunteers, no interactions were observed between entacapone
and
imipramine or between entacapone
and moclobemide. Similarly, no interactions between entacapone
and selegiline were observed in repeated-dose studies in parkinsonian patients. However, the
experience of the clinical use of entacapone with several medicinal products, including MAO-A
inhibitors, tricyclic antidepressants, noradrenaline reuptake inhibitors such as desipramine, maprotiline
and venlafaxine, and medicinal products that are metabolised by COMT (e.g. catechol-structured
compounds: rimiterole, isoprenaline, adrenaline, noradrenaline, dopamine, dobutamine, alpha-
methyldopa, apomorphine, and paroxetine) is still limited. Caution should be exercised when these
medicinal products are used concomitantly with entacapone
(see also sections 4.3 and section 4.4).
Entacapone may be used with selegiline (a selective MAO-B inhibitor), but the daily dose of selegiline
should not exceed 10 mg.
Entacapone may form chelates with iron in the gastrointestinal tract. Entacapone and iron preparations
should be taken at least 2-3 hours apart (see section 4.8).
Entacapone binds to human albumin binding site II which also binds several other medicinal products,
including diazepam and ibuprofen. Clinical interaction studies with diazepam and non-steroidal anti-
inflammatory medicinal products have not been carried out. According to
in vitro
studies, significant
displacement is not anticipated at therapeutic concentrations of the medicinal products.
Due to its affinity to cytochrome P450 2C9
in vitro
(see section 5.2), entacapone may potentially
interfere with medicinal products with metabolism dependent on this isoenzyme, such as S-warfarin.
4
However, in an interaction study with healthy volunteers, entacapone did not change the plasma levels
of S-warfarin, while the AUC for R-warfarin increased on average by 18% [CI
90
11–26%]. The INR
values increased on average by 13% [CI
90
6–19%]. Thus, control of INR is recommended when
entacapone treatment is initiated for patients receiving warfarin.
No overt teratogenic or primary foetotoxic effects were observed in animal studies in which the
exposure levels of entacapone were markedly higher than the therapeutic exposure levels. As there is
no experience in pregnant women, entacapone should not be used during pregnancy.
In animal studies entacapone was excreted in milk. The safety of entacapone
in infants is unknown.
Women should not breast-feed during treatment with entacapone.
Comtess in association with levodopa may have major influence on the ability to drive and use
machines. Entacapone may, together with levodopa, cause dizziness and symptomatic orthostatism.
Therefore, caution should be exercised when driving or using machines.
Patients being treated with entacapone in association with levodopa and presenting with somnolence
and/or sudden sleep onset episodes must be instructed 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 have resolved (see also section 4.4).
The most frequent adverse reactions caused by entacapone relate to the increased dopaminergic
activity and occur most commonly at the beginning of the treatment. Reduction of levodopa dosage
decreases the severity and frequency of these reactions. The other major class of adverse reactions are
gastrointestinal symptoms, including nausea, vomiting, abdominal pain, constipation and diarrhoea.
Urine may be discoloured reddish-brown by entacapone, but this is a harmless phenomenon.
Usually the adverse reactions caused by entacapone are mild to moderate. In clinical studies the most
common adverse reactions leading to discontinuation of entacapone
treatment have been
gastrointestinal symptoms (e.g. diarrhoea, 2.5%) and increased dopaminergic adverse reactions of
levodopa (e.g. dyskinesias, 1.7%).
Dyskinesias (27%), nausea (11%), diarrhoea (8%), abdominal pain (7%) and dry mouth (4.2%) were
reported significantly more often with entacapone than with placebo in pooled data from clinical
studies involving 406 patients taking the medicinal product and 296 patients taking placebo.
Some of the adverse reactions, such as dyskinesia, nausea, and abdominal pain, may be more common
with the higher doses (1,400 to 2,000 mg per day) than with the lower doses of entacapone.
The following adverse reactions, listed below in Table 1, have been accumulated both from clinical
studies with entacapone and since the introduction of entacapone into the market.
5
Table 1. Adverse drug reactions*
Psychiatric disorders
Common:
Insomnia, hallucinations, confusion, paroniria
Very rare:
Agitation
Nervous system disorders
Very common: Dyskinesia
Common:
Parkinsonism aggravated, dizziness, dystonia, hyperkinesia
Cardiac disorders**
Common:
Ischemic heart disease events other than myocardial
infarction (e.g. angina pectoris)
Uncommon:
Myocardial infarction
Gastrointestinal disorders
Very common: Nausea
Common:
Diarrhoea, abdominal pain, dry mouth, constipation, vomiting
Not known:
Anorexia
Hepatobiliary disorders
Rare: Hepatic function tests abnormal
Not known: Hepatitis with mainly cholestatic features (see section 4.4.)
Skin and subcutaneous tissue disorders
Rare:
Erythematous or maculopapular rash
Very rare:
Urticaria
Not known:
Skin, hair, beard and nail discolorations
Renal and urinary disorders
Very common: Urine discoloration
General disorders and administration site conditions
Common:
Fatigue, sweating increased, fall
Very rare:
Weight decrease
*
Adverse reactions are ranked under headings of frequency, the most frequent first, using the
following convention: 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, since no valid estimate can be derived from clinical trials
or epidemiological studies).
**
The incidence rates of myocardial infarction and other ischemic heart disease events (0.43%
and 1.54%, respectively) are derived from an analysis of 13 double-blind studies involving
2082 patients with end-of-dose motor fluctuations receiving entacapone.
Entacapone in association with levodopa has been associated with isolated cases of excessive daytime
somnolence and sudden sleep onset episodes.
Parkinson’s disease patients treated with dopamine agonists and other dopaminergic treatments such
as entacapone in association with levodopa, especially at high doses, have been reported as exhibiting
signs of pathological gambling, increased libido and hypersexuality, which were generally reversible
upon reduction of the dose or treatment discontinuation.
Isolated cases of NMS have been reported following abrupt reduction or discontinuation of entacapone
and other dopaminergic treatments.
Isolated cases of rhabdomyolysis have been reported.
The post-marketing data include isolated cases of overdose in which the reported highest daily dose of
entacapone has been 16,000 mg. The acute symptoms and signs in these cases of overdose included
6
Very rare:
Colitis
confusion, decreased activity, somnolence, hypotonia, skin discolouration and urticaria. Management
of acute overdose is symptomatic.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
other dopaminergic agents, ATC code:
N04BX02.
Entacapone belongs to a new therapeutic class, catechol-O-methyl transferase (COMT) inhibitors. It is
a reversible, specific, and mainly peripherally acting COMT inhibitor designed for concomitant
administration with levodopa preparations. Entacapone decreases the metabolic loss of levodopa to 3-
O-methyldopa (3-OMD) by inhibiting the COMT enzyme. This leads to a higher levodopa AUC. The
amount of levodopa available to the brain is increased. Entacapone thus prolongs the clinical response
to levodopa.
Entacapone inhibits the COMT enzyme mainly in peripheral tissues. COMT inhibition in red blood
cells closely follows the plasma concentrations of entacapone, thus clearly indicating the reversible
nature of COMT inhibition.
Clinical studies
In two phase III double-blind studies in a total of 376 patients with Parkinson’s disease and end-of-
dose motor fluctuations, entacapone or placebo was given with each levodopa/dopa decarboxylase
inhibitor dose. The results are given in Table 2. In study I, daily ON time (hours) was measured from
home diaries and in study II, the proportion of daily ON time.
Table 2. Daily ON time (Mean ±SD)
Study I: Daily On time (h)
Entacapone (n=85)
Placebo (n=86)
Difference
Baseline
9.3±2.2
9.2±2.5
Week 8-24
10.7±2.2
9.4±2.6
1 h 20 min
(8.3%)
CI
95%
45 min, 1 h 56 min
Study II: Proportion of daily On time (%)
Entacapone (n=103) Placebo (n=102)
Difference
Baseline
60.0±15.2
60.8±14.0
Week 8-24
66.8±14.5
62.8±16.80
4.5% (0 h 35 min)
CI
95%
0.93%, 7.97%
There were corresponding decreases in OFF time.
The % change from baseline in OFF time was –24% in the entacapone group and 0% in the placebo
group in study I. The corresponding figures in study II were –18% and –5%.
5.2 Pharmacokinetic properties
General characteristics of the active substance
Absorption
There are large intra- and interindividual variations in the absorption
of entacapone
.
The peak concentration (C
max
) in plasma is usually reached about one hour after ingestion of a 200 mg
entacapone tablet. The substance is subject to extensive first-pass metabolism. The bioavailability of
7
entacapone is about 35% after an oral dose. Food does not affect the absorption of entacapone to any
significant extent.
Distribution
After absorption from the gastrointestinal
tract, entacapone is rapidly distributed to the peripheral
tissues with a distribution volume of 20 litres at steady state (Vd
ss
). Approximately 92 % of the dose is
eliminated during ß-phase with a short elimination half-life of 30 minutes. The total clearance of
entacapone is about 800 ml/min.
Entacapone is extensively bound to plasma
proteins, mainly to albumin. In human plasma the unbound
fraction is about 2.0% in the therapeutic concentration range. At therapeutic concentrations,
entacapone does not displace other extensively bound substances (e.g. warfarin, salicylic acid,
phenylbutazone, or diazepam), nor is it displaced to any significant extent by any of these substances at
therapeutic or higher concentrations.
Metabolism
A small amount of entacapone, the
(E)
-isomer, is converted to its
(Z)
-isomer. The
(E)
-isomer accounts
for 95% of the AUC of entacapone. The
(Z)
-isomer and traces of other metabolites account for the
remaining 5%.
Data from
in vitro
studies using human liver microsomal preparations indicate that entacapone
inhibits cytochrome P450 2C9 (IC
50
∼4 µM). Entacapone showed little or no inhibition of other types
of P450 isoenzymes (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19) (see section
4.5).
Elimination
The elimination of entacapone
occurs mainly by non-renal metabolic routes. It is estimated that 80-
90% of the dose is excreted in faeces, although this has not been confirmed in man. Approximately 10-
20% is excreted in urine. Only traces of entacapone are found unchanged in urine. The major part
(95%) of the product excreted in urine is conjugated with glucuronic acid. Of the metabolites found in
urine only about 1% have been formed through oxidation.
Characteristics in patients
The pharmacokinetic properties of entacapone are similar in both young and elderly adults. The
metabolism of the medicinal product is slowed in patients with mild to moderate liver insufficiency
(Child-Pugh Class A and B), which leads to an increased plasma concentration of entacapone in both
the absorption and elimination phases (see section 4.3). Renal impairment does not affect the
pharmacokinetics of entacapone. However, a longer dosing interval may be considered for patients
who are receiving dialysis therapy.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. In repeated dose
toxicity studies, anaemia most likely due to iron chelating properties of entacapone was observed.
Regarding reproduction toxicity, decreased foetal weight and a slightly delayed bone development
were noticed in rabbits at systemic exposure levels in the therapeutic range.
6.
6.1 List of excipients
Tablet core:
Microcrystalline cellulose
Croscarmellose sodium
8
Povidone
Magnesium stearate
Film-coating:
Polyvinyl alcohol, partly hydrolysed
Talc
Macrogol
Soybean lecithin
Yellow iron oxide (E 172)
Red iron oxide (E 172)
Titanium dioxide (E 171)
6.2 Incompatibilities
Not applicable.
6.3 Shelf- life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
White high-density polyethylene (HDPE) bottles with white tamper proof polypropylene (PP) closures
containing 30, 60, 100 or 175 tablets.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal
No special requirements.
7.
Orion Corporation
Orionintie 1
FI-02200 Espoo
Finland
8.
EU/1/98/082/001-003
EU/1/98/082/005
9.
Date of first authorisation: 16.09.98
Date of last renewal: 3.9.2008
10.
9
Detailed information on this product is available on the website of the European Medicines Agency
(EMA)
http://www.ema.europa.eu
10
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
11
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Orion Corporation
Orionintie 1
FI-02200 Espoo
Finland
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
Not applicable.
12
ANNEX III
LABELLING AND PACKAGE LEAFLET
13
A. LABELLING
14
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
CARTON AND BOTTLE LABEL
1.
Comtess 200 mg film-coated tablets
entacapone
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 200 mg of entacapone.
3.
LIST OF EXCIPIENTS
4.
30 film-coated tablets
60 film-coated tablets
100 film-coated tablets
175 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
15
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Orion Corporation
Orionintie 1
FI-02200 Espoo
Finland
EU/1/98/082/001
30 film-coated tablets
EU/1/98/082/002
100 film-coated tablets
EU/1/98/082/005
175 film-coated tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
comtess 200 mg [folding box only]
16
EU/1/98/082/003
60 film-coated tablets
B. PACKAGE LEAFLET
17
PACKAGE LEAFLET: INFORMATION FOR THE USER
Comtess 200 mg film-coated tablets
Entacapone
Read all of this leaflet carefully before you start taking this medicine.
•
Keep this leaflet. You may need to read it again.
•
If you have any further questions, ask your doctor or pharmacist.
•
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if
their symptoms are the same as yours.
•
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What Comtess is and what it is used for
2.
Before you take Comtess
4.
Possible side effects
5.
How to store Comtess
6.
Further information
1.
WHAT COMTESS IS AND WHAT IT IS USED FOR
Comtess tablets contain entacapone and are used together with levodopa to treat Parkinson’s disease.
Comtess aids levodopa in relieving the symptoms of Parkinson's disease. Comtess has no effect on
relieving the symptoms of Parkinson´s disease unless taken with levodopa.
2.
BEFORE YOU TAKE COMTESS
Do not take
Comtess
•
if you are allergic (hypersensitive) to entacapone or any of the other ingredients of Comtess;
•
if you have a tumour of the adrenal gland (known as pheochromocytoma; this may increase the
risk of severe high blood pressure);
if you are taking certain antidepressants (ask your doctor or pharmacist whether your
antidepressive medicine can be taken together with Comtess);
•
if you have liver disease;
•
if you have ever suffered from a rare reaction to antipsychotic medicines called neuroleptic
malignant syndrome (NMS). See section 4 Possible side effects for the characteristics of NMS;
•
if you have ever suffered from a rare muscle disorder called rhabdomyolysis which was not
caused by injury.
Take special care with Comtess
Talk to your doctor if any of the following applies to you:
•
if you have ever had a heart attack or any other diseases of the heart
•
if you are taking a medicine which may cause dizziness or light-headedness (low blood
pressure) when rising from a chair or bed;
•
if you experience prolonged diarrhoea consult your doctor as it may be a sign of inflammation
of the colon
•
if you experience diarrhoea, monitoring of your weight is recommended in order to avoid
potentially excessive weight loss;
•
if you experience excessive gambling or excessive sexual activity.
•
if you experience increasing loss of appetite, weakness, exhaustion and weight loss within a
relatively short period of time, a general medical evaluation including liver function should be
considered.
18
3.
How to take Comtess
•
As Comtess tablets will be taken together with other levodopa medicines, please also read the package
leaflets of these medicines carefully.
The dose of other medicines to treat Parkinson’s disease may need to be adjusted when you start
taking Comtess. Follow the instructions that your doctor has given you.
Neuroleptic Malignant Syndrome (NMS) is a serious but rare reaction to certain medicines, and may
occur especially when Comtess and other medicines to treat Parkinson’s disease are suddenly stopped
or the dose is suddenly reduced. For the characteristics of NMS see Section 4 Possible side effects.
Your doctor may advise you to slowly discontinue the treatment with Comtess and other medicines to
treat Parkinson’s disease.
Comtess taken with levodopa may cause drowsiness and may cause you to sometimes suddenly fall
asleep. If this happens, you should not drive or use any tools or machines (see Driving and using
machines).
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken other medicines,
including medicines obtained without a prescription or herbal medicines. In particular please tell your
doctor if you are taking any of the following:
•
rimiterole, isoprenaline, adrenaline, noradrenaline, dopamine, dobutamine, alpha-
methyldopa, apomorphine;
•
antidepressants including desipramine, maprotiline, venlafaxine, paroxetine;
•
warfarin used to thin the blood;
•
iron supplements. Comtess may make it harder for you to digest iron. Therefore, do not take
Comtess and iron supplements at the same time. After taking one of them, wait at least 2 to 3
hours before taking the other.
Pregnancy and breast-feeding
Do not use Comtess during pregnancy or if you are breast-feeding. Ask your doctor or pharmacist for
advice before taking any medicine.
Driving and using machines
Comtess taken together with levodopa may lower your blood pressure, which may make you feel
light-headed or dizzy. Be particularly careful when you drive or when you use tools or machinery.
In addition, Comtess taken with levodopa may make you feel very drowsy, or cause you to
sometimes suddenly fall asleep.
Do not drive or operate machinery if you experience these side effects.
3.
HOW TO TAKE COMTESS
Always take Comtess exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
Comtess is taken together with medicines containing levodopa (either levodopa/carbidopa preparations
or levodopa/benserazide preparations). You may also use other medicines to treat Parkinson’s disease
at the same time.
The usual dose of Comtess is one 200 mg tablet with each levodopa dose. The maximum
recommended dose is 10 tablets per day, i.e. 2,000 mg of Comtess.
19
If you are receiving dialysis for renal insufficiency, your doctor may tell you to increase the time
between doses.
Use in children
Experience with Comtess in patients under 18 years is limited. Therefore, the use of Comtess in
children cannot be recommended.
If you take more Comtess than you should
In the event of an overdose, consult your doctor, pharmacist or the nearest hospital immediately.
If you forget to take Comtess
If you forget to take the Comtess tablet with your levodopa dose, you should continue the treatment by
taking the next Comtess
tablet with your next levodopa dose.
Do not take a double dose to make up for a forgotten tablet.
If you stop taking Comtess
Do not stop taking Comtess unless your doctor tells you to.
When stopping your doctor may need to re-adjust the dosage of your other medicines to treat
Parkinson´s disease. Suddenly stopping Comtess and other medicines to treat Parkinson´s disease
may result in unwanted side effects. See Section 2 Take special care.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Comtess can cause side effects, although not everybody gets them. Usually side
effects caused by Comtess
are mild to moderate.
Some of the side effects are often caused by the increased effects of levodopa therapy and are most
common at the start of treatment. If you experience such effects at the start of treatment with
Comtess you should contact your doctor who may decide to adjust your dosage of levodopa.
The frequencies are defined as:
Very common (
affects more than 1 patient in 10
)
Common (
affects 1 to 10 patients in 100
)
Uncommon (
affects 1 to 10 patients in 1,000
)
Rare (
affects 1 to 10 patients in 10,000
)
Very rare (
affects less than 1 patient in 10,000
)
Not known (
frequency cannot be estimated from the available data
).
Very common:
•
Uncontrollable movements with difficulty in performing voluntary movements (dyskinesias);
•
feeling sick (nausea);
•
harmless reddish-brown discoloration of urine.
Common:
•
Excessive movements (hyperkinesias), worsening of symptoms of Parkinson´s disease, prolonged
muscle cramps (dystonia);
•
being sick (vomiting), diarrhoea, abdominal pain, constipation, dry mouth;
•
dizziness, tiredness, increased sweating, fall ;
•
hallucinations (seeing/hearing/feeling/smelling things that are not really there), sleeplessness,
vivid dreams, and confusion.
•
heart or artery disease events (e.g. chest pain).
20
Uncommon:
•
Heart attack.
Rare:
•
Rashes;
•
abnormal results in liver function test.
Very rare:
•
Agitation;;
•
decreased appetite, weight loss;;
•
hives.
Not known:
•
Inflammation of the colon (colitis), inflammation of the liver (hepatitis) with yellowing of the
skin and whites of the eyes;
•
discolouration of skin, hair, beard and nails.
When Comtess is given at higher doses:
In doses of 1,400 to 2,000 mg per day, the following side effects are more common:
•
Uncontrollable movements;
•
nausea;
•
abdominal pain.
Other important side effects which may occur:
•
Comtess taken with levodopa may rarely make you feel very drowsy during the day, and cause you
to suddenly fall asleep;
•
Neuroleptic Malignant Syndrome (NMS) is a rare severe reaction to medicines used to treat
disorders of the nervous system. It is characterised by stiffness, muscle twitching, shaking,
agitation and confusion, coma, high body temperature, increased heart rate, and unstable blood
pressure;
•
a rare severe muscle disorder (rhabdomyolysis) which causes pain, tenderness and weakness of the
muscles and may lead to kidney problems .
•
behavioural changes may occur such as an urge to gamble (pathological gambling) or increased
sexual desire and urges (increased libido and hypersexuality)
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor.
5.
HOW TO STORE COMTESS
Keep out of the reach and sight of children.
Do not use Comtess after the expiry date which is stated on the carton and on the bottle label. The
expiry date refers to the last day of that month.
This medicinal product does not require any special storage conditions.
6.
FURTHER INFORMATION
What Comtess contains
-
The active substance is entacapone. Each tablet contains 200 mg of entacapone.
21
-
The other ingredients in the tablet core are microcrystalline cellulose, croscarmellose sodium,
povidone and magnesium stearate.
-
The film-coating contains partly hydrolysed polyvinyl alcohol, talc, macrogol, soybean lecithin,
yellow iron oxide (E 172), red iron oxide (E 172) and titanium dioxide (E 171).
What Comtess looks like and contents of the pack
Comtess 200 mg film-coated tablets are brownish-orange, oval tablets with "COMT" engraved on one
side. They are packed in bottles.
There are four different pack sizes (bottles containing 30, 60, 100 or 175 tablets). Not all pack sizes
may be marketed.
Marketing Authorisation Holder and Manufacturer:
Orion Corporation
Orionintie 1
FI-02200 Espoo
Finland
For further information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
Belgique/België/Belgien
Orion Corporation
Tél./Tel: +358 10 4261
Luxembourg/Luxemburg
Orion Corporation
Tél./Tel: +358 10 4261
България
Orion Corporation
Тел.: +358 10 4261
Magyarország
Orion Corporation
Tel.: +358 10 4261
Česká republika
Orion Corporation
Tel: +358 10 4261
Malta
Orion Corporation
Tel: +358 10 4261
Danmark
Orion Pharma A/S
Tlf: +45 49 12 66 00
Nederland
Orion Corporation
Tel: +358 10 4261
Deutschland
Orion Pharma GmbH
Tel: +49 40 899 689-0
Norge
Orion Pharma AS
Tlf.: +47 40 00 42 10
Eesti
Orion Pharma Eesti OÜ
Tel: +372 6 616 863
Österreich
Orion Corporation
Tel: +358 10 4261
Ελλάδα
Orion Corporation
Tηλ: +358 10 4261
Polska
Orion Oyj S.A. Przedstawicielstwo w Polsce
Tel.: +48 22 8333177, 8321036
España
Orion Corporation
Tel: +358 10 4261
Portugal
Orion Corporation
Tel: +358 10 4261
France
Orion Corporation
Tél.: +358 10 4261
România
Orion Corporation
Tel: +358 10 4261
22
Ireland
Orion Pharma (Ireland) Ltd.
c/o Allphar Services Ltd.
Tel: +353 1 428 7777
Slovenija
Orion Corporation
Tel: +358 10 4261
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Orion Corporation
Tel: +358 10 4261
Italia
Orion Corporation
Tel: +358 10 4261
Suomi/Finland
Orion Corporation
Puh./Tel: +358 10 4261
Κύπρος
Orion Corporation
Tηλ: +358 10 4261
Sverige
Orion Pharma AB
Tel: +46 8 623 6440
Latvija
Orion Corporation
Orion Pharma pārstāvniecība
Tel: +371 7455563
United Kingdom
Orion Pharma (UK) Ltd.
Tel: +44 1635 520 300
Lietuva
UAB Orion Pharma
Tel: +370 5 276 9499
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicine’s Agency (EMA) web
site: http://www.ema.europa.eu
23
Source: European Medicines Agency
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