ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Stalevo 50 mg/12.5 mg/200 mg film-coated tablets
Each tablet contains 50 mg of levodopa, 12.5 mg of carbidopa and 200 mg of entacapone.
Excipient:
Each tablet contains 1.2 mg of sucrose
.
For a full list of excipients, see section 6.1.
Film-coated tablet
Brownish or greyish red, round, convex, unscored film-coated tablets marked with ‘LCE 50’ on one
side.
Stalevo is indicated for the treatment of adult patients with Parkinson’s disease and end-of-dose motor
fluctuations not stabilised on levodopa/dopa decarboxylase (DDC) inhibitor treatment.
Each tablet is to be taken orally either with or without food (see section 5.2). One tablet contains one
treatment dose and the tablet may only be administered as whole tablets.
The optimum daily dose must be determined by careful titration of levodopa in each patient. The daily
dose should be preferably optimised using one of the six available tablet strengths
(50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg 100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg
150 mg/37.5 mg/200 mg or 200 mg/50 mg/200 mg levodopa/carbidopa/entacapone).
Patients should be instructed to take only one Stalevo tablet per dose administration. Patients
receiving less than 70-100 mg carbidopa a day are more likely to experience nausea and vomiting.
While the experience with total daily dose greater than 200 mg carbidopa is limited, the maximum
recommended daily dose of entacapone is 2,000 mg and therefore the maximum dose is 10 tablets per
day for the Stalevo strengths of 50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg
100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg and 150 mg/37.5 mg/200 mg. Ten tablets of Stalevo
150 mg/37.5 mg/200 mg equals 375 mg of carbidopa a day. According to this daily carbidopa dose,
the maximum recommended daily Stalevo 200 mg/50 mg/200 mg dose is 7 tablets per day.
Usually Stalevo is to be used in patients who are currently treated with corresponding doses of
standard release levodopa/DDC inhibitor and entacapone.
How to transfer patients taking levodopa/DDC inhibitor (carbidopa or benserazide) preparations and
entacapone tablets to Stalevo
a
. Patients who are currently treated with entacapone and with standard release levodopa/carbidopa in
doses equal to Stalevo tablet
strengths can be directly transferred to corresponding Stalevo tablets.
2
For example, a patient taking one tablet of 50 mg/12.5 mg of levodopa/carbidopa with one tablet of
entacapone 200 mg four times daily can take one 50 mg/12.5 mg/200 mg Stalevo tablet four times
daily in place of their usual levodopa/carbidopa and entacapone doses.
b.
When initiating Stalevo therapy for patients currently treated with entacapone and
levodopa/carbidopa in doses not equal to Stalevo 50 mg/12.5 mg/200 mg, (or 75 mg/18.75 mg/200 mg
or 100 mg/25 mg/200 mg or 125 mg/31.25 mg/200 mg or 150 mg/37.5 mg/200 mg or
200 mg/50 mg/200 mg) tablets, Stalevo dosing should be carefully titrated for optimal clinical
response. At the initiation, Stalevo should be adjusted to correspond as closely as possible to the total
daily dose of levodopa currently used.
c.
When initiating Stalevo in patients currently treated with entacapone and levodopa/benserazide in a
standard release formulation, discontinue dosing of levodopa/benserazide the previous night, and start
Stalevo the next morning. Begin with a dose of Stalevo that will provide either the same amount of
levodopa or slightly (5-10%) more.
How to transfer patients not currently treated with entacapone to Stalevo
Initiation of Stalevo may be considered at corresponding doses to current treatment in some patients
with Parkinson's disease and end-of-dose motor fluctuations, who are not stabilised on their current
standard release levodopa/DDC inhibitor treatment. However, a direct switch from levodopa/DDC
inhibitor to Stalevo is not recommended for patients who have dyskinesias or whose daily levodopa
dose is above 800 mg. In such patients it is advisable to introduce entacapone treatment as a separate
treatment (entacapone tablets) and adjust the levodopa dose if necessary, before switching to Stalevo.
Entacapone enhances the effects of levodopa. It may therefore be necessary, particularly in patients
with dyskinesia, to reduce levodopa dose by 10-30% within the first days to first weeks after initiating
Stalevo treatment. The daily dose of levodopa can be reduced by extending the dosing intervals and/or
by reducing the amount of levodopa per dose, according to the clinical condition of the patient.
Dose adjustment during the course of the treatment
When more levodopa is required, an increase in the frequency of doses and/or the use of an alternative
strength of Stalevo should be considered, within the dose recommendations.
When less levodopa is required, the total daily dose of Stalevo should be reduced either by decreasing
the frequency of administration by extending the time between doses, or by decreasing the strength of
Stalevo at an administration.
If other levodopa products are used concomitantly with a Stalevo tablet, the maximum dose
recommendations should be followed.
Discontinuation of Stalevo therapy
:
If Stalevo treatment (levodopa/carbidopa/entacapone) is
discontinued and the patient is transferred to levodopa/DDC inhibitor therapy without entacapone, it
is necessary to adjust the dosing of other antiparkinsonian treatments, especially levodopa, to achieve
a sufficient level of control of the parkinsonian symptoms.
Children and adolescents
:
Stalevo is not recommended for use in children below 18 years due to a
lack of data on safety and efficacy.
Elderly
:
No dose adjustment of Stalevo is required for elderly patients.
Hepatic impairment
:
It is advised that Stalevo should be administered cautiously to patients with mild
to moderate hepatic impairment. Dose reduction may be needed (see section 5.2).
For severe hepatic
impairment see section 4.3.
3
Renal impairment:
Renal
impairment
does not affect the pharmacokinetics of entacapone. No
particular studies are reported on the pharmacokinetics of levodopa and carbidopa in patients with
renal insufficiency, therefore Stalevo therapy should be administered cautiously to patients in severe
renal impairment including those receiving dialysis therapy (see section 5.2).
-
Hypersensitivity to the active substances or to any of the excipients.
-
Severe hepatic impairment.
-
Narrow-angle glaucoma.
-
Pheochromocytoma.
-
Concomitant use of Stalevo with non-selective monoamine oxidase (MAO-A and MAO-B)
inhibitors (e.g. phenelzine, tranylcypromine).
-
Concomitant use of a selective MAO-A inhibitor and a selective MAO-B inhibitor (see section
4.5).
-
A previous history of Neuroleptic Malignant Syndrome (NMS) and/or non-traumatic
rhabdomyolysis.
-
Stalevo is not recommended for the treatment of drug-induced extrapyramidal reactions
-
Stalevo therapy should be administered cautiously to patients with ischemic heart disease,
severe cardiovascular or pulmonary disease, bronchial asthma, renal or endocrine disease,
history of peptic ulcer disease or history of convulsions.
-
In patients with a history of myocardial infarction who have residual atrial nodal or ventricular
arrhythmias; cardiac function should be monitored with particular care during the period of
initial dose adjustments.
-
All patients treated with Stalevo should be monitored carefully for the development of mental
changes, depression with suicidal tendencies, and other serious antisocial behaviour. Patients
with past or current psychosis should be treated with caution.
-
Concomitant administration of antipsychotics with dopamine receptor-blocking properties,
particularly D
2
receptor antagonists should be carried out with caution, and the patient carefully
observed for loss of antiparkinsonian effect or worsening of parkinsonian symptoms.
-
Patients with chronic wide-angle glaucoma may be treated with Stalevo with caution, provided
the intra-ocular pressure is well controlled and the patient is monitored carefully for changes in
intra-ocular pressure.
-
Stalevo may induce orthostatic hypotension. Therefore Stalevo should be given cautiously to
patients who are taking other medicinal products which may cause orthostatic hypotension.
-
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 section 4.7).
-
In clinical studies, dopaminergic adverse reactions, 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 Stalevo treatment is
substituted for a patient currently not treated with entacapone.
-
Rhabdomyolysis secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS) has
been observed rarely in patients with Parkinson’s disease. Therefore, any abrupt dose reduction
or withdrawal of levodopa should be carefully observed, particularly in patients who are also
receiving neuroleptics. 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. The early diagnosis is important for the appropriate management of
NMS. A syndrome resembling the neuroleptic malignant syndrome including muscular rigidity,
elevated body temperature, mental changes and increased serum creatine phosphokinase has
4
been reported with the abrupt withdrawal of antiparkinsonian agents. Neither NMS nor
rhabdomyolysis have been reported in association with entacapone treatment from controlled
trials in which entacapone was discontinued abruptly. Since the introduction of entacapone 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, the replacement of Stalevo with levodopa and DDC inhibitor without
entacapone or other dopaminergic treatment should proceed slowly and an increase in levodopa
dose may be necessary.
-
If general anaesthesia is required, therapy with Stalevo may be continued for as long as the
patient is permitted to take fluids and medicinal products by mouth. If therapy has to be stopped
temporarily, Stalevo may be restarted as soon as oral medicinal products can be taken at the
same daily dose as before.
-
Periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function is
recommended during extended therapy with Stalevo.
-
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
Stalevo.
-
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.
-
Stalevo contains sucrose, and therefore patients with rare hereditary problems of fructose
intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not
take this medicine.
Other antiparkinsonian medicinal products
: To date there has been no indication of interactions that
would preclude concurrent use of standard antiparkinsonian medicinal products with Stalevo therapy.
Entacapone in high doses may affect the absorption of carbidopa. However, no interaction with
carbidopa has been observed with the recommended treatment schedule (200 mg of entacapone up to
10 times daily). Interactions between entacapone and selegiline have been investigated in repeated
dose studies in Parkinson's disease patients treated with levodopa/DDC inhibitor and no interaction
was observed. When used with Stalevo, the daily dose of selegiline should not exceed 10 mg.
Caution should be exercised when the following active substances are administered concomitantly
with levodopa therapy.
Antihypertensives
: Symptomatic postural hypotension may occur when levodopa is added to the
treatment of patients already receiving antihypertensives. Dose adjustment of the antihypertensive
agent may be required.
Antidepressants:
Rarely, reactions including hypertension and dyskinesia have been reported with the
concomitant use of tricyclic antidepressants and levodopa/carbidopa. Interactions between entacapone
and imipramine and between entacapone and moclobemide have been investigated in single dose
studies in healthy volunteers. No pharmacodynamic interactions were observed. A significant number
of Parkinson's disease patients have been treated with the combination of levodopa, carbidopa and
entacapone with several active substances 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, paroxetine). No
pharmacodynamic interactions have been observed. However, caution should be exercised when these
medicinal products are used concomitantly with Stalevo (see sections 4.3 and 4.4).
5
Other active substances:
Dopamine receptor antagonists (e.g. some antipsychotics and antiemetics),
phenytoin and papaverine may reduce the therapeutic effect of levodopa. Patients taking these
medicinal products with Stalevo should be carefully observed for loss of therapeutic response.
Due to entacapone's affinity to cytochrome P450 2C9
in vitro
(see section 5.2), Stalevo may
potentially interfere with active substances whose metabolism is dependent on this isoenzyme, such as
S-warfarin. 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, a control of INR is
recommended when Stalevo is initiated for patients receiving warfarin.
Other forms of interactions:
Since levodopa competes with certain amino acids, the absorption of
Stalevo may be impaired in some patients on high protein diet.
Levodopa and entacapone may form chelates with iron in the gastrointestinal tract. Therefore, Stalevo
and iron preparations should be taken at least 2-3 hours apart (see section 4.8).
In vitro data:
Entacapone binds to human albumin binding site II which also binds several other
medicinal products, including diazepam and ibuprofen. According to
in vitro
studies, significant
displacement is not anticipated at therapeutic concentrations of the medicinal products. Accordingly,
to date there has been no indication of such interactions.
There are no adequate data from the use of the combination of levodopa/carbidopa/entacapone in
pregnant women. Studies in animals have shown reproductive toxicity of the separate compounds (see
section 5.3). The potential risk for humans is unknown. Stalevo should not be used during pregnancy
unless the benefits for the mother outweigh the possible risks to the foetus.
Levodopa is excreted in human breast milk. There is evidence that lactation is suppressed during
treatment with levodopa. Carbidopa and entacapone were excreted in milk in animals but is not known
whether they are excreted in human breast milk. The safety of levodopa, carbidopa or entacapone in
the infant is not known. Women should not breast-feed during treatment with Stalevo.
Stalevo may have major influence on the ability to drive and use machines. Levodopa, carbidopa and
entacapone together may cause dizziness and symptomatic orthostatism. Therefore, caution should be
exercised when driving or using machines.
Patients being treated with Stalevo 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 section 4.4).
a.
Summary of the safety profile
The most frequently reported adverse reactions with Stalevo are dyskinesias occurring in
approximately 19% of patients; gastrointestinal symptoms including nausea and diarrhoea occurring
in approximately 15% and 12% of patients, respectively; muscle, musculoskeletal and connective
tissue pain occurring in approximately 12% of patients; and harmless reddish-brown discolouration of
urine (chromaturia) occurring in approximately 10% of patients. Serious events of gastrointestinal
haemorrhage (uncommon) and angioedema (rare) have been identified from the clinical trials with
Stalevo or entacapone combined with levodopa/DDC inhibitor. Serious hepatitis with mainly
6
cholestatic features, rhabdomyolysis and neuroleptic malignant syndrome may occur with Stalevo
although no cases have been identified from the clinical trial data.
b.
Tabulated list of adverse reactions
The following adverse reactions, listed in Table 1, have been accumulated both from a pooled data of
eleven double-blind clinical trials consisting of 3230 patients (1810 treated with Stalevo or
entacapone combined with levodopa/DDC inhibitor, and 1420 treated with placebo combined with
levodopa/DDC inhibitor or cabergoline combined with levodopa/ DDC inhibitor), and from the post-
marketing data since the introduction of entacapone into the market for the combination use of
entacapone with levodopa/DDC inhibitor.
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).
Table 1.
Adverse reactions
Blood and lymphatic system disorders
Common:
Anaemia
Uncommon:
Thrombocytopenia
Metabolism and nutrition disorders
Common:
Weight decreased*, decreased appetite*
Psychiatric disorders
Common: Depression, hallucination, confusional state*, abnormal dreams*,
anxiety, insomnia
Uncommon :
Psychosis, agitation*
Not known:
Suicidal behaviour
Nervous system disorders
Very common: Dyskinesia*
Common: Parkinsonism aggravated (e.g. bradykinesia)*,tremor, on
and off phenomenon, dystonia, mental impairment (e.g. memory
impairment, dementia), somnolence, dizziness*, headache
Not known:
Neuroleptic malignant syndrome*
Eye disorders
Common:
Blurred vision
Cardiac disorders
Common: Ischemic heart disease events other than myocardial infarction (e.g. angina
pectoris)**, irregular heart rhythm
Uncommon:
Myocardial infarction**
Vascular disorders:
Common:
Orthostatic hypotension, hypertension
Uncommon:
Gastrointestinal haemorrhage
Respiratory, thoracic and mediastinal disorders
Common:
Dyspnoea
Gastrointestinal disorders
Very common: Diarrhoea*, nausea*
7
Common: Constipation*, vomiting*, dyspepsia, abdominal pain and discomfort*, dry mouth*
Uncommon:
Colitis*, dysphagia
Hepatobiliary disorders
Uncommon:
Hepatic function test abnormal*
Not known:
Hepatitis with mainly cholestatic features (see section 4.4)*
Skin and subcutaneous tissue disorders
Common:
Rash*, hyperhidrosis
Uncommon:
Discolourations other than urine (e.g. skin, nail, hair, sweat)*
Rare:
Angioedema
Not known:
Urticaria*
Musculoskeletal and connective tissue disorders
Very common: Muscle, musculoskeletal and connective tissue pain*
Common:
Muscle spasms, arthralgia
Not known:
Rhabdomyolysis*
Renal and urinary disorders
Very common: Chromaturia*
Common:
Urinary tract infection
Uncommon:
Urinary retention
General disorders and administration site conditions
Common: Chest pain, peripheral oedema, fall, gait disturbance, asthenia, fatigue
Uncommon:
Malaise
*Adverse reactions that are mainly attributable to entacapone or are more frequent (by the frequency
difference of at least 1% in the clinical trial data) with entacapone than levodopa/DDC inhibitor
alone. See section c.
**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.
Convulsions have occurred rarely with levodopa/carbidopa; however a causal relationship to
levodopa/carbidopa therapy has not been established.
Parkinson’s disease patients treated with dopamine agonists and other dopaminergic treatments such
as Stalevo, especially at high doses, have been reported as exhibiting signs of pathological gambling,
increased libido, hypersexuality and other urges, generally reversible upon reduction of the dose or
treatment discontinuation.
Entacapone in association with levodopa has been associated with isolated cases of excessive daytime
somnolence and sudden sleep onset episodes.
Levodopa/carbidopa may cause false positive result when a dipstick is used to test for urinary ketone
and this reaction is not altered by boiling the urine sample. The use of glucose oxidase methods may
give false negative results for glycosuria.
c.
Description of selected adverse reactions
Adverse reactions that are mainly attributable to entacapone or are more frequent with entacapone
than levodopa/DDC inhibitor alone are indicated with an asterisk in Table 1, section 4.8b. Some of
these adverse reactions relate to the increased dopaminergic activity (e.g. dyskinesia, nausea and
vomiting) and occur most commonly at the beginning of the treatment. Reduction of levodopa dose
8
decreases the severity and frequency of these dopaminergic reactions. Few adverse reactions are
known to be directly attributable to the active substance entacapone including diarrhoea and reddish-
brown discolouration of urine. Entacapone may in some cases cause also discolouration of e.g. skin,
nail, hair and sweat. Other adverse reactions with an asterisk in Table 1, section 4.8b are marked
based on either their more frequent occurring (by the frequency difference of at least 1%) in the
clinical trial data with entacapone than levodopa/DDCI alone or the individual case safety reports
received after the introduction of entacapone into the market.
The post-marketing data includes isolated cases of overdose in which the reported highest daily doses
of levodopa and entacapone have been at least 10,000 mg and 40,000 mg, respectively. The acute
symptoms and signs in these cases of overdose included agitation, confusional state, coma,
bradycardia, ventricular tachycardia, Cheyne-Stokes respiration, discolourations of skin, tongue and
conjunctiva, and chromaturia. Management of acute overdose with Stalevo therapy is similar to acute
overdose with levodopa. Pyridoxine, however, is not effective in reversing the actions of Stalevo.
Hospitalisation is advised and general supportive measures should be employed with immediate
gastric lavage and repeated doses of charcoal over time. This may hasten the elimination of
entacapone in particular by decreasing its absorption/reabsorption from the GI tract. The adequacy of
the respiratory, circulatory and renal systems should be carefully monitored and appropriate
supportive measures employed. ECG monitoring should be started and the patient carefully monitored
for the possible development of arrhythmias. If required, appropriate anti-arrhythmic therapy should
be given. The possibility that the patient has taken other active substances in addition to Stalevo
should be taken into consideration. The value of dialysis in the treatment of overdose is not known.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: dopa and dopa derivatives, ATC code:
N04BA03
According to the current understanding, the symptoms of Parkinson’s disease are related to depletion
of dopamine in the corpus striatum. Dopamine does not cross the blood-brain barrier. Levodopa, the
precursor of dopamine, crosses the blood brain barrier and relieves the symptoms of the disease. As
levodopa is extensively metabolised in the periphery, only a small portion of a given dose reaches the
central nervous system when levodopa is administered without metabolic enzyme inhibitors.
Carbidopa and benserazide are peripheral DDC inhibitors which reduce the peripheral metabolism of
levodopa to dopamine, and thus, more levodopa is available to the brain. When decarboxylation of
levodopa is reduced with the co-administration of a DDC inhibitor, a lower dose of levodopa can be
used and the incidence of undesirable effects such as nausea is reduced.
With inhibition of the decarboxylase by a DDC inhibitor, catechol-
O
-methyltransferase (COMT)
becomes the major peripheral metabolic pathway catalyzing the conversion of levodopa to 3-O-
methyldopa (3-OMD), a potentially harmful metabolite of levodopa. Entacapone is a reversible,
specific and mainly peripherally acting COMT inhibitor designed for concomitant administration with
levodopa. Entacapone slows the clearance of levodopa from the bloodstream resulting in an increased
area under the curve (AUC) in the pharmacokinetic profile of levodopa. Consequently the clinical
response to each dose of levodopa is enhanced and prolonged.
The evidence of the therapeutic effects of Stalevo is based on two phase III double-blind studies, in
which 376 Parkinson’s disease patients with end-of-dose motor fluctuations received either
entacapone or placebo with each levodopa/DDC inhibitor dose. Daily ON time with and without
entacapone was recorded in home-diaries by patients. In the first study, entacapone increased the
mean daily ON time by 1 h 20 min (CI
95%
45 min, 1 h 56 min) from baseline. This corresponded to an
9
8.3% increase in the proportion of daily ON time. Correspondingly, the decrease in daily OFF time
was 24% in the entacapone group and 0% in the placebo group. In the second study, the mean
proportion of daily ON time increased by 4.5% (CI
95%
0.93%, 7.97%) from baseline. This is translated
to a mean increase of 35 min in the daily ON time. Correspondingly, the daily OFF time decreased by
18% on entacapone and by 5% on placebo. Because the effects of Stalevo tablets are equivalent with
entacapone 200 mg tablet administered concomitantly with the commercially available standard
release carbidopa/levodopa preparations in corresponding doses these results are applicable to
describe the effects of Stalevo as well.
5.2 Pharmacokinetic properties
General characteristics of the active substances
Absorption/Distribution
:
There are substantial inter- and intra-individual variations in the absorption
of levodopa, carbidopa
and entacapone. Both levodopa and entacapone are rapidly absorbed and
eliminated. Carbidopa is absorbed and eliminated slightly slower compared with levodopa. When
given separately without the two other active substances, the bioavailability for levodopa is 15-33%,
for carbidopa 40-70% and for entacapone 35% after a 200 mg oral dose. Meals rich in large neutral
amino acids may delay and reduce the absorption of levodopa. Food does not significantly affect the
absorption of entacapone. The distribution volume of both levodopa (Vd 0.36-1.6 l/kg) and
entacapone (Vd
ss
0.27 l/kg) is moderately small while no data for carbidopa are available.
Levodopa is bound to plasma protein only to a minor extent of about 10-30% and carbidopa is bound
approximately 36%, while entacapone is extensively bound to plasma proteins (about 98%) –mainly to
serum albumin. At therapeutic concentrations, entacapone does not displace other extensively bound
active 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 and Elimination
:
Levodopa is extensively metabolised to various metabolites:
decarboxylation by dopa decarboxylase (DDC) and O-methylation by catechol-O-methyltransferase
(COMT) being the most important pathways.
Carbidopa is metabolized to two main metabolites which are excreted in the urine as glucuronides and
unconjugated compounds. Unchanged carbidopa accounts for 30% of the total urinary excretion.
Entacapone is almost completely metabolized prior to excretion via urine (10 to 20%) and bile/faeces
(80 to 90%). The main metabolic pathway is glucuronidation of entacapone and its active metabolite,
the cis-isomer, which accounts for about 5% of plasma total amount.
Total clearance for levodopa is in the range of 0.55-1.38 l/kg/h and for entacapone is in the range of
0.70 l/kg/h. The elimination-half life is (t
1/2
) is 0.6-1.3 hours for levodopa, 2-3 hours for carbidopa and
0.4-0.7 hours for entacapone, each given separately.
Due to short elimination half-lives, no true accumulation of levodopa or entacapone occurs on
repeated administration.
Data from
in vitro
studies using human liver microsomal preparations indicate that entacapone
inhibits cytochrome P450 2C9 (IC50 ~ 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.
Characteristics in patients
Elderly
: When given without carbidopa and entacapone, the absorption of levodopa is greater and
elimination is slower in elderly than in young subjects. However, after combination of carbidopa with
levodopa, the absorption of levodopa is similar between the elderly and the young, but the AUC is still
10
1.5 fold greater in the elderly due to decreased DDC activity and lower clearance by aging. There are
no significant differences in the AUC of carbidopa or entacapone between younger (45–64 years) and
elderly subjects (65–75 years).
Gender
:
Bioavailability of levodopa is significantly higher in women than in men. In the
pharmacokinetic studies with Stalevo
the bioavailability of levodopa is higher in women than in men,
primarily due to the difference in body weight, while there is no gender difference with carbidopa and
entacapone.
Hepatic impairment
:
The metabolism of entacapone is slowed in patients with mild to moderate
hepatic impairment (Child-Pugh Class A and B) leading to an increased plasma concentration of
entacapone both in the absorption and elimination phases (see sections 4.2 and 4.3). No particular
studies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic impairment are
reported, however, it is advised that Stalevo
should be administered cautiously to patients with mild or
moderate hepatic impairment.
Renal impairment
: Renal impairment does not affect the pharmacokinetics of entacapone. No
particular studies are reported on the pharmacokinetics of levodopa and carbidopa in patients with
renal impairment. However, a longer dosing interval of Stalevo may be considered for patients who
are receiving dialysis therapy (see section 4.2).
5.3 Preclinical safety data
Preclinical data of levodopa, carbidopa and entacapone, tested alone or in combination, revealed no
special hazard for humans based on conventional studies of safety pharmacology, repeated dose
toxicity, genotoxicity, and carcinogenic potential. In repeated dose toxicity studies with entacapone,
anaemia most likely due to iron chelating properties of entacapone was observed. Regarding
reproduction toxicity of entacapone, decreased foetal weight and a slightly delayed bone development
were noticed in rabbits treated at systemic exposure levels in the therapeutic range. Both levodopa and
combinations of carbidopa and levodopa have caused visceral and skeletal malformations in rabbits.
6.1 List of excipients
Tablet core
:
Croscarmellose sodium
Magnesium stearate
Maize starch
Mannitol (E421)
Povidone (E1201)
Film-coating
:
Glycerol (85 per cent) (E422)
Hypromellose
Magnesium stearate
Polysorbate 80
Red iron oxide (E172)
Sucrose
Titanium dioxide (E171)
Yellow iron oxide (E172)
6.2 Incompatibilities
Not applicable.
11
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
HDPE bottle with a child resistant PP-closure.
Pack sizes:
10, 30, 100, 130, 175 and 250 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
Orion Corporation
Orionintie 1
FI-02200 Espoo
Finland
8. MARKETING AUTHORISATION NUMBERS
EU/1/03/260/001-004
EU/1/03/260/013
EU/1/03/260/016
Date of first authorisation: 17 October 2003
Date of last renewal: 15 September 2008
Detailed information on this medicine is available on the European Medicine’s Agency (EMA) web
site:
http://www.ema.europa.eu
12
Stalevo 75 mg/18.75 mg/200 mg film-coated tablets
Each tablet contains 75 mg of levodopa, 18.75 mg of carbidopa and 200 mg of entacapone.
Excipient: Each tablet contains 1.4 mg of sucrose.
For a full list of excipients, see section 6.1.
Film-coated tablet
Light brownish red, oval film-coated tablets marked with ‘LCE 75’ on one side.
Stalevo is indicated for the treatment of adult patients with Parkinson’s disease and end-of-dose motor
fluctuations not stabilised on levodopa/dopa decarboxylase (DDC) inhibitor treatment.
Each tablet is to be taken orally either with or without food (see section 5.2). One tablet contains one
treatment dose and the tablet may only be administered as whole tablets.
The optimum daily dose must be determined by careful titration of levodopa in each patient. The daily
dose should be preferably optimised using one of the six available tablet strengths
(50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg, 100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg,
150 mg/37.5 mg/200 mg or 200 mg/50 mg/200 mg levodopa/carbidopa/entacapone).
Patients should be instructed to take only one Stalevo tablet per dose administration. Patients
receiving less than 70-100 mg carbidopa a day are more likely to experience nausea and vomiting.
While the experience with total daily dose greater than 200 mg carbidopa is limited, the maximum
recommended daily dose of entacapone is 2,000 mg and therefore the maximum dose is 10 tablets per
day for the Stalevo strengths of 50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg,
100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg and 150 mg/37.5 mg/200 mg. Ten tablets of Stalevo
150 mg/37.5 mg/200 mg equals 375 mg of carbidopa a day. According to this daily carbidopa dose,
the maximum recommended daily Stalevo 200 mg/50 mg/200 mg dose is 7 tablets per day.
Usually Stalevo is to be used in patients who are currently treated with corresponding doses of
standard release levodopa/DDC inhibitor and entacapone.
How to transfer patients taking levodopa/DDC inhibitor (carbidopa or benserazide) preparations and
entacapone tablets to Stalevo
a
. Patients who are currently treated with entacapone and with standard release levodopa/carbidopa in
doses equal to Stalevo tablet
strengths can be directly transferred to corresponding Stalevo tablets.
For example, a patient taking one tablet of 50 mg/12.5 mg of levodopa/carbidopa with one tablet of
13
entacapone 200 mg four times daily can take one 50 mg/12.5 mg/200 mg Stalevo tablet four times
daily in place of their usual levodopa/carbidopa and entacapone doses.
b.
When initiating Stalevo therapy for patients currently treated with entacapone and
levodopa/carbidopa in doses not equal to Stalevo, 75 mg/18.75 mg/200 mg (or 50 mg/12.5 mg/200 mg
or 100 mg/25 mg/200 mg or 125 mg/31.25 mg/200 mg or 150 mg/37.5 mg/200 mg or
200 mg/50 mg/200 mg) tablets, Stalevo dosing should be carefully titrated for optimal clinical
response. At the initiation, Stalevo should be adjusted to correspond as closely as possible to the total
daily dose of levodopa currently used.
c.
When initiating Stalevo in patients currently treated with entacapone and levodopa/benserazide in a
standard release formulation, discontinue dosing of levodopa/benserazide the previous night, and start
Stalevo the next morning. Begin with a dose of Stalevo that will provide either the same amount of
levodopa or slightly (5-10%) more.
How to transfer patients not currently treated with entacapone to Stalevo
Initiation of Stalevo may be considered at corresponding doses to current treatment in some patients
with Parkinson's disease and end-of-dose motor fluctuations, who are not stabilised on their current
standard release levodopa/DDC inhibitor treatment. However, a direct switch from levodopa/DDC
inhibitor to Stalevo is not recommended for patients who have dyskinesias or whose daily levodopa
dose is above 800 mg. In such patients it is advisable to introduce entacapone treatment as a separate
treatment (entacapone tablets) and adjust the levodopa dose if necessary, before switching to Stalevo.
Entacapone enhances the effects of levodopa. It may therefore be necessary, particularly in patients
with dyskinesia, to reduce levodopa dose by 10-30% within the first days to first weeks after initiating
Stalevo treatment. The daily dose of levodopa can be reduced by extending the dosing intervals and/or
by reducing the amount of levodopa per dose, according to the clinical condition of the patient.
Dose adjustment during the course of the treatment
When more levodopa is required, an increase in the frequency of doses and/or the use of an alternative
strength of Stalevo should be considered, within the dose recommendations.
When less levodopa is required, the total daily dose of Stalevo should be reduced either by decreasing
the frequency of administration by extending the time between doses, or by decreasing the strength of
Stalevo at an administration.
If other levodopa products are used concomitantly with a Stalevo tablet, the maximum dose
recommendations should be followed.
Discontinuation of Stalevo therapy
:
If Stalevo treatment (levodopa/carbidopa/entacapone) is
discontinued and the patient is transferred to levodopa/DDC inhibitor therapy without entacapone, it
is necessary to adjust the dosing of other antiparkinsonian treatments, especially levodopa, to achieve
a sufficient level of control of the parkinsonian symptoms.
Children and adolescents
:
Stalevo is not recommended for use in children below 18 years due to a
lack of data on safety and efficacy.
Elderly
:
No dose adjustment of Stalevo is required for elderly patients.
Hepatic impairment
:
It is advised that Stalevo should be administered cautiously to patients with mild
to moderate hepatic impairment. Dose reduction may be needed (see section 5.2).
For severe hepatic
impairment see section 4.3.
14
Renal impairment:
Renal
impairment
does not affect the pharmacokinetics of entacapone. No
particular studies are reported on the pharmacokinetics of levodopa and carbidopa in patients with
renal insufficiency, therefore Stalevo therapy should be administered cautiously to patients in severe
renal impairment including those receiving dialysis therapy (see section 5.2).
-
Hypersensitivity to the active substances or to any of the excipients.
-
Severe hepatic impairment.
-
Narrow-angle glaucoma.
-
Pheochromocytoma.
-
Concomitant use of Stalevo with non-selective monoamine oxidase (MAO-A and MAO-B)
inhibitors (e.g. phenelzine, tranylcypromine).
-
Concomitant use of a selective MAO-A inhibitor and a selective MAO-B inhibitor (see section
4.5).
-
A previous history of Neuroleptic Malignant Syndrome (NMS) and/or non-traumatic
rhabdomyolysis.
-
Stalevo is not recommended for the treatment of drug-induced extrapyramidal reactions
-
Stalevo therapy should be administered cautiously to patients with ischemic heart disease,
severe cardiovascular or pulmonary disease, bronchial asthma, renal or endocrine disease,
history of peptic ulcer disease or history of convulsions.
-
In patients with a history of myocardial infarction who have residual atrial nodal or ventricular
arrhythmias; cardiac function should be monitored with particular care during the period of
initial dose adjustments.
-
All patients treated with Stalevo should be monitored carefully for the development of mental
changes, depression with suicidal tendencies, and other serious antisocial behaviour. Patients
with past or current psychosis should be treated with caution.
-
Concomitant administration of antipsychotics with dopamine receptor-blocking properties,
particularly D
2
receptor antagonists should be carried out with caution, and the patient carefully
observed for loss of antiparkinsonian effect or worsening of parkinsonian symptoms.
-
Patients with chronic wide-angle glaucoma may be treated with Stalevo with caution, provided
the intra-ocular pressure is well controlled and the patient is monitored carefully for changes in
intra-ocular pressure.
-
Stalevo may induce orthostatic hypotension. Therefore Stalevo should be given cautiously to
patients who are taking other medicinal products which may cause orthostatic hypotension.
-
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 section 4.7).
-
In clinical studies, dopaminergic adverse reactions, 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 Stalevo treatment is
substituted for a patient currently not treated with entacapone.
-
Rhabdomyolysis secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS) has
been observed rarely in patients with Parkinson’s disease. Therefore, any abrupt dose reduction
or withdrawal of levodopa should be carefully observed, particularly in patients who are also
receiving neuroleptics. 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. The early diagnosis is important for the appropriate management of
NMS. A syndrome resembling the neuroleptic malignant syndrome including muscular rigidity,
elevated body temperature, mental changes and increased serum creatine phosphokinase has
15
been reported with the abrupt withdrawal of antiparkinsonian agents. Neither NMS nor
rhabdomyolysis have been reported in association with entacapone treatment from controlled
trials in which entacapone was discontinued abruptly. Since the introduction of entacapone 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, the replacement of Stalevo with levodopa and DDC inhibitor without
entacapone or other dopaminergic treatment should proceed slowly and an increase in levodopa
dose may be necessary.
-
If general anaesthesia is required, therapy with Stalevo may be continued for as long as the
patient is permitted to take fluids and medicinal products by mouth. If therapy has to be stopped
temporarily, Stalevo may be restarted as soon as oral medicinal products can be taken at the
same daily dose as before.
-
Periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function is
recommended during extended therapy with Stalevo.
-
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
Stalevo.
-
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.
-
Stalevo contains sucrose, and therefore patients with rare hereditary problems of fructose
intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not
take this medicine.
Other antiparkinsonian medicinal products
: To date there has been no indication of interactions that
would preclude concurrent use of standard antiparkinsonian medicinal products with Stalevo therapy.
Entacapone in high doses may affect the absorption of carbidopa. However, no interaction with
carbidopa has been observed with the recommended treatment schedule (200 mg of entacapone up to
10 times daily). Interactions between entacapone and selegiline have been investigated in repeated
dose studies in Parkinson's disease patients treated with levodopa/DDC inhibitor and no interaction
was observed. When used with Stalevo, the daily dose of selegiline should not exceed 10 mg.
Caution should be exercised when the following active substances are administered concomitantly
with levodopa therapy.
Antihypertensives
: Symptomatic postural hypotension may occur when levodopa is added to the
treatment of patients already receiving antihypertensives. Dose adjustment of the antihypertensive
agent may be required.
Antidepressants:
Rarely, reactions including hypertension and dyskinesia have been reported with the
concomitant use of tricyclic antidepressants and levodopa/carbidopa. Interactions between entacapone
and imipramine and between entacapone and moclobemide have been investigated in single dose
studies in healthy volunteers. No pharmacodynamic interactions were observed. A significant number
of Parkinson's disease patients have been treated with the combination of levodopa, carbidopa and
entacapone with several active substances 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, paroxetine). No
pharmacodynamic interactions have been observed. However, caution should be exercised when these
medicinal products are used concomitantly with Stalevo (see sections 4.3 and 4.4).
16
Other active substances:
Dopamine receptor antagonists (e.g. some antipsychotics and antiemetics),
phenytoin and papaverine may reduce the therapeutic effect of levodopa. Patients taking these
medicinal products with Stalevo should be carefully observed for loss of therapeutic response.
Due to entacapone's affinity to cytochrome P450 2C9
in vitro
(see section 5.2), Stalevo may
potentially interfere with active substances whose metabolism is dependent on this isoenzyme, such as
S-warfarin. 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, a control of INR is
recommended when Stalevo is initiated for patients receiving warfarin.
Other forms of interactions:
Since levodopa competes with certain amino acids, the absorption of
Stalevo may be impaired in some patients on high protein diet.
Levodopa and entacapone may form chelates with iron in the gastrointestinal tract. Therefore, Stalevo
and iron preparations should be taken at least 2-3 hours apart (see section 4.8).
In vitro data:
Entacapone binds to human albumin binding site II which also binds several other
medicinal products, including diazepam and ibuprofen. According to
in vitro
studies, significant
displacement is not anticipated at therapeutic concentrations of the medicinal products. Accordingly,
to date there has been no indication of such interactions.
There are no adequate data from the use of the combination of levodopa/carbidopa/entacapone in
pregnant women. Studies in animals have shown reproductive toxicity of the separate compounds (see
section 5.3). The potential risk for humans is unknown. Stalevo should not be used during pregnancy
unless the benefits for the mother outweigh the possible risks to the foetus.
Levodopa is excreted in human breast milk. There is evidence that lactation is suppressed during
treatment with levodopa. Carbidopa and entacapone were excreted in milk in animals but is not known
whether they are excreted in human breast milk. The safety of levodopa, carbidopa or entacapone in
the infant is not known. Women should not breast-feed during treatment with Stalevo.
Stalevo may have major influence on the ability to drive and use machines. Levodopa, carbidopa and
entacapone together may cause dizziness and symptomatic orthostatism. Therefore, caution should be
exercised when driving or using machines.
Patients being treated with Stalevo 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 section 4.4).
a.
Summary of the safety profile
The most frequently reported adverse reactions with Stalevo are dyskinesias occurring in
approximately 19% of patients; gastrointestinal symptoms including nausea and diarrhoea occurring
in approximately 15% and 12% of patients, respectively; muscle, musculoskeletal and connective
tissue pain occurring in approximately 12% of patients; and harmless reddish-brown discolouration of
urine (chromaturia) occurring in approximately 10% of patients. Serious events of gastrointestinal
haemorrhage (uncommon) and angioedema (rare) have been identified from the clinical trials with
Stalevo or entacapone combined with levodopa/DDC inhibitor. Serious hepatitis with mainly
17
cholestatic features, rhabdomyolysis and neuroleptic malignant syndrome may occur with Stalevo
although no cases have been identified from the clinical trial data.
b.
Tabulated list of adverse reactions
The following adverse reactions, listed in Table 1, have been accumulated both from a pooled data of
eleven double-blind clinical trials consisting of 3230 patients (1810 treated with Stalevo or
entacapone combined with levodopa/DDC inhibitor, and 1420 treated with placebo combined with
levodopa/DDC inhibitor or cabergoline combined with levodopa/ DDC inhibitor), and from the post-
marketing data since the introduction of entacapone into the market for the combination use of
entacapone with levodopa/DDC inhibitor.
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).
Table 1.
Adverse reactions
Blood and lymphatic system disorders
Common:
Anaemia
Uncommon:
Thrombocytopenia
Metabolism and nutrition disorders
Common:
Weight decreased*, decreased appetite*
Psychiatric disorders
Common: Depression, hallucination, confusional state*, abnormal dreams*,
anxiety, insomnia
Uncommon :
Psychosis, agitation*
Not known:
Suicidal behaviour
Nervous system disorders
Very common: Dyskinesia*
Common: Parkinsonism aggravated (e.g. bradykinesia)*,tremor, on
and off phenomenon, dystonia, mental impairment (e.g. memory
impairment, dementia), somnolence, dizziness*, headache
Not known:
Neuroleptic malignant syndrome*
Eye disorders
Common:
Blurred vision
Cardiac disorders
Common: Ischemic heart disease events other than myocardial infarction (e.g. angina
pectoris)**, irregular heart rhythm
Uncommon:
Myocardial infarction**
Vascular disorders:
Common:
Orthostatic hypotension, hypertension
Uncommon:
Gastrointestinal haemorrhage
Respiratory, thoracic and mediastinal disorders
Common:
Dyspnoea
Gastrointestinal disorders
Very common: Diarrhoea*, nausea*
18
Common: Constipation*, vomiting*, dyspepsia, abdominal pain and discomfort*, dry mouth*
Uncommon:
Colitis*, dysphagia
Hepatobiliary disorders
Uncommon:
Hepatic function test abnormal*
Not known:
Hepatitis with mainly cholestatic features (see section 4.4)*
Skin and subcutaneous tissue disorders
Common:
Rash*, hyperhidrosis
Uncommon:
Discolourations other than urine (e.g. skin, nail, hair, sweat)*
Rare:
Angioedema
Not known:
Urticaria*
Musculoskeletal and connective tissue disorders
Very common: Muscle, musculoskeletal and connective tissue pain*
Common:
Muscle spasms, arthralgia
Not known:
Rhabdomyolysis*
Renal and urinary disorders
Very common: Chromaturia*
Common:
Urinary tract infection
Uncommon:
Urinary retention
General disorders and administration site conditions
Common: Chest pain, peripheral oedema, fall, gait disturbance, asthenia, fatigue
Uncommon:
Malaise
*Adverse reactions that are mainly attributable to entacapone or are more frequent (by the frequency
difference of at least 1% in the clinical trial data) with entacapone than levodopa/DDC inhibitor
alone. See section c.
**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.
Convulsions have occurred rarely with levodopa/carbidopa; however a causal relationship to
levodopa/carbidopa therapy has not been established.
Parkinson’s disease patients treated with dopamine agonists and other dopaminergic treatments such
as Stalevo, especially at high doses, have been reported as exhibiting signs of pathological gambling,
increased libido, hypersexuality and other urges, generally reversible upon reduction of the dose or
treatment discontinuation.
Entacapone in association with levodopa has been associated with isolated cases of excessive daytime
somnolence and sudden sleep onset episodes.
Levodopa/carbidopa may cause false positive result when a dipstick is used to test for urinary ketone
and this reaction is not altered by boiling the urine sample. The use of glucose oxidase methods may
give false negative results for glycosuria.
c.
Description of selected adverse reactions
Adverse reactions that are mainly attributable to entacapone or are more frequent with entacapone
than levodopa/DDC inhibitor alone are indicated with an asterisk in Table 1, section 4.8b. Some of
these adverse reactions relate to the increased dopaminergic activity (e.g. dyskinesia, nausea and
vomiting) and occur most commonly at the beginning of the treatment. Reduction of levodopa dose
19
decreases the severity and frequency of these dopaminergic reactions. Few adverse reactions are
known to be directly attributable to the active substance entacapone including diarrhoea and reddish-
brown discolouration of urine. Entacapone may in some cases cause also discolouration of e.g. skin,
nail, hair and sweat. Other adverse reactions with an asterisk in Table 1, section 4.8b are marked
based on either their more frequent occurring (by the frequency difference of at least 1%) in the
clinical trial data with entacapone than levodopa/DDCI alone or the individual case safety reports
received after the introduction of entacapone into the market.
The post-marketing data includes isolated cases of overdose in which the reported highest daily doses
of levodopa and entacapone have been at least 10,000 mg and 40,000 mg, respectively. The acute
symptoms and signs in these cases of overdose included agitation, confusional state, coma,
bradycardia, ventricular tachycardia, Cheyne-Stokes respiration, discolourations of skin, tongue and
conjunctiva, and chromaturia. Management of acute overdose with Stalevo therapy is similar to acute
overdose with levodopa. Pyridoxine, however, is not effective in reversing the actions of Stalevo.
Hospitalisation is advised and general supportive measures should be employed with immediate
gastric lavage and repeated doses of charcoal over time. This may hasten the elimination of
entacapone in particular by decreasing its absorption/reabsorption from the GI tract. The adequacy of
the respiratory, circulatory and renal systems should be carefully monitored and appropriate
supportive measures employed. ECG monitoring should be started and the patient carefully monitored
for the possible development of arrhythmias. If required, appropriate anti-arrhythmic therapy should
be given. The possibility that the patient has taken other active substances in addition to Stalevo
should be taken into consideration. The value of dialysis in the treatment of overdose is not known.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: dopa and dopa derivatives, ATC code:
N04BA03
According to the current understanding, the symptoms of Parkinson’s disease are related to depletion
of dopamine in the corpus striatum. Dopamine does not cross the blood-brain barrier. Levodopa, the
precursor of dopamine, crosses the blood brain barrier and relieves the symptoms of the disease. As
levodopa is extensively metabolised in the periphery, only a small portion of a given dose reaches the
central nervous system when levodopa is administered without metabolic enzyme inhibitors.
Carbidopa and benserazide are peripheral DDC inhibitors which reduce the peripheral metabolism of
levodopa to dopamine, and thus, more levodopa is available to the brain. When decarboxylation of
levodopa is reduced with the co-administration of a DDC inhibitor, a lower dose of levodopa can be
used and the incidence of undesirable effects such as nausea is reduced.
With inhibition of the decarboxylase by a DDC inhibitor, catechol-
O
-methyltransferase (COMT)
becomes the major peripheral metabolic pathway catalyzing the conversion of levodopa to 3-O-
methyldopa (3-OMD), a potentially harmful metabolite of levodopa. Entacapone is a reversible,
specific and mainly peripherally acting COMT inhibitor designed for concomitant administration with
levodopa. Entacapone slows the clearance of levodopa from the bloodstream resulting in an increased
area under the curve (AUC) in the pharmacokinetic profile of levodopa. Consequently the clinical
response to each dose of levodopa is enhanced and prolonged.
The evidence of the therapeutic effects of Stalevo is based on two phase III double-blind studies, in
which 376 Parkinson’s disease patients with end-of-dose motor fluctuations received either
entacapone or placebo with each levodopa/DDC inhibitor dose. Daily ON time with and without
entacapone was recorded in home-diaries by patients. In the first study, entacapone increased the
mean daily ON time by 1 h 20 min (CI
95%
45 min, 1 h 56 min) from baseline. This corresponded to an
20
8.3% increase in the proportion of daily ON time. Correspondingly, the decrease in daily OFF time
was 24% in the entacapone group and 0% in the placebo group. In the second study, the mean
proportion of daily ON time increased by 4.5% (CI
95%
0.93%, 7.97%) from baseline. This is translated
to a mean increase of 35 min in the daily ON time. Correspondingly, the daily OFF time decreased by
18% on entacapone and by 5% on placebo. Because the effects of Stalevo tablets are equivalent with
entacapone 200 mg tablet administered concomitantly with the commercially available standard
release carbidopa/levodopa preparations in corresponding doses these results are applicable to
describe the effects of Stalevo as well.
5.2 Pharmacokinetic properties
General characteristics of the active substances
Absorption/Distribution
:
There are substantial inter- and intra-individual variations in the absorption
of levodopa, carbidopa
and entacapone. Both levodopa and entacapone are rapidly absorbed and
eliminated. Carbidopa is absorbed and eliminated slightly slower compared with levodopa. When
given separately without the two other active substances, the bioavailability for levodopa is 15-33%,
for carbidopa 40-70% and for entacapone 35% after a 200 mg oral dose. Meals rich in large neutral
amino acids may delay and reduce the absorption of levodopa. Food does not significantly affect the
absorption of entacapone. The distribution volume of both levodopa (Vd 0.36-1.6 l/kg) and
entacapone (Vd
ss
0.27 l/kg) is moderately small while no data for carbidopa are available.
Levodopa is bound to plasma protein only to a minor extent of about 10-30% and carbidopa is bound
approximately 36%, while entacapone is extensively bound to plasma proteins (about 98%) –mainly to
serum albumin. At therapeutic concentrations, entacapone does not displace other extensively bound
active 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 and Elimination
:
Levodopa is extensively metabolised to various metabolites:
decarboxylation by dopa decarboxylase (DDC) and O-methylation by catechol-O-methyltransferase
(COMT) being the most important pathways.
Carbidopa is metabolized to two main metabolites which are excreted in the urine as glucuronides and
unconjugated compounds. Unchanged carbidopa accounts for 30% of the total urinary excretion.
Entacapone is almost completely metabolized prior to excretion via urine (10 to 20%) and bile/faeces
(80 to 90%). The main metabolic pathway is glucuronidation of entacapone and its active metabolite,
the cis-isomer, which accounts for about 5% of plasma total amount.
Total clearance for levodopa is in the range of 0.55-1.38 l/kg/h and for entacapone is in the range of
0.70 l/kg/h. The elimination-half life is (t
1/2
) is 0.6-1.3 hours for levodopa, 2-3 hours for carbidopa and
0.4-0.7 hours for entacapone, each given separately.
Due to short elimination half-lives, no true accumulation of levodopa or entacapone occurs on
repeated administration.
Data from
in vitro
studies using human liver microsomal preparations indicate that entacapone
inhibits cytochrome P450 2C9 (IC50 ~ 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.
Characteristics in patients
Elderly
: When given without carbidopa and entacapone, the absorption of levodopa is greater and
elimination is slower in elderly than in young subjects. However, after combination of carbidopa with
levodopa, the absorption of levodopa is similar between the elderly and the young, but the AUC is still
21
1.5 fold greater in the elderly due to decreased DDC activity and lower clearance by aging. There are
no significant differences in the AUC of carbidopa or entacapone between younger (45–64 years) and
elderly subjects (65–75 years).
Gender
:
Bioavailability of levodopa is significantly higher in women than in men. In the
pharmacokinetic studies with Stalevo
the bioavailability of levodopa is higher in women than in men,
primarily due to the difference in body weight, while there is no gender difference with carbidopa and
entacapone.
Hepatic impairment
:
The metabolism of entacapone is slowed in patients with mild to moderate
hepatic impairment (Child-Pugh Class A and B) leading to an increased plasma concentration of
entacapone both in the absorption and elimination phases (see sections 4.2 and 4.3). No particular
studies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic impairment are
reported, however, it is advised that Stalevo
should be administered cautiously to patients with mild or
moderate hepatic impairment.
Renal impairment
: Renal impairment does not affect the pharmacokinetics of entacapone. No
particular studies are reported on the pharmacokinetics of levodopa and carbidopa in patients with
renal impairment. However, a longer dosing interval of Stalevo may be considered for patients who
are receiving dialysis therapy (see section 4.2).
5.3 Preclinical safety data
Preclinical data of levodopa, carbidopa and entacapone, tested alone or in combination, revealed no
special hazard for humans based on conventional studies of safety pharmacology, repeated dose
toxicity, genotoxicity, and carcinogenic potential. In repeated dose toxicity studies with entacapone,
anaemia most likely due to iron chelating properties of entacapone was observed. Regarding
reproduction toxicity of entacapone, decreased foetal weight and a slightly delayed bone development
were noticed in rabbits treated at systemic exposure levels in the therapeutic range. Both levodopa and
combinations of carbidopa and levodopa have caused visceral and skeletal malformations in rabbits.
6.1 List of excipients
Tablet core
:
Croscarmellose sodium
Magnesium stearate
Maize starch
Mannitol (E421)
Povidone (E1201)
Film-coating
:
Glycerol (85 per cent) (E422)
Hypromellose
Magnesium stearate
Polysorbate 80
Red iron oxide (E172)
Sucrose
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable.
22
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
HDPE bottle with a child resistant PP-closure.
Pack sizes:
10, 30, 100, 130 and 175 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
Orion Corporation
Orionintie 1
FI-02200 Espoo
Finland
8. MARKETING AUTHORISATION NUMBERS
EU/1/03/260/024-028
Date of first authorisation: 17 October 2003
Date of last renewal: 15 September 2008
Detailed information on this medicine is available on the European Medicine’s Agency (EMA) web
site:
http://www.ema.europa.eu
23
1.
Stalevo 100 mg/25 mg/200 mg film-coated tablets
Each tablet contains 100 mg of levodopa, 25 mg of carbidopa and 200 mg of entacapone.
Excipient:
Each tablet contains
1.6 mg
of sucrose
.
For a full list of excipients, see section 6.1.
Film-coated tablet
Brownish or greyish red, oval, unscored film-coated tablets marked with ‘LCE 100’ on one side.
Stalevo is indicated for the treatment of adult patients with Parkinson’s disease and end-of-dose motor
fluctuations not stabilised on levodopa/dopa decarboxylase (DDC) inhibitor treatment.
Each tablet is to be taken orally either with or without food (see section 5.2). One tablet contains one
treatment dose and the tablet may only be administered as whole tablets.
The optimum daily dose must be determined by careful titration of levodopa in each patient. The daily
dose should be preferably optimised using one of the six available tablet strengths
(50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg, 100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg
150 mg/37.5 mg/200 mg or 200 mg/50 mg/200 mg levodopa/carbidopa/entacapone).
Patients should be instructed to take only one Stalevo tablet per dose administration. Patients
receiving less than 70-100 mg carbidopa a day are more likely to experience nausea and vomiting.
While the experience with total daily dose greater than 200 mg carbidopa is limited, the maximum
recommended daily dose of entacapone is 2,000 mg and therefore the maximum dose is 10 tablets per
day
for the Stalevo strengths of 50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg,
100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg and 150 mg/37.5 mg/200 mg. Ten tablets of Stalevo
150 mg/37.5 mg/200 mg equals 375 mg of carbidopa a day. According to this daily carbidopa dose,
the maximum recommended daily Stalevo 200 mg/50 mg/200 mg dose is 7 tablets per day.
Usually Stalevo is to be used in patients who are currently treated with corresponding doses of
standard release levodopa/DDC inhibitor and entacapone.
How to transfer patients taking levodopa/DDC inhibitor (carbidopa or benserazide) preparations and
entacapone tablets to Stalevo
a
. Patients who are currently treated with entacapone and with standard release levodopa/carbidopa in
doses equal to Stalevo tablet
strengths can be directly transferred to corresponding Stalevo tablets.
For example, a patient taking one tablet of 100 mg/25 mg of levodopa/carbidopa with one tablet of
24
entacapone 200 mg four times daily can take one 100 mg/25 mg/200 mg Stalevo tablet four times
daily in place of their usual levodopa/carbidopa and entacapone doses.
b.
When initiating Stalevo therapy for patients currently treated with entacapone and
levodopa/carbidopa in doses not equal to Stalevo 100 mg/25 mg/200 mg, (or 50 mg/12.5 mg/200 mg
or 75 mg/18.75 mg/200 mg or 125 mg/31.25 mg/200 mg or 150 mg/37.5 mg/200 mg or
200 mg/50 mg/200 mg) tablets, Stalevo dosing should be carefully titrated for optimal clinical
response. At the initiation, Stalevo should be adjusted to correspond as closely as possible to the total
daily dose of levodopa currently used.
c.
When initiating Stalevo in patients currently treated with entacapone and levodopa/benserazide in a
standard release formulation, discontinue dosing of levodopa/benserazide the previous night, and start
Stalevo the next morning. Begin with a dose of Stalevo that will provide either the same amount of
levodopa or slightly (5-10%) more.
How to transfer patients not currently treated with entacapone to Stalevo
Initiation of Stalevo may be considered at corresponding doses to current treatment in some patients
with Parkinson's disease and end-of-dose motor fluctuations, who are not stabilised on their current
standard release levodopa/DDC inhibitor treatment. However, a direct switch from levodopa/DDC
inhibitor to Stalevo is not recommended for patients who have dyskinesias or whose daily levodopa
dose is above 800 mg. In such patients it is advisable to introduce entacapone treatment as a separate
treatment (entacapone tablets) and adjust the levodopa dose if necessary, before switching to Stalevo.
Entacapone enhances the effects of levodopa. It may therefore be necessary, particularly in patients
with dyskinesia, to reduce levodopa dose by 10-30% within the first days to first weeks after initiating
Stalevo treatment. The daily dose of levodopa can be reduced by extending the dosing intervals and/or
by reducing the amount of levodopa per dose, according to the clinical condition of the patient.
Dose adjustment during the course of the treatment
When more levodopa is required, an increase in the frequency of doses and/or the use of an alternative
strength of Stalevo should be considered, within the dose recommendations.
When less levodopa is required, the total daily dose of Stalevo should be reduced either by decreasing
the frequency of administration by extending the time between doses, or by decreasing the strength of
Stalevo at an administration.
If other levodopa products are used concomitantly with a Stalevo tablet, the maximum dose
recommendations should be followed.
Discontinuation of Stalevo therapy
:
If Stalevo treatment (levodopa/carbidopa/entacapone) is
discontinued and the patient is transferred to levodopa/DDC inhibitor therapy without entacapone, it
is necessary to adjust the dosing of other antiparkinsonian treatments, especially levodopa, to achieve
a sufficient level of control of the parkinsonian symptoms.
Children and adolescents
:
Stalevo is not recommended for use in children below 18 years due to a
lack of data on safety and efficacy.
Elderly
:
No dose adjustment of Stalevo is required for elderly patients.
Hepatic impairment
:
It is advised that Stalevo should be administered cautiously to patients with mild
to moderate hepatic impairment. Dose reduction may be needed (see section 5.2).
For severe hepatic
impairment see section 4.3
25
Renal impairment:
Renal
impairment
does not affect the pharmacokinetics of entacapone. No
particular studies are reported on the pharmacokinetics of levodopa and carbidopa in patients with
renal insufficiency, therefore Stalevo therapy should be administered cautiously to patients in severe
renal impairment including those receiving dialysis therapy (see section 5.2).
-
Hypersensitivity to the active substances or to any of the excipients.
-
Severe hepatic impairment.
-
Narrow-angle glaucoma.
-
Pheochromocytoma.
-
Concomitant use of Stalevo with non-selective monoamine oxidase (MAO-A and MAO-B)
inhibitors (e.g. phenelzine, tranylcypromine).
-
Concomitant use of a selective MAO-A inhibitor and a selective MAO-B inhibitor (see section
4.5).
-
A previous history of Neuroleptic Malignant Syndrome (NMS) and/or non-traumatic
rhabdomyolysis.
-
Stalevo is not recommended for the treatment of drug-induced extrapyramidal reactions
-
Stalevo therapy should be administered cautiously to patients with ischemic heart disease,
severe cardiovascular or pulmonary disease, bronchial asthma, renal or endocrine disease,
history of peptic ulcer disease or history of convulsions.
-
In patients with a history of myocardial infarction who have residual atrial nodal or ventricular
arrhythmias; cardiac function should be monitored with particular care during the period of
initial dose adjustments.
-
All patients treated with Stalevo should be monitored carefully for the development of mental
changes, depression with suicidal tendencies, and other serious antisocial behaviour. Patients
with past or current psychosis should be treated with caution.
-
Concomitant administration of antipsychotics with dopamine receptor-blocking properties,
particularly D
2
receptor antagonists should be carried out with caution, and the patient carefully
observed for loss of antiparkinsonian effect or worsening of parkinsonian symptoms.
-
Patients with chronic wide-angle glaucoma may be treated with Stalevo with caution, provided
the intra-ocular pressure is well controlled and the patient is monitored carefully for changes in
intra-ocular pressure.
-
Stalevo may induce orthostatic hypotension. Therefore Stalevo should be given cautiously to
patients who are taking other medicinal products which may cause orthostatic hypotension.
-
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 section 4.7).
-
In clinical studies, dopaminergic adverse reactions, 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 Stalevo treatment is
substituted for a patient currently not treated with entacapone.
-
Rhabdomyolysis secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS) has
been observed rarely in patients with Parkinson’s disease. Therefore, any abrupt dose reduction
or withdrawal of levodopa should be carefully observed, particularly in patients who are also
receiving neuroleptics. 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. The early diagnosis is important for the appropriate management of
NMS. A syndrome resembling the neuroleptic malignant syndrome including muscular rigidity,
elevated body temperature, mental changes and increased serum creatine phosphokinase has
26
been reported with the abrupt withdrawal of antiparkinsonian agents. Neither NMS nor
rhabdomyolysis have been reported in association with entacapone treatment from controlled
trials in which entacapone was discontinued abruptly. Since the introduction of entacapone 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, the replacement of Stalevo with levodopa and DDC inhibitor without
entacapone or other dopaminergic treatment should proceed slowly and an increase in levodopa
dose may be necessary.
-
If general anaesthesia is required, therapy with Stalevo may be continued for as long as the
patient is permitted to take fluids and medicinal products by mouth. If therapy has to be stopped
temporarily, Stalevo may be restarted as soon as oral medicinal products can be taken at the
same daily dose as before.
-
Periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function is
recommended during extended therapy with Stalevo.
-
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
Stalevo.
-
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.
-
Stalevo contains sucrose, and therefore patients with rare hereditary problems of fructose
intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take
this medicine.
Other antiparkinsonian medicinal products
: To date there has been no indication of interactions that
would preclude concurrent use of standard antiparkinsonian medicinal products with Stalevo therapy.
Entacapone in high doses may affect the absorption of carbidopa. However, no interaction with
carbidopa has been observed with the recommended treatment schedule (200 mg of entacapone up to
10 times daily). Interactions between entacapone and selegiline have been investigated in repeated
dose studies in Parkinson's disease patients treated with levodopa/DDC inhibitor and no interaction
was observed. When used with Stalevo, the daily dose of selegiline should not exceed 10 mg.
Caution should be exercised when the following active substances are administered concomitantly
with levodopa therapy.
Antihypertensives
: Symptomatic postural hypotension may occur when levodopa is added to the
treatment of patients already receiving antihypertensives. Dose adjustment of the antihypertensive
agent may be required.
Antidepressants:
Rarely, reactions including hypertension and dyskinesia have been reported with the
concomitant use of tricyclic antidepressants and levodopa/carbidopa. Interactions between entacapone
and imipramine and between entacapone and moclobemide have been investigated in single dose
studies in healthy volunteers. No pharmacodynamic interactions were observed. A significant number
of Parkinson's disease patients have been treated with the combination of levodopa, carbidopa and
entacapone with several active substances 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, paroxetine). No
pharmacodynamic interactions have been observed. However, caution should be exercised when these
medicinal products are used concomitantly with Stalevo (see sections 4.3 and 4.4).
27
Other active substances:
Dopamine receptor antagonists (e.g. some antipsychotics and antiemetics),
phenytoin and papaverine may reduce the therapeutic effect of levodopa. Patients taking these
medicinal products with Stalevo should be carefully observed for loss of therapeutic response.
Due to entacapone's affinity to cytochrome P450 2C9
in vitro
(see section 5.2), Stalevo may
potentially interfere with active substances whose metabolism is dependent on this isoenzyme, such as
S-warfarin. 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, a control of INR is
recommended when Stalevo is initiated for patients receiving warfarin.
Other forms of interactions:
Since levodopa competes with certain amino acids, the absorption of
Stalevo may be impaired in some patients on high protein diet.
Levodopa and entacapone may form chelates with iron in the gastrointestinal tract. Therefore, Stalevo
and iron preparations should be taken at least 2-3 hours apart (see section 4.8).
In vitro data:
Entacapone binds to human albumin binding site II which also binds several other
medicinal products, including diazepam and ibuprofen. According to
in vitro
studies, significant
displacement is not anticipated at therapeutic concentrations of the medicinal products. Accordingly,
to date there has been no indication of such interactions.
There are no adequate data from the use of the combination of levodopa/carbidopa/entacapone in
pregnant women. Studies in animals have shown reproductive toxicity of the separate compounds (see
section 5.3). The potential risk for humans is unknown. Stalevo should not be used during pregnancy
unless the benefits for the mother outweigh the possible risks to the foetus.
Levodopa is excreted in human breast milk. There is evidence that lactation is suppressed during
treatment with levodopa. Carbidopa and entacapone were excreted in milk in animals but is not known
whether they are excreted in human breast milk. The safety of levodopa, carbidopa or entacapone in
the infant is not known. Women should not breast-feed during treatment with Stalevo.
Stalevo may have major influence on the ability to drive and use machines. Levodopa, carbidopa and
entacapone together may cause dizziness and symptomatic orthostatism. Therefore, caution should be
exercised when driving or using machines.
Patients being treated with Stalevo 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 section 4.4).
a.
Summary of the safety profile
The most frequently reported adverse reactions with Stalevo are dyskinesias occurring in
approximately 19% of patients; gastrointestinal symptoms including nausea and diarrhoea occurring
in approximately 15% and 12% of patients, respectively; muscle, musculoskeletal and connective
tissue pain occurring in approximately 12% of patients; and harmless reddish-brown discolouration of
urine (chromaturia) occurring in approximately 10% of patients. Serious events of gastrointestinal
haemorrhage (uncommon) and angioedema (rare) have been identified from the clinical trials with
Stalevo or entacapone combined with levodopa/DDC inhibitor. Serious hepatitis with mainly
28
cholestatic features, rhabdomyolysis and neuroleptic malignant syndrome may occur with Stalevo
although no cases have been identified from the clinical trial data.
b.
Tabulated list of adverse reactions
The following adverse reactions, listed in Table 1, have been accumulated both from a pooled data of
eleven double-blind clinical trials consisting of 3230 patients (1810 treated with Stalevo or
entacapone combined with levodopa/DDC inhibitor, and 1420 treated with placebo combined with
levodopa/DDC inhibitor or cabergoline combined with levodopa/ DDC inhibitor), and from the post-
marketing data since the introduction of entacapone into the market for the combination use of
entacapone with levodopa/DDC inhibitor.
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).
Table 1.
Adverse reactions
Blood and lymphatic system disorders
Common:
Anaemia
Uncommon:
Thrombocytopenia
Metabolism and nutrition disorders
Common:
Weight decreased*, decreased appetite*
Psychiatric disorders
Common: Depression, hallucination, confusional state*, abnormal dreams*,
anxiety, insomnia
Uncommon :
Psychosis, agitation*
Not known:
Suicidal behaviour
Nervous system disorders
Very common: Dyskinesia*
Common: Parkinsonism aggravated (e.g. bradykinesia)*,tremor, on
and off phenomenon, dystonia, mental impairment (e.g. memory
impairment, dementia), somnolence, dizziness*, headache
Not known:
Neuroleptic malignant syndrome*
Eye disorders
Common:
Blurred vision
Cardiac disorders
Common: Ischemic heart disease events other than myocardial infarction (e.g. angina
pectoris)**, irregular heart rhythm
Uncommon:
Myocardial infarction**
Vascular disorders:
Common:
Orthostatic hypotension, hypertension
Uncommon:
Gastrointestinal haemorrhage
Respiratory, thoracic and mediastinal disorders
Common:
Dyspnoea
Gastrointestinal disorders
Very common: Diarrhoea*, nausea*
29
Common: Constipation*, vomiting*, dyspepsia, abdominal pain and discomfort*, dry mouth*
Uncommon:
Colitis*, dysphagia
Hepatobiliary disorders
Uncommon:
Hepatic function test abnormal*
Not known:
Hepatitis with mainly cholestatic features (see section 4.4)*
Skin and subcutaneous tissue disorders
Common:
Rash*, hyperhidrosis
Uncommon:
Discolourations other than urine (e.g. skin, nail, hair, sweat)*
Rare:
Angioedema
Not known:
Urticaria*
Musculoskeletal and connective tissue disorders
Very common: Muscle, musculoskeletal and connective tissue pain*
Common:
Muscle spasms, arthralgia
Not known:
Rhabdomyolysis*
Renal and urinary disorders
Very common: Chromaturia*
Common:
Urinary tract infection
Uncommon:
Urinary retention
General disorders and administration site conditions
Common: Chest pain, peripheral oedema, fall, gait disturbance, asthenia, fatigue
Uncommon:
Malaise
*Adverse reactions that are mainly attributable to entacapone or are more frequent (by the frequency
difference of at least 1% in the clinical trial data) with entacapone than levodopa/DDC inhibitor
alone. See section c.
**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.
Convulsions have occurred rarely with levodopa/carbidopa; however a causal relationship to
levodopa/carbidopa therapy has not been established.
Parkinson’s disease patients treated with dopamine agonists and other dopaminergic treatments such
as Stalevo, especially at high doses, have been reported as exhibiting signs of pathological gambling,
increased libido, hypersexuality and other urges, generally reversible upon reduction of the dose or
treatment discontinuation.
Entacapone in association with levodopa has been associated with isolated cases of excessive daytime
somnolence and sudden sleep onset episodes.
Levodopa/carbidopa may cause false positive result when a dipstick is used to test for urinary ketone
and this reaction is not altered by boiling the urine sample. The use of glucose oxidase methods may
give false negative results for glycosuria.
c.
Description of selected adverse reactions
Adverse reactions that are mainly attributable to entacapone or are more frequent with entacapone
than levodopa/DDC inhibitor alone are indicated with an asterisk in Table 1, section 4.8b. Some of
these adverse reactions relate to the increased dopaminergic activity (e.g. dyskinesia, nausea and
vomiting) and occur most commonly at the beginning of the treatment. Reduction of levodopa dose
30
decreases the severity and frequency of these dopaminergic reactions. Few adverse reactions are
known to be directly attributable to the active substance entacapone including diarrhoea and reddish-
brown discolouration of urine. Entacapone may in some cases cause also discolouration of e.g. skin,
nail, hair and sweat. Other adverse reactions with an asterisk in Table 1, section 4.8b are marked
based on either their more frequent occurring (by the frequency difference of at least 1%) in the
clinical trial data with entacapone than levodopa/DDCI alone or the individual case safety reports
received after the introduction of entacapone into the market.
The post-marketing data includes isolated cases of overdose in which the reported highest daily doses
of levodopa and entacapone have been at least 10,000 mg and 40,000 mg, respectively. The acute
symptoms and signs in these cases of overdose included agitation, confusional state, coma,
bradycardia, ventricular tachycardia, Cheyne-Stokes respiration, discolourations of skin, tongue and
conjunctiva, and chromaturia. Management of acute overdose with Stalevo therapy is similar to acute
overdose with levodopa. Pyridoxine, however, is not effective in reversing the actions of Stalevo.
Hospitalisation is advised and general supportive measures should be employed with immediate
gastric lavage and repeated doses of charcoal over time. This may hasten the elimination of
entacapone in particular by decreasing its absorption/reabsorption from the GI tract. The adequacy of
the respiratory, circulatory and renal systems should be carefully monitored and appropriate
supportive measures employed. ECG monitoring should be started and the patient carefully monitored
for the possible development of arrhythmias. If required, appropriate anti-arrhythmic therapy should
be given. The possibility that the patient has taken other active substances in addition to Stalevo
should be taken into consideration. The value of dialysis in the treatment of overdose is not known.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: dopa and dopa derivatives, ATC code:
N04BA03
According to the current understanding, the symptoms of Parkinson’s disease are related to depletion
of dopamine in the corpus striatum. Dopamine does not cross the blood-brain barrier. Levodopa, the
precursor of dopamine, crosses the blood brain barrier and relieves the symptoms of the disease. As
levodopa is extensively metabolised in the periphery, only a small portion of a given dose reaches the
central nervous system when levodopa is administered without metabolic enzyme inhibitors.
Carbidopa and benserazide are peripheral DDC inhibitors which reduce the peripheral metabolism of
levodopa to dopamine, and thus, more levodopa is available to the brain. When decarboxylation of
levodopa is reduced with the co-administration of a DDC inhibitor, a lower dose of levodopa can be
used and the incidence of undesirable effects such as nausea is reduced.
With inhibition of the decarboxylase by a DDC inhibitor, catechol-
O
-methyltransferase (COMT)
becomes the major peripheral metabolic pathway catalyzing the conversion of levodopa to 3-O-
methyldopa (3-OMD), a potentially harmful metabolite of levodopa. Entacapone is a reversible,
specific and mainly peripherally acting COMT inhibitor designed for concomitant administration with
levodopa. Entacapone slows the clearance of levodopa from the bloodstream resulting in an increased
area under the curve (AUC) in the pharmacokinetic profile of levodopa. Consequently the clinical
response to each dose of levodopa is enhanced and prolonged.
The evidence of the therapeutic effects of Stalevo is based on two phase III double-blind studies, in
which 376 Parkinson’s disease patients with end-of-dose motor fluctuations received either
entacapone or placebo with each levodopa/DDC inhibitor dose. Daily ON time with and without
entacapone was recorded in home-diaries by patients. In the first study, entacapone increased the
mean daily ON time by 1 h 20 min (CI
95%
45 min, 1 h 56 min) from baseline. This corresponded to an
31
8.3% increase in the proportion of daily ON time. Correspondingly, the decrease in daily OFF time
was 24% in the entacapone group and 0% in the placebo group. In the second study, the mean
proportion of daily ON time increased by 4.5% (CI
95%
0.93%, 7.97%) from baseline. This is translated
to a mean increase of 35 min in the daily ON time. Correspondingly, the daily OFF time decreased by
18% on entacapone and by 5% on placebo. Because the effects of Stalevo tablets are equivalent with
entacapone 200 mg tablet administered concomitantly with the commercially available standard
release carbidopa/levodopa preparations in corresponding doses these results are applicable to
describe the effects of Stalevo as well.
5.2 Pharmacokinetic properties
General characteristics of the active substances
Absorption/Distribution
:
There are substantial inter- and intra-individual variations in the absorption
of levodopa, carbidopa
and entacapone. Both levodopa and entacapone are rapidly absorbed and
eliminated. Carbidopa is absorbed and eliminated slightly slower compared with levodopa. When
given separately without the two other active substances, the bioavailability for levodopa is 15-33%,
for carbidopa 40-70% and for entacapone 35% after a 200 mg oral dose. Meals rich in large neutral
amino acids may delay and reduce the absorption of levodopa. Food does not significantly affect the
absorption of entacapone. The distribution volume of both levodopa (Vd 0.36-1.6 l/kg) and
entacapone (Vd
ss
0.27 l/kg) is moderately small while no data for carbidopa are available.
Levodopa is bound to plasma protein only to a minor extent of about 10-30% and carbidopa is bound
approximately 36%, while entacapone is extensively bound to plasma proteins (about 98%) –mainly to
serum albumin. At therapeutic concentrations, entacapone does not displace other extensively bound
active 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 and Elimination
:
Levodopa is extensively metabolised to various metabolites:
decarboxylation by dopa decarboxylase (DDC) and O-methylation by catechol-O-methyltransferase
(COMT) being the most important pathways.
Carbidopa is metabolized to two main metabolites which are excreted in the urine as glucuronides and
unconjugated compounds. Unchanged carbidopa accounts for 30% of the total urinary excretion.
Entacapone is almost completely metabolized prior to excretion via urine (10 to 20%) and bile/faeces
(80 to 90%). The main metabolic pathway is glucuronidation of entacapone and its active metabolite,
the cis-isomer, which accounts for about 5% of plasma total amount.
Total clearance for levodopa is in the range of 0.55-1.38 l/kg/h and for entacapone is in the range of
0.70 l/kg/h. The elimination-half life is (t
1/2
) is 0.6-1.3 hours for levodopa, 2-3 hours for carbidopa and
0.4-0.7 hours for entacapone, each given separately.
Due to short elimination half-lives, no true accumulation of levodopa or entacapone occurs on
repeated administration.
Data from
in vitro
studies using human liver microsomal preparations indicate that entacapone
inhibits cytochrome P450 2C9 (IC50 ~ 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.
Characteristics in patients
Elderly
: When given without carbidopa and entacapone, the absorption of levodopa is greater and
elimination is slower in elderly than in young subjects. However, after combination of carbidopa with
levodopa, the absorption of levodopa is similar between the elderly and the young, but the AUC is still
32
1.5 fold greater in the elderly due to decreased DDC activity and lower clearance by aging. There are
no significant differences in the AUC of carbidopa or entacapone between younger (45–64 years) and
elderly subjects (65–75 years).
Gender
:
Bioavailability of levodopa is significantly higher in women than in men. In the
pharmacokinetic studies with Stalevo
the bioavailability of levodopa is higher in women than in men,
primarily due to the difference in body weight, while there is no gender difference with carbidopa and
entacapone.
Hepatic impairment
:
The metabolism of entacapone is slowed in patients with mild to moderate
hepatic impairment (Child-Pugh Class A and B) leading to an increased plasma concentration of
entacapone both in the absorption and elimination phases (see sections 4.2 and 4.3). No particular
studies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic impairment are
reported, however, it is advised that Stalevo
should be administered cautiously to patients with mild or
moderate hepatic impairment.
Renal impairment
: Renal impairment does not affect the pharmacokinetics of entacapone. No
particular studies are reported on the pharmacokinetics of levodopa and carbidopa in patients with
renal impairment. However, a longer dosing interval of Stalevo may be considered for patients who
are receiving dialysis therapy (see section 4.2).
5.3 Preclinical safety data
Preclinical data of levodopa, carbidopa and entacapone, tested alone or in combination, revealed no
special hazard for humans based on conventional studies of safety pharmacology, repeated dose
toxicity, genotoxicity, and carcinogenic potential. In repeated dose toxicity studies with entacapone,
anaemia most likely due to iron chelating properties of entacapone was observed. Regarding
reproduction toxicity of entacapone, decreased foetal weight and a slightly delayed bone development
were noticed in rabbits treated at systemic exposure levels in the therapeutic range. Both levodopa and
combinations of carbidopa and levodopa have caused visceral and skeletal malformations in rabbits.
6.1 List of excipients
Tablet core
:
Croscarmellose sodium
Magnesium stearate
Maize starch
Mannitol (E421)
Povidone (E1201)
Film-coating
:
Glycerol (85 per cent) (E422)
Hypromellose
Magnesium stearate
Polysorbate 80
Red iron oxide (E172)
Sucrose
Titanium dioxide (E171)
Yellow iron oxide (E172)
6.2 Incompatibilities
Not applicable.
33
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
HDPE bottle with a child resistant PP-closure.
Pack sizes:
10, 30, 100, 130, 175 and 250 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
Orion Corporation
Orionintie 1
FI-02200 Espoo
Finland
8. MARKETING AUTHORISATION NUMBERS
EU/1/03/260/005-008
EU/1/03/260/014
EU/1/03/260/017
Date of first authorisation: 17 October 2003
Date of last renewal: 15 September 2008
Detailed information on this medicine is available on the European Medicine’s Agency (EMA) web
site:
http://www.ema.europa.eu
34
FURTHER INFORMATION
124
What Stalevo contains
-
The active substances of Stalevo are levodopa, carbidopa and entacapone.
-
Each Stalevo 200 mg/50 mg/200 mg tablet contains 200 mg of levodopa, 50 mg of carbidopa and
200 mg of entacapone.
-
The other ingredients in the tablet core are croscarmellose sodium, magnesium stearate, maize
starch, mannitol (E421) and povidone (E1201).
-
The ingredients in the film-coating are glycerol (85 per cent) (E422), hypromellose, magnesium
stearate, polysorbate 80, red iron oxide (E172), sucrose and titanium dioxide (E171).
What Stalevo looks like and contents of the pack
Stalevo 200 mg/50 mg/200 mg: dark brownish red, oval, unscored film-coated tablets marked with
‘LCE 200’ on one side.
Stalevo 200 mg/50 mg/200 mg tablet comes in five different pack sizes (10, 30, 100, 130 or 175
tablets). Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Orion Corporation
Orionintie 1
FI-02200 Espoo
Finland
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
Belgique/België/Belgien
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11
Luxembourg/Luxemburg
Novartis Pharma GmbH
Allemagne/Deutschland
Tél/Tel: +49 911 273 0
България
Novartis Pharma Services Inc.
Тел.: +359 2 489 98 28
Magyarország
Novartis Hungária Kft. Pharma
Tel.: +36 1 457 65 00
Česká republika
Novartis s.r.o.
Tel: +420 225 775 111
Malta
Novartis Pharma Services Inc.
Tel: + 356 2298 3217
Danmark
Orion Pharma A/S
Tlf: +45 49 12 66 00
Nederland
Novartis Pharma B.V.
Tel: +31 26 37 82 111
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 66 44 551
Österreich
Novartis Pharma GmbH
Tel: +43 1 86 6570
Ελλά
Novartis (Hellas) Α.Δ.Β.Δ.
Τηλ: + 30 210 281 17 12
Polska
Orion Pharma Poland Sp z.o.o.
Tel.: + 48 22 8333177, 8321036
125
España
Novartis Farmacéutica, S.A.
Tel: +34 93 306 42 00
Portugal
Novartis Farma - Produtos Farmacęuticos, S.A.
Tel: +351 21 000 8600
France
Novartis Pharma S.A.S.
Tél: +33 1 55 47 66 00
România
Novartis Pharma Services Inc.
Tel: +40 21 31299 01
Ireland
Orion Pharma (Ireland) Ltd.
c/o Allphar Services Ltd.
Tel: +353 1 404 16 00
Slovenija
Novartis Pharma Services Inc.
Tel: +386 1 300 75 50
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Novartis Slovakìa s.r.o.
Tel: +421 2 5542 5439
Italia
Novartis Farma S.p.A.
Tel: +39 02 96 54 1
Suomi/Finland
Orion Corporation
Puh./Tel: +358 10 4261
Κύπρς
Γημητριάης κι Ππέλληνς Λτ
Τηλ: +357 22 690 690
Sverige
Orion Pharma AB
Tel: +46 8 623 6440
Latvija
Orion Corporation
Orion Pharma pārstāvniecība
Tel: +371 745 55 63
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 on {date}
Detailed information on this medicine is available on the European Medicine’s Agency (EMA) web
site:
http://www.ema.europa.eu
126
Source: European Medicines Agency
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