ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Tasmar 100 mg film-coated tablets
2.
Each film-coated tablet contains 100 mg tolcapone.
Excipients: Each tablet contains 7.5 mg lactose
For a full list of excipients, see section 6.1
3.
Film-coated tablet.
Pale to light yellow, hexagonal, biconvex, film-coated tablet. “TASMAR” and “100” are engraved on
one side.
4.
Tasmar is indicated in combination with levodopa/benserazide or levodopa/carbidopa for use in
patients with levodopa-responsive idiopathic Parkinson’s disease and motor fluctuations, who failed to
respond to or are intolerant of other catechol-O-methyltransferase COMT inhibitors (see section 5.1).
Because of the risk of potentially fatal, acute liver injury, Tasmar should not be considered as a first-
line adjunct therapy to levodopa/benserazide or levodopa/carbidopa (see sections 4.4 and 4.8).
Since Tasmar should be used only in combination with levodopa/benserazide and levodopa/carbidopa,
the prescribing information for these levodopa preparations is also applicable to their concomitant use
with Tasmar.
The administration of Tasmar is restricted to prescription and supervision by physicians experienced
in the management of advanced Parkinson's disease.
The first dose of the day of Tasmar should be taken together the first dose of the day of a levodopa
preparation, and the subsequent doses should be given approximately 6 and 12 hours later. Tasmar
may be taken with or without food (see section 5.2).
The recommended dose of Tasmar is 100 mg three times daily, always as an adjunct to
levodopa/benserazide or levodopa/carbidopa therapy. Only in exceptional circumstances, when the
anticipated incremental clinical benefit justifies the increased risk of hepatic reactions, should the dose
be increased to 200 mg three times daily. (see sections 4.4 and 4.8). If substantial clinical benefits are
not seen within 3 weeks of the initiation of the treatment (regardless of dose) Tasmar should be
discontinued.
The maximum therapeutic dose of 200 mg three times daily should not be exceeded, as there is no
evidence of additional efficacy at higher doses.
Liver function should be checked before starting treatment with Tasmar and then monitored every 2
weeks for the first year of therapy, every 4 weeks for the next 6 months and every 8 weeks thereafter.
If the dose is increased to 200 mg tid, liver enzyme monitoring should take place before increasing the
dose and then be reinitiated following the same sequence of frequencies as above (see sections 4.4
and 4.8).
2
Tasmar treatment should also be discontinued if ALT (alanine amino transferase) and/or AST
(aspartate amino transferase) exceed the upper limit of normal or symptoms or signs suggest the onset
of hepatic failure (see section 4.4).
Levodopa adjustments during Tasmar treatment:
As Tasmar decreases the breakdown of levodopa in the body, side effects due to increased levodopa
concentrations may occur when beginning Tasmar treatment. In clinical trials, more than 70 % of
patients required a decrease in their daily levodopa dose if their daily dose of levodopa was >600 mg
or if patients had moderate or severe dyskinesias before beginning treatment.
The average reduction in daily levodopa dose was about 30 % in those patients requiring a levodopa
dose reduction. When beginning Tasmar, all patients should be informed of the symptoms of excessive
levodopa dose and what to do if it occurs.
Levodopa adjustments when Tasmar is discontinued:
The following suggestions are based on pharmacological considerations and have not been evaluated
in clinical trials. Levodopa dose should not be decreased when Tasmar therapy is being discontinued
due to side effects related to too much levodopa. However, when Tasmar therapy is being
discontinued for reasons other than too much levodopa, levodopa dosemay have to be increased to
levels equal to or greater than before initiation of Tasmar therapy, especially if the patient had large
decreases in levodopa when starting Tasmar. In all cases, patients should be educated on the
symptoms of levodopa under-dose and what to do if it occurs. Adjustments in levodopa are most likely
to be required within 1-2 days of Tasmar discontinuation.
Patients with renal impairment (see section 5.2)
:
No dose adjustment of Tasmar is recommended for
patients with mild or moderate renal impairment (creatinine clearance of 30 ml/min or greater).
Patients with severe renal impairment (creatinine clearance <30 ml/min) should be treated with
caution. No information on the tolerability of tolcapone in these populations is available (see section
5.2)
Patients with hepatic impairment (see section 4.3)
:
Tasmar is contraindicated for patients with liver
disease or increased liver enzymes.
Elderly patients
:
No dose adjustment of Tasmar is recommended for elderly patients.
Children and adolscents
:
Tasmar is not recommended for use in children below the age of 18 due to
insufficient data on safety or efficacy. There is no relevant indication for use in children and
adolescents.
Method of administration
Tasmar is administered orally three times daily.
Tasmar may be taken with or without food (see section 5.2).
Tasmar tablets are film-coated and should be swallowed whole because tolcapone has a bitter taste.
Tasmar can be combined with all pharmaceutical formulations of levodopa/benserazide and
levodopa/carbidopa (see also section 4.5).
•
Hypersensitivity to tolcapone or any of its other ingredients.
•
Evidence of liver disease or increased liver enzymes
•
A previous history of Neuroleptic Malignant Syndrome (NMS) Symptom Complex and /or
non-traumatic Rhabdomyolysis or Hyperthermia.
•
Phaeochromocytoma.
•
Treatment with non-selective mono amino oxidase (MAO) inhibitors
3
•
Severe dyskinesia
Tasmar therapy should only be initiated by physicians experienced in the management of
advanced Parkinson’s disease, to ensure an appropriate risk-benefit assessment. Tasmar should
not be prescribed until there has been a complete informative discussion of the risks with the
patient.
Tasmar should be discontinued if substantial clinical benefits are not seen within 3 weeks of the
initiation of the treatment regardless of dose.
Liver injury:
Because of the risk of rare but potentially fatal acute liver injury, Tasmar is only indicated for
use in patients with levodopa-responsive idiopathic Parkinson’s disease and motor fluctuations,
who failed to respond to or are intolerant of other COMT inhibitors. Periodic monitoring of
liver enzymes cannot reliably predict the occurrence of fulminant hepatitis. However, it is
generally believed that early detection of medicine-induced hepatic injury along with immediate
withdrawal of the suspect medication enhances the likelihood for recovery. Liver injury has
most often occurred between 1 month and 6 months after starting treatment with Tasmar.
Additionally late onset hepatitis after approximately 18 months of treatment has been reported
rarely.
It should also be noted that female patients may have a higher risk of liver injury (see section
4.8).
Before starting treatment: If liver function tests are abnormal or there are signs of impaired
liver function, Tasmar should not be prescribed. If Tasmar is to be prescribed, the patient
should be informed about the signs and symptoms which may indicate liver injury, and to
contact the physician immediately.
During treatment: Liver function should be monitored every 2 weeks for the first year of
therapy, every 4 weeks for the next 6 months and every 8 weeks thereafter. If the dose is
increased to 200 mg tid, liver enzyme monitoring should take place before increasing the dose
and then be re-initiated following the sequence of frequencies as above. Treatment should be
immediately discontinued if ALT and/or AST exceed the upper limit of normal or if symptoms
or signs suggesting the onset of hepatic failure (persistent nausea, fatigue, lethargy, anorexia,
jaundice, dark urine, pruritus, right upper quadrant tenderness) develop.
If treatment is discontinued: Patients who show evidence of acute liver injury while on Tasmar
and are withdrawn from the medicinal product may be at increased risk for liver injury if
Tasmar is re-introduced. Accordingly, such patients should not be considered for re-treatment.
Neuroleptic Malignant Syndrome (NMS):
In Parkinson`s patients, NMS tends to occur when discontinuing or stopping dopaminergic-
enhancing medications. Therefore, if symptoms occur after discontinuing Tasmar, physicians
should consider increasing the patient’s levodopa dose (see section 4.2).
Isolated cases consistent with NMS have been associated with Tasmar treatment. Symptoms
have usually onset during Tasmar treatment or shortly after Tasmar has been discontinued.
NMS is characterised by motor symptoms (rigidity, myoclonus and tremor), mental status
changes (agitation, confusion, stupor and coma), elevated temperature, autonomic dysfunction
(labile blood pressure, tachycardia) and elevated serum creatine phosphokinase (CPK) which
may be a consequence of myolysis. A diagnosis of NMS should be considered even if not all the
above findings are present. Under such a diagnosis Tasmar should be immediately discontinued
and the patient should be followed up closely.
4
Before starting treatment: To reduce the risk of NMS, Tasmar should not be prescribed for
patients with severe dyskinesia or a previous history of NMS including rhabdomyolysis or
hyperthermia (see section 4.3). Patients receiving multiple medications with effects on different
central nervous system (CNS) pathways (e.g. antidepressants, neuroleptics, anticholinergics)
may be at greater risk of developing NMS.
Patients treated for Parkinson’s Disease with medications that increase central dopaminergic tone,
especially at high doses, have been reported as exhibiting increased libido, hypersexuality, and
pathological gambling, generally reversible upon reduction of the dose or treatment discontinuation.
Dyskinesia, nausea and other levodopa-associated adverse reactions:
Patients may experience an
increase in levodopa-associated adverse reactions. Reducing the dose of levodopa (see section 4.2)
may often mitigate these adverse reactions.
Diarrhoea:
In clinical trials, diarrhoea developed in 16 % and 18 % of patients receiving Tasmar
100 mg tid and 200 mg tid respectively, compared to 8 % of patients receiving placebo. Diarrhoea
associated with Tasmar usually began 2 to 4 months after initiation of therapy. Diarrhoea led to
withdrawal of 5% and 6% of patients receiving Tasmar 100 mg tid and 200 mg tid respectively,
compared to 1 % of patients receiving placebo.
Benserazide interaction:
Due to the interaction between high dose benserazide and tolcapone (resulting
in increased levels of benserazide), the prescriber should, until more experience has been gained, be
observant of dose-related adverse reactions (see section 4.5).
MAO inhibitors:
Tasmar should not be given in conjunction with non-selective monoamine oxidase
(MAO) inhibitors (e.g. phenelzine and tranylcypromine). The combination of MAO-A and MAO-B
inhibitors is equivalent to non-selective MAO-inhibition, therefore they should not both be given
concomitantly with Tasmar and levodopa preparations (see also section 4.5). Selective MAO-B
inhibitors should not be used at higher than recommended doses (e.g. selegiline 10 mg/day) when co-
administered with Tasmar.
Warfarin:
Since clinical information is limited regarding the combination of warfarin and tolcapone,
coagulation parameters should be monitored when these drugs are co-administered.
Special populations:
Patients with severe renal impairment (creatinine clearance <30 ml/min) should
be treated with caution. No information on the tolerability of tolcapone in these populations is
available (see section 5.2).
Lactose intolerance:
Tasmar contains lactose. Patients with hereditary problems of galactose
intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this
medicine.
Tasmar, as a COMT inhibitor, is known to increase the bioavailability of the co-adminstered levodopa.
The consequent increase in dopaminergic stimulation can lead to the dopaminergic adverse reactions
observed after treatment with COMT inhibitors. The most common of these are increased dyskinesia,
nausea, vomiting, abdominal pain, syncope, orthostatic complains, constipation, sleep disorders,
somnolence, hallucination.
Levodopa has been associated with somnolence and episodes of sudden sleep onset. Sudden onset of
sleep during daily activities, in some cases without awareness or warning signs, has been reported very
rarely. Patients must be informed of this and advised to exercise caution while driving or operating
machines during treatment with levodopa. Patients who have experienced somnolence and/or an
episode of sudden sleep onset must refrain from driving or operating machines (see section 4.7).
Furthermore a reduction of levodopa dose or termination of therapy may be considered.
5
Catechols and other drugs metabolised by catechol-O-methyltransferase (COMT):
Tolcapone may
influence the pharmacokinetics of drugs metabolised by COMT. No effects were seen on the
pharmacokinetics of the COMT substrate carbidopa. An interaction was observed with benserazide,
which may lead to increased levels of benserazide and its active metabolite. The magnitude of the
effect was dependent on the dose of benserazide. The plasma concentrations of benserazide observed
after co-administration of tolcapone and benserazide-25 mg/levodopa were still within the range of
values observed with levodopa/benserazide alone. On the other hand, after co-administration of
tolcapone and benserazide-50 mg/levodopa the benserazide plasma concentrations could be increased
above the levels usually observed with levodopa/benserazide alone. The effect of tolcapone on the
pharmacokinetics of other drugs metabolised by COMT such as
-
methyldopa, dobutamine,
apomorphine, adrenaline and isoprenaline have not been evaluated. The prescriber should be observant
of adverse reactions caused by putative increased plasma levels of these drugs when combined with
Tasmar.
Effect of tolcapone on the metabolism of other drugs:
Due to its affinity for cytochrome
CYP2C9 in
vitro,
tolcapone may interfere with drugs whose clearance is dependent on this metabolic pathway,
such as tolbutamide and warfarin. In an interaction study, tolcapone did not change the
pharmacokinetics of tolbutamide. Therefore, clinically relevant interactions involving cytochrome
CYP2C9
appear unlikely.
Since clinical information is limited regarding the combination of warfarin and tolcapone, coagulation
parameters should be monitored when these drugs are co-administered.
Drugs that increase catecholamines:
Since tolcapone interferes with the metabolism of catecholamines,
interactions with other drugs affecting catecholamine levels are theoretically possible.
When Tasmar was given together with levodopa/carbidopa and desipramine, there was no significant
change in blood pressure, pulse rate and plasma concentrations of desipramine. Overall, the frequency
of adverse reactions increased slightly. These adverse reactions were predictable based on the known
adverse reactions to each of the three drugs individually. Therefore, caution should be exercised when
potent noradrenaline uptake inhibitors such as desipramine, maprotiline, or venlafaxine are
administered to Parkinson’s disease patients being treated with Tasmar and levodopa preparations.
In clinical trials, patients receiving Tasmar/levodopa preparations reported a similar adverse reaction
profile independent of whether or not they were also concomitantly administered selegiline (a MAO-B
inhibitor).
In rats and rabbits, embryo-foetal toxicity was observed after tolcapone administration (see section
5.3). The potential risk for humans is unknown.
There are no adequate data from the use of tolcapone in pregnant women. Therefore, Tasmar should
be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
In animal studies, tolcapone was excreted into maternal milk.
The safety of tolcapone in infants is unknown; therefore, women should not breast-feed during
treatment with Tasmar.
No studies on the effects of Tasmar on the ability to drive and use machines have been performed.
There is no evidence from clinical studies that Tasmar adversely influences a patient’s ability to drive
and use machines. However patients should be advised that their ability to drive and operate machines
may be compromised due to their Parkinson’s disease symptoms.
6
Tasmar, as a COMT inhibitor, is known to increase the bioavailability of the co-adminstered levodopa.
The consequent increase in dopaminergic stimulation can lead to the dopaminergic side effects
observed after treatment with COMT inhibitors. Patients being treated with Levodopa and presenting
with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging
in activities where impaired alertness may put themselves or others at risk of serious injury or death
(e.g. operating machines) until such recurrent episodes and somnolence have resolved (see also section
4.4)
The most commonly observed adverse reactions associated with the use of Tasmar, occurring more
frequently than in placebo-treated patients are listed in the table below. However, Tasmar, as a COMT
inhibitor, is known to increase the bioavailability of the co-administered levodopa. The consequent
increase in dopaminergic stimulation can lead to the dopaminergic side effects observed after
treatment with COMT inhibitors. The most common of these are increased dyskinesia, nausea,
vomiting, abdominal pain, syncope, orthostatic complains, constipation, sleep disorders, somnolence,
hallucination.
The only adverse reactions commonly leading to discontinuation of Tasmar in clinical trials was
diarrhoea (see section 4.4).
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)
Experience with Tasmar obtained in parallel placebo-controlled randomised studies in patients with
Parkinson’s disease is shown in the following table, which lists adverse reactions with a potential
relationship to Tasmar.
Summary of potentially Tasmar-related adverse reactions, with crude incidence rates for the phase III
placebo-controlled studies:
System organ class
Incidence
Adverse Events
Infections and infestations
Common
Upper respiratory tract infection
Psychiatric disorders
Very common
Sleep disorder
Excessive dreaming
Somnolence
Confusion
Hallucination
Nervous system disorders
Very common
Dyskinesia
Dystonia
Headache
Dizziness
Common
Hypokinesia
Vascular disorders
Very common
Orthostatic complaints
Common
Syncope
Respiratory, thoracic and
mediastinal disorders
Common
Influenza
Gastrointestinal disorders
Very common
Nausea
Anorexia
Diarrhoea
7
System organ class
Incidence
Adverse Events
Common
Vomiting
Constipation
Xerostomia
Abdominal pain
Dyspepsia
Skin and subcutaneous tissue
disorders
Common
Sweating increased
Renal and urinary disorders
Common
Urine discoloration
General disorders and
administration site conditions
Common
Chest pain
Increases to more than three times the upper limit of normal (ULN) in alanine aminotransferase
(ALT)occurred in 1 % of patients receiving Tasmar 100 mg three times daily, and 3 % of patients at
200 mg three times daily. Increases were approximately two times more likely in females. The
increases usually appeared within 6 to 12 weeks of starting treatment, and were not associated with
any clinical signs or symptoms. In about half the cases, transaminase levels returned spontaneously to
baseline values whilst patients continued Tasmar treatment. For the remainder, when treatment was
discontinued, transaminase levels returned to pre-treatment levels.
Rare cases of severe hepatocellular injury resulting in death have been reported during marketed use
(see section 4.4).
Isolated cases of patients with symptoms suggestive of Neuroleptic Malignant Syndrome Symptom
Complex (see section 4.4) have been reported following reduction or discontinuation of Tasmar and
following introduction of Tasmar when this was accompanied by a significant reduction in other
concomitant dopaminergic medications. In addition, rhabdomyolysis, secondary to NMS or severe
dyskinesia, has been observed.
Urine discolouration:
Tolcapone and its metabolites are yellow and can cause a harmless
intensification in the colour of the patient’s urine.
Isolated cases of either accidental or intentional overdose with tolcapone tablets have been reported.
However clinical circumstances of these cases were so diverse, that no general conclusions can be
drawn from the cases.
The highest dose of tolcapone administered to humans was 800 mg three times daily, with and without
levodopa coadministration, in a one week study in healthy elderly volunteers. The peak plasma
concentrations of tolcapone at this dose were on average 30 µg/ml (compared to 3 and 6 µg/ml with
100 mg tid and 200 mg tid of tolcapone respectively). Nausea, vomiting and dizziness were observed,
particularly in combination with levodopa.
Management of overdose:
Hospitalisation is advised. General supportive care is indicated. Based on
the physicochemical properties of the compound, hemodialysis is unlikely to be of benefit.
5.
5.1 Pharmacodynamic properties
Pharmaco-therapeutic group: Anti-Parkinson drugs, other dopaminergic agents, ATC code: NO4BX01
8
Tolcapone is an orally active, selective and reversible catechol-
O-
methyltransferase (COMT)
inhibitor. Administered concomitantly with levodopa and an aromatic amino acid decarboxylase
inhibitor (AADC-I), it leads to more stable plasma levels of levodopa by reducing metabolism of
levodopa to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD).
High levels of plasma 3-OMD have been associated with poor response to levodopa in Parkinson’s
disease patients. Tolcapone markedly reduces the formation of 3-OMD.
Clinical pharmacology
Studies in healthy volunteers have shown that tolcapone reversibly inhibits human erythrocyte COMT
activity after oral administration. The inhibition is closely related to plasma tolcapone concentration.
With 200 mg tolcapone, maximum inhibition of erythrocyte COMT activity is, on average, greater
than 80 %. During dosing with Tasmar 200 mg three times daily, erythrocyte COMT inhibition at
trough is 30 % to 45 %, with no development of tolerance.
Transient elevation above pretreatment levels of erythrocyte COMT activity was observed after
withdrawal of tolcapone. However, a study in Parkinson’s patients confirmed that after treatment
discontinuation there was no significant change in levodopa pharmacokinetics or in patient response to
levodopa compared to pretreatment levels.
When Tasmar is administered together with levodopa, it increases the relative bioavailability (AUC)
of levodopa approximately twofold. This is due to a decrease in clearance in L-dopa resulting in a
prolongation of the terminal elimination half-life (
t
1/2
) of levodopa. In general, the average peak
levodopa plasma concentration (
C
max
) and the time of its occurrence (
t
max
) were unaffected. The onset
of effect occurs after the first administration. Studies in healthy volunteers and parkinsonian patients
have confirmed that the maximum effect occurs with 100 – 200 mg tolcapone. Plasma levels of 3-
OMD were markedly and dose-dependently decreased by tolcapone when given with
levodopa/AADC-I (aromatic amino acid decarboxylase - inhibitor) (benserazide or carbidopa).
Tolcapone’s effect on levodopa pharmacokinetics is similar with all pharmaceutical formulations of
levodopa/benserazide and levodopa/carbidopa; it is independent of levodopa dose, levodopa/AADC-I
(benserazide or carbidopa) ratio and the use of sustained-release formulations.
Clinical studies
Double blind placebo controlled clinical studies have shown a significant reduction of approximately
20 % to 30 % in OFF time and a similar increase in ON time, accompanied by reduced severity of
symptoms in fluctuating patients receiving Tasmar. Investigator’s global assessments of efficacy also
showed significant improvement.
A double-blind trial compared Tasmar with entacapone in Parkinson's disease patients who had at least
three hours of OFF time per day while receiving optimised levodopa therapy. The primary outcome
was the proportion of patients with a 1 or more hour increase in ON time (see Table 1).
Tab. 1 Primary and Secondary Outcome of double-blind Trial
Entacapone
N=75
Tolcapon
e N=75
p value 95 % CI
Primary Outcome
Number (proportion) with ≥1 hour ON time response 32 (43 %)
40 (53 %) p=0.191 -5.2;26.6
Secondary Outcome
Number (proportion) with moderate or marked
improvement
19 (25 %)
29 (39 %) p=0.080 -1.4;28.1
Number (proportion) improved on both primary and
secondary outcome
13 (17 %)
24 (32 %) NA
NA
9
5.2 Pharmacokinetic properties
In the therapeutic range, tolcapone pharmacokinetics are linear and independent of levodopa/AADC-I
(benserazide or carbidopa) coadministration.
Absorption:
Tolcapone is rapidly absorbed with a
t
max
of approximately 2 hours. The absolute
bioavailability of an oral administration is around 65 %. Tolcapone does not accumulate with three
times daily dosing of 100 or 200 mg. At these doses,
C
max
is approximately 3 and 6 µg/ml,
respectively. Food delays and decreases the absorption of tolcapone, but the relative bioavailability of
a dose of tolcapone taken with a meal is still 80 % to 90 %.
Distribution:
The volume of distribution (
V
ss
) of tolcapone is small (9 l). Tolcapone does not distribute
widely into tissues due to its high plasma protein binding (>99.9 %).
In vitro
experiments have shown
that tolcapone binds mainly to serum albumin.
Metabolism/Elimination:
Tolcapone is almost completely metabolised prior to excretion, with only a
very small amount (0.5 % of dose) found unchanged in urine. The main metabolic pathway of
tolcapone is conjugation to its inactive glucuronide. In addition, the compound is methylated by
COMT to 3-O-methyl-tolcapone and metabolised by cytochromes
P
450 3A4 and
P
450 2A6 to a
primary alcohol (hydroxylation of the methyl group), which is subsequently oxidised to the carboxylic
acid. The reduction to a putative amine, as well as the subsequent
N
-acetylation, occurs to a minor
extent. After oral administration, 60 % of drug-related material is excreted into urine and 40 % into
faeces.
Tolcapone is a low-extraction-ratio drug (extraction ratio = 0.15), with a moderate systemic clearance
of about 7 L/h. The
t
1/2
of tolcapone is approximately 2 hours.
Hepatic impairment:
Because of the risk of liver injury observed during post-marketing use, Tasmar is
contraindicated in patients with liver disease or increased liver enzymes. A study in patients with
hepatic impairment has shown that moderate non-cirrhotic liver disease had no impact on the
pharmacokinetics of tolcapone. However, in patients with moderate cirrhotic liver disease, clearance
of unbound tolcapone was reduced by almost 50 %. This reduction may increase the average
concentration of unbound drug two-fold.
Renal impairment:
The pharmacokinetics of tolcapone have not been investigated in patients with
renal impairment. However, the relationship of renal function and tolcapone pharmacokinetics has
been investigated using population pharmacokinetics during clinical trials. The data of more than 400
patients have confirmed that over a wide range of creatinine clearance values (30-130 mL/min) the
pharmacokinetics of tolcapone are unaffected by renal function. This could be explained by the fact
that only a negligible amount of unchanged tolcapone is excreted in the urine, and the main
metabolite, tolcapone-glucuronide, is excreted both in urine and in bile (faeces).
5.3 Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
Carcinogenesis, mutagenesis:
3 % and 5 % of rats in the mid- and high- dose groups, respectively,
of
the 24-month carcinogenicity study were shown to have renal epithelial tumours (adenomas or
carcinomas). However, no evidence of renal toxicity was observed in the low-dose group. An
increased incidence of uterine adenocarcinomas was seen in the high-dose group of the rat
carcinogenicity study. There were no similar renal findings in the mouse or dogs carcinogenicity
studies.
Mutagenesis:
Tolcapone was shown not to be genotoxic in a complete series of mutagenicity studies.
Toxicity to reproduction:
Tolcapone, when administered alone, was shown to be neither teratogenic
nor to have any relevant effects on fertility.
10
6.
6.1 List of excipients
Tablet core:
Calcium hydrogen phosphate
Microcrystalline cellulose
Povidone K30
Sodium starch glycollate
Lactose
Talc
Magnesium stearate.
Film-coat:
Hydroxypropylmethylcellulose
Talc
Yellow iron oxide
Ethylcellulose
Titanium dioxide
Triacetin
Sodium lauril sulfate
6.2 Incompatibilities
Not applicable
6.3 Shelf life
5 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions
6.5 Nature and contents of container
Tasmar is available in PVC/PE/PVDC blisters (pack sizes of 30 and 60 film-coated tablets) and in
amber glass bottles without desiccant (pack sizes of 30, 60 and 100 film-coated tablets).
Not all pack sizes may be marketed
6.6 Special precautions for disposal
No special requirements.
7.
Meda AB
Pipers väg 2A
S-170 09 Solna
Sweden
8.
11
EU/1/97/044/001-3, 7-8
9.
Date of first authorisation: 27 August 1997
Renewal of the authorisation: 31 August 2004
Date of latest renewal:
12
1.
Tasmar 200 mg film coated tablets
2.
Each film-coated tablet contains 200 mg tolcapone.
Excipients: Each tablet contains 15 mg lactose
For a full list of excipients, see section 6.1
3.
Film-coated tablet.
Orange yellow to brown yellow, hexagonal, biconvex, film-coated tablet. “TASMAR” and “200” are
engraved on one side.
4.
Tasmar is indicated in combination with levodopa/benserazide or levodopa/carbidopa for use in
patients with levodopa-responsive idiopathic Parkinson’s disease and motor fluctuations, who failed to
respond to or are intolerant of other catechol-o-methyltransferase (COMT) inhibitors (see section 5.1).
Because of the risk of potentially fatal, acute liver injury, Tasmar should not be considered as a first-
line adjunct therapy to levodopa/benserazide or levodopa/carbidopa (see sections 4.4 and 4.8).
Since Tasmar should be used only in combination with levodopa/benserazide and levodopa/carbidopa,
the prescribing information for these levodopa preparations is also applicable to their concomitant use
with Tasmar.
The administration of Tasmar is restricted to prescription and supervision by physicians experienced
in the management of advanced Parkinson's disease.
The first dose of the day of Tasmar should be taken together the first dose of the day of a levodopa
preparation, and the subsequent doses should be given approximately 6 and 12 hours later. Tasmar
may be taken with or without food (see section 5.2).
The recommended dose of Tasmar is 100 mg three times daily, always as an adjunct to
levodopa/benserazide or levodopa/carbidopa therapy. Only in exceptional circumstances, when the
anticipated incremental clinical benefit justifies the increased risk of hepatic reactions, should the dose
be increased to 200 mg three times daily. (see sections 4.4 and 4.8). If substantial clinical benefits are
not seen within 3 weeks of the initiation of the treatment (regardless of dose) Tasmar should be
discontinued.
The maximum therapeutic dose of 200 mg three times daily should not be exceeded, as there is no
evidence of additional efficacy at higher doses.
Liver function should be checked before starting treatment with Tasmar and then monitored every 2
weeks for the first year of therapy, every 4 weeks for the next 6 months and every 8 weeks thereafter.
If the dose is increased to 200 mg tid, liver enzyme monitoring should take place before increasing the
dose and then be reinitiated following the same sequence of frequencies as above (see sections 4.4 and
4.8).
13
Tasmar treatment should also be discontinued if ALT (alanine amino transferase) and/or AST
(aspartate amino transferase) exceed the upper limit of normal or symptoms or signs suggest the onset
of hepatic failure (see section 4.4).
Levodopa adjustments during Tasmar treatment:
As Tasmar decreases the breakdown of levodopa in the body, side effects due to increased levodopa
concentrations may occur when beginning Tasmar treatment. In clinical trials, more than 70 % of
patients required a decrease in their daily levodopa dose if their daily dose of levodopa was >600 mg
or if patients had moderate or severe dyskinesias before beginning treatment.
The average reduction in daily levodopa dose was about 30 % in those patients requiring a levodopa
dose reduction. When beginning Tasmar, all patients should be informed of the symptoms of excessive
levodopa dose and what to do if it occurs.
Levodopa adjustments when Tasmar is discontinued:
The following suggestions are based on pharmacological considerations and have not been evaluated
in clinical trials. Levodopa dose should not be decreased when Tasmar therapy is being discontinued
due to side effects related to too much levodopa. However, when Tasmar therapy is being
discontinued for reasons other than too much levodopa, levodopa dose may have to be increased to
levels equal to or greater than before initiation of Tasmar therapy, especially if the patient had large
decreases in levodopa when starting Tasmar. In all cases, patients should be educated on the
symptoms of levodopa under-dose and what to do if it occurs. Adjustments in levodopa are most likely
to be required within 1-2 days of Tasmar discontinuation.
Patients with renal impairement (see section 5.2):
No dose adjustment of Tasmar is recommended for
patients with mild or moderate renal impairment (creatinine clearance of 30 ml/min or greater).
Patients with severe renal impairement (creatinine clearance <30 ml/min) should be treated with
caution. No information on the tolerability of tolcapone in these populations is available (see section
5.2)
Patients with hepatic impairment (see section 4.3):
Tasmar is contraindicated for patients with liver
disease or increased liver enzymes.
Elderly patients:
No dose adjustment of Tasmar is recommended for elderly patients.
Children and adolescents:
. Tasmar is not recommended for use in children below the age of 18 due to
insufficient data on safety or efficacy. There is no relevant indication for use of Tasmar in children and
adolescents.
Method of administration
Tasmar is administered orally three times daily.
Tasmar may be taken with or without food (see section 5.2).
Tasmar tablets are film-coated and should be swallowed whole because tolcapone has a bitter taste.
Tasmar can be combined with all pharmaceutical formulations of levodopa/benserazide and
levodopa/carbidopa (see also section 4.5).
•
Hypersensitivity to tolcapone or any of its other ingredients.
•
Evidence of liver disease or increased liver enzymes
•
A previous history of Neuroleptic Malignant Syndrome (NMS) Symptom Complex and /or
non-traumatic Rhabdomyolysis or Hyperthermia.
•
Phaeochromocytoma.
•
Treatment with non-selective mono amino oxidase (MAO) inhibitors
14
•
Severe dyskinesia
Tasmar therapy should only be initiated by physicians experienced in the management of
advanced Parkinson’s disease, to ensure an appropriate risk-benefit assessment. Tasmar should
not be prescribed until there has been a complete informative discussion of the risks with the
patient.
Tasmar should be discontinued if substantial clinical benefits are not seen within 3 weeks of the
initiation of the treatment regardless of dose.
Liver injury:
Because of the risk of rare but potentially fatal acute liver injury, Tasmar is only indicated for
use in patients with levodopa-responsive idiopathic Parkinson’s disease and motor fluctuations,
who failed to respond to or are intolerant of other COMT inhibitors. Periodic monitoring of
liver enzymes cannot reliably predict the occurrence of fulminant hepatitis. However, it is
generally believed that early detection of medicine-induced hepatic injury along with immediate
withdrawal of the suspect medication enhances the likelihood for recovery. Liver injury has
most often occurred between 1 month and 6 months after starting treatment with Tasmar.
Additionally late onset hepatitis after approximately 18 months of treatment has been reported
rarely.
It should also be noted that female patients may have a higher risk of liver injury (see section
4.8).
Before starting treatment: If liver function tests are abnormal or there are signs of impaired
liver function, Tasmar should not be prescribed. If Tasmar is to be prescribed, the patient
should be informed about the signs and symptoms which may indicate liver injury, and to
contact the physician immediately.
During treatment: Liver function should be monitored every 2 weeks for the first year of
therapy, every 4 weeks for the next 6 months and every 8 weeks thereafter. If the dose is
increased to 200 mg tid, liver enzyme monitoring should take place before increasing the dose
and then be re-initiated following the sequence of frequencies as above. Treatment should be
immediately discontinued if ALT and/or AST exceed the upper limit of normal or if symptoms
or signs suggesting the onset of hepatic failure (persistent nausea, fatigue, lethargy, anorexia,
jaundice, dark urine, pruritus, right upper quadrant tenderness) develop.
If treatment is discontinued: Patients who show evidence of acute liver injury while on Tasmar
and are withdrawn from the medicinal product may be at increased risk for liver injury if
Tasmar is re-introduced. Accordingly, such patients should not be considered for re-treatment.
Neuroleptic Malignant Syndrome (NMS):
In Parkinson`s patients, NMS tends to occur when discontinuing or stopping dopaminergic-
enhancing medications. Therefore, if symptoms occur after discontinuing Tasmar, physicians
should consider increasing the patient’s levodopa dose (see section 4.2).
Isolated cases consistent with NMS have been associated with Tasmar treatment. Symptoms
have usually onset during Tasmar treatment or shortly after Tasmar has been discontinued.
NMS is characterised by motor symptoms (rigidity, myoclonus and tremor), mental status
changes (agitation, confusion, stupor and coma), elevated temperature, autonomic dysfunction
(labile blood pressure, tachycardia) and elevated serum creatine phosphokinase (CPK) which
may be a consequence of myolysis. A diagnosis of NMS should be considered even if not all the
above findings are present. Under such a diagnosis Tasmar should be immediately discontinued
and the patient should be followed up closely.
15
Before starting treatment: To reduce the risk of NMS, Tasmar should not be prescribed for
patients with severe dyskinesia or a previous history of NMS including rhabdomyolysis or
hyperthermia (see section 4.3). Patients receiving multiple medications with effects on different
central nervous system (CNS) pathways (e.g. antidepressants, neuroleptics, anticholinergics)
may be at greater risk of developing NMS.
Patients treated for Parkinson’s Disease with medications that increase central dopaminergic tone,
especially at high doses, have been reported as exhibiting increased libido, hypersexuality, and
pathological gambling, generally reversible upon reduction of the dose or treatment discontinuation.
Dyskinesia, nausea and other levodopa-associated adverse reactions:
Patients may experience an
increase in levodopa-associated adverse reactions. Reducing the dose of levodopa (see section 4.2)
may often mitigate these adverse reactions.
Diarrhoea:
In clinical trials, diarrhoea developed in 16 % and 18 % of patients receiving Tasmar
100 mg tid and 200 mg tid respectively, compared to 8 % of patients receiving placebo. Diarrhoea
associated with Tasmar usually began 2 to 4 months after initiation of therapy. Diarrhoea led to
withdrawal of 5% and 6% of patients receiving Tasmar 100 mg tid and 200 mg tid respectively,
compared to 1 % of patients receiving placebo.
Benserazide interaction:
Due to the interaction between high dose benserazide and tolcapone (resulting
in increased levels of benserazide), the prescriber should, until more experience has been gained, be
observant of dose-related adverse reactions (see section 4.5).
MAO inhibitors:
Tasmar should not be given in conjunction with non-selective monoamine oxidase
(MAO) inhibitors (e.g. phenelzine and tranylcypromine). The combination of MAO-A and MAO-B
inhibitors is equivalent to non-selective MAO-inhibition, therefore they should not both be given
concomitantly with Tasmar and levodopa preparations (see also section 4.5). Selective MAO-B
inhibitors should not be used at higher than recommended doses (e.g. selegiline 10 mg/day) when co-
administered with Tasmar.
Warfarin:
Since clinical information is limited regarding the combination of warfarin and tolcapone,
coagulation parameters should be monitored when these drugs are co-administered.
Special populations:
Patients with severe renal impairment (creatinine clearance <30 ml/min) should
be treated with caution. No information on the tolerability of tolcapone in these populations is
available (see section 5.2).
Lactose intolerance: Tasmar contains lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose malabsorption should not take this medicine.
Tasmar, as a COMT inhibitor, is known to increase the bioavailability of the co-adminstered levodopa.
The consequent increase in dopaminergic stimulation can lead to the dopaminergic adverse reactions
observed after treatment with COMT inhibitors. The most common of these are increased dyskinesia,
nausea, vomiting, abdominal pain, syncope, orthostatic complains, constipation, sleep disorders,
somnolence, hallucination.
Levodopa has been associated with somnolence and episodes of sudden sleep onset. Sudden onset of
sleep during daily activities, in some cases without awareness or warning signs, has been reported very
rarely. Patients must be informed of this and advised to exercise caution while driving or operating
machines during treatment with levodopa. Patients who have experienced somnolence and/or an
episode of sudden sleep onset must refrain from driving or operating machines. Furthermore a
reduction of levodopa dose or termination of therapy may be considered (see section 4.7).
16
Catechols and other drugs metabolised by catechol-O-methyltransferase (COMT):
Tolcapone may
influence the pharmacokinetics of drugs metabolised by COMT. No effects were seen on the
pharmacokinetics of the COMT substrate carbidopa. An interaction was observed with benserazide,
which may lead to increased levels of benserazide and its active metabolite. The magnitude of the
effect was dependent on the dose of benserazide. The plasma concentrations of benserazide observed
after co-administration of tolcapone and benserazide-25 mg/levodopa were still within the range of
values observed with levodopa/benserazide alone. On the other hand, after co-administration of
tolcapone and benserazide-50 mg/levodopa the benserazide plasma concentrations could be increased
above the levels usually observed with levodopa/benserazide alone. The effect of tolcapone on the
pharmacokinetics of other drugs metabolised by COMT such as
-
methyldopa, dobutamine,
apomorphine, adrenaline and isoprenaline have not been evaluated. The prescriber should be observant
of adverse reactions caused by putative increased plasma levels of these drugs when combined with
Tasmar.
Effect of tolcapone on the metabolism of other drugs:
Due to its affinity for cytochrome
CYP2C9 in
vitro,
tolcapone may interfere with drugs whose clearance is dependent on this metabolic pathway,
such as tolbutamide and warfarin. In an interaction study, tolcapone did not change the
pharmacokinetics of tolbutamide. Therefore, clinically relevant interactions involving cytochrome
CYP2C9
appear unlikely.
Since clinical information is limited regarding the combination of warfarin and tolcapone, coagulation
parameters should be monitored when these drugs are co-administered.
Drugs that increase catecholamines:
Since tolcapone interferes with the metabolism of catecholamines,
interactions with other drugs affecting catecholamine levels are theoretically possible.
When Tasmar was given together with levodopa/carbidopa and desipramine, there was no significant
change in blood pressure, pulse rate and plasma concentrations of desipramine. Overall, the frequency
of adverse reactions increased slightly. These adverse reactions were predictable based on the known
adverse reactions to each of the three drugs individually. Therefore, caution should be exercised when
potent noradrenaline uptake inhibitors such as desipramine, maprotiline, or venlafaxine are
administered to Parkinson’s disease patients being treated with Tasmar and levodopa preparations.
In clinical trials, patients receiving Tasmar/levodopa preparations reported a similar adverse reaction
profile independent of whether or not they were also concomitantly administered selegiline (a MAO-B
inhibitor).
In rats and rabbits, embryo-foetal toxicity was observed after tolcapone administration (see section
5.3). The potential risk for humans is unknown.
There are no adequate data from the use of tolcapone in pregnant women. Therefore, Tasmar should
be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
In animal studies, tolcapone was excreted into maternal milk.
The safety of tolcapone in infants is unknown; therefore, women should not breast-feed during
treatment with Tasmar.
No studies on the effects of Tasmar on the ability to drive and use machines have been performed.
There is no evidence from clinical studies that Tasmar adversely influences a patient’s ability to drive
and use machines. However patients should be advised that their ability to drive and operate machines
may be compromised due to their Parkinson’s disease symptoms.
17
Tasmar, as a COMT inhibitor, is known to increase the bioavailability of the co-adminstered levodopa.
The consequent increase in dopaminergic stimulation can lead to the dopaminergic side effects
observed after treatment with COMT inhibitors. Patients being treated with Levodopa and presenting
with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging
in activities where impaired alertness may put themselves or others at risk of serious injury or death
(e.g. operating machines) until such recurrent episodes and somnolence have resolved (see also section
4.4)
The most commonly observed adverse reaction associated with the use of Tasmar, occurring more
frequently than in placebo-treated patients are listed in the table below. However, Tasmar, as a COMT
inhibitor, is known to increase the bioavailability of the co-administered levodopa. The consequent
increase in dopaminergic stimulation can lead to the dopaminergic side effects observed after
treatment with COMT inhibitors. The most common of these are increased dyskinesia, nausea,
vomiting, abdominal pain, syncope, orthostatic complains, constipation, sleep disorders, somnolence,
hallucination.
The only adverse reaction commonly leading to discontinuation of Tasmar in clinical trials was
diarrhoea (see section 4.4).
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)
Experience with Tasmar obtained in parallel placebo-controlled randomised studies in patients with
Parkinson’s disease is shown in the following table, which lists adverse reactions with a potential
relationship to Tasmar.
Summary of potentially Tasmar-related adverse reactions, with crude incidence rates for the phase III
placebo-controlled studies:
System organ class
Incidence
Adverse Events
Infections and infestations
Common
Upper respiratory tract infection
Psychiatric disorders
Very common
Sleep disorder
Excessive dreaming
Somnolence
Confusion
Hallucination
Nervous system disorders
Very common
Dyskinesia
Dystonia
Headache
Dizziness
Common
Hypokinesia
Vascular disorders
Very common
Orthostatic complaints
Common
Syncope
Respiratory, thoracic and
mediastinal disorders
Common
Influenza
Gastrointestinal disorders
Very common
Nausea
Anorexia
Diarrhoea
18
System organ class
Incidence
Adverse Events
Common
Vomiting
Constipation
Xerostomia
Abdominal pain
Dyspepsia
Skin and subcutaneous tissue
disorders
Common
Sweating increased
Renal and urinary disorders
Common
Urine discoloration
General disorders and
administration site conditions
Common
Chest pain
Increases to more than three times the upper limit of normal (ULN) in alanine aminotransferase (ALT)
occurred in 1 % of patients receiving Tasmar 100 mg three times daily, and 3 % of patients at 200 mg
three times daily. Increases were approximately two times more likely in females. The increases
usually appeared within 6 to 12 weeks of starting treatment, and were not associated with any clinical
signs or symptoms. In about half the cases, transaminase levels returned spontaneously to baseline
values whilst patients continued Tasmar treatment. For the remainder, when treatment was
discontinued, transaminase levels returned to pre-treatment levels.
Rare cases of severe hepatocellular injury resulting in death have been reported during marketed use
(see section 4.4).
Isolated cases of patients with symptoms suggestive of Neuroleptic Malignant Syndrome Symptom
Complex (see sectiom 4.4) have been reported following reduction or discontinuation of Tasmar and
following introduction of Tasmar when this was accompanied by a significant reduction in other
concomitant dopaminergic medications. In addition, rhabdomyolysis, secondary to NMS or severe
dyskinesia, has been observed.
Urine discolouration:
Tolcapone and its metabolites are yellow and can cause a harmless
intensification in the colour of the patient’s urine.
Isolated cases of either accidental or intentional overdose with tolcapone tablets have been reported.
However clinical circumstances of these cases were so diverse, that no general conclusions can be
drawn from the cases.
The highest dose of tolcapone administered to humans was 800 mg three times daily, with and without
levodopa coadministration, in a one week study in healthy elderly volunteers. The peak plasma
concentrations of tolcapone at this dose were on average 30 µg/ml (compared to 3 and 6 µg/ml with
100 mg tid and 200 mg tid of tolcapone respectively). Nausea, vomiting and dizziness were observed,
particularly in combination with levodopa.
Management of overdose:
Hospitalisation is advised. General supportive care is indicated. Based on
the physicochemical properties of the compound, hemodialysis is unlikely to be of benefit.
5.
5.1 Pharmacodynamic properties
Pharmaco-therapeutic group: Anti-Parkinson drugs, other dopaminergic agents, ATC code: NO4BX01
19
Tolcapone is an orally active, selective and reversible catechol-
O-
methyltransferase (COMT)
inhibitor. Administered concomitantly with levodopa and an aromatic amino acid decarboxylase
inhibitor (AADC-I), it leads to more stable plasma levels of levodopa by reducing metabolism of
levodopa to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD).
High levels of plasma 3-OMD have been associated with poor response to levodopa in Parkinson’s
disease patients. Tolcapone markedly reduces the formation of 3-OMD.
Clinical pharmacology
Studies in healthy volunteers have shown that tolcapone reversibly inhibits human erythrocyte COMT
activity after oral administration. The inhibition is closely related to plasma tolcapone concentration.
With 200 mg tolcapone, maximum inhibition of erythrocyte COMT activity is, on average, greater
than 80 %. During dosing with Tasmar 200 mg three times daily, erythrocyte COMT inhibition at
trough is 30 % to 45 %, with no development of tolerance.
Transient elevation above pretreatment levels of erythrocyte COMT activity was observed after
withdrawal of tolcapone. However, a study in Parkinson’s patients confirmed that after treatment
discontinuation there was no significant change in levodopa pharmacokinetics or in patient response to
levodopa compared to pretreatment levels.
When Tasmar is administered together with levodopa, it increases the relative bioavailability (AUC)
of levodopa approximately twofold. This is due to a decrease in clearance in L-dopa resulting in a
prolongation of the terminal elimination half-life (
t
1/2
) of levodopa. In general, the average peak
levodopa plasma concentration (
C
max
) and the time of its occurrence (
t
max
) were unaffected. The onset
of effect occurs after the first administration. Studies in healthy volunteers and parkinsonian patients
have confirmed that the maximum effect occurs with 100 – 200 mg tolcapone. Plasma levels of 3-
OMD were markedly and dose-dependently decreased by tolcapone when given with
levodopa/AADC-I (aromatic amino acid decarboxylase - inhibitor) (benserazide or carbidopa).
Tolcapone’s effect on levodopa pharmacokinetics is similar with all pharmaceutical formulations of
levodopa/benserazide and levodopa/carbidopa; it is independent of levodopa dose, levodopa/AADC-I
(benserazide or carbidopa) ratio and the use of sustained-release formulations.
Clinical studies
Double blind placebo controlled clinical studies have shown a significant reduction of approximately
20 % to 30 % in OFF time and a similar increase in ON time, accompanied by reduced severity of
symptoms in fluctuating patients receiving Tasmar. Investigator’s global assessments of efficacy also
showed significant improvement.
A double-blind trial compared Tasmar with entacapone in Parkinson's disease patients who had at least
three hours of OFF time per day while receiving optimised levodopa therapy. The primary outcome
was the proportion of patients with a 1 or more hour increase in ON time (see Table 1).
Tab. 1 Primary and Secondary Outcome of double-blind Trial
Entacapone
N=75
Tolcapon
e N=75
p value 95 % CI
Primary Outcome
Number (proportion) with ≥1 hour ON time response 32 (43 %)
40 (53 %) p=0.191 -5.2;26.6
Secondary Outcome
Number (proportion) with moderate or marked
improvement
19 (25 %)
29 (39 %) p=0.080 -1.4;28.1
Number (proportion) improved on both primary and
secondary outcome
13 (17 %)
24 (32 %) NA
NA
20
5.2 Pharmacokinetic properties
In the therapeutic range, tolcapone pharmacokinetics are linear and independent of levodopa/AADC-I
(benserazide or carbidopa) coadministration.
Absorption:
Tolcapone is rapidly absorbed with a
t
max
of approximately 2 hours. The absolute
bioavailability of an oral administration is around 65 %. Tolcapone does not accumulate with three
times daily dosing of 100 or 200 mg. At these doses,
C
max
is approximately 3 and 6 µg/ml,
respectively. Food delays and decreases the absorption of tolcapone, but the relative bioavailability of
a dose of tolcapone taken with a meal is still 80 % to 90 %.
Distribution:
The volume of distribution (
V
ss
) of tolcapone is small (9 l). Tolcapone does not distribute
widely into tissues due to its high plasma protein binding (>99.9 %).
In vitro
experiments have shown
that tolcapone binds mainly to serum albumin.
Metabolism/Elimination:
Tolcapone is almost completely metabolised prior to excretion, with only a
very small amount (0.5 % of dose) found unchanged in urine. The main metabolic pathway of
tolcapone is conjugation to its inactive glucuronide. In addition, the compound is methylated by
COMT to 3-O-methyl-tolcapone and metabolised by cytochromes
P
450 3A4 and
P
450 2A6 to a
primary alcohol (hydroxylation of the methyl group), which is subsequently oxidised to the carboxylic
acid. The reduction to a putative amine, as well as the subsequent
N
-acetylation, occurs to a minor
extent. After oral administration, 60 % of drug-related material is excreted into urine and 40 % into
faeces.
Tolcapone is a low-extraction-ratio drug (extraction ratio = 0.15), with a moderate systemic clearance
of about 7 L/h. The
t
1/2
of tolcapone is approximately 2 hours.
Hepatic impairment:
Because of the risk of liver injury observed during post-marketing use, Tasmar is
contraindicated in patients with liver disease or increased liver enzymes. A study in patients with
hepatic impairment has shown that moderate non-cirrhotic liver disease had no impact on the
pharmacokinetics of tolcapone. However, in patients with moderate cirrhotic liver disease, clearance
of unbound tolcapone was reduced by almost 50 %. This reduction may increase the average
concentration of unbound drug two-fold.
Renal impairment:
The pharmacokinetics of tolcapone have not been investigated in patients with
renal impairment. However, the relationship of renal function and tolcapone pharmacokinetics has
been investigated using population pharmacokinetics during clinical trials. The data of more than 400
patients have confirmed that over a wide range of creatinine clearance values (30-130 mL/min) the
pharmacokinetics of tolcapone are unaffected by renal function. This could be explained by the fact
that only a negligible amount of unchanged tolcapone is excreted in the urine, and the main
metabolite, tolcapone-glucuronide, is excreted both in urine and in bile (faeces).
5.3 Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
Carcinogenesis, mutagenesis:
3 % and 5 % of rats in the mid- and high- dose groups, respectively,
of
the 24-month carcinogenicity study were shown to have renal epithelial tumours (adenomas or
carcinomas). However, no evidence of renal toxicity was observed in the low-dose group. An
increased incidence of uterine adenocarcinomas was seen in the high-dose group of the rat
carcinogenicity study. There were no similar renal findings in the mouse or dogs carcinogenicity
studies.
Mutagenesis:
Tolcapone was shown not to be genotoxic in a complete series of mutagenicity studies.
Toxicity to reproduction:
Tolcapone, when administered alone, was shown to be neither teratogenic
nor to have any relevant effects on fertility.
21
6.
6.1 List of excipients
Tablet core:
Calcium hydrogen phosphate
Microcrystalline cellulose
Povidone K30
Sodium starch glycollate
Lactose
Talc
Magnesium stearate.
Film-coat:
Hydroxypropylmethylcellulose,
Talc
Yellow iron oxide
Ethylcellulose
Titanium dioxide
Triacetin
Sodium lauril sulfate
6.2 Incompatibilities
Not applicable
6.3 Shelf life
5 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions
6.5 Nature and contents of container
Tasmar is available in PVC/PE/PVDC blisters (pack sizes of 30 and 60 film-coated tablets) and in
amber glass bottles without desiccant (pack sizes of 100 film-coated tablets).
Not all pack sizes may be marketed
6.6 Special precautions for disposal
No special requirements.
7.
Meda AB
Pipers väg 2A
S-170 09 Solna
Sweden
8.
22
EU/1/97/044/004-6
9.
Date of first authorisation: 27 August 1997
Renewal of the authorisation: 31 August 2004
Date of latest renewal:
23
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
24
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
ICN Polfa Rzeszów S.A.
ul. Przemysłowa 2
35-959 Rzeszów
Poland
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, 4.2)
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
OTHER CONDITIONS
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities
detailed in the Pharmacovigilance Plan, as agreed in version 3.0 of the Risk Management Plan
(RMP) presented in Module 1.8.2. of the Marketing Authorisation and any subsequent updates
of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
*
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
*
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
*
At the request of the EMEA
PSURs
PSURs will have to be submitted with a 1-year frequency, until otherwise specified by the CHMP.
25
ANNEX III
LABELLING AND PACKAGE LEAFLET
26
A. LABELLING
27
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
Bottle Packs and bottle label, 30, 60 and 100 Film-Coated Tablets
1.
Tasmar 100 mg film-coated tablets
Tolcapone
2.
STATEMENT OF ACTIVE SUBSTANCE
Each film-coated tablet contains 100 mg tolcapone
3.
LIST OF EXCIPIENTS
Also contains lactose.
See leaflet for further information
4.
30 film-coated tablets
60 film-coated tablets
100 film-coated tablets
5.
METHOD AND ROUTE OF ADMINISTRATION
Read the package leaflet before use. For oral use.
The tablets should be swallowed whole. Do not break or crush tablet.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Meda AB
Pipers väg 2A
S-170 09 Solna
Sweden
28
12. MARKETING AUTHORISATION NUMBER
EU/1/97/044/007 30 tablets
EU/1/97/044/008 60 tablets
EU/1/97/044/003 100 tablets
13. MANUFACTURER’S BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Tasmar 100 mg (only applicable for the outer carton)
29
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
Blister Packs, 30, and 60 Film-Coated Tablets
1.
Tasmar 100 mg film-coated tablets
Tolcapone
2.
STATEMENT OF ACTIVE SUBSTANCE
Each film-coated tablet contains 100 mg tolcapone
3.
LIST OF EXCIPIENTS
Also contains lactose.
See leaflet for further information
4.
30 film-coated tablets
60 film-coated tablets
5.
METHOD AND ROUTE OF ADMINISTRATION
Read the package leaflet before use. For oral use.
The tablets should be swallowed whole. Do not break or crush tablet.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Meda AB
Pipers väg 2A
S-170 09 Solna
Sweden
30
12. MARKETING AUTHORISATION NUMBER
EU/1/97/044/001 30 tablets
EU/1/97/044/002 60 tablets
13. MANUFACTURER’S BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Tasmar 100 mg (only applicable for the outer packaging)
31
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Tasmar 100 mg film-coated tablets
Tolcapone
2.
Meda AB.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
32
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
Bottle Packs and bottle label, 100 Film-Coated Tablets
1.
Tasmar 200 mg film-coated tablets
Tolcapone
2.
STATEMENT OF ACTIVE SUBSTANCE
Each film-coated tablet contains 200 mg tolcapone
tolcapone 200 mg
3.
LIST OF EXCIPIENTS
Also contains lactose.
See leaflet for further information
4.
100 film-coated tablets
5.
METHOD AND ROUTE OF ADMINISTRATION
Read the package leaflet before use. For oral use.
The tablets should be swallowed whole. Do not break or crush tablet.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Meda AB
Pipers väg 2A
S-170 09 Solna
Sweden
12. MARKETING AUTHORISATION NUMBER
33
EU/1/97/044/006 100 tablets
13. MANUFACTURER’S BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Tasmar 200 mg (only applicable for the outer packaging)
34
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
Blister Packs, 30 and 60 Film-Coated Tablets
1.
Tasmar 200 mg film-coated tablets
Tolcapone
2.
STATEMENT OF ACTIVE SUBSTANCE
Each film-coated tablet contains 200 mg tolcapone
tolcapone 200 mg
3.
LIST OF EXCIPIENTS
Also contains lactose
See leaflet for further information.
4.
30 film-coated tablets
60 film-coated tablets
5.
METHOD AND ROUTE OF ADMINISTRATION
Read the package leaflet before use. For oral use
The tablets should be swallowed whole. Do not break or crush tablet.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Meda AB
Pipers väg 2A
S-170 09 Solna
Sweden
35
12. MARKETING AUTHORISATION NUMBER
EU/1/97/044/004 30 tablets
EU/1/97/044/005 60 tablets
13. MANUFACTURER’S BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Tasmar 200 mg (only applicable for the outer packaging)
36
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Tasmar 200 mg film-coated tablets
Tolcapone
2.
Meda AB
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
37
B. PACKAGE LEAFLET
38
PACKAGE LEAFLET: INFORMATION FOR THE USER
Tasmar 100 mg film-coated tablets
Tolcapone
Read all of this leaflet carefully before you start taking this medicine.
-
If you have further questions, please ask your doctor or your pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What Tasmar is and what it is used for
3.
How to take Tasmar
4.
Possible side effects
5.
How to store Tasmar
6.
Further information
1.
WHAT TASMAR IS AND WHAT IT IS USED FOR
Tasmar is used together with levodopa/benserazide or levodopa/carbidopa when all other alternative
medicines cannot stabilise your Parkinson’s disease.
Catechol-O-methyltransferase (COMT) is a natural enzyme in your body that breaks down the
levodopa medication used to treat your Parkinson’s disease. Tasmar blocks COMT and slows the
breakdown of levodopa. This means when it is taken together with levodopa (as levodopa/benserazide
or levodopa/carbidopa) you should have an improvement in your symptoms of Parkinson’s disease.
2.
BEFORE YOU TAKE TASMAR
Do not take Tasmar:
-
if you have severe dyskinesia (involuntary movement)
-
if you have a previous history of Neuroleptic Malignant Syndrome (NMS) Symptom Complex
(severe symptoms of muscle stiffening, fever or mental confusion ) and /or if you have non-
traumatic Rhabdomyolysis (damage of skeletal muscle tissue) or Hyperthermia (fever).
-
if you are hypersensitive (allergic) to tolcapone or to any of the other ingredients of Tasmar.
-
if you take non-selective mono amino oxidase (MAO) inhibitors (used to treat depression and
anxiety)
Take special care with Tasmar:
-
you
should not start taking Tasmar until your doctor has described the risks of treatment with
Tasmar and measures necessary to minimise those risks, and answered any questions you may
have. You should only receive Tasmar if your Parkinson’s disease is not adequately controlled
by the use of other therapies. In addition, your doctor will stop Tasmar treatment if after 3
weeks you do not improve enough to justify the risks of continuing treatment.
-
Liver Injury:
Tasmar may cause rare but potentially fatal liver injury. Liver injury has occurred most often
after 1 month and before 6 months. Injury occurring earlier or later is also possible.
It should also be noted that female patients may have a higher risk of liver injury.
39
-
Keep this leaflet. You may need to read it again.
2.
Before you take Tasmar
-
if you have liver disease or increased liver enzymes
-
if you have Phaeochromocytoma (a special type of tumor)
Before beginning treatment: To reduce the risk of liver injury you should not use Tasmar if 1)
you have liver disease or 2) blood tests done before starting treatment show any liver
abnormality (tests of ALT, alanine amino transferase and AST, aspartate amino transferase).
While receiving treatment: Blood tests will be done every 2 weeks for the first year of therapy,
every 4 weeks for the next 6 months and every 8 weeks thereafter and treatment will be stopped
if they become abnormal.
-
the treatment with Tasmar may sometimes lead to disturbances in the way the liver works.
Therefore, if you experience symptoms such as nausea, vomiting, pain in your stomach
(particulary over the liver in the right upper area), loss of appetite, weakness, fever, darkening
of urine, jaundice (yellow of the skin or eyes) or if you tire more easily, you should contact
your doctor immediately.
-
if you have taken already Tasmar and developed acute liver injury while on Tasmar, it should
not be re-introduced again.
-
NMS (Neuroleptic Malignant Syndrome):
Symptoms of Neuroleptic Malignant Syndrome may occur during Tasmar treatment.
NMS (Neuroleptic Malignant Syndrome) consists of some or all of the following: severe muscle
stiffness, jerking movements of muscles, arms or legs, and soreness of muscles. Muscle injury
can sometimes cause dark urine. Other important symptoms are high fever and mental
confusion. Very rarely, after abruptly reducing or stopping Tasmar or other antiparkinsonian
drugs, you may experience severe symptoms of muscle stiffening, fever or mental confusion. If
this happens notify your doctor.
Before beginning treatment: To reduce the risk of NMS you should not use Tasmar if your
doctor says you have severe dyskinesia (involuntary movement) or a previous illness that may
have been NMS. Inform your doctor of all prescription and non-prescription medications as the
risk of NMS may be increased if you are taking medications that may alter the effects of the
brain messenger molecules of dopamine and serotonin.
While receiving treatment: If you develop symptoms as described above, that you think may be
NMS, you should report them to your doctor immediately. Do not stop Tasmar or any other
Parkinson’s medications without telling your doctor as this may increase the risk of NMS.
-
if you have any illnesses other than Parkinson’s disease.
-
soon after beginning and during your treatment with Tasmar, you may have symptoms caused
by levodopa such as dyskinesia (involuntary movement) and nausea. If you feel unwell, you
should contact your doctor because you may need to take less levodopa.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
even those not prescribed (non-prescription medicines and herbals).
Please inform your doctor about all other medicines you are taking especially antidepressants,
alpha
-
methyldopa (used to treat increases blood pressure), apomorphine (used for Parkinson’s disease),
dobutamine (used for the chronic heart disease), adrenaline and isoprenaline (both used for heart
attacks).
When you are taking Tasmar with anticoagulants (that prevent blood clotting) of the warfarin type,
your doctor may perform regular blood tests to monitor how easily the blood clots.
If you go to hospital or if you are prescribed a new medicine, you must tell your doctor that you are
taking Tasmar.
Taking Tasmar with food and drink
Tasmar can be taken with or without food.
Pregnancy and breast-feeding
You must tell your doctor if you are pregnant or intend to become pregnant. Your doctor will discuss
the risks and benefits of taking Tasmar during pregnancy.
40
-
if you are allergic to other medicines, foods and dyes.
The effects of Tasmar have not been studied in infants. You should not breast-feed your infant during
treatment with Tasmar.
Driving and using machines
Tasmar has an effect on your symptoms of Parkinson’s disease. Since your ability to drive a car or
operate machinery may be affected by Parkinson’s disease, you should discuss this with your doctor.
Tasmar used with your other Parkinson medicines can cause somnolence (excessive drowsiness) and
sudden sleep onset episodes (you may suddenly fall asleep). Therefore you must refrain from driving
or engaging in activities where impaired alertness may put yourself or others at risk of serious injury
or death (e.g. operating machines) until such recurrent episodes and somnolence have resolved.
Important information about some of the ingrediensts of Tasmar
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor
before taking this medicine.
3.
HOW TO TAKE TASMAR
Always take Tasmar exactly as your doctor has told you. You should check with your doctor if you are
unsure. Do not break or crush tablets. Swallow Tasmar with water.
Dose and frequency of administration
When beginning and during treatment with Tasmar, your dose of levodopa may need to be changed.
Your doctor will advise you what to do.
Your doctor should always begin your treatment with the standard dose (100 mg (1 tablet) three times
a day). If benefits are not seen within 3 weeks of the initiation of the treatment, Tasmar should be
discontinued. The dose should only be increased to the higher dose (200 mg three times a day) if the
increase in how your Parkinson’s disease symptoms are controlled outweighs the expected increase in
side effects. The side effects at the higher dose can often be severe and affect your liver. If you do not
get better at the higher dose after a total of 3 weeks, your doctor should stop your treatment with
Tasmar.
The first dose of Tasmar is taken with the first dose of the day of levodopa and the other doses of
Tasmar are taken about 6 and 12 hours later. Take one tablet in the morning, one tablet in the middle
of the day and one tablet in the evening.
If you take more Tasmar than you should
Contact a doctor, pharmacist or hospital immediately as you may need urgent medical attention.
If another person accidentally takes your medicine, contact a doctor or hospital immediately as he or
she may need urgent medical attention.
Symptoms of overdose may include nausea, vomiting, dizziness and breathing difficulties.
If you forget to take Tasmar
Take it as soon as you remember, then continue to take it at the usual times. If you have missed several
doses, please inform your doctor and follow the advice given to you. Do not take a double dose to
make up for forgotten individual doses.
If you stop taking Tasmar
Do not reduce or stop taking your medicine unless your doctor tells you to. Always follow the
instructions of your doctor about the duration of the treatment with Tasmar.
41
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Tasmar can have side effects, although not everybody gets them.
Tell your doctor or a pharmacist as soon as possible if you do not feel well while you are taking
Tasmar
Disturbances in the way the liver works, sometimes severe hepatitis, have been observed.
Therefore, if you experience symptoms such as nausea, vomiting, abdominal pain, loss of
appetite, weakness, fever, darkening of urine or jaundice you should contact your doctor
immediately.
The frequency of possible side effects listed below is defined using the following convention:
Very common (affects more than 1 user in 10)
Common (affects 1 to 10 users in 100)
Uncommon (affects 1 to 10 users in 1,000)
Rare (affects 1 to 10 users in 10,000)
Very rare (affects less than 1 user in 10,000)
Not known (frequency cannot be estimated from the available data).
Side effects that may occur very commonly are: dyskinesia (involuntary movement), nausea, sleeping
problems, decreased appetite, diarrhoea, fainting, feeling lightheaded when you stand, hallucination,
headache, confusion and sleepiness.
Commonly, chest pain, constipation, vomiting, stomach ache, dry mouth and increased sweating may
occur during treatment with Tasmar. Further common side effects that may occur are, dystonia,
influenza and influenza like symptoms
Very rarely, patients develop Neuroleptic Malignant Syndrome (severe symptoms of muscle
stiffening, fever or mental confusion) when antiparkinsonian treatments are abruptly reduced or
withdrawn.
Soon after beginning and during your treatment with Tasmar, you may have symptoms caused by
levodopa such as involuntary movement and nausea. Therefore, if you feel unwell, you should contact
your doctor since you may need to have your levodopa dose changed.
Contact your doctor if you develop persistent or severe diarrhoea.
This medicine can cause a harmless yellow urine discoloration. However if you notice a darkening of
your urine this could be a sign of muscle injury or liver injury, please inform your doctor.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE TASMAR
Keep out of the reach and sight of children.
Do not use after the expiry date stated on the pack.
This medicinal product does not require any special storage conditions
Do not use Tasmar if you notice that the tablets are damaged.
42
6.
FURTHER INFORMATION
What Tasmar contains
-
The active substance is tolcapone (100 mg in each film- coated tablet)
-
Tablet core
:
Calcium hydrogen phosphate, Microcrystalline cellulose,
Povidone K30, Sodium starch glycollate, Lactose, Talc, Magnesium stearate.
Film-coat
:
Hydroxypropylmethylcellulose, Talc, Yellow iron oxide, Ethylcellulose,
Titanium dioxide, Triacetin, Sodium lauril sulfate.
What Tasmar looks like and contents of the pack
Tasmar is a pale to light yellow, oval shaped, film-coated tablet. “TASMAR” and “100” are engraved
on one side. Tasmar is supplied as film-coated tablets containing 100 mg tolcapone. It is available in
blisters in pack sizes of 30 and 60 tablets and in glass bottles in pack sizes of 30, 60 and 100 tablets.
Not all pack-sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
The marketing authorisation holder is:
Meda AB
Pipers väg 2A
S-170 09 Solna
Sweden
The manufacturer responsible for batch release is:
ICN Polfa Rzeszów S.A.
ul. Przemysłowa 2
35-959 Rzeszów
Poland
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
België/Belgique/Belgien
MEDA Pharma S.A./N.V.
Chaussée de la Hulpe 166/
Terhulpsesteenweg 166
B-1170 Brussels
Tél/Tel: +32 2 5 04 08 11
Luxembourg/Luxemburg
MEDA Pharma S.A./N.V.
Chaussée de la Hulpe 166/
Terhulpsesteenweg 166
B-1170 Brussels
Belgique/Belgien
Tél/Tel: +32 2 5 04 08 11
България
БУЛГЕРМЕД
Ул. Светослав Тертер 24
София 1124
Тел: +359 02 942 70 70
Magyarország
MEDA PHARMA Hungary Kereskedelmi Kft.
H-1139 Budapest
Váci ut 91
Tel.: +36 1 236 3410
Česká republika
MEDA Pharma s.r.o.
Kodaňská 1441/46
CZ 100 10 Praha 10
Tel: +420 234 064 203
Malta
Vivian Corporation Ltd.
Sanitas Building, Tower Street
Msida MSD 1824
Tel: +356 21 320 338
43
The other ingredients are:
Danmark
Meda A/S
Solvang 8
DK-3450 Allerød
Tlf: +45 44 52 88 88
Nederland
MEDA Pharma B.V.
Krijgsman 20
NL-1186 DM Amstelveen
Tel: +31 20 751 65 00
Deutschland
MEDA Pharma GmbH & Co. KG
Benzstraße 1
D-61352 Bad Homburg v.d.H.
Tel: + 49 6172 888 01
Norge
Meda A/S
Askerveien 61
N-1384 Asker
Tlf: +47 66 75 33 00
Eesti
Meda Pharma
Narva mnt 11D
EE - 10151 Tallinn, Eesti
Tel. + 372 6261 025
Österreich
MEDA Pharma GmbH
Guglgasse 15
A-1110 Wien
Tel: + 43 1 86 390 0
Ελλάδα
Vianex S.A.
Οδός Τατοϊου,
18ο χλμ Εθνικής Οδού Αθηνών - Λαμίας,
GR-14671 Νέα Ερυθραία Ταχ. Θυρίδα 52894
Τηλ: +30.210.8009111
Polska
Meda Pharmaceuticals Sp.z.o.o.
Al. Jana Pawla II/15
PL-00-828 Warszawa
Tel: +48 22 697 7100
España
MEDA Pharma S.A.U.
Avenida de Castilla, 2
Parque Empresarial San Fernando
Edificio Berlin
E-28830 San Fernando de Henares (Madrid)
Tel: +34 91 669 93 00
Portugal
MEDA Pharma Produtos Farmacêuticos, SA
Rua do Centro Cultural 13
P-1749-066 Lisboa
Tel: +351 21 842 0300
France
MEDA PHARMA SAS
25 Bd. de l´Amiral Bruix
F-75016 Paris
Tél : +33 156 64 10 70
România
MEDA Pharma GmbH & Co. KG
Benzstraße 1
D-61352 Bad Homburg v.d.H.
Germania
Tel: + 49 6172 888 01
Ireland
Meda Health Sales Ireland Ltd.
Office 10
Dunboyne Business Park
Dunboyne
IRL - Co Meath
Tel: +353 1 802 66 24
Slovenija
MEDA Pharma GmbH
Guglgasse 15
A-1110 Wien
Avstrija
Tel: + 43 1 86 390 0
Ísland
Meda AB
Box 906
S-170 09 Solna
Svíþjóð.
Sími: +46 8 630 1900
Slovenská republika
MEDA Pharma spol. s r.o.
Trnavská cesta 50
SK-821 02 Bratislava
Tel: +421 2 4914 0172
44
Italia
Meda Pharma S.p.A.
Viale Brenta, 18
I-20139 Milano
Tel: +39 02 57 416 1
Suomi/Finland
Meda Oy
Vaisalantie 4/ Vaisalavägen 4
FIN-02130 Espoo/ Esbo
Puh/Tel: +358 20 720 9550
Κύπρος
C.A.Papaellinas & Co Ltd
Χ. Α. ΠΑΠΑΕΛΛΗΝΑΣ κ ΣΙΑ
Λεωφ. Γ. Κρανιδιώτη 179
CY-2235, Λατσιά, Λευκωσία,
τηλ: (+357) 22741741
Sverige
Meda AB
Box 906
S-170 09 Solna
Tel: +46 8 630 1900
Latvija
Meda Pharma SIA
O. Vaciesa str. 13
LV-1004 Riga, Latvia
Tel.: +371 67 805140
United Kingdom
Meda Pharmaceuticals Ltd.
Skyway House
Parsonage Road
Takeley
Bishop's Stortford
CM22 6PU - UK
Tel: +44 845 460 0000
Lietuva
Meda Pharma
Veiverių g. 134,
LT-46352 Kaunas, Lithuania
Tel. + 370 37330509
This leaflet was last approved in:
45
PACKAGE LEAFLET: INFORMATION FOR THE USER
Tasmar 200 mg film-coated tablets
Tolcapone
Read all of this leaflet carefully before you start taking this medicine.
-
If you have further questions, please ask your doctor or your pharmacist.
-
This medicine has been prescribed for you personally and you. Do not pass it on to others. It
may harm them, even if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What Tasmar is and what it is used for
3.
How to take Tasmar
4.
Possible side effects
5.
How to store Tasmar
6.
Further information
1. WHAT TASMAR IS AND WHAT IT IS USED FOR
Tasmar is used together with levodopa/benserazide or levodopa/carbidopa when all other alternative
medicines cannot stabilise your Parkinson’s disease.
Catechol-O-methyltransferase (COMT) is a natural enzyme in your body that breaks down the
levodopa medication used to treat your Parkinson’s disease. Tasmar blocks COMT and slows the
breakdown of levodopa. This means when it is taken together with levodopa (as levodopa/benserazide
or levodopa/carbidopa) you should have an improvement in your symptoms of Parkinson’s disease.
2.
BEFORE YOU TAKE TASMAR
Do not take Tasmar:
-
if you have severe dyskinesia (involuntary movement)
-
if you have a previous history of Neuroleptic Malignant Syndrome (NMS) Symptom Complex
(severe symptoms of muscle stiffening, fever or mental confusion) and /or if you have non-
traumatic Rhabdomyolysis (damage of skeletal muscle tissue) or Hyperthermia (fever).
-
if you are hypersensitive (allergic) to tolcapone or to any of the other ingredients of Tasmar.
-
if you take non-selective mono amino oxidase (MAO) inhibitors (used to treat depression and
anxiety)
Take special care with Tasmar:
-
you
should not start taking Tasmar until your doctor has described the risks of treatment with
Tasmar and measures necessary to minimise those risks, and answered any questions you may
have. You should only receive Tasmar if your Parkinson’s disease is not adequately controlled
by the use of other therapies. In addition, your doctor will stop Tasmar treatment if after 3
weeks you do not improve enough to justify the risks of continuing treatment.
-
Liver Injury:
Tasmar may cause rare but potentially fatal liver injury. Liver injury has occurred most often
after 1 month and before 6 months. Injury occurring earlier or later is also possible.
It should also be noted that female patients may have a higher risk of liver injury.
46
-
Keep this leaflet. You may need to read it again.
2.
Before you take Tasmar
-
if you have liver disease or increased liver enzymes
-
if you have Phaeochromocytoma (a special type of tumor)
Before beginning treatment: To reduce the risk of liver injury you should not use Tasmar if 1)
you have liver disease or 2) blood tests done before starting treatment show any liver
abnormality (tests of ALT, alanine amino transferase and AST, aspartate amino transferase).
While receiving treatment: Blood tests will be done every 2 weeks for the first year of therapy,
every 4 weeks for the next 6 months and every 8 weeks thereafter and treatment will be stopped
if they become abnormal.
-
the treatment with Tasmar may sometimes lead to disturbances in the way the liver works.
Therefore, if you experience symptoms such as nausea, vomiting, pain in your stomach
(particularly over the liver in the right upper area), loss of appetite, weakness, fever, darkening
of urine, jaundice (yellow of the skin or eyes) or if you tire more easily, you should contact your
doctor immediately
-
if you have taken already Tasmar and developed acute liver injury while on Tasmar, it should
not be re-introduced again.
-
NMS (Neuroleptic Malignant Syndrome):
Symptoms of Neuroleptic Malignant Syndrome may occur during Tasmar treatment.
NMS (Neuroleptic Malignant Syndrome) consists of some or all of the following: severe muscle
stiffness, jerking movements of muscles, arms or legs, and soreness of muscles. Muscle injury
can sometimes cause dark urine. Other important symptoms are high fever and mental
confusion. Very rarely, after abruptly reducing or stopping Tasmar or other antiparkinsonian
drugs, you may experience severe symptoms of muscle stiffening, fever or mental confusion. If
this happens notify your doctor.
Before beginning treatment: To reduce the risk of NMS you should not use Tasmar if your
doctor says you have severe dyskinesia (involuntary movement) or a previous illness that may
have been NMS. Inform your doctor of all prescription and non-prescription medications as the
risk of NMS may be increased if you are taking medications that may alter the effects of the
brain messenger molecules of dopamine and serotonin.
While receiving treatment: If you develop symptoms as described above, that you think may be
NMS, you should report them to your doctor immediately. Do not stop Tasmar or any other
Parkinson’s medications without telling your doctor as this may increase the risk of NMS.
-
if you have any illnesses other than Parkinson’s disease.
-
soon after beginning and during your treatment with Tasmar, you may have symptoms caused
by levodopa such as dyskinesia (involuntary movement) and nausea. If you feel unwell, you
should contact your doctor because you may need to take less levodopa.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
even those not prescribed (non-prescription medicines and herbals).
Please inform your doctor about all other medicines you are taking especially antidepressants,
alpha
-
methyldopa (used to treat increased blood pressure), apomorphine (used for Parkinson’s disease),
dobutamine (used for the chronic heart disease), adrenaline and isoprenaline (both used for heart
attacks).
When you are taking Tasmar with anticoagulants (that prevent blood clotting) of the warfarin type,
your doctor may perform regular blood tests to monitor how easily the blood clots.
If you go to hospital or if you are prescribed a new medicine, you must tell your doctor that you are
taking Tasmar.
Taking Tasmar with food and drink
Tasmar can be taken with or without food.
Pregnancy and breast-feeding
You must tell your doctor if you are pregnant or intend to become pregnant. Your doctor will discuss
the risks and benefits of taking Tasmar during pregnancy.
47
-
if you are allergic to other medicines, foods and dyes.
The effects of Tasmar have not been studied in infants. You should not breast-feed your infant during
treatment with Tasmar.
Driving and using machines
Tasmar has an effect on your symptoms of Parkinson’s disease. Since your ability to drive a car or
operate machinery may be affected by Parkinson’s disease, you should discuss this with your doctor.
Tasmar used with your other Parkinson medicines can cause somnolence (excessive drowsiness) and
sudden sleep onset episodes (you may suddenly fall asleep). Therefore you must refrain from driving
or engaging in activities where impaired alertness may put yourself or others at risk of serious injury
or death (e.g. operating machines) until such recurrent episodes and somnolence have resolved.
Important information about some of the ingredients of Tasmar
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor
before taking this medicine.
3.
HOW TO TAKE TASMAR
Always take Tasmar exactly as your doctor has told you. You should check with your doctor if you are
unsure. Do not break or crush tablets. Swallow Tasmar with water.
Dose and frequency of administration
When beginning and during treatment with Tasmar, your dose of levodopa may need to be changed.
Your doctor will advise you what to do.
Your doctor should always begin your treatment with the standard dose (100 mg (1 tablet) three times
a day). If benefits are not seen within 3 weeks of the initiation of the treatment, Tasmar should be
discontinued. The dose should only be increased to the higher dose (200 mg three times a day) if the
increase in how your Parkinson’s disease symptoms are controlled outweighs the expected increase in
side effects. The side effects at the higher dose can often be severe and affect your liver. If you do not
get better at the higher dose after a total of 3 weeks, your doctor should stop your treatment with
Tasmar.
The first dose of Tasmar is taken with the first dose of the day of levodopa and the other doses of
Tasmar are taken about 6 and 12 hours later. Take one tablet in the morning, one tablet in the middle
of the day and one tablet in the evening.
If you take more Tasmar than you should
Contact a doctor, pharmacist or hospital immediately as you may need urgent medical attention.
If another person accidentally takes your medicine, contact a doctor or hospital immediately as he or
she may need urgent medical attention.
Symptoms of overdose may include nausea, vomiting, dizziness and breathing difficulties.
If you forget to take Tasmar
Take it as soon as you remember, then continue to take it at the usual times. If you have missed several
doses, please inform your doctor and follow the advice given to you. Do not take a double dose to
make up for forgotten individual doses.
If you stop taking Tasmar
Do not reduce or stop taking your medicine unless your doctor tells you to. Always follow the
instructions of your doctor about the duration of the treatment with Tasmar.
48
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Tasmar can have side effects, although not everybody gets them.
Tell your doctor or a pharmacist as soon as possible if you do not feel well while you are taking
Tasmar.
Disturbances in the way the liver works, sometimes severe hepatitis, have been observed.
Therefore, if you experience symptoms such as nausea, vomiting, abdominal pain, loss of
appetite, weakness, fever, darkening of urine or jaundice you should contact your doctor
immediately.
The frequency of possible side effects listed below is defined using the following convention:
Very common (affects more than 1 user in 10)
Common (affects 1 to 10 users in 100)
Uncommon (affects 1 to 10 users in 1,000)
Rare (affects 1 to 10 users in 10,000)
Very rare (affects less than 1 user in 10,000)
Not known (frequency cannot be estimated from the available data).
Side effects that may occur very commonly are: dyskinesia (involuntary movement), nausea, sleeping
problems, decreased appetite, diarrhoea, fainting, feeling lightheaded when you stand, hallucination,
headache, confusion and sleepiness.
Commonly, chest pain, constipation, vomiting, stomach ache, dry mouth and increased sweating may
occur during treatment with Tasmar. Further common side effects that may occur are, dystonia,
influenza and influenza like symptoms.
Very rarely, patients develop Neuroleptic Malignant Syndrome (severe symptoms of muscle
stiffening, fever or mental confusion) when antiparkinsonian treatments are abruptly reduced or
withdrawn.
Soon after beginning and during your treatment with Tasmar, you may have symptoms caused by
levodopa such as involuntary movement and nausea. Therefore, if you feel unwell, you should contact
your doctor since you may need to have your levodopa dose changed.
Contact your doctor if you develop persistent or severe diarrhoea.
This medicine can cause a harmless yellow urine discoloration. However if you notice a darkening of
your urine this could be a sign of muscle injury or liver injury, please inform your doctor.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE TASMAR
Keep out of the reach and sight of children.
Do not use after the expiry date on the pack.
This medicinal product does not require any special storage conditions
Do not use Tasmar if you notice that the tablets are damaged.
6.
FURTHER INFORMATION
49
What Tasmar contains
-
The active substance is tolcapone (200 mg in each film- coated tablet)
Tablet core
:
Calcium hydrogen phosphate, Microcrystalline cellulose,
Povidone K30, Sodium starch glycollate, Lactose monohydrate, Talc, Magnesium stearate.
Film-coat
:
Hydroxypropylmethylcellulose, Talc, Yellow iron oxide, Ethylcellulose,
Titanium dioxide, Triacetin, Sodium lauril sulfate.
What Tasmar looks like and contents of the pack
Tasmar is an orange yellow to brown yellow, oval shaped, film-coated tablet. “TASMAR” and “200”
are engraved on one side. Tasmar is supplied as film-coated tablets containing 200 mg tolcapone. It
is available in blisters in pack sizes of 30 and 60 tablets and in glass bottles in pack sizes of 100
tablets.
Not all pack sizes may be marketed.
The marketing authorisation holder is:
Meda AB
Pipers väg 2A
S-170 09 Solna
Sweden
The manufacturer responsible for batch release is:
ICN Polfa Rzeszów S.A.
ul. Przemysłowa 2
35-959 Rzeszów
Poland
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
België/Belgique/Belgien
MEDA Pharma S.A./N.V.
Chaussée de la Hulpe 166/
Terhulpsesteenweg 166
B-1170 Brussels
Tél/Tel: +32 2 5 04 08 11
Luxembourg/Luxemburg
MEDA Pharma S.A./N.V.
Chaussée de la Hulpe 166/
Terhulpsesteenweg 166
B-1170 Brussels
Belgique/Belgien
Tél/Tel: +32 2 5 04 08 11
България
БУЛГЕРМЕД
Ул. Светослав Тертер 24
София 1124
Тел: +359 02 942 70 70
Magyarország
MEDA PHARMA Hungary Kereskedelmi Kft.
H-1139 Budapest
Váci ut 91
Tel.: +36 1 236 3410
Česká republika
MEDA Pharma s.r.o.
Kodaňská 1441/46
CZ 100 10 Praha 10
Tel: +420 234 064 203
Malta
Vivian Corporation Ltd.
Sanitas Building, Tower Street
Msida MSD 1824
Tel: +356 21 320 338
50
-
The other ingredients are:
Danmark
Meda A/S
Solvang 8
DK-3450 Allerød
Tlf: +45 44 52 88 88
Nederland
MEDA Pharma B.V.
Krijgsman 20
NL-1186 DM Amstelveen
Tel: +31 20 751 65 00
Deutschland
MEDA Pharma GmbH & Co. KG
Benzstraße 1
D-61352 Bad Homburg v.d.H.
Tel: + 49 6172 888 01
Norge
Meda A/S
Askerveien 61
N-1384 Asker
Tlf: +47 66 75 33 00
Eesti
Meda Pharma
Narva mnt 11D
EE - 10151 Tallinn, Eesti
Tel. + 372 6261 025
Österreich
MEDA Pharma GmbH
Guglgasse 15
A-1110 Wien
Tel: + 43 1 86 390 0
Ελλάδα
Vianex S.A.
Οδός Τατοϊου,
18ο χλμ Εθνικής Οδού Αθηνών - Λαμίας,
GR-14671 Νέα Ερυθραία Ταχ. Θυρίδα 52894
Τηλ: +30.210.8009111
Polska
Meda Pharmaceuticals Sp.z.o.o.
Al. Jana Pawla II/15
PL-00-828 Warszawa
Tel: +48 22 697 7100
España
MEDA Pharma S.A.U.
Avenida de Castilla, 2
Parque Empresarial San Fernando
Edificio Berlin
E-28830 San Fernando de Henares (Madrid)
Tel: +34 91 669 93 00
Portugal
MEDA Pharma Produtos Farmacêuticos, , SA
Rua do Centro Cultural 13
P-1749-066 Lisboa
Tel: +351 21 842 0300
France
MEDA PHARMA SAS
25 Bd. de l´Amiral Bruix
F-75016 Paris
Tél : +33 156 64 10 70
România
MEDA Pharma GmbH & Co. KG
Benzstraße 1
D-61352 Bad Homburg v.d.H.
Germania
Tel: + 49 6172 888 01
Ireland
Meda Health Sales Ireland Ltd.
Office 10
Dunboyne Business Park
Dunboyne
IRL - Co Meath
Tel: +353 1 802 66 24
Slovenija
MEDA Pharma GmbH
Guglgasse 15
A-1110 Wien
Avstrija
Tel: + 43 1 86 390 0
Ísland
Meda AB
Box 906
S-170 09 Solna
Svíþjóð.
Sími: +46 8 630 1900
Slovenská republika
MEDA Pharma spol. s r.o.
Trnavská cesta 50
SK-821 02 Bratislava
Tel: +421 2 4914 0172
51
Italia
Meda Pharma S.p.A.
Viale Brenta, 18
I-20139 Milano
Tel: +39 02 57 416 1
Suomi/Finland
Meda Oy
Vaisalantie 4/ Vaisalavägen 4
FIN-02130 Espoo/ Esbo
Puh/Tel: +358 20 720 9550
Κύπρος
C.A.Papaellinas & Co Ltd
Χ. Α. ΠΑΠΑΕΛΛΗΝΑΣ κ ΣΙΑ
Λεωφ. Γ. Κρανιδιώτη 179
CY-2235, Λατσιά, Λευκωσία,
τηλ: (+357) 22741741
Sverige
Meda AB
Box 906
S-170 09 Solna
Tel: +46 8 630 1900
Latvija
Meda Pharma SIA
O. Vaciesa str. 13
LV-1004 Riga, Latvia
Tel.: +371 67 805140
United Kingdom
Meda Pharmaceuticals Ltd.
Skyway House
Parsonage Road
Takeley
Bishop's Stortford
CM22 6PU - UK
Tel: +44 845 460 0000
Lietuva
Meda Pharma
Veiverių g. 134,
LT-46352 Kaunas, Lithuania
Tel. + 370 37330509
This leaflet was last approved in:
52
ANNEX IV
GROUNDS FOR ONE ADDITIONAL RENEWAL
53
GROUNDS FOR ONE ADDITIONAL RENEWAL
Tasmar was suspended from 1998 to 2004 mainly due to increasing concerns over reports of severe
hepatotoxicity, including cases with a total of outcome. As part of the conclusion for the lifting of the
suspension on the 22 April 2004, the MAH has committed to specify measures including intensive
monitoring of hepatic reaction and Neuroleptic Malignant Syndrome.
Based on the above and on the review of the data that have become available since the lifting of the
suspension, the CHMP considers that the benefit-risk balance of Tasmar remains positive, but
considers that its safety profile is to be closely monitored for the following reasons:
Since the lifting of the suspension there has been a relatively limited exposure in Europe. The
CHMP also noted that this is effectively the first renewal since the lifting of the suspension.
Specific measures are still in place in relation to be monitoring of particular safety issues including
hepatotoxicity and NMS, also remaining submission of yearly PSURs
Therefore, the CHMP concluded that the MAH should submit one additional renewal application in 5
years time.
54
Source: European Medicines Agency
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