ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Oprymea 0.088 mg tablets
2.
Each tablet contains 0.088 mg pramipexole base (as 0.125 mg pramipexole dihydrochloride
monohydrate).
Please note:
Pramipexole doses as published in the literature refer to the salt form.
Therefore, doses will be expressed in terms of both pramipexole base and pramipexole salt (in
brackets).
For a full list of excipients, see section 6.1.
3.
Tablet.
0.088 mg: white, round, with bevelled edges and imprint "P6" on one side of the tablet.
4.
Oprymea is indicated for treatment of the signs and symptoms of idiopathic Parkinson's disease, alone
(without levodopa) or in combination with levodopa, i.e. over the course of the disease, through to late
stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of the
therapeutic effect occur (end of dose or “on off” fluctuations).
Posology
Parkinson’s disease
The daily dosage is administered in equally divided doses 3 times a day.
Initial treatment
Dosages should be increased gradually from a starting-dose of 0.264 mg of base (0.375 mg of salt) per
day and then increased every 5 - 7 days. Providing patients do not experience intolerable undersirable
effects, the dosage should be titrated to achieve a maximal therapeutic effect.
Ascending – Dose Schedule of OPRYMEA
Week
Dosage
(mg of base)
Total Daily Dose
(mg of base)
Dosage
(mg of salt)
Total Daily Dose
(mg of salt)
1
3 x 0.088
0.264
3 x 0.125
0.375
2
3 x 0.18
0.54
3 x 0.25
0.75
3
3 x 0.35
1.1
3 x 0.5
1.50
If a further dose increase is necessary the daily dose should be increased by 0.54 mg base (0.75 mg
salt) at weekly intervals up to a maximum dose of 3.3 mg of base (4.5 mg of salt) per day.
2
However, it should be noted that the incidence of somnolence is increased at doses higher than
1.5 mg/day (see section 4.8).
The individual dose should be in the range of 0.264 mg of base (0.375 mg of salt) to a maximum of
3.3 mg of base (4.5 mg of salt) per day. During dose escalation in three pivotal studies
,
efficacy was
observed starting at a daily dose of 1.1 mg of base (1.5 mg of salt). Further dose adjustments should be
done based on the clinical response and the occurrence of adverse reactions. In clinical trials
approximately 5% of patients were treated at doses below 1.1 mg (1.5 mg of salt). In advanced
Parkinson’s disease, doses higher than 1.1 mg (1.5 mg of salt) per day can be useful in patients where
a reduction of the levodopa therapy is intended. It is recommended that the dosage of levodopa is
reduced during both the dose escalation and the maintenance treatment with Oprymea, depending on
reactions in individual patients (see section 4.5).
Abrupt discontinuation of dopaminergic therapy can lead to the development of a neuroleptic
malignant syndrome. Pramipexole
should be tapered off at a rate of 0.54 mg of base (0.75 mg of salt)
per day until the daily dose has been reduced to 0.54 mg of base (0.75 mg of salt). Thereafter the dose
should be reduced by 0.264 mg of base (0.375 mg of salt) per day (see section 4.4).
The elimination of pramipexole is dependent on renal function. The following dosage schedule is
suggested for initiation of therapy:
Patients with a creatinine clearance above 50 ml/min require no reduction in daily dose or dosing
frequency.
In patients with a creatinine clearance between 20 and 50 ml/min, the initial daily dose of Oprymea
should be administered in two divided doses, starting at 0.088 mg of base (0.125 mg of salt) twice a
day (0.176 mg of base/0.25 mg of salt daily).
A maximum daily dose of 1.57 mg pramipexole base
(2.25 mg of salt) should not be exceeded.
In patients with a creatinine clearance less than 20 ml/min, the daily dose of Oprymea should be
administered in a single dose, starting at 0.088 mg of base (0.125 mg of salt) daily.
A maximum daily
dose of 1.1 mg pramipexole base (1.5 mg of salt) should not be exceeded.
If renal function declines during maintenance therapy reduce Oprymea daily dose by the same
percentage as the decline in creatinine clearance, i.e. if creatinine clearance declines by 30%, then
reduce the Oprymea daily dose by 30%. The daily dose can be administered in two divided doses if
creatinine clearance is between 20 and 50 ml/min, and as a single daily dose if creatinine clearance is
less than 20 ml/min.
Dose adjustment in patients with hepatic failure is probably not necessary, as approx. 90% of absorbed
active substance is excreted through the kidneys. However, the potential influence of hepatic
insufficiency on Oprymea pharmacokinetics has not been investigated.
Paediatric population
The safety and efficacy of Oprymea in children below 18 years has not been established. There is no
relevant use of Oprymea in the paediatric population in Parkinson’s Disease.
Tourette Disorder
Paediatric population
Oprymea is not recommended for use in children and adolescents below 18 years since the efficacy
and safety has not been established in this population. Oprymea should not be used in children or
3
Maintenance treatment
Treatment discontinuation
Dosing in patients with renal impairment
Dosing in patients with hepatic impairment
adolescents with Tourette Disorder because of a negative benefit-risk balance for this disorder (see
section 5.1).
Hypersensitivity to the active substance or to any of the excipients.
When prescribing Oprymea in a patient with Parkinson’s disease with renal impairment a reduced
dose is suggested in line with section 4.2.
Hallucinations
Hallucinations are known as a side-effect of treatment with dopamine agonists and levodopa. Patients
should be informed that (mostly visual) hallucinations can occur.
Dyskinesias
In advanced Parkinson’s disease, in combination treatment with levodopa, dyskinesias can occur
during the initial titration of Oprymea. If they occur, the dose of levodopa should be decreased.
Pramipexole has been associated with somnolence and episodes of sudden sleep onset, particularly in
patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without
awareness or warning signs, has been reported uncommonly. Patients must be informed of this and
advised to exercise caution while driving or operating machines during treatment with Oprymea.
Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from
driving or operating machines. Furthermore a reduction of dosage or termination of therapy may be
considered. Because of possible additive effects, caution should be advised when patients are taking
other sedating medication or alcohol in combination with pramipexole (see sections 4.5, 4.7 and
section 4.8).
Pathological gambling, increased libido and hypersexuality have been reported in patients treated with
dopamine agonists for Parkinson’s disease, including pramipexole. Furthermore, patients and
caregivers should be aware of the fact that other behavioural symptoms of impulse control disorders
and compulsions such as binge eating and compulsive shopping can occur. Dose reduction/tapered or
discontinuation should be considered.
Patients with psychotic disorders
Patients with psychotic disorders should only be treated with dopamine agonists if the potential
benefits outweigh the risks.
Coadministration of antipsychotic medicinal products with pramipexole should be avoided (see
section 4.5).
Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
In case of severe cardiovascular disease, care should be taken. It is recommended to monitor blood
pressure, especially at the beginning of treatment, due to the general risk of postural hypotension
associated with dopaminergic therapy.
Neuroleptic malignant syndrome
Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal
of dopaminergic therapy (see section 4.2)
4
Sudden onset of sleep and somnolence
Impulse control disorders and compulsive behaviours
Ophthalmologic monitoring
Severe cardiovascular disease
Augmentation
Reports in the literature indicate that treatment of another indication with dopaminergic medicinal
products can result in augmentation. Augmentation refers to the earlier onset of symptoms in the
evening (or even afternoon), increase in symptoms, and spread of symptoms to involve other
extremities. Augmentation was specifically investigated in a controlled clinical trial over 26 weeks.
Augmentation was observed in 11.8% of patients in the pramipexole group (N = 152) and 9.4% of
patients in the placebo group (N = 149). Kaplan-Meier analysis of time to augmentation showed no
significant difference between pramipexole and placebo groups.
Pramipexole is bound to plasma proteins to a very low (< 20%) extent, and little biotransformation is
seen in man. Therefore, interactions with other medicinal products affecting plasma protein binding or
elimination by biotransformation are unlikely. As anticholinergics are mainly eliminated by
biotransformation, the potential for an interaction is limited, although an interaction with
anticholinergics has not been investigated. There is no pharmacokinetic interaction with selegiline and
levodopa.
Inhibitors/competitors of active renal elimination pathway
Cimetidine reduced the renal clearance of pramipexole by approximately 34%, presumably by
inhibition of the cationic secretory transport system of the renal tubules. Therefore, medicinal products
that are inhibitors of this active renal elimination pathway or are eliminated by this pathway, such as
cimetidine,amantadine mexiletine, zidovudine, cisplatin, quinine, and procainamide, may interact with
pramipexole resulting in reduced clearance of pramipexole. Reduction of the pramipexole dose should
be considered when these medicinal products are administered concomitantly.
Combination with levodopa
When Oprymea is given in combination with levodopa, it is recommended that the dosage of levodopa
is reduced and the dosage of other anti-parkinsonian medicinal products is kept constant while
increasing the dose of Oprymea.
Because of possible additive effects, caution should be advised when patients are taking other sedating
medicinal products or alcohol in combination with pramipexole.
Antipsychotic medicinal products
Coadministration of antipsychotic medicinal products with pramipexole should be avoided (see
section 4.4), e.g. if antagonistic effects can be expected.
Pregnancy
The effect on pregnancy and lactation has not been investigated in humans. Pramipexole was not
teratogenic in rats and rabbits, but was embryotoxic in the rat at maternotoxic doses (see section 5.3).
Oprymea should not be used during pregnancy unless clearly necessary, i.e. if the potential benefit
justifies the potential risk to the foetus.
Brest-feeding
As pramipexole treatment inhibits secretion of prolactin in humans, inhibition of lactation is expected.
The excretion of pramipexole into breast milk has not been studied in women. In rats, the
concentration of active substance-related radioactivity was higher in breast milk than in plasma. In the
absence of human data, Oprymea should not be used during breast-feeding. However, if its use is
unavoidable, breast-feeding should be discontinued.
Fertility
5
Plasma protein binding
No studies on the effect on human fertility have been conducted. In animal studies, pramipexole
affected oestrous cycles and reduced female fertility as expected for a dopamine agonist. However,
these studies did not indicate direct or indirect harmful effects with respect to male fertility.
Oprymea can have a major influence on the ability to drive and use machines.
Hallucinations or somnolence can occur.
Patients being treated with Oprymea 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 sections 4.4, 4.5, and 4.8).
The following adverse reactions are expected under the use of pramipexole: abnormal dreams,
amnesia, behavioural symptoms of impulse control disorders and compulsions such as binge eating,
compulsive shopping, hypersexuality and pathological gambling; confusion, constipation, delusion,
dizziness, dyskinesia, dyspnoea, fatigue, hallucinations, headache, hiccups, hyperkinesia, hyperphagia,
hypotension, insomnia, libido disorders, nausea, paranoia, peripheral oedema, pneumonia, pruritus,
rash and other hypersensitivity; restlessness, somnolence, sudden onset of sleep, syncope, visual
impairment including diplopia, vision blurred and visual acuity reduced, vomiting, weight decrease
including decreased appetite, weight increase.
Based on the analysis of pooled placebo-controlled trials, comprising a total of 1,923 patients on
pramipexole and 1,354 patients on placebo, adverse drug reactions were frequently reported for both
groups. 63 % of patients on pramipexole and 52% of patients on placebo reported at least one adverse
drug reaction.
Tables 1 and 2 display the frequency of adverse reactions from placebo-controlled clinical trials. The
adverse reactions reported in these tables are those events that occurred in 0,1% or more of patients
treated with pramipexole and were reported significantly more often in patients taking pramipexole
than placebo, or where the event was considered clinically relevant. However, the majority of common
adverse reactions were mild to moderate, they usually start early in therapy, and most tended to
disappear even as therapy was continued.
Within the system organ classes, adverse reactions are listed under headings of frequency (number of
patients expected to experience the reaction), using the following categories: very common ( ≥ 1/10);
common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare
(< 1/10,000); not known (cannot be estimated from the available data).
Parkinson’s disease, most common adverse effects
The most commonly (≥5%) reported adverse reactions in patients with Parkinson’s disease more
frequent with pramipexole treatment than with placebo were nausea, dyskinesia, hypotension,
dizziness, somnolence, insomnia, constipation, hallucination, headache and fatigue. The incidence of
somnolence is increased at doses higher than 1.5 mg/day (see section 4.2). More frequent adverse drug
reaction in combination with levodopa was dyskinesia. Hypotension may occur at the beginning of
treatment, especially if pramipexole is titrated too fast.
Table 1: Parkinson’s diseas
e
System Organ Class
Adverse Drug Reaction
Infections and infestations
Uncommon
pneumonia
Psychiatric disorders
6
Expected adverse effects
Common
abnormal dreams, behavioural symptoms of impulse control
disorders and compulsions, confusion, hallucinations, insomnia
Uncommon
binge eating, compulsive shopping, delusion, hyperphagia,
hypersexuality, libido disorder, paranoia, pathological gambling,
restlessness
Nervous system disorders
Very common
dizziness, dyskinesia, somnolence
Common
headache
Uncommon
amnesia, hyperkinesia, sudden onset of sleep, syncope
Eye disorders
Common
visual impairment including diplopia, vision blurred and visual
acuity reduced
Vascular disorders
Common
hypotension
Respiratory, thoracic, and m
ediastinal disorders
Uncommon
dyspnoea, hiccups
Gastrointestinal disorders
Very common
nausea
Common
constipation, vomiting
Skin and subcutaneous tissu
e disorders
Uncommon
hypersensitivity, pruritus, rash
General disorders and admi
nistration site conditions
Common
fatigue, peripheral oedema
Investigations
Common
weight decrease including decreased appetite
Uncommon
weight increase
The most commonly (≥ 5%) reported adverse drug reactions in patients with other indication treated
with pramipexole were nausea, headache, dizziness and fatigue. Nausea and fatigue were more often
reported in female patients (20.8% and 10.5%, respectively) compared to males (6.7% and 7.3%,
respectively).
Table 2: Other indication
System Organ Class
Adverse Drug Reaction
Infections and infestations
Uncommon
pneumonia
Psychiatric disorders
Common
abnormal dreams, insomnia
Uncommon
behavioural symptoms of impulse control disorders and
compulsions such as binge eating, compulsive shopping,
hypersexuality, and pathological gambling; confusion, delusion,
hallucinations, hyperphagia, libido disorder, paranoia,
restlessness
Nervous system disorders
Common
dizziness, headache, somnolence
Uncommon
amnesia, dyskinesia, hyperkinesia, sudden onset of sleep, syncope
Eye disorders
Uncommon
visual impairment including diplopia, vision blurred and visual
acuity reduced
Vascular disorders
Uncommon
hypotension
Respiratory, thoracic, and m
ediastinal disorders
Uncommon
dyspnoea, hiccups
Gastrointestinal disorders
7
Other indication, most common adverse effects
Very common
nausea
Common
constipation, vomiting
Skin and subcutaneous tissu
e disorders
Uncommon
hypersensitivity, pruritus, rash
General disorders and admi
nistration site conditions
Common
fatigue
Uncommon
peripheral oedema
Investigations
Uncommon
weight decrease including decreased appetite, weight increase
Somnolence
Pramipexole is associated with somnolence (8.6%) and has been associated uncommonly with
excessive daytime somnolence and sudden sleep onset episodes (0.1%). (See also section 4.4).
Pramipexole may be associated with libido disorders (increased or decreased).
Patients treated with dopamine agonists for Parkinson’s disease, including pramipexole, especially at
high doses, have been reported as exhibiting signs of pathological gambling, increase libido and
hypersexuality, generally reversible upon treatment discontinuation
(see also section 4.4)
.
In a cross-sectional, retrospective screening and case-control study including 3090 Parkinson’s disease
patients, 13.6% of all patients receiving dopaminergic or non-dopaminergic treatment had symptoms
of an impulse control disorder during the past six months. Manifestations observed include
pathological gambling, compulsive shopping, binge eating, and compulsive sexual behaviour
(hypersexuality). Possible independent risk factors for impulse control disorders included
dopaminergic treatments and higher doses of dopaminergic treatment, younger age (≤ 65 years), not
being married and self-reported family history of gambling behaviours.
There is no clinical experience with massive overdose. The expected adverse events would be those
related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting,
hyperkinesia, hallucinations, agitation and hypotension. There is no established antidote for overdose
of a dopamine agonist. If signs of central nervous system stimulation are present, a neuroleptic agent
may be indicated. Management of the overdose may require general supportive measures, along with
gastric lavage, intravenous fluids, administration of activated charcoal and electrocardiogram
monitoring.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: dopamine agonists, ATC code: N04BC05.
Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D
2
subfamily
of dopamine receptors of which it has a preferential affinity to D
3
receptors, and has full intrinsic
activity.
Pramipexole alleviates Parkinsonian motor deficits by stimulation of dopamine receptors in the
striatum. Animal studies have shown that pramipexole inhibits dopamine synthesis, release, and
turnover.
In human volunteers, a dose-dependent decrease in prolactin was observed.
8
Libido disorders
Impulse control disorders and compulsive behaviours
Clinical trials in Parkinson’s disease
In patients pramipexole alleviates signs and symptoms of idiopathic Parkinson' s disease. Placebo-
controlled clinical trials included approximately
1800
patients of Hoehn and Yahr stages
stages
I – IV. Out of these, approximately 1000
were in more advanced stages, received concomitant
levodopa therapy, and suffered from motor complications.
In early and advanced Parkinson’s disease, efficacy of pramipexole in the controlled clinical trials was
maintained for approximately six months. In open continuation trials lasting for more than three years
there were no signs of decreasing efficacy.
In a controlled double blind clinical trial of 2 year duration
,
initial treatment with pramipexole
significantly delayed the onset of motor complications, and reduced their occurrence compared to
initial treatment with levodopa. This delay in motor complications with pramipexole should be
balanced against a greater improvement in motor function with levodopa (as measured by the mean
change in UPDRS-score). The overall incidence of hallucinations and somnolence was generally
higher in the escalation phase with the pramipexole group. However there was no significant
difference during the maintenance phase. These points should be considered when initiating
pramipexole treatment in patients with Parkinson´s disease.
The European Medicines Agency has waived the obligation to submit the results of studies with
pramipexle in all subsets of the paediatric population in Parkinson’s Disease (see section 4.2 for
information on paediatric use).
Clinical trial in Tourette Disorder
The efficacy of pramipexole (0.0625-0.5 mg/day) with paediatric patients aged 6-17 years with
Tourette Disorder was evaluated in a 6-week, double-blind, randomised, placebo-controlled flexible
dose study. A total of 63 patients were randomised (43 on pramipexole, 20 on placebo). The primary
endpoint was change from baseline on the Total Tic Score (TTS) of the Yale Global Tic Severity
Scale (YGTSS). No difference was observed for pramipexole as compared to placebo for either the
primary endpoint or for any of the secondary efficacy endpoints including YGTSS total score, Patient
Global Impression of Improvement (PGI-I), Clinical Global Impression of Improvement (CGI-I), or
Clinical Global Impressions of Severity of Illness (CGI-S). Adverse events occurring in at least 5% of
patients in the pramipexole group and more common in the pramipexole-treated patients than in
patients on placebo were: headache (27.9%, placebo 25.0%), somnolence (7.0%, placebo 5.0%),
nausea (18.6%, placebo 10.0%), vomiting (11.6%, placebo 0.0%), upper abdominal pain (7.0%,
placebo 5.0%), orthostatic hypotension (9.3%, placebo 5.0%), myalgia (9.3%, placebo 5.0%), sleep
disorder (7.0%, placebo 0.0%), dyspnoea (7.0%, placebo 0.0%) and upper respiratory tract infection
(7.0%, placebo 5.0%). Other significant adverse events leading to discontinuation of study medication
for patients receiving pramipexole were confusional state, speech disorder and aggravated condition
(see section 4.2).
5.2 Pharmacokinetic properties
Pramipexole is rapidly and completely absorbed following oral administration. The absolute
bioavailability is greater than 90% and the maximum plasma concentrations occur between 1 and 3
hours. Concomitant administration with food did not reduce the extent of pramipexole absorption, but
the rate of absorption was reduced. Pramipexole shows linear kinetics and a small inter-patient
variation of plasma levels. In humans, the protein binding of pramipexole is very low (< 20%) and the
volume of distribution is large (400 l). High brain tissue concentrations were observed in the rat
(approx. 8-fold compared to plasma).
Pramipexole is metabolised in man only to a small extent.
Renal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of
14
C-labelled dose is excreted through the kidneys while less than 2% is found in the faeces. The total
9
clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately
400 ml/min. The elimination half-life (t
½
) varies from 8 hours in the young to 12 hours in the elderly.
5.3 Preclinical safety data
Repeated dose toxicity studies showed that pramipexole exerted functional effects, mainly involving
the CNS and female reproductive system, and probably resulting from an exaggerated
pharmacodynamic effect of pramipexole.
Decreases in diastolic and systolic pressure and heart rate were noted in the mini pig, and a tendency
to an hypotensive effect was discerned in the monkey.
The potential effects of pramipexole on reproductive function have been investigated in rats and
rabbits. Pramipexole was not teratogenic in rats and rabbits but was embryotoxic in the rat at
maternally toxic doses. Due to the selection of animal species and the limited parameters investigated,
the adverse effects of pramipexole on pregnancy and male fertility have not been fully elucidated.
A delay in sexual development (i.e., preputial separation and vaginal opening) was observed in rats.
The relevance for humans is unknown.
Pramipexole was not genotoxic. In a carcinogenicity study, male rats developed Leydig cell
hyperplasia and adenomas, explained by the prolactin-inhibiting effect of pramipexole. This finding is
not clinically relevant to man. The same study also showed that, at doses of 2 mg/kg (of salt) and
higher, pramipexole was associated with retinal degeneration in albino rats. The latter finding was not
observed in pigmented rats, nor in a 2-year albino mouse carcinogenicity study or in any other species
investigated.
6.
6.1 List of excipients
Mannitol
Maize starch
Pregelatinised maize starch
Colloidal anhydrous silica
Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in the original package in order to protect from light.
6.5
Nature and contents of container
Blister pack (Al/Al foil): 20, 30, 60, 90 or 100 tablets.
Not all pack sizes may be marketed.
10
Povidone K25
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
KRKA, d. d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
8.
20 tablets: EU/1/08/469/001
30 tablets: EU/1/08/469/002
60 tablets: EU/1/08/469/003
90 tablets: EU/1/08/469/004
100 tablets: EU/1/08/469/005
9.
12/9/2008
Detailed information on this product is available on the website of the European Medicines Agency
11
1.
Oprymea 0.18 mg tablets
2.
Each tablet contains 0.18 mg pramipexole base (as 0.25 mg pramipexole dihydrochloride
monohydrate).
Please note:
Pramipexole doses as published in the literature refer to the salt form.
Therefore, doses will be expressed in terms of both pramipexole base and pramipexole salt (in
brackets).
For a full list of excipients, see section 6.1.
3.
Tablet.
0.18 mg: white, oval, with bevelled edges, both sides scored, with imprint "P7" on both halves of one
side of the tablet. The tablet can be divided into equal halves.
4.
Oprymea is indicated for treatment of the signs and symptoms of idiopathic Parkinson's disease, alone
(without levodopa) or in combination with levodopa, i.e. over the course of the disease, through to late
stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of the
therapeutic effect occur (end of dose or “on off” fluctuations).
Posology
The daily dosage is administered in equally divided doses 3 times a day.
Initial treatment
Dosages should be increased gradually from a starting-dose of 0.264 mg of base (0.375 mg of salt) per
day and then increased every 5 - 7 days. Providing patients do not experience intolerable undersirable
effects, the dosage should be titrated to achieve a maximal therapeutic effect.
Ascending – Dose Schedule of OPRYMEA
Week
Dosage
(mg of base)
Total Daily Dose
(mg of base)
Dosage
(mg of salt)
Total Daily Dose
(mg of salt)
1
3 x 0.088
0.264
3 x 0.125
0.375
2
3 x 0.18
0.54
3 x 0.25
0.75
3
3 x 0.35
1.1
3 x 0.5
1.50
If a further dose increase is necessary the daily dose should be increased by 0.54 mg base (0.75 mg
salt) at weekly intervals up to a maximum dose of 3.3 mg of base (4.5 mg of salt) per day.
12
Parkinson’s disease
However, it should be noted that the incidence of somnolence is increased at doses higher than
1.5 mg/day (see section 4.8).
Maintenance treatment
The individual dose should be in the range of 0.264 mg of base (0.375 mg of salt) to a maximum of
3.3 mg of base (4.5 mg of salt) per day. During dose escalation in three pivotal studies
,
efficacy was
observed starting at a daily dose of 1.1 mg of base (1.5 mg of salt). Further dose adjustments should be
done based on the clinical response and the occurrence of adverse reactions. In clinical trials
approximately 5% of patients were treated at doses below 1.1 mg (1.5 mg of salt). In advanced
Parkinson’s disease, doses higher than 1.1 mg (1.5 mg of salt) per day can be useful in patients where
a reduction of the levodopa therapy is intended. It is recommended that the dosage of levodopa is
reduced during both the dose escalation and the maintenance treatment with Oprymea, depending on
reactions in individual patients (see section 4.5).
Treatment discontinuation
Abrupt discontinuation of dopaminergic therapy can lead to the development of a neuroleptic
malignant syndrome. Pramipexole
should be tapered off at a rate of 0.54 mg of base (0.75 mg of salt)
per day until the daily dose has been reduced to 0.54 mg of base (0.75 mg of salt). Thereafter the dose
should be reduced by 0.264 mg of base (0.375 mg of salt) per day (see section 4.4).
Dosing in patients with renal impairment
The elimination of pramipexole is dependent on renal function. The following dosage schedule is
suggested for initiation of therapy:
Patients with a creatinine clearance above 50 ml/min require no reduction in daily dose or dosing
frequency.
In patients with a creatinine clearance between 20 and 50 ml/min, the initial daily dose of Oprymea
should be administered in two divided doses, starting at 0.088 mg of base (0.125 mg of salt) twice a
day (0.176 mg of base/0.25 mg of salt daily).
A maximum daily dose of 1.57 mg pramipexole base
(2.25 mg of salt) should not be exceeded.
In patients with a creatinine clearance less than 20 ml/min, the daily dose of Oprymea should be
administered in a single dose, starting at 0.088 mg of base (0.125 mg of salt) daily.
A maximum daily
dose of 1.1 mg pramipexole base (1.5 mg of salt) should not be exceeded.
If renal function declines during maintenance therapy reduce Oprymea daily dose by the same
percentage as the decline in creatinine clearance, i.e. if creatinine clearance declines by 30%, then
reduce the Oprymea daily dose by 30%. The daily dose can be administered in two divided doses if
creatinine clearance is between 20 and 50 ml/min, and as a single daily dose if creatinine clearance is
less than 20 ml/min.
Dosing in patients with hepatic impairment
Dose adjustment in patients with hepatic failure is probably not necessary, as approx. 90% of absorbed
active substance is excreted through the kidneys. However, the potential influence of hepatic
insufficiency on Oprymea pharmacokinetics has not been investigated.
The safety and efficacy of Oprymea in children below 18 years has not been established. There is no
relevant use of Oprymea in the paediatric population in Parkinson’s Disease.
Tourette Disorder
Oprymea is not recommended for use in children and adolescents below 18 years since the efficacy
and safety has not been established in this population. Oprymea should not be used in children or
13
Paediatric population
Paediatric population
adolescents with Tourette Disorder because of a negative benefit-risk balance for this disorder (see
section 5.1).
Hypersensitivity to the active substance or to any of the excipients.
When prescribing Oprymea in a patient with Parkinson’s disease with renal impairment a reduced
dose is suggested in line with section 4.2.
Hallucinations
Hallucinations are known as a side-effect of treatment with dopamine agonists and levodopa. Patients
should be informed that (mostly visual) hallucinations can occur.
Dyskinesias
In advanced Parkinson’s disease, in combination treatment with levodopa, dyskinesias can occur
during the initial titration of Oprymea. If they occur, the dose of levodopa should be decreased.
Pramipexole has been associated with somnolence and episodes of sudden sleep onset, particularly in
patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without
awareness or warning signs, has been reported uncommonly. Patients must be informed of this and
advised to exercise caution while driving or operating machines during treatment with Oprymea.
Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from
driving or operating machines. Furthermore a reduction of dosage or termination of therapy may be
considered. Because of possible additive effects, caution should be advised when patients are taking
other sedating medication or alcohol in combination with pramipexole (see sections 4.5, 4.7 and
section 4.8).
Pathological gambling, increased libido and hypersexuality have been reported in patients treated with
dopamine agonists for Parkinson’s disease, including pramipexole. Furthermore, patients and
caregivers should be aware of the fact that other behavioural symptoms of impulse control disorders
and compulsions such as binge eating and compulsive shopping can occur. Dose reduction/tapered or
discontinuation should be considered.
Patients with psychotic disorders
Patients with psychotic disorders should only be treated with dopamine agonists if the potential
benefits outweigh the risks.
Coadministration of antipsychotic medicinal products with pramipexole should be avoided (see
section 4.5).
Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
In case of severe cardiovascular disease, care should be taken. It is recommended to monitor blood
pressure, especially at the beginning of treatment, due to the general risk of postural hypotension
associated with dopaminergic therapy.
Neuroleptic malignant syndrome
Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal
of dopaminergic therapy (see section 4.2)
14
Sudden onset of sleep and somnolence
Impulse control disorders and compulsive behaviours
Ophthalmologic monitoring
Severe cardiovascular disease
Augmentation
Reports in the literature indicate that treatment of another indication with dopaminergic medicinal
products can result in augmentation. Augmentation refers to the earlier onset of symptoms in the
evening (or even afternoon), increase in symptoms, and spread of symptoms to involve other
extremities. Augmentation was specifically investigated in a controlled clinical trial over 26 weeks.
Augmentation was observed in 11.8% of patients in the pramipexole group (N = 152) and 9.4% of
patients in the placebo group (N = 149). Kaplan-Meier analysis of time to augmentation showed no
significant difference between pramipexole and placebo groups.
Pramipexole is bound to plasma proteins to a very low (< 20%) extent, and little biotransformation is
seen in man. Therefore, interactions with other medicinal products affecting plasma protein binding or
elimination by biotransformation are unlikely. As anticholinergics are mainly eliminated by
biotransformation, the potential for an interaction is limited, although an interaction with
anticholinergics has not been investigated. There is no pharmacokinetic interaction with selegiline and
levodopa.
Inhibitors/competitors of active renal elimination pathway
Cimetidine reduced the renal clearance of pramipexole by approximately 34%, presumably by
inhibition of the cationic secretory transport system of the renal tubules. Therefore, medicinal products
that are inhibitors of this active renal elimination pathway or are eliminated by this pathway, such as
cimetidine,amantadine mexiletine, zidovudine, cisplatin, quinine, and procainamide, may interact with
pramipexole resulting in reduced clearance of pramipexole. Reduction of the pramipexole dose should
be considered when these medicinal products are administered concomitantly.
Combination with levodopa
When Oprymea is given in combination with levodopa, it is recommended that the dosage of levodopa
is reduced and the dosage of other anti-parkinsonian medicinal products is kept constant while
increasing the dose of Oprymea.
Because of possible additive effects, caution should be advised when patients are taking other sedating
medicinal products or alcohol in combination with pramipexole.
Antipsychotic medicinal products
Coadministration of antipsychotic medicinal products with pramipexole should be avoided (see
section 4.4), e.g. if antagonistic effects can be expected.
Pregnancy
The effect on pregnancy and lactation has not been investigated in humans. Pramipexole was not
teratogenic in rats and rabbits, but was embryotoxic in the rat at maternotoxic doses (see section 5.3).
Oprymea should not be used during pregnancy unless clearly necessary, i.e. if the potential benefit
justifies the potential risk to the foetus.
Brest-feeding
As pramipexole treatment inhibits secretion of prolactin in humans, inhibition of lactation is expected.
The excretion of pramipexole into breast milk has not been studied in women. In rats, the
concentration of active substance-related radioactivity was higher in breast milk than in plasma. In the
absence of human data, Oprymea should not be used during breast-feeding. However, if its use is
unavoidable, breast-feeding should be discontinued.
Fertility
15
Plasma protein binding
No studies on the effect on human fertility have been conducted. In animal studies, pramipexole
affected oestrous cycles and reduced female fertility as expected for a dopamine agonist. However,
these studies did not indicate direct or indirect harmful effects with respect to male fertility.
Oprymea can have a major influence on the ability to drive and use machines.
Hallucinations or somnolence can occur.
Patients being treated with Oprymea 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 sections 4.4, 4.5, and 4.8).
The following adverse reactions are expected under the use of pramipexole: abnormal dreams,
amnesia, behavioural symptoms of impulse control disorders and compulsions such as binge eating,
compulsive shopping, hypersexuality and pathological gambling; confusion, constipation, delusion,
dizziness, dyskinesia, dyspnoea, fatigue, hallucinations, headache, hiccups, hyperkinesia, hyperphagia,
hypotension, insomnia, libido disorders, nausea, paranoia, peripheral oedema, pneumonia, pruritus,
rash and other hypersensitivity; restlessness, somnolence, sudden onset of sleep, syncope, visual
impairment including diplopia, vision blurred and visual acuity reduced, vomiting, weight decrease
including decreased appetite, weight increase.
Based on the analysis of pooled placebo-controlled trials, comprising a total of 1,923 patients on
pramipexole and 1,354 patients on placebo, adverse drug reactions were frequently reported for both
groups. 63 % of patients on pramipexole and 52% of patients on placebo reported at least one adverse
drug reaction.
Tables 1 and 2 display the frequency of adverse reactions from placebo-controlled clinical trials. The
adverse reactions reported in these tables are those events that occurred in 0.1% or more of patients
treated with pramipexole and were reported significantly more often in patients taking pramipexole
than placebo, or where the event was considered clinically relevant. However, the majority of common
adverse reactions were mild to moderate, they usually start early in therapy, and most tended to
disappear even as therapy was continued.
Within the system organ classes, adverse reactions are listed under headings of frequency (number of
patients expected to experience the reaction), using the following categories: very common ( ≥ 1/10);
common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare
(< 1/10,000); not known (cannot be estimated from the available data).
Parkinson’s disease, most common adverse effects
The most commonly (≥5%) reported adverse reactions in patients with Parkinson’s disease more
frequent with pramipexole treatment than with placebo were nausea, dyskinesia, hypotension,
dizziness, somnolence, insomnia, constipation, hallucination, headache and fatigue. The incidence of
somnolence is increased at doses higher than 1.5 mg/day (see section 4.2). More frequent adverse drug
reaction in combination with levodopa was dyskinesia. Hypotension may occur at the beginning of
treatment, especially if pramipexole is titrated too fast.
Table 1: Parkinson’s diseas
e
System Organ Class
Adverse Drug Reaction
Infections and infestations
Uncommon
pneumonia
Psychiatric disorders
16
Expected adverse effects
Common
abnormal dreams, behavioural symptoms of impulse control
disorders and compulsions, confusion, hallucinations, insomnia
Uncommon
binge eating, compulsive shopping, delusion, hyperphagia,
hypersexuality, libido disorder, paranoia, pathological gambling,
restlessness
Nervous system disorders
Very common
dizziness, dyskinesia, somnolence
Common
headache
Uncommon
amnesia, hyperkinesia, sudden onset of sleep, syncope
Eye disorders
Common
visual impairment including diplopia, vision blurred and visual
acuity reduced
Vascular disorders
Common
hypotension
Respiratory, thoracic, and m
ediastinal disorders
Uncommon
dyspnoea, hiccups
Gastrointestinal disorders
Very common
nausea
Common
constipation, vomiting
Skin and subcutaneous tissu
e disorders
Uncommon
hypersensitivity, pruritus, rash
General disorders and admi
nistration site conditions
Common
fatigue, peripheral oedema
Investigations
Common
weight decrease including decreased appetite
Uncommon
weight increase
The most commonly (≥ 5%) reported adverse drug reactions in patients with other indication treated
with pramipexole were nausea, headache, dizziness and fatigue. Nausea and fatigue were more often
reported in female patients (20.8% and 10.5%, respectively) compared to males (6.7% and 7.3%,
respectively).
Table 2: Other indication
System Organ Class
Adverse Drug Reaction
Infections and infestations
Uncommon
pneumonia
Psychiatric disorders
Common
abnormal dreams, insomnia
Uncommon
behavioural symptoms of impulse control disorders and
compulsions such as binge eating, compulsive shopping,
hypersexuality, and pathological gambling; confusion, delusion,
hallucinations, hyperphagia, libido disorder, paranoia,
restlessness
Nervous system disorders
Common
dizziness, headache, somnolence
Uncommon
amnesia, dyskinesia, hyperkinesia, sudden onset of sleep, syncope
Eye disorders
Uncommon
visual impairment including diplopia, vision blurred and visual
acuity reduced
Vascular disorders
Uncommon
hypotension
Respiratory, thoracic, and m
ediastinal disorders
Uncommon
dyspnoea, hiccups
Gastrointestinal disorders
17
Other indication, most common adverse effects
Very common
nausea
Common
constipation, vomiting
Skin and subcutaneous tissu
e disorders
Uncommon
hypersensitivity, pruritus, rash
General disorders and admi
nistration site conditions
Common
fatigue
Uncommon
peripheral oedema
Investigations
Uncommon
weight decrease including decreased appetite, weight increase
Somnolence
Pramipexole is associated with somnolence (8.6%) and has been associated uncommonly with
excessive daytime somnolence and sudden sleep onset episodes (0.1%). (See also section 4.4).
Pramipexole may be associated with libido disorders (increased or decreased).
Patients treated with dopamine agonists for Parkinson’s disease, including pramipexole, especially at
high doses, have been reported as exhibiting signs of pathological gambling, increase libido and
hypersexuality, generally reversible upon treatment discontinuation
(see also section 4.4)
.
In a cross-sectional, retrospective screening and case-control study including 3090 Parkinson’s disease
patients, 13.6% of all patients receiving dopaminergic or non-dopaminergic treatment had symptoms
of an impulse control disorder during the past six months. Manifestations observed include
pathological gambling, compulsive shopping, binge eating, and compulsive sexual behaviour
(hypersexuality). Possible independent risk factors for impulse control disorders included
dopaminergic treatments and higher doses of dopaminergic treatment, younger age (≤ 65 years), not
being married and self-reported family history of gambling behaviours.
There is no clinical experience with massive overdose. The expected adverse events would be those
related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting,
hyperkinesia, hallucinations, agitation and hypotension. There is no established antidote for overdose
of a dopamine agonist. If signs of central nervous system stimulation are present, a neuroleptic agent
may be indicated. Management of the overdose may require general supportive measures, along with
gastric lavage, intravenous fluids, administration of activated charcoal and electrocardiogram
monitoring.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: dopamine agonists, ATC code: N04BC05.
Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D
2
subfamily
of dopamine receptors of which it has a preferential affinity to D
3
receptors, and has full intrinsic
activity.
Pramipexole alleviates Parkinsonian motor deficits by stimulation of dopamine receptors in the
striatum. Animal studies have shown that pramipexole inhibits dopamine synthesis, release, and
turnover.
In human volunteers, a dose-dependent decrease in prolactin was observed.
18
Libido disorders
Impulse control disorders and compulsive behaviours
Clinical trials in Parkinson’s disease
In patients pramipexole alleviates signs and symptoms of idiopathic Parkinson' s disease. Placebo-
controlled clinical trials included approximately
1800
patients of Hoehn and Yahr stages
stages
I – IV. Out of these, approximately 1000
were in more advanced stages, received concomitant
levodopa therapy, and suffered from motor complications.
In early and advanced Parkinson’s disease, efficacy of pramipexole in the controlled clinical trials was
maintained for approximately six months. In open continuation trials lasting for more than three years
there were no signs of decreasing efficacy.
In a controlled double blind clinical trial of 2 year duration
,
initial treatment with pramipexole
significantly delayed the onset of motor complications, and reduced their occurrence compared to
initial treatment with levodopa. This delay in motor complications with pramipexole should be
balanced against a greater improvement in motor function with levodopa (as measured by the mean
change in UPDRS-score). The overall incidence of hallucinations and somnolence was generally
higher in the escalation phase with the pramipexole group. However there was no significant
difference during the maintenance phase. These points should be considered when initiating
pramipexole treatment in patients with Parkinson´s disease.
The European Medicines Agency has waived the obligation to submit the results of studies with
pramipexle in all subsets of the paediatric population in Parkinson’s Disease (see section 4.2 for
information on paediatric use).
Clinical trial in Tourette Disorder
The efficacy of pramipexole (0.0625-0.5 mg/day) with paediatric patients aged 6-17 years with
Tourette Disorder was evaluated in a 6-week, double-blind, randomised, placebo-controlled flexible
dose study. A total of 63 patients were randomised (43 on pramipexole, 20 on placebo). The primary
endpoint was change from baseline on the Total Tic Score (TTS) of the Yale Global Tic Severity
Scale (YGTSS). No difference was observed for pramipexole as compared to placebo for either the
primary endpoint or for any of the secondary efficacy endpoints including YGTSS total score, Patient
Global Impression of Improvement (PGI-I), Clinical Global Impression of Improvement (CGI-I), or
Clinical Global Impressions of Severity of Illness (CGI-S). Adverse events occurring in at least 5% of
patients in the pramipexole group and more common in the pramipexole-treated patients than in
patients on placebo were: headache (27.9%, placebo 25.0%), somnolence (7.0%, placebo 5.0%),
nausea (18.6%, placebo 10.0%), vomiting (11.6%, placebo 0.0%), upper abdominal pain (7.0%,
placebo 5.0%), orthostatic hypotension (9.3%, placebo 5.0%), myalgia (9.3%, placebo 5.0%), sleep
disorder (7.0%, placebo 0.0%), dyspnoea (7.0%, placebo 0.0%) and upper respiratory tract infection
(7.0%, placebo 5.0%). Other significant adverse events leading to discontinuation of study medication
for patients receiving pramipexole were confusional state, speech disorder and aggravated condition
(see section 4.2).
5.2 Pharmacokinetic properties
Pramipexole is rapidly and completely absorbed following oral administration. The absolute
bioavailability is greater than 90% and the maximum plasma concentrations occur between 1 and 3
hours. Concomitant administration with food did not reduce the extent of pramipexole absorption, but
the rate of absorption was reduced. Pramipexole shows linear kinetics and a small inter-patient
variation of plasma levels. In humans, the protein binding of pramipexole is very low (< 20%) and the
volume of distribution is large (400 l). High brain tissue concentrations were observed in the rat
(approx. 8-fold compared to plasma).
Pramipexole is metabolised in man only to a small extent.
Renal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of
14
C-labelled dose is excreted through the kidneys while less than 2% is found in the faeces. The total
19
clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately
400 ml/min. The elimination half-life (t
½
) varies from 8 hours in the young to 12 hours in the elderly.
5.3 Preclinical safety data
Repeated dose toxicity studies showed that pramipexole exerted functional effects, mainly involving
the CNS and female reproductive system, and probably resulting from an exaggerated
pharmacodynamic effect of pramipexole.
Decreases in diastolic and systolic pressure and heart rate were noted in the mini pig, and a tendency
to an hypotensive effect was discerned in the monkey.
The potential effects of pramipexole on reproductive function have been investigated in rats and
rabbits. Pramipexole was not teratogenic in rats and rabbits but was embryotoxic in the rat at
maternally toxic doses. Due to the selection of animal species and the limited parameters investigated,
the adverse effects of pramipexole on pregnancy and male fertility have not been fully elucidated.
A delay in sexual development (i.e., preputial separation and vaginal opening) was observed in rats.
The relevance for humans is unknown.
Pramipexole was not genotoxic. In a carcinogenicity study, male rats developed Leydig cell
hyperplasia and adenomas, explained by the prolactin-inhibiting effect of pramipexole. This finding is
not clinically relevant to man. The same study also showed that, at doses of 2 mg/kg (of salt) and
higher, pramipexole was associated with retinal degeneration in albino rats. The latter finding was not
observed in pigmented rats, nor in a 2-year albino mouse carcinogenicity study or in any other species
investigated.
6.
6.1 List of excipients
Mannitol
Maize starch
Pregelatinised maize starch
Colloidal anhydrous silica
Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in the original package in order to protect from light.
6.5 Nature and contents of container
Blister pack (Al/Al foil): 20, 30, 60, 90 or 100 tablets.
Not all pack sizes may be marketed.
20
Povidone K25
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
KRKA, d. d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
8.
20 tablets: EU/1/08/469/006
30 tablets: EU/1/08/469/007
60 tablets: EU/1/08/469/008
90 tablets: EU/1/08/469/009
100 tablets: EU/1/08/469/010
9.
12/9/2008
Detailed information on this product is available on the website of the European Medicines Agency
21
1.
Oprymea 0.35 mg tablets
2.
Each tablet contains 0.35 mg pramipexole base (as 0.5 mg pramipexole dihydrochloride
monohydrate).
Please note:
Pramipexole doses as published in the literature refer to the salt form.
Therefore, doses will be expressed in terms of both pramipexole base and pramipexole salt (in
brackets).
For a full list of excipients, see section 6.1.
3.
Tablet.
0.35 mg: white, oval, with bevelled edges, both sides scored, with imprint "P8" on both halves of one
side of the tablet. The tablet can be divided into equal halves.
4.
Oprymea is indicated for treatment of the signs and symptoms of idiopathic Parkinson's disease, alone
(without levodopa) or in combination with levodopa, i.e. over the course of the disease, through to late
stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of the
therapeutic effect occur (end of dose or “on off” fluctuations).
Posology
The daily dosage is administered in equally divided doses 3 times a day.
Dosages should be increased gradually from a starting-dose of 0.264 mg of base (0.375 mg of salt) per
day and then increased every 5 - 7 days. Providing patients do not experience intolerable undersirable
effects, the dosage should be titrated to achieve a maximal therapeutic effect.
Ascending – Dose Schedule of OPRYMEA
Week
Dosage
(mg of base)
Total Daily Dose
(mg of base)
Dosage
(mg of salt)
Total Daily Dose
(mg of salt)
1
3 x 0.088
0.264
3 x 0.125
0.375
2
3 x 0.18
0.54
3 x 0.25
0.75
3
3 x 0.35
1.1
3 x 0.5
1.50
If a further dose increase is necessary the daily dose should be increased by 0.54 mg base (0.75 mg
salt) at weekly intervals up to a maximum dose of 3.3 mg of base (4.5 mg of salt) per day.
22
Parkinson’s disease
Initial treatment
However, it should be noted that the incidence of somnolence is increased at doses higher than
1.5 mg/day (see section 4.8).
The individual dose should be in the range of 0.264 mg of base (0.375 mg of salt) to a maximum of
3.3 mg of base (4.5 mg of salt) per day. During dose escalation in three pivotal studies
,
efficacy was
observed starting at a daily dose of 1.1 mg of base (1.5 mg of salt). Further dose adjustments should be
done based on the clinical response and the occurrence of adverse reactions. In clinical trials
approximately 5% of patients were treated at doses below 1.1 mg (1.5 mg of salt). In advanced
Parkinson’s disease, doses higher than 1.1 mg (1.5 mg of salt) per day can be useful in patients where
a reduction of the levodopa therapy is intended. It is recommended that the dosage of levodopa is
reduced during both the dose escalation and the maintenance treatment with Oprymea, depending on
reactions in individual patients (see section 4.5).
Abrupt discontinuation of dopaminergic therapy can lead to the development of a neuroleptic
malignant syndrome. Pramipexole
should be tapered off at a rate of 0.54 mg of base (0.75 mg of salt)
per day until the daily dose has been reduced to 0.54 mg of base (0.75 mg of salt). Thereafter the dose
should be reduced by 0.264 mg of base (0.375 mg of salt) per day (see section 4.4).
The elimination of pramipexole is dependent on renal function. The following dosage schedule is
suggested for initiation of therapy:
Patients with a creatinine clearance above 50 ml/min require no reduction in daily dose or dosing
frequency.
In patients with a creatinine clearance between 20 and 50 ml/min, the initial daily dose of Oprymea
should be administered in two divided doses, starting at 0.088 mg of base (0.125 mg of salt) twice a
day (0.176 mg of base/0.25 mg of salt daily).
A maximum daily dose of 1.57 mg pramipexole base
(2.25 mg of salt) should not be exceeded.
In patients with a creatinine clearance less than 20 ml/min, the daily dose of Oprymea should be
administered in a single dose, starting at 0.088 mg of base (0.125 mg of salt) daily.
A maximum daily
dose of 1.1 mg pramipexole base (1.5 mg of salt) should not be exceeded.
If renal function declines during maintenance therapy reduce Oprymea daily dose by the same
percentage as the decline in creatinine clearance, i.e. if creatinine clearance declines by 30%, then
reduce the Oprymea daily dose by 30%. The daily dose can be administered in two divided doses if
creatinine clearance is between 20 and 50 ml/min, and as a single daily dose if creatinine clearance is
less than 20 ml/min.
Dose adjustment in patients with hepatic failure is probably not necessary, as approx. 90% of absorbed
active substance is excreted through the kidneys. However, the potential influence of hepatic
insufficiency on Oprymea pharmacokinetics has not been investigated.
Paediatric population
The safety and efficacy of Oprymea in children below 18 years has not been established. There is no
relevant use of Oprymea in the paediatric population in Parkinson’s Disease.
Tourette Disorder
Paediatric population
Oprymea is not recommended for use in children and adolescents below 18 years since the efficacy
and safety has not been established in this population. Oprymea should not be used in children or
23
Maintenance treatment
Treatment discontinuation
Dosing in patients with renal impairment
Dosing in patients with hepatic impairment
adolescents with Tourette Disorder because of a negative benefit-risk balance for this disorder (see
section 5.1).
Hypersensitivity to the active substance or to any of the excipients.
When prescribing Oprymea in a patient with Parkinson’s disease with renal impairment a reduced
dose is suggested in line with section 4.2.
Hallucinations
Hallucinations are known as a side-effect of treatment with dopamine agonists and levodopa. Patients
should be informed that (mostly visual) hallucinations can occur.
Dyskinesias
In advanced Parkinson’s disease, in combination treatment with levodopa, dyskinesias can occur
during the initial titration of Oprymea. If they occur, the dose of levodopa should be decreased.
Pramipexole has been associated with somnolence and episodes of sudden sleep onset, particularly in
patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without
awareness or warning signs, has been reported uncommonly. Patients must be informed of this and
advised to exercise caution while driving or operating machines during treatment with Oprymea.
Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from
driving or operating machines. Furthermore a reduction of dosage or termination of therapy may be
considered. Because of possible additive effects, caution should be advised when patients are taking
other sedating medication or alcohol in combination with pramipexole (see sections 4.5, 4.7 and
section 4.8).
Pathological gambling, increased libido and hypersexuality have been reported in patients treated with
dopamine agonists for Parkinson’s disease, including pramipexole. Furthermore, patients and
caregivers should be aware of the fact that other behavioural symptoms of impulse control disorders
and compulsions such as binge eating and compulsive shopping can occur. Dose reduction/tapered or
discontinuation should be considered.
Patients with psychotic disorders
Patients with psychotic disorders should only be treated with dopamine agonists if the potential
benefits outweigh the risks.
Coadministration of antipsychotic medicinal products with pramipexole should be avoided (see
section 4.5).
Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
In case of severe cardiovascular disease, care should be taken. It is recommended to monitor blood
pressure, especially at the beginning of treatment, due to the general risk of postural hypotension
associated with dopaminergic therapy.
Neuroleptic malignant syndrome
Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal
of dopaminergic therapy (see section 4.2)
24
Sudden onset of sleep and somnolence
Impulse control disorders and compulsive behaviours
Ophthalmologic monitoring
Severe cardiovascular disease
Augmentation
Reports in the literature indicate that treatment of another indication with dopaminergic medicinal
products can result in augmentation. Augmentation refers to the earlier onset of symptoms in the
evening (or even afternoon), increase in symptoms, and spread of symptoms to involve other
extremities. Augmentation was specifically investigated in a controlled clinical trial over 26 weeks.
Augmentation was observed in 11.8% of patients in the pramipexole group (N = 152) and 9.4% of
patients in the placebo group (N = 149). Kaplan-Meier analysis of time to augmentation showed no
significant difference between pramipexole and placebo groups.
Pramipexole is bound to plasma proteins to a very low (< 20%) extent, and little biotransformation is
seen in man. Therefore, interactions with other medicinal products affecting plasma protein binding or
elimination by biotransformation are unlikely. As anticholinergics are mainly eliminated by
biotransformation, the potential for an interaction is limited, although an interaction with
anticholinergics has not been investigated. There is no pharmacokinetic interaction with selegiline and
levodopa.
Inhibitors/competitors of active renal elimination pathway
Cimetidine reduced the renal clearance of pramipexole by approximately 34%, presumably by
inhibition of the cationic secretory transport system of the renal tubules. Therefore, medicinal products
that are inhibitors of this active renal elimination pathway or are eliminated by this pathway, such as
cimetidine,amantadine mexiletine, zidovudine, cisplatin, quinine, and procainamide, may interact with
pramipexole resulting in reduced clearance of pramipexole. Reduction of the pramipexole dose should
be considered when these medicinal products are administered concomitantly.
Combination with levodopa
When Oprymea is given in combination with levodopa, it is recommended that the dosage of levodopa
is reduced and the dosage of other anti-parkinsonian medicinal products is kept constant while
increasing the dose of Oprymea.
Because of possible additive effects, caution should be advised when patients are taking other sedating
medicinal products or alcohol in combination with pramipexole.
Antipsychotic medicinal products
Coadministration of antipsychotic medicinal products with pramipexole should be avoided (see
section 4.4), e.g. if antagonistic effects can be expected.
Pregnancy
The effect on pregnancy and lactation has not been investigated in humans. Pramipexole was not
teratogenic in rats and rabbits, but was embryotoxic in the rat at maternotoxic doses (see section 5.3).
Oprymea should not be used during pregnancy unless clearly necessary, i.e. if the potential benefit
justifies the potential risk to the foetus.
Brest-feeding
As pramipexole treatment inhibits secretion of prolactin in humans, inhibition of lactation is expected.
The excretion of pramipexole into breast milk has not been studied in women. In rats, the
concentration of active substance-related radioactivity was higher in breast milk than in plasma. In the
absence of human data, Oprymea should not be used during breast-feeding. However, if its use is
unavoidable, breast-feeding should be discontinued.
Fertility
25
Plasma protein binding
No studies on the effect on human fertility have been conducted. In animal studies, pramipexole
affected oestrous cycles and reduced female fertility as expected for a dopamine agonist. However,
these studies did not indicate direct or indirect harmful effects with respect to male fertility.
Oprymea can have a major influence on the ability to drive and use machines.
Hallucinations or somnolence can occur.
Patients being treated with Oprymea 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 sections 4.4, 4.5, and 4.8).
The following adverse reactions are expected under the use of pramipexole: abnormal dreams,
amnesia, behavioural symptoms of impulse control disorders and compulsions such as binge eating,
compulsive shopping, hypersexuality and pathological gambling; confusion, constipation, delusion,
dizziness, dyskinesia, dyspnoea, fatigue, hallucinations, headache, hiccups, hyperkinesia, hyperphagia,
hypotension, insomnia, libido disorders, nausea, paranoia, peripheral oedema, pneumonia, pruritus,
rash and other hypersensitivity; restlessness, somnolence, sudden onset of sleep, syncope, visual
impairment including diplopia, vision blurred and visual acuity reduced, vomiting, weight decrease
including decreased appetite, weight increase.
Based on the analysis of pooled placebo-controlled trials, comprising a total of 1,923 patients on
pramipexole and 1,354 patients on placebo, adverse drug reactions were frequently reported for both
groups. 63 % of patients on pramipexole and 52% of patients on placebo reported at least one adverse
drug reaction.
Tables 1 and 2 display the frequency of adverse reactions from placebo-controlled clinical trials. The
adverse reactions reported in these tables are those events that occurred in 1% or more of patients
treated with pramipexole and were reported significantly more often in patients taking pramipexole
than placebo, or where the event was considered clinically relevant. However, the majority of common
adverse reactions were mild to moderate, they usually start early in therapy, and most tended to
disappear even as therapy was continued.
Within the system organ classes, adverse reactions are listed under headings of frequency (number of
patients expected to experience the reaction), using the following categories: very common ( ≥ 1/10);
common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare
(< 1/10,000); not known (cannot be estimated from the available data).
Parkinson’s disease, most common adverse effects
The most commonly (≥5%) reported adverse reactions in patients with Parkinson’s disease more
frequent with pramipexole treatment than with placebo were nausea, dyskinesia, hypotension,
dizziness, somnolence, insomnia, constipation, hallucination, headache and fatigue. The incidence of
somnolence is increased at doses higher than 1.5 mg/day (see section 4.2). More frequent adverse drug
reaction in combination with levodopa was dyskinesia. Hypotension may occur at the beginning of
treatment, especially if pramipexole is titrated too fast.
Table 1: Parkinson’s diseas
e
System Organ Class
Adverse Drug Reaction
Infections and infestations
Uncommon
pneumonia
Psychiatric disorders
26
Expected adverse effects
Common
abnormal dreams, behavioural symptoms of impulse control
disorders and compulsions, confusion, hallucinations, insomnia
Uncommon
binge eating, compulsive shopping, delusion, hyperphagia,
hypersexuality, libido disorder, paranoia, pathological gambling,
restlessness
Nervous system disorders
Very common
dizziness, dyskinesia, somnolence
Common
headache
Uncommon
amnesia, hyperkinesia, sudden onset of sleep, syncope
Eye disorders
Common
visual impairment including diplopia, vision blurred and visual
acuity reduced
Vascular disorders
Common
hypotension
Respiratory, thoracic, and m
ediastinal disorders
Uncommon
dyspnoea, hiccups
Gastrointestinal disorders
Very common
nausea
Common
constipation, vomiting
Skin and subcutaneous tissu
e disorders
Uncommon
hypersensitivity, pruritus, rash
General disorders and admi
nistration site conditions
Common
fatigue, peripheral oedema
Investigations
Common
weight decrease including decreased appetite
Uncommon
weight increase
The most commonly (≥ 5%) reported adverse drug reactions in patients with other indication treated
with pramipexole were nausea, headache, dizziness and fatigue. Nausea and fatigue were more often
reported in female patients (20.8% and 10.5%, respectively) compared to males (6.7% and 7.3%,
respectively).
Table 2: Other indication
System Organ Class
Adverse Drug Reaction
Infections and infestations
Uncommon
pneumonia
Psychiatric disorders
Common
abnormal dreams, insomnia
Uncommon
behavioural symptoms of impulse control disorders and
compulsions such as binge eating, compulsive shopping,
hypersexuality, and pathological gambling; confusion, delusion,
hallucinations, hyperphagia, libido disorder, paranoia,
restlessness
Nervous system disorders
Common
dizziness, headache, somnolence
Uncommon
amnesia, dyskinesia, hyperkinesia, sudden onset of sleep, syncope
Eye disorders
Uncommon
visual impairment including diplopia, vision blurred and visual
acuity reduced
Vascular disorders
Uncommon
hypotension
Respiratory, thoracic, and m
ediastinal disorders
Uncommon
dyspnoea, hiccups
Gastrointestinal disorders
27
Other indication, most common adverse effects
Very common
nausea
Common
constipation, vomiting
Skin and subcutaneous tissu
e disorders
Uncommon
hypersensitivity, pruritus, rash
General disorders and admi
nistration site conditions
Common
fatigue
Uncommon
peripheral oedema
Investigations
Uncommon
weight decrease including decreased appetite, weight increase
Somnolence
Pramipexole is associated with somnolence (8.6%) and has been associated uncommonly with
excessive daytime somnolence and sudden sleep onset episodes (0.1%). (See also section 4.4).
Pramipexole may be associated with libido disorders (increased or decreased).
Patients treated with dopamine agonists for Parkinson’s disease, including pramipexole, especially at
high doses, have been reported as exhibiting signs of pathological gambling, increase libido and
hypersexuality, generally reversible upon treatment discontinuation
(see also section 4.4)
.
In a cross-sectional, retrospective screening and case-control study including 3090 Parkinson’s disease
patients, 13.6% of all patients receiving dopaminergic or non-dopaminergic treatment had symptoms
of an impulse control disorder during the past six months. Manifestations observed include
pathological gambling, compulsive shopping, binge eating, and compulsive sexual behaviour
(hypersexuality). Possible independent risk factors for impulse control disorders included
dopaminergic treatments and higher doses of dopaminergic treatment, younger age (≤ 65 years), not
being married and self-reported family history of gambling behaviours.
There is no clinical experience with massive overdose. The expected adverse events would be those
related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting,
hyperkinesia, hallucinations, agitation and hypotension. There is no established antidote for overdose
of a dopamine agonist. If signs of central nervous system stimulation are present, a neuroleptic agent
may be indicated. Management of the overdose may require general supportive measures, along with
gastric lavage, intravenous fluids, administration of activated charcoal and electrocardiogram
monitoring.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: dopamine agonists, ATC code: N04BC05.
Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D
2
subfamily
of dopamine receptors of which it has a preferential affinity to D
3
receptors, and has full intrinsic
activity.
Pramipexole alleviates Parkinsonian motor deficits by stimulation of dopamine receptors in the
striatum. Animal studies have shown that pramipexole inhibits dopamine synthesis, release, and
turnover.
In human volunteers, a dose-dependent decrease in prolactin was observed.
28
Libido disorders
Impulse control disorders and compulsive behaviours
Clinical trials in Parkinson’s disease
In patients pramipexole alleviates signs and symptoms of idiopathic Parkinson' s disease. Placebo-
controlled clinical trials included approximately
1800
patients of Hoehn and Yahr stages
stages
I – IV. Out of these, approximately 1000
were in more advanced stages, received concomitant
levodopa therapy, and suffered from motor complications.
In early and advanced Parkinson’s disease, efficacy of pramipexole in the controlled clinical trials was
maintained for approximately six months. In open continuation trials lasting for more than three years
there were no signs of decreasing efficacy.
In a controlled double blind clinical trial of 2 year duration
,
initial treatment with pramipexole
significantly delayed the onset of motor complications, and reduced their occurrence compared to
initial treatment with levodopa. This delay in motor complications with pramipexole should be
balanced against a greater improvement in motor function with levodopa (as measured by the mean
change in UPDRS-score). The overall incidence of hallucinations and somnolence was generally
higher in the escalation phase with the pramipexole group. However there was no significant
difference during the maintenance phase. These points should be considered when initiating
pramipexole treatment in patients with Parkinson´s disease.
The European Medicines Agency has waived the obligation to submit the results of studies with
pramipexle in all subsets of the paediatric population in Parkinson’s Disease (see section 4.2 for
information on paediatric use).
Clinical trial in Tourette Disorder
The efficacy of pramipexole (0.0625-0.5 mg/day) with paediatric patients aged 6-17 years with
Tourette Disorder was evaluated in a 6-week, double-blind, randomised, placebo-controlled flexible
dose study. A total of 63 patients were randomised (43 on pramipexole, 20 on placebo). The primary
endpoint was change from baseline on the Total Tic Score (TTS) of the Yale Global Tic Severity
Scale (YGTSS). No difference was observed for pramipexole as compared to placebo for either the
primary endpoint or for any of the secondary efficacy endpoints including YGTSS total score, Patient
Global Impression of Improvement (PGI-I), Clinical Global Impression of Improvement (CGI-I), or
Clinical Global Impressions of Severity of Illness (CGI-S). Adverse events occurring in at least 5% of
patients in the pramipexole group and more common in the pramipexole-treated patients than in
patients on placebo were: headache (27.9%, placebo 25.0%), somnolence (7.0%, placebo 5.0%),
nausea (18.6%, placebo 10.0%), vomiting (11.6%, placebo 0.0%), upper abdominal pain (7.0%,
placebo 5.0%), orthostatic hypotension (9.3%, placebo 5.0%), myalgia (9.3%, placebo 5.0%), sleep
disorder (7.0%, placebo 0.0%), dyspnoea (7.0%, placebo 0.0%) and upper respiratory tract infection
(7.0%, placebo 5.0%). Other significant adverse events leading to discontinuation of study medication
for patients receiving pramipexole were confusional state, speech disorder and aggravated condition
(see section 4.2).
5.2 Pharmacokinetic properties
Pramipexole is rapidly and completely absorbed following oral administration. The absolute
bioavailability is greater than 90% and the maximum plasma concentrations occur between 1 and 3
hours. Concomitant administration with food did not reduce the extent of pramipexole absorption, but
the rate of absorption was reduced. Pramipexole shows linear kinetics and a small inter-patient
variation of plasma levels. In humans, the protein binding of pramipexole is very low (< 20%) and the
volume of distribution is large (400 l). High brain tissue concentrations were observed in the rat
(approx. 8-fold compared to plasma).
Pramipexole is metabolised in man only to a small extent.
Renal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of
14
C-labelled dose is excreted through the kidneys while less than 2% is found in the faeces. The total
29
clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately
400 ml/min. The elimination half-life (t
½
) varies from 8 hours in the young to 12 hours in the elderly.
5.3 Preclinical safety data
Repeated dose toxicity studies showed that pramipexole exerted functional effects, mainly involving
the CNS and female reproductive system, and probably resulting from an exaggerated
pharmacodynamic effect of pramipexole.
Decreases in diastolic and systolic pressure and heart rate were noted in the mini pig, and a tendency
to an hypotensive effect was discerned in the monkey.
The potential effects of pramipexole on reproductive function have been investigated in rats and
rabbits. Pramipexole was not teratogenic in rats and rabbits but was embryotoxic in the rat at
maternally toxic doses. Due to the selection of animal species and the limited parameters investigated,
the adverse effects of pramipexole on pregnancy and male fertility have not been fully elucidated.
A delay in sexual development (i.e., preputial separation and vaginal opening) was observed in rats.
The relevance for humans is unknown.
Pramipexole was not genotoxic. In a carcinogenicity study, male rats developed Leydig cell
hyperplasia and adenomas, explained by the prolactin-inhibiting effect of pramipexole. This finding is
not clinically relevant to man. The same study also showed that, at doses of 2 mg/kg (of salt) and
higher, pramipexole was associated with retinal degeneration in albino rats. The latter finding was not
observed in pigmented rats, nor in a 2-year albino mouse carcinogenicity study or in any other species
investigated.
6.
6.1 List of excipients
Mannitol
Maize starch
Pregelatinised maize starch
Colloidal anhydrous silica
Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in the original package in order to protect from light.
6.5 Nature and contents of container
Blister pack (Al/Al foil): 20, 30, 60, 90 or 100 tablets.
Not all pack sizes may be marketed.
30
Povidone K25
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
KRKA, d. d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
8.
20 tablets: EU/1/08/469/011
30 tablets: EU/1/08/469/012
60 tablets: EU/1/08/469/013
90 tablets: EU/1/08/469/014
100 tablets: EU/1/08/469/015
9.
12/9/2008
Detailed information on this product is available on the website of the European Medicines Agency
31
1.
FURTHER INFORMATION
What Oprymea contains
-
The active substance is pramipexole. Each tablet contains 0.088 mg, 0.18 mg, 0.35 mg, 0.7 mg
or 1.1 mg pramipexole as 0.125 mg, 0.25 mg, 0.5 mg, 1 mg or 1.5 mg pramipexole
dihydrochloride monohydrate, respectively.
-
The other ingredients are mannitol, maize starch, pregelatinised maize starch, povidone K25,
colloidal anhydrous silica and magnesium stearate.
What Oprymea looks like and contents of the pack
Tablets of 0.088 mg are white, round, with bevelled edges and imprint "P6" on one side of the tablet.
Tablets of 0.18 mg are white, oval, with bevelled edges, both sides scored, with imprint "P7" on both
halves of one side of the tablet. The tablet can be divided into equal halves.
Tablets of 0.35 mg are white, oval, with bevelled edges, both sides scored, with imprint "P8" on both
halves of one side of the tablet. The tablet can be divided into equal halves.
Tablets of 0.70 mg are white, round, with bevelled edges, both sides scored, with imprint "P9" on both
halves of one side of the tablet. The tablet can be divided into equal halves.
Tablets of 1.1 mg are white, round, with bevelled edges, both sides scored. The tablet can be divided
into equal halves.
Boxes of 20, 30, 60, 90 and 100 tablets in blisters of 10 tablets are available.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
KRKA, d. d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
Manufacturer
KRKA, d. d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
TAD Pharma GmbH, Heinz-Lohmann-Straße 5, 27472 Cuxhaven, Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
KRKA, d.d., Novo mesto
Tél/Tel:
+
32 (0)3 321 63 52
Luxembourg/Luxemburg
KRKA, d.d., Novo mesto
Tél/Tel:
+
32 (0)3 321 63 52
България
Представителство на KRKA в България
Teл.:
+
359 (02)
962 34 50
Magyarország
KRKA Magyarország Kereskedelmi Kft.
Tel.:
+
361 (0) 355 8490
Česká republika
KRKA ČR, s.r.o.
Tel:
+
420 (0) 221 115 150
Malta
KRKA Pharma Dublin, Ltd.
Tel:
+
46 8 643 67 66
Danmark
KRKA Sverige AB
Tlf:
+
46 (0)8 643 67 66 (SE)
Nederland
KRKA, d.d., Novo mesto
Tel:
+
32 3 321 63 52 (BE)
117
Deutschland
TAD Pharma GmbH
Tel:
+
49 (0) 4721 6060
Norge
KRKA Sverige AB
Tlf:
+
46 (0)8 643 67 66 (SE)
Eesti
KRKA, d.d., Novo mesto Eesti filiaal
Tel:
+
372 (0)6 671 658
Österreich
KRKA Pharma GmbH, Wien
Tel:
+
43 (0)1 66 24 300
Ελλάδα
QUALIA PHARMA S.A.
Τηλ:
+30 (0)210 2832941
Polska
KRKA-POLSKA Sp. z o.o.
Tel.:
+
48 (0)22 573 7500
España
KRKA, d.d., Novo mesto
Tel:
+
34 (0)61 5089 809
Portugal
KRKA Farmacêutica, Unipessoal Lda.
Tel:
+
351 (0)21 46 43 650
France
KRKA, d.d., Novo mesto
Tél:
+
32 3 321 63 52 (BE)
România
KRKA Romania S.R.L., Bucharest
Tel:
+
402 (0)1 310 66 05
Ireland
KRKA Pharma Dublin, Ltd.
Tel:
+
46 8 643 67 66
Slovenija
KRKA, d.d., Novo mesto
Tel:
+
386 (0) 1 47 51 100
Ísland
KRKA Sverige AB
Sími:
+
46 (0)8 643 67 66 (SE)
Slovenská republika
KRKA Slovensko, s.r.o.,
Tel:
+
421 (0) 2 571 04 501
Italia
KRKA, d.d., Novo mesto
Tel:
+
39 069448827
Suomi/Finland
KRKA Sverige AB
Puh/Tel:
+
46 (0)8 643 67 66 (SE)
Κύπρος
Kipa Pharmacal Ltd.
Τηλ:
+
357 24 651 882
Sverige
KRKA Sverige AB
Tel:
+
46 (0)8 643 67 66 (SE)
Latvija
KRKA, d.d., Novo mesto
Tel:
+
371 6 733 86 10
United Kingdom
Consilient Health (UK) Ltd.
Tel: + 44 (0)2089562310
Lietuva
UAB KRKA Lietuva
Tel:
+
370 5 236 27 40
This leaflet was last approved in .
Detailed information on this medicine is available on the European Medicines Agency web site:
118
Source: European Medicines Agency
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