ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Pramipexole Teva 0.088 mg tablets
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.
Tablet.
White, round, flat face bevel edge tablet, 5.55 mm diameter, embossed with “93” on one side and “P1”
on the other side.
Pramipexole Teva 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).
The tablets should be taken orally, swallowed with water, and can be taken either with or without
food. 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 side-effects,
the dosage should be titrated to achieve a maximal therapeutic effect.
Ascending – Dose schedule of Pramipexole Teva
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
1.05
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.
However, it should be noted that the incidence of somnolence is increased at doses higher than 1.5 mg/
day (see section 4.8).
2
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 Pramipexole Teva,
depending on reactions in individual patients.
Treatment discontinuation
:
Abrupt discontinuation of dopaminergic therapy can lead to the development of aneuroleptic
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.
In patients with a creatinine clearance between 20 and 50 ml/min, the initial daily dose of Pramipexole
Teva 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).
In patients with a creatinine clearance less than 20 ml/min, the daily dose of Pramipexole Teva should
be administered in a single dose, starting at 0.088 mg of base (0.125 mg of salt) daily.
If renal function declines during maintenance therapy, reduce Pramipexole Teva daily dose by the
same percentage as the decline in creatinine clearance, i.e. if creatinine clearance declines by 30 %,
then reduce the Pramipexole Teva 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 pramipexole pharmacokinetics has not been investigated.
Dosing in children and adolescents
Pramipexole is not recommended for use in children and adolescents below 18 years due to lack of
data on safety and efficacy.
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special warnings and special precautions for use
When prescribing Pramipexole Teva in a patient with Parkinson’s disease with renal impairment a
reduced dose is suggested in line with section 4.2.
3
Hallucinations
Hallucinations are known as an adverse event of treatment with dopamine agonists and levodopa.
Patients should be informed that (mostly visual) hallucinations can occur.
Dyskinesia
In advanced Parkinson’s disease, in combination treatment with levodopa, dyskinesias can occur
during the initial titration of Pramipexole Teva. If they occur, the dose of levodopa should be
decreased.
Sudden onset of sleep and somnolence
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 pramipexole.
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 medicinal products or alcohol in combination with pramipexole (see section 4.7 and
section 4.8).
Impulse control disorders and compulsive behaviours
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
Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
Severe cardiovascular disease
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)
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 the afternoon), increase in symptoms, and spread of symptoms to involve other
extremities. The frequency of augmentation after longer use of pramipexole and the appropriate
management of these events have not been evaluated in controlled clinical trials.
Plasma protein binding
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
4
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 with Pramipexole Teva.
Combination with levodopa
When Pramipexole Teva 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 Pramipexole Teva.
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).
Pramipexole Teva should not be used during pregnancy unless clearly necessary, i.e. if the potential
benefit justifies the potential risk to the foetus.
Breast-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, Pramipexole Teva should not be used during breast-feeding. However, if its
use is unavoidable, breast-feeding should be discontinued.
Fertility
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.
Pramipexole Teva can have a major influence on the ability to drive and use machines.
Hallucinations or somnolence can occur.
Patients being treated with Pramipexole Teva 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 ).
5
Expected adverse events
The following adverse reactions are expected under the use of Pramipexole Teva: 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 and 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
reaction.
Table 1 and 2 displays the frequency of adverse reactions from placebo-controlled clinical trials in
Parkinson’s disease and another indication. 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 events
The most commonly (≥ 5 %) reported adverse drug 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
reactions 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 disease
System Organ Class
Adverse Drug Reaction
Infections and infestations
Uncommon
pneumonia
Psychiatric disorders
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, hyperkinesias, sudden onset of sleep, syncope
Eye disorders
Common
visual impairment including diplopia, vision blurred and
visual acuity reduced
6
Vascular disorders
Common hypotension
Respiratory, thoracic, and mediastinal disorders
Uncommon Dyspnoea, hiccups
Gastrointestinal disorders
Very common nausea
Common constipation, vomiting
Skin and subcutaneous tissue disorders
Uncommon hypersensitivity, pruritus, rash
General disorders and administration site conditions
Common
fatigue, peripheral oedema
Investigations
Common
weight decrease including decreased appetite
Uncommon
weight increase
Other indication, most common adverse events
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 treated with pramipexole (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, hallucination, 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 mediastinal disorders
Uncommon Dyspnoea, hiccups
Gastrointestinal disorders
Very common nausea
Common constipation, vomiting
Skin and subcutaneous tissue disorders
Uncommon hypersensitivity, pruritus, rash
General disorders and administration site conditions
Common
fatigue
Uncommon
peripheral oedema
Investigations
Uncommon
weight decrease including decreased appetite, weight increase
Somnolence
7
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.
Libido disorders
Pramipexole may be associated with libido disorders (increased (0.1 %) or decreased (0.4 %)).
Impulse control disorders and compulsive behaviours
Patients treated with dopamine agonists for Parkison’s disease, including pramipexole, especially at
high doses, have been reported as exhibiting sings of pathological gambling, increased libido and
hypersexuality, generally reversible upon reduction of the dose or 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 reactions 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: dopamine agonists, ATC code: N04BC05
Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D2 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.
Clinical trials in Parkinson’s disease
In patients pramipexole alleviates signs and symptoms of idiopathic Parkinson' s disease. Controlled
clinical trials included approximately 2100 patients of Hoehn and Yahr stages I – IV. Out of these,
approximately 900 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
8
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.
In a placebo-controlled polysomnography study over 3 weeks pramipexole significantly reduced the
number of periodic limb movements during time in bed.
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
14ºC-labelled dose is excreted through the kidneys while less than 2 % is found in the faeces. The total
clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately
400 ml/min. The elimination half-life (t½) 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 minipig, and a tendency to
a 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.
6.1 List of excipients
Mannitol
Microcrystalline cellulose
9
Sodium starch glycolate
Povidone K25
Magnesium stearate
Sodium stearyl fumarate
Colloidal silicon dioxide.
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not store above 25 °C.
Store in the original package in order to protect from light and moisture.
6.5 Nature and contents of container
Aluminium/Aluminium Blister
Pack sizes: 30, 30 x 1, 50 x 1, 100 x 1 and 100 tablets
Polyethylene tablet container with CRC polypropylene cap. Pack sizes: 90 tablets.
Not all pack sizes may be marketed
6.6 Special precautions for disposal
No special requirements
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
EU/1/08/490/001
EU/1/08/490/002
EU/1/08/490/003
EU/1/08/490/004
EU/1/08/490/017
EU/1/08/490/018
18/12/2008
10
Detailed information on this product is available on the website of the European Medicines Agency
(EMA)
http://www.ema.europa.eu
11
Pramipexole Teva 0.18 mg tablets
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.
Tablets.
White, round, flat face bevel edge tablet, 7.00 mm diameter, embossed with "P2" over "P2" on the
scored side and "93" on the other side. The tablet can be divided into equal halves.
Pramipexole Teva 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).
The tablets should be taken orally, swallowed with water, and can be taken either with or without
food. 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 side-effects,
the dosage should be titrated to achieve a maximal therapeutic effect.
Ascending – Dose schedule of Pramipexole Teva
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
1.05
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.
However, it should be noted that the incidence of somnolence is increased at doses higher than 1.5 mg/
day (see section 4.8).
12
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 Pramipexole Teva,
depending on reactions in individual patients.
Treatment discontinuation:
Abrupt discontinuation of dopaminergic therapy can lead to the development of aneuroleptic
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.
In patients with a creatinine clearance between 20 and 50 ml/min, the initial daily dose of Pramipexole
Teva 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).
In patients with a creatinine clearance less than 20 ml/min, the daily dose of Pramipexole Teva should
be administered in a single dose, starting at 0.088 mg of base (0.125 mg of salt) daily.
If renal function declines during maintenance therapy, reduce Pramipexole Teva daily dose by the
same percentage as the decline in creatinine clearance, i.e. if creatinine clearance declines by 30 %,
then reduce the Pramipexole Teva 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 pramipexole pharmacokinetics has not been investigated.
Dosing in children and adolescents
Pramipexole is not recommended for use in children and adolescents below 18 years due to lack of
data on safety and efficacy.
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special warnings and special precautions for use
When prescribing Pramipexole Teva tablets in a patient with Parkinson’s disease with renal
impairment a reduced dose is suggested in line with section 4.2.
13
Hallucinations
Hallucinations are known as an adverse event of treatment with dopamine agonists and levodopa.
Patients should be informed that (mostly visual) hallucinations can occur.
Dyskinesia
In advanced Parkinson’s disease, in combination treatment with levodopa, dyskinesias can occur
during the initial titration of Pramipexole Teva. If they occur, the dose of levodopa should be
decreased.
Sudden onset of sleep and somnolence
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 pramipexole.
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 medicinal products or alcohol in combination with pramipexole (see section 4.7 and
section 4.8).
Impulse control disorders and compulsive behaviours
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
Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
Severe cardiovascular disease
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)
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 the afternoon), increase in symptoms, and spread of symptoms to involve other
extremities. The frequency of augmentation after longer use of pramipexole and the appropriate
management of these events have not been evaluated in controlled clinical trials.
Plasma protein binding
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
14
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 ofpramipexole. Reduction of the pramipexole dose
should be considered when these medicinal products are administered concomitantly with
Pramipexole Teva.
Combination with levodopa
When Pramipexole Teva 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 Pramipexole Teva.
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).
Pramipexole Teva should not be used during pregnancy unless clearly necessary, i.e. if the potential
benefit justifies the potential risk to the foetus.
Breast-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, Pramipexole Teva should not be used during breast-feeding. However, if its
use is unavoidable, breast-feeding should be discontinued.
Fertility
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.
Pramipexole Teva can have a major influence on the ability to drive and use machines.
Hallucinations or somnolence can occur.
Patients being treated with Pramipexole Teva and presenting with somnolence and/or sudden sleep
episodes must be informed to refrain from driving or engaging in activities where impaired alertness
15
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 ).
Expected adverse events
The following adverse reactions are expected under the use of Pramipexole Teva: 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, hyperkinesias,
hyperphagia, hypotension, insomnia, libido disorders, nausea, paranoia, peripheral oedema,
pneumonia, pruritus, rash and other hypersensitivity, compulsive shopping and other abnormal
behaviour; 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.
Table 1 and 2 displays the frequency of adverse reactions from placebo-controlled clinical trials in
Parkinson’s disease and another indication. 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 events
The most commonly (≥ 5 %) reported adverse drug 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 disease
System Organ Class
Adverse Drug Reaction
Infections and infestations
Uncommon
pneumonia
Psychiatric disorders
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
16
Uncommon
amnesia, hyperkinesias, 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 mediastinal disorders
Uncommon Dyspnoea, hiccups
Gastrointestinal disorders
Very common nausea
Common constipation, vomiting
Skin and subcutaneous tissue disorders
Uncommon hypersensitivity, pruritus, rash
General disorders and administration site conditions
Common
fatigue, peripheral oedema
Investigations
Common
weight decrease including decreased appetite
Uncommon
weight increase
Other Indication, most common adverse events
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 treated with pramipexole (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, hallucination, hyperphagia, libido disorder, paranoia,
restlessness
Nervous system disorders
Common
dizziness, headache, somnolence
Uncommon
amnesia, dyskinesia, hyperkinesias, sudden onset of sleep,
syncope
Eye disorders
Uncommon
visual disturbance including vision blurred and visual acuity
reduced
Vascular disorders
Uncommon hypotension
Respiratory, thoracic, and mediastinal disorders
Uncommon Dyspnoea, hiccups
Gastrointestinal disorders
Very common nausea
Common constipation, vomiting
Skin and subcutaneous tissue disorders
Uncommon hypersensitivity, pruritus, rash
General disorders and administration site conditions
Common
fatigue
Uncommon
peripheral oedema
17
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.
Libido disorders
Pramipexole may be associated with libido disorders (increased (0.1 %) or decreased (0.4 %)).
Impulse control disorders and compulsive behaviours
Patients treated with dopamine agonists for Parkinson’s disease, including, especially at high doses,
have been reported as exhibiting sings of pathological gambling, increased libido and
hypersexuality,generally reversible upon reduction of the dose or 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 reactions 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: dopamine agonists, ATC code: N04BC05
Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D2 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.
Clinical trials in Parkinson’s disease
In patients pramipexole alleviates signs and symptoms of idiopathic Parkinson' s disease. Controlled
clinical trials included approximately 2100 patients of Hoehn and Yahr stages I – IV. Out of these,
approximately 900 were in more advanced stages, received concomitant levodopa therapy, and
suffered from motor complications.
18
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.
In a placebo-controlled polysomnography study over 3 weeks pramipexole significantly reduced the
number of periodic limb movements during time in bed.
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
14ºC-labelled dose is excreted through the kidneys while less than 2 % is found in the faeces. The total
clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately
400 ml/min. The elimination half-life (t½) 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 minipig, and a tendency to
a 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.
19
6.1 List of excipients
Mannitol
Microcrystalline cellulose
Sodium starch glycolate
Povidone K25
Magnesium stearate
Sodium stearyl fumarate
Colloidal silicon dioxide.
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not store above 25 °C.
Store in the original package in order to protect from light and moisture.
6.5 Nature and contents of container
Aluminium/Aluminium Blister Strips
Pack sizes: 30, 30 x 1, 50 x 1 , 100 x 1 and 100 tablets
Polyethylene tablet container with CRC polypropylene cap. Pack sizes: 90 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
EU/1/08/490/005
EU/1/08/490/006
EU/1/08/490/007
EU/1/08/490/008
EU/1/08/490/019
EU/1/08/490/020
20
18/12/2008
Detailed information on this product is available on the website of the European Medicines Agency
(EMA)
http://www.ema.europa.eu
21
Pramipexole Teva 0.35 mg tablets
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.
Tablets.
White to off-white, oval, biconvex tablets, engraved with 9 vertical scoreline 3 on the scored side, and
8023 on the other side. The tablet can be divided into equal halves.
Pramipexole Teva 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).
The tablets should be taken orally, swallowed with water, and can be taken either with or without
food. 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 side-effects,
the dosage should be titrated to achieve a maximal therapeutic effect.
Ascending – Dose schedule of Pramipexole Teva
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
1.05
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.
However, it should be noted that the incidence of somnolence is increased at doses higher than
1.5 mg/day (see section 4.8).
22
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 Pramipexole Teva,
depending on reactions in individual patients.
Treatment discontinuation:
Abrupt discontinuation of dopaminergic therapy can lead to the development of aneuroleptic
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.
In patients with a creatinine clearance between 20 and 50 ml/min, the initial daily dose of Pramipexole
Teva 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).
In patients with a creatinine clearance less than 20 ml/min, the daily dose of Pramipexole Teva should
be administered in a single dose, starting at 0.088 mg of base (0.125 mg of salt) daily.
If renal function declines during maintenance therapy, reduce Pramipexole Teva daily dose by the
same percentage as the decline in creatinine clearance, i.e. if creatinine clearance declines by 30 %,
then reduce the Pramipexole Teva 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 pramipexole pharmacokinetics has not been investigated.
Dosing in children and adolescents
Pramipexole is not recommended for use in children and adolescents below 18 years due to lack of
data on safety and efficacy.
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special warnings and special precautions for use
When prescribing Pramipexole Teva in a patient with Parkinson’s disease with renal impairment a
reduced dose is suggested in line with section 4.2.
23
Hallucinations
Hallucinations are known as an adverse event of treatment with dopamine agonists and levodopa.
Patients should be informed that (mostly visual) hallucinations can occur.
Dyskinesia
In advanced Parkinson’s disease, in combination treatment with levodopa, dyskinesias can occur
during the initial titration of Pramipexole Teva. If they occur, the dose of levodopa should be
decreased.
Sudden onset of sleep and somnolence
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 pramipexole.
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 medicinal products or alcohol in combination with pramipexole (see section 4.7 and
section 4.8).
Impulse control disorders and compulsive behaviours
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
Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
Severe cardiovascular disease
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)
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 the afternoon), increase in symptoms, and spread of symptoms to involve other
extremities. The frequency of augmentation after longer use of pramipexole and the appropriate
management of these events have not been evaluated in controlled clinical trials.
Plasma protein binding
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
24
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 with
Pramipexole Teva.
Combination with levodopa
When Pramipexole Teva is given in combination with levodopa, it is recommended that the dosage of
levodopa is reduced and the dosage of other anti-parkinsonian medication is kept constant while
increasing the dose of Pramipexole Teva.
Because of possible additive effects, caution should be advised when patients are taking other sedating
medication 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).
Pramipexole Teva should not be used during pregnancy unless clearly necessary, i.e. if the potential
benefit justifies the potential risk to the foetus.
Breast-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, Pramipexole Teva should not be used during breast-feeding. However, if its
use is unavoidable, breast-feeding should be discontinued.
Fertility
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.
Pramipexole Teva can have a major influence on the ability to drive and use machines.
Hallucinations or somnolence can occur.
Patients being treated with Pramipexole Teva 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 ).
25
Expected adverse events
The following adverse reactions are expected under the use of Pramipexole Teva: 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.
Table 1 and 2 displays the frequency of adverse reactions from placebo-controlled clinical trials in
Parkinson’s disease and another indication. 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 events
The most commonly (≥ 5 %) reported adverse drug 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 disease
System Organ Class
Adverse Drug Reaction
Infections and infestations
Uncommon
pneumonia
Psychiatric disorders
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, hyperkinesias, sudden onset of sleep, syncope
Eye disorders
Common
visual impairment including diplopia, vision blurred and
26
visual acuity reduced
Vascular disorders
Common hypotension
Respiratory, thoracic, and mediastinal disorders
Uncommon Dyspnoea, hiccups
Gastrointestinal disorders
Very common nausea
Common constipation, vomiting
Skin and subcutaneous tissue disorders
Uncommon hypersensitivity, pruritus, rash
General disorders and administration site conditions
Common
fatigue, peripheral oedema
Investigations
Common
weight decrease including decreased appetite
Uncommon
weight increase
Other Indication, most common adverse events
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 treated with pramipexole (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, hallucination, hyperphagia, libido disorder, paranoia,
restlessness
Nervous system disorders
Common
dizziness, headache, somnolence
Uncommon
amnesia, dyskinesia, hyperkinesias, 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 mediastinal disorders
Uncommon dyspnoea, hiccups
Gastrointestinal disorders
Very common nausea
Common constipation, vomiting
Skin and subcutaneous tissue disorders
Uncommon hypersensitivity, pruritus, rash
General disorders and administration site conditions
Common
fatigue
Uncommon
peripheral oedema
Investigations
Uncommon
weight decrease including decreased appetite, weight increase
27
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.
Libido disorders
Pramipexole may be associated with libido disorders (increased (0.1 %) or decreased (0.4 %)).
Impulse control disorders and compulsive behaviours
Patients treated with dopamine agonists for Parkison’s disease, including pramipexole, especially at
high doses, have been reported as exhibiting sings of pathological gambling, increased libido and
hypersexuality, generally reversible upon reduction of the dose or 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 reactions 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: dopamine agonists, ATC code: N04BC05
Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D2 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.
Clinical trials in Parkinson’s disease
In patients pramipexole alleviates signs and symptoms of idiopathic Parkinson' s disease. Controlled
clinical trials included approximately 2100 patients of Hoehn and Yahr stages I – IV. Out of these,
approximately 900 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
28
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.
In a placebo-controlled polysomnography study over 3 weeks pramipexole significantly reduced the
number of periodic limb movements during time in bed.
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
14ºC-labelled dose is excreted through the kidneys while less than 2 % is found in the faeces. The total
clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately 400
ml/min. The elimination half-life (t½) 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 minipig, and a tendency to
a 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.
6.1 List of excipients
Mannitol
29
Microcrystalline cellulose
Sodium starch glycolate
Povidone K25
Magnesium stearate
Sodium stearyl fumarate
Colloidal silicon dioxide.
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not store above 25 °C.
Store in the original package in order to protect from light and moisture.
6.5 Nature and contents of container
Aluminium/Aluminium Blister Strips
Pack sizes: 30, 30 x 1, 50 x 1 , 100 x 1 and 100 tablets
Polyethylene tablet container with CRC polypropylene cap. Pack sizes: 90 tablets.
Not all pack sizes may be marketed.
6.6 Instructions for use and handling
No special requirements
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
EU/1/08/490/009
EU/1/08/490/010
EU/1/08/490/011
EU/1/08/490/012
EU/1/08/490/021
EU/1/08/490/022
18/12/2008
30
Detailed information on this product is available on the website of the European Medicines Agency
(EMA)
http://www.ema.europa.eu
31
Pramipexole Teva 0.7 mg tablets
Each tablet contains 0.7 mg pramipexole base (as 1 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.
Tablets.
White, round, flat face bevel edge tablet, 8.82 mm diameter, embossed with "8024" over "8024" on the
scored side and "93" on the other side. The tablet can be divided into equal halves.
Pramipexole Teva 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).
The tablets should be taken orally, swallowed with water, and can be taken either with or without
food. 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 side-effects,
the dosage should be titrated to achieve a maximal therapeutic effect.
Ascending – Dose schedule of Pramipexole Teva
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
1.05
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.
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
32
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 Pramipexole Teva,
depending on reactions in individual patients.
Treatment discontinuation:
Abrupt discontinuation of dopaminergic therapy can lead to the development of aneuroleptic
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.
In patients with a creatinine clearance between 20 and 50 ml/min, the initial daily dose of Pramipexole
Teva 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).
In patients with a creatinine clearance less than 20 ml/min, the daily dose of Pramipexole Teva should
be administered in a single dose, starting at 0.088 mg of base (0.125 mg of salt) daily.
If renal function declines during maintenance therapy, reduce Pramipexole Teva daily dose by the
same percentage as the decline in creatinine clearance, i.e. if creatinine clearance declines by 30 %,
then reduce the Pramipexole Teva 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 pramipexole pharmacokinetics has not been investigated.
Dosing in children and adolescents
Pramipexole is not recommended for use in children and adolescents below 18 years due to lack of
data on safety and efficacy.
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special warnings and special precautions for use
When prescribing Pramipexole Teva tablets 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 an adverse event of treatment with dopamine agonists and levodopa.
Patients should be informed that (mostly visual) hallucinations can occur.
Dyskinesia
33
In advanced Parkinson’s disease, in combination treatment with levodopa, dyskinesias can occur
during the initial titration of Pramipexole Teva. If they occur, the dose of levodopa should be
decreased.
Sudden onset of sleep and somnolence
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 pramipexole.
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 medicinal products or alcohol in combination with pramipexole (see section 4.7 and
section 4.8).
Impulse control disorders and compulsive behaviours
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
Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
Severe cardiovascular disease
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.)
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 the afternoon), increase in symptoms, and spread of symptoms to involve other
extremities. The frequency of augmentation after longer use of pramipexole and the appropriate
management of these events have not been evaluated in controlled clinical trials.
Plasma protein binding
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
34
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 and mexiletine, zidovudine, cisplatin, quinine, and procainamide, may interact
with pramipexole resulting in reduced clearance ofpramipexole. Reduction of the pramipexole dose
should be considered when these medicinal products are administered concomitantly with
Pramipexole Teva.
Combination with levodopa
When Pramipexole Teva 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 Pramipexole Teva.
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).
Pramipexole Teva should not be used during pregnancy unless clearly necessary, i.e. if the potential
benefit justifies the potential risk to the foetus.
Breast-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, Pramipexole Teva should not be used during breast-feeding. However, if its
use is unavoidable, breast-feeding should be discontinued.
Fertility
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.
Pramipexole Teva can have a major influence on the ability to drive an use machines.
Hallucinations or somnolence can occur.
Patients being treated with Pramipexole Teva 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 ).
Expected adverse events
35
The following adverse reactions are expected under the use of Pramipexole Teva: 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.
Table 1 and 2 displays the frequency of adverse reactions from placebo-controlled clinical trials in
Parkinson’s disease and another indication. 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 events
The most commonly (≥ 5 %) reported adverse drug 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 disease
System Organ Class
Adverse Drug Reaction
Infections and infestations
Uncommon
pneumonia
Psychiatric disorders
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 mediastinal disorders
36
Uncommon dyspnoea, hiccups
Gastrointestinal disorders
Very common nausea
Common constipation, vomiting
Skin and subcutaneous tissue disorders
Uncommon hypersensitivity, pruritus, rash
General disorders and administration site conditions
Common
fatigue, peripheral oedema
Investigations
Common
weight decrease, including decreased appetite
Uncommon
weight increase
Other Indication, most common adverse events
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 treated with pramipexole (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, hallucination, hyperphagia, libido disorder, paranoia,
restlessness
Nervous system disorders
Common
dizziness, headache, somnolence
Uncommon
amnesia, dyskinesia, hyperkinesias, 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 mediastinal disorders
Uncommon dyspnoea, hiccups
Gastrointestinal disorders
Very common nausea
Common constipation, vomiting
Skin and subcutaneous tissue disorders
Uncommon hypersensitivity, pruritus, rash
General disorders and administration 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.
Libido disorders
37
Pramipexole may be associated with libido disorders (increased (0.1 %) or decreased (0.4 %)).
Impulse control disorders and compulsive behaviours
Patients treated with dopamine agonists for Parkison’s disease, including pramipexole, especially at
high doses, have been reported as exhibiting sings of pathological gambling, increased libido and
hypersexuality, generally reversible upon reduction of the dose or 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 reactions 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: dopamine agonists, ATC code: N04BC05
Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D2 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.
Clinical trials in Parkinson’s disease
In patients pramipexole alleviates signs and symptoms of idiopathic Parkinson' s disease. Controlled
clinical trials included approximately 2100 patients of Hoehn and Yahr stages I – IV. Out of these,
approximately 900 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
38
was no significant difference during the maintenance phase. These points should be considered when
initiating pramipexole treatment in patients with Parkinson´s disease.
In a placebo-controlled polysomnography study over 3 weeks pramipexole significantly reduced the
number of periodic limb movements during time in bed.
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
14ºC-labelled dose is excreted through the kidneys while less than 2 % is found in the faeces. The total
clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately
400 ml/min. The elimination half-life (t½) 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 minipig, and a tendency to
a 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.
6.1 List of excipients
Mannitol
Microcrystalline cellulose
Sodium starch glycolate
Povidone K25
Magnesium stearate
39
Sodium stearyl fumarate
Colloidal silicon dioxide.
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not store above 25 °C.
Store in the original package in order to protect from light and moisture.
6.5 Nature and contents of container
Aluminium/Aluminium Blister Strips
Pack sizes: 30, 30 x 1, 50 x 1 , 100 x 1 and 100 tablets
Polyethylene tablet container with CRC polypropylene cap. Pack sizes: 90 tablets.
Not all pack sizes may be marketed.
6.6 Instructions for use and handling
No special requirements
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
EU/1/08/490/013
EU/1/08/490/014
EU/1/08/490/015
EU/1/08/490/016
EU/1/08/490/023
EU/1/08/490/024
18/12/2008
Detailed information on this product is available on the website of the European Medicines Agency
(EMA)
http://www.ema.europa.eu
40
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
41
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Teva Pharmaceutical Works Co. Ltd.
Pallagi Street 13
H-4042 Debrecen
Hungary
TEVA Pharmaceutical Works Private Limited Company
H-2100 Gödöllő,
Táncsics Mihály út 82
Hungary
TEVA UK Ltd
Brampton Road,
Hampden Park,
Eastbourne,
East Sussex,
BN22 9AG
United Kingdom
Pharmachemie B.V.
Swensweg 5,
Postbus 552,
2003 RN Haarlem
The Netherlands
TEVA Santé Sa,
Rue Bellocier, 89107,
Sens,
France
Teva Czech Industries s.r.o.
Ostravska 29, c.p. 305
747 70 Opava-Komarov
Czech Republic
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch
42
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
PSURs
The PSUR submission schedule for Pramipexole Teva tablets should follow PSURs submission
schedule for the reference medicinal product.
43
ANNEX III
LABELLING AND PACKAGE LEAFLET
44
A. LABELLING
45
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton – Pramipexole Teva 0.088 mg Tablets
1.
Pramipexole Teva 0.088 mg tablets
Pramipexole
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 0.088 mg pramipexole
equivalent to
0.125 mg pramipexole dihydrochloride
monohydrate.
3.
LIST OF EXCIPIENTS
4.
Tablets
Blisters:
30 tablets
50 x 1 tablets
100 tablets
30 x 1 tablets
100 x 1 tablets
Tablet container:
90 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use. Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
46
Do not store above 25 °C.
Store in the original package in order to protect from light and moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
EU/1/08/490/001
EU/1/08/490/002
EU/1/08/490/003
EU/1/08/490/004
EU/1/08/490/017
EU/1/08/490/018
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Pramipexole Teva 0.088 mg
47
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister - Pramipexole Teva 0.088 mg Tablets
1.
Pramipexole Teva 0.088 mg tablets
Pramipexole
2.
Teva Pharma B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
BN
5.
OTHER
48
PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING UNITS
Self-adhesive, paper label -Pramipexole Teva 0.088 mg Tablets
1.
Pramipexole Teva 0.088 mg tablets
Pramipexole
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 0.088 mg pramipexole
equivalent to
0.125 mg pramipexole dihydrochloride
monohydrate.
3.
LIST OF EXCIPIENTS
4.
Tablets
90 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use. Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25 °C.
Store in the original package in order to protect from light and moisture.
49
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
EU/1/08/490/004
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
50
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton – Pramipexole Teva 0.18 mg tablets
1.
Pramipexole Teva 0.18 mg tablets
Pramipexole
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 0.18 mg pramipexole
equivalent to
0.25 mg pramipexole dihydrochloride
monohydrate.
3.
LIST OF EXCIPIENTS
4.
Tablets
Blisters:
30 tablets
50 x 1 tablets
100 tablets
30 x 1 tablets
100 x 1 tablets
Tablet container:
90 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use. Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
51
Do not store above 25 °C.
Store in the original package in order to protect from light and moisture
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
EU/1/08/490/005
EU/1/08/490/006
EU/1/08/490/007
EU/1/08/490/008
EU/1/08/490/019
EU/1/08/490/020
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Pramipexole Teva 0.18 mg
52
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister – Pramipexole Teva 0.18 mg tablets
1.
Pramipexole Teva 0.18 mg tablets
Pramipexole
2.
Teva Pharma B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
BN
5.
OTHER
53
PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING UNITS
self-adhesive, paper label - Pramipexole Teva 0.18 mg tablets
1.
Pramipexole Teva 0.18 mg tablets
Pramipexole
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 0.18 mg pramipexole
equivalent to
0.25 mg pramipexole dihydrochloride
monohydrate.
3.
LIST OF EXCIPIENTS
4.
Tablets
90 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use. Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25 °C.
Store in the original package in order to protect from light and moisture
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
54
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
EU/1/08/490/008
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
55
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton – Pramipexole Teva 0.35 mg Tablets
1.
Pramipexole Teva 0.35 mg tablets
Pramipexole
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 0.35 mg pramipexole
equivalent to
0.5 mg pramipexole dihydrochloride
monohydrate.
3.
LIST OF EXCIPIENTS
4.
Tablets
Blisters:
30 tablets
50 x 1 tablets
100 tablets
30 x 1 tablets
100 x 1 tablets
Tablet container:
90 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use. Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
56
Do not store above 25°C.
Store in the original package in order to protect from light and moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
EU/1/08/490/009
EU/1/08/490/010
EU/1/08/490/011
EU/1/08/490/012
EU/1/08/490/021
EU/1/08/490/022
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Pramipexole Teva 0.35 mg
57
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister – Pramipexole Teva 0.35 mg Tablets
1.
Pramipexole Teva 0.35 mg tablets
Pramipexole
2.
Teva Pharma B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
BN
5.
OTHER
58
PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING UNITS
Self-adhesive, paper label – Pramipexole Teva 0.35 mg Tablets
1.
Pramipexole Teva 0.35 mg tablets
Pramipexole
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 0.35 mg pramipexole
equivalent to
0.5 mg pramipexole dihydrochloride
monohydrate.
3.
LIST OF EXCIPIENTS
4.
Tablets
90 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use. Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25 °C.
Store in the original package in order to protect from light and moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
59
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
EU/1/08/490/012
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
Not applicable
16. INFORMATION IN BRAILLE
60
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton – Pramipexole Teva 0.7 mg tablets
1.
Pramipexole Teva 0.7 mg tablets
Pramipexole
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 0.7 mg pramipexole
equivalent to
1 mg pramipexole dihydrochloride
monohydrate.
3.
LIST OF EXCIPIENTS
4.
Tablets
Blisters:
30 tablets
50 x 1 tablets
100 tablets
30 x 1
100 x 1
Tablet container:
90 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use. Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
61
Do not store above 25 °C.
Store in the original package in order to protect from light and moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
EU/1/08/490/013
EU/1/08/490/014
EU/1/08/490/015
EU/1/08/490/016
EU/1/08/490/023
EU/1/08/490/024
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
Not applicable
16. INFORMATION IN BRAILLE
Pramipexole Teva 0.7 mg
62
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister – Pramipexole Teva 0.7
mg tablets
1.
Pramipexole Teva 0.7 mg tablets
Pramipexole
2.
Teva Pharma B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
BN
5.
OTHER
Not applicable
63
PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING UNITS
self-adhesive, paper label - Pramipexole Teva 0.7 mg tablets
1.
Pramipexole Teva 0.7 mg tablets
Pramipexole
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 0.7 mg pramipexole
equivalent to
1 mg pramipexole dihydrochloride
monohydrate.
3.
LIST OF EXCIPIENTS
4.
Tablets
90 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use. Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25 °C.
Store in the original package in order to protect from light and moisture
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
64
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
EU/1/08/490/016
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
Not applicable
16. INFORMATION IN BRAILLE
65
B. PACKAGE LEAFLET
66
PACKAGE LEAFLET: INFORMATION FOR THE USER
PRAMIPEXOLE TEVA 0.088 MG TABLETS
PRAMIPEXOLE TEVA 0.18 MG TABLETS
PRAMIPEXOLE TEVA 0.35 MG TABLETS
PRAMIPEXOLE TEVA 0.7 MG TABLETS
Pramipexole
Read all of this leaflet carefully before you start taking this medicine.
•
Keep this leaflet. You may need to read it again.
•
If you have any further questions, ask your doctor or pharmacist.
•
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
•
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What Pramipexole Teva is and what it is used for
2. Before you take Pramipexole Teva
3. How to take Pramipexole Teva
4. Possible side effects
5.
How to store Pramipexole Teva
6. Further information
1.
WHAT PRAMIPEXOLE TEVA IS AND WHAT IT IS USED FOR
Pramipexole Teva is a dopamine agonist
and works by stimulating dopamine receptors in the brain. In
Parkinson’s disease levels of dopamine in the brain are low and Pramipexole Teva works by
mimicking the action of dopamine.
Pramipexole Teva is used in the treatment of Parkinson’s disease alone or in combination with another
medicine called levodopa .
2. BEFORE YOU TAKE PRAMIPEXOLE TEVA
Do NOT take Pramipexole Teva
•
If you are allergic (hypersensitive) to pramipexole or any of the other ingredients of this
medicine.
Take special care with Pramipexole Teva
Tell your doctor before you start to take this medicine if:
•
You have kidney problems (you may need a lower dose of Pramipexole Teva)
•
You have hallucinations (seeing, hearing or feeling things that are not there). Most
hallucinations are visual.
•
You have dyskinesia (e.g. abnormal, uncontrolled movements of the limbs)
If you have advanced Parkinson’s disease and are also taking levodopa, you might develop
dyskinesia during the uptitration of Pramipexole Teva.
•
You have a mental illness such as schizophrenia or depression
•
You have heart problems (your doctor may decide to do check-ups more often during treatment
to make sure that your blood pressure does not fall too low).
67
You should tell your doctor if you experience sleepiness or episodes of suddenly falling asleep.
You should tell your doctor if you (or your carer) notice any changes in your behaviour. Such changes
may be an abnormal desire to gamble, compulsive shopping, increased libido (sex drive) or excessive
and uncontrollable overeating. Your doctor may lower the dose of Pramipexole Teva or stop your
treatment.
You should tell your doctor if you notice any changes to your eyesight. Your eyes may need regular
check-ups.
Taking other medicines
The effects of Pramipexole Teva may be altered or side effects may occur if you are also taking other
medicines. Talk to your doctor if you are taking any of the following:
•
Medicines which affect kidney function or are excreted by the kidneys, e.g. cimetidine (used to
treat indigestion and other stomach problems) and amantidine (used to manage Parkinson’s
disease)
•
Levodopa (used to manage Parkinson’s disease)
•
Medicines used to treat mental illnesses such as schizophrenia or depression
•
Other medicines which can cause drowsiness since the drowsiness may become worse in the
combination with Pramipexole Teva.
•
zidovudine (which can be used to treat the acquired immune deficiency syndrome (AIDS), a
disease of the human immune system);
•
cisplatin (to treat various types of cancers);
•
quinine (which can be used for the prevention of painful night-time leg cramps and for the
treatment of a type of malaria known as falciparum malaria (malignant malaria));
•
procainamide (to treat irregular heart beat).
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Taking Pramipexole Teva with food and drink
Pramipexole Teva can be taken with or without food and should be swallowed with a sufficient
amount of water. If you experience drowsiness this can be made worse if you drink alcohol.
Pregnancy and breast-feeding
If you are pregnant or planning to become pregnant Pramipexole Teva should only be used if your
doctor considers it to be absolutely necessary. The effects of Pramipexole Teva on the unborn child
are not known.
You should not take Pramipexole Teva if you are breast-feeding. Pramipexole Teva may stop milk
production. Also, it can pass into the breast milk and can reach your baby and the effects of this are
not known.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Pramipexole Teva may cause hallucinations and sleepiness, and you may fall asleep suddenly without
any warning. If you experience these effects, do not drive, operate machinery or perform any other
dangerous task that requires your full attention. You should also tell your doctor as he/she may need to
lower your dose of Pramipexole Teva or stop your treatment altogether.
68
3. HOW TO TAKE PRAMIPEXOLE TEVA
Always take Pramipexole Teva exactly as your doctor has told you. You should check with your
doctor if you are not sure.
Pramipexole Teva should be taken three times a day. The tablets can be taken with or without food
and should be swallowed with a glass of water. You can break the tablets to make it easier to swallow
them if necessary.
The treatment with Pramipexole Teva normally starts with a low dose which is gradually increased
every 5 to 7 days until the right dose for your needs is reached (the “maintenance dose”).
The normal starting dose is one Pramipexole Teva 0.088 mg tablet three times a day (a daily dose of
0.264 mg of pramipexole).
The usual maintenance dose is 1.1 mg per day. However, your dose may have to be increased even
further. If necessary, your doctor may increase your tablet dose up to a maximum of 3.3 mg of
pramipexole a day. A lower maintenance dose of three Pramipexole Teva 0.088 mg tablets a day is
also possible.
Your doctor may decide to change your maintenance dose depending on your response to the
treatment and any side effects that you experience.
If your doctor decides to stop your treatment, the dose will be reduced slowly until treatment is
stopped.
Patients with kidney disease
If you have moderate or severe kidney disease, your doctor will prescribe a lower dose. In this case,
you will have to take the tablets only once or twice a day. If you have moderate kidney disease, the
usual starting dose is 1 tablet Pramipexole Teva 0.088 mg twice a day. In severe kidney disease, the
usual starting dose is just 1 tablet Pramipexole Teva 0.088 mg a day.
If you take more Pramipexole Teva than you should
If you (or someone else) swallow a lot of the tablets all together, or if you think a child has swallowed
any of the tablets, contact your nearest hospital casualty department or your doctor immediately. An
overdose is likely to cause nausea, vomiting, abnormal muscular movements, hallucinations, agitation
and low blood pressure (which might cause light-headedness and dizziness). Please take this leaflet,
any remaining tablets and the container with you to the hospital or doctor so that they know which
tablets were consumed. Medical treatment may be necessary.
If you forget to take Pramipexole Teva
If you miss a tablet then you should take it as soon as you remember. However, if it is nearly time for
your next tablet then you should skip the dose you missed and take your next tablet as normal. Do not
take a double dose to make up for a forgotten tablet.
If you stop taking Pramipexole Teva
You should not stop taking your medicine or reduce your dose without discussing it with your doctor
first. It is dangerous to stop taking this medicine suddenly. If you need to stop your treatment your
doctor will reduce your dose slowly.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
69
4. POSSIBLE SIDE EFFECTS
Like all medicines, Pramipexole Teva can cause side effects, although not everybody gets them.
Evaluation of the side effects is based on the following frequencies:
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
Very common:
•
Dyskinesia (e.g. abnormal, uncontrolled movement of the limbs)
•
Sleepiness
•
Dizziness
•
Nausea (sickness)
Common:
•
Urge to behave in an unusual way
•
Hallucinations (seeing, hearing or feeling things that are not there)
•
Confusion
•
Tiredness (fatigue)
•
Sleeplessness (insomnia)
•
Excess fluid, usually in the legs (peripheral oedema)
•
Headache
•
Hypotension (Low blood pressure)
•
Abnormal dreams
•
Constipation
•
Visual impairment
•
Vomiting (being sick)
•
Weight loss including decreased appetite
Uncommon:
•
Paranoia (e.g. excessive fear for one’s own well-being)
•
Delusion
•
Excessive daytime sleepiness and falling asleep suddenly
•
Amnesia (memory disturbance)
•
Hyperkinesia (increased movements and inability to keep still)
•
Weight increase
•
Increased sexual desire drive (e.g. increased libido)
•
Allergic reactions (e.g. rash, itching, hypersensitivity)
•
Fainting
•
Pathological gambling, especially when taking high doses of Pramipexole Teva
•
Hypersexuality
•
Increased eating (binge eating, hyperphagia)
•
Restlessness
•
Compulsive shopping
•
Dyspnoea (difficulties to breathe)
•
hiccups
•
Pneumonia (infection of the lungs)
70
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor.
5. HOW TO STORE PRAMIPEXOLE TEVA
Keep out of the reach and sight of children.
Do not use Pramipexole Teva after the expiry date that is stated on the outer packaging. The expiry
date refers to the last day of that month.
Do not store above 25 ºC.
Store in the original package in order to protect from light and moisture.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6. FURTHER INFORMATION
What Pramipexole Teva contains
The active substance is pramipexole.
Pramipexole Teva 0.088 mg tablets: one tablet contains 0.088 mg pramipexole equivalent to 0.125 mg
pramipexole dihydrochloride monohydrate
Pramipexole Teva 0.18 mg tablets: one tablet contains 0.18 mg pramipexole equivalent to 0.25 mg of
pramipexole dihydrochloride monohydrate
Pramipexole Teva 0.35 mg tablets: one tablet contains 0.35 mg pramipexole equivalent to 0.5 mg
pramipexole dihydrochloride monohydrate
Pramipexole Teva 0.7 mg tablets: one tablet contains 0.7 mg pramipexole equivalent to 1.0 mg
pramipexole dihydrochloride monohydrate
The other ingredients are mannitol, microcrystalline cellulose, sodium starch glycolate, povidone,
magnesium stearate, sodium stearyl fumarate, colloidal silicon dioxide
.
What Pramipexole Teva looks like and contents of the pack
•
Pramipexole Teva 0.088 mg tablets are white, round tablets, embossed with "93" on one side and
"P1" on the other side.
•
Pramipexole Teva 0.18 mg tablets are white round, scored tablets embossed with "P2" over "P2"
on the scored side and "93" on the other side. The tablet can be divided into equal halves.
•
Pramipexole Teva 0.35 mg tablets are white, oval, biconvex tablets, engraved with 9 vertical
scoreline 3 on the scored side, and 8023 on the other side. The tablet can be divided into equal
halves.
•
Pramipexole Teva 0.7 mg tablets are white, round, scored tablets embossed with "8024" over
"8024" on the scored side and "93" on the other side. The tablet can be divided into equal halves.
•
Pramipexole Teva tablets are available in blister packs of 30, 30 x 1, 50 x 1, 100 x 1 and 100
tablets and bottles containing 90 tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
Manufacturer:
TEVA Pharmaceutical Works Private Limited Company
Pallagi út 13,
71
4042 Debrecen,
Hungary
Or:
TEVA Pharmaceutical Works Private Limited Company
H-2100 Gödöllő,
Táncsics Mihály út 82
Hungary
Or:
TEVA UK Ltd
Brampton Road,
Hampden Park,
Eastbourne,
East Sussex,
BN22 9AG
United Kingdom
Or:
Pharmachemie B.V.
Swensweg 5,
Postbus 552,
2003 RN Haarlem
The Netherlands
Or:
TEVA Santé Sa,
Rue Bellocier, 89107,
Sens,
France
Or
Teva Czech Industries s.r.o
Ostravska 29, c.p. 305
747 70 Opava-Komarov
Czech Republic
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A.
Tel/Tél: +32 3 820 73 73
Luxembourg/Luxemburg
Teva Pharma Belgium N.V./S.A./AG.
Tél: +32 3 820 73 73
България
Тева Фармасютикълс България ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420
606 763 892
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
72
Danmark
Teva Denmark A.S.
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor Biotech
Eesti filiaal
Tel: +372 611 2409
Österreich
Teva GmbH
Tel: (49) 351 834 0
Ελλάδα
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
Tel.: +(48) 22 345 93 00
España
Teva Pharma, S.L.U
Tél: +(34) 91 387 32 80
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
Tel: (351) 214 235 910
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 230 65 24
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Teva UK Limited
Tel: +(44) 1323 501 111
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB “Sicor Biotech” Latvian Affiliate
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu
73
Source: European Medicines Agency
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