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Pipexus 1.05 mg prolonged-release tablets


Each prolonged-release tablet contains 1.5 mg pramipexole dihydrochloride
monohydrate equivalent to 1.05 mg pramipexole.
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 the full list of excipients, see section 6.1.


Prolonged-release tablet.
Pipexus 1.05 mg prolonged-release tablets: The round tablets of 10 mm diameter are
white or nearly white, biconvex and are marked with 105 on one side




Therapeutic indications
Pipexus is indicated in adults for treatment of the signs and symptoms of idiopathic
Parkinson’s disease, alone (without levodopa) or in combination with levodopa, i.e.
over the course of the disease, through to late stages when the effect of levodopa
wears off or becomes inconsistent and fluctuations of the therapeutic effect occur
(end of dose or “on off” fluctuations).


Posology and method of administration
Pipexus prolonged-release tablets are a once-a-day oral formulation of pramipexole.
Initial treatment
Doses should be increased gradually from a starting dose of 0.26 mg of base (0.375
mg of salt) per day and then increased every 5 - 7 days. Providing patients do not
experience intolerable undesirable effects, the dose should be titrated to achieve a
maximal therapeutic effect.

Ascending dose schedule of Pipexus prolonged-release tablets

Daily dose (mg of base)

Daily dose (mg of salt)










If a further dose increase is necessary the daily dose should be increased by 0.52 mg
of base (0.75 mg of salt) at weekly intervals up to a maximum dose of 3.15 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 1.05 mg of base (1.5 mg of salt) per day
(see section 4.8).
Patients already taking pramipexole tablets may be switched to Pipexus prolongedrelease tablets overnight, at the same daily dose. After switching to Pipexus
prolonged-release tablets, the dose may be adjusted depending on the patient's
therapeutic response (see section 5.1).
Maintenance treatment
The individual dose of pramipexole should be in the range of 0.26 mg of base (0.375
mg of salt) to a maximum of 3.15 mg of base (4.5 mg of salt) per day. During dose
escalation in pivotal studies, efficacy was observed starting at a daily dose of 1.05 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 1.05 mg of base (1.5 mg of
salt). In advanced Parkinson's disease, pramipexole doses higher than 1.05 mg of base
(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 dose of levodopa is reduced during
both the dose escalation and the maintenance treatment with Pipexus, depending on
reactions in individual patients (see section 4.5).
Missed dose
When the intake of a dose is missed, Pipexus prolonged-release tablets should be
taken within 12 hours after the regularly scheduled time. After 12 hours, the missed
dose should be left out and the next dose should be taken on the following day at the
next regularly scheduled time.

Treatment discontinuation
Abrupt discontinuation of dopaminergic therapy can lead to the development of a
neuroleptic malignant syndrome. Pramipexole should be tapered off at a rate of 0.52
mg of base (0.75 mg of salt) per day until the daily dose has been reduced to 0.52 mg
of base (0.75 mg of salt). Thereafter the dose should be reduced by 0.26 mg of base
(0.375 mg of salt) per day (see section 4.4).
Patients with renal impairment
The elimination of pramipexole is dependent on renal function. The following dose
schedule is suggested:
Patients with a creatinine clearance above 50 ml/min require no reduction in daily
dose or dosing frequency.
In patients with a creatinine clearance between 30 and 50 ml/min, treatment should be
started with 0.26 mg Pipexus prolonged-release tablets every other day. Caution
should be exercised and careful assessment of therapeutic response and tolerability
should be made before increasing to daily dosing after one week. If a further dose
increase is necessary, doses should be increased by 0.26 mg pramipexole base at
weekly intervals up to a maximum dose of 1.57 mg pramipexole base (2.25 mg of
salt) per day.
The treatment of patients with a creatinine clearance below 30 ml/min with Pipexus
prolonged-release tablets is not recommended as no data are available for this patient
population. The use of pramipexole tablets should be considered.
If renal function declines during maintenance therapy, the recommendations given
above should be followed.
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 Pipexus pharmacokinetics has not been
Paediatric population
The safety and efficacy of Pipexus in children below 18 years has not been
established. There is no relevant use of Pipexus prolonged-release tablets in the
paediatric population in Parkinson's Disease.

Method of administration
The tablets should be swallowed whole with water, and must not be chewed, divided
or crushed. The tablets may be taken either with or without food and should be taken
each day at about the same time.


Hypersensitivity to the active substance or to any of the excipients listed in section


Special warnings and precautions for use
When prescribing Pipexus in a patient with Parkinson's disease with renal impairment
a reduced dose is suggested in line with section 4.2.
Hallucinations are known as a side effect of treatment with dopamine agonists and
levodopa. Patients should be informed that (mostly visual) hallucinations can occur.
In advanced Parkinson's disease, in combination treatment with levodopa, dyskinesia
can occur during the initial titration of Pipexus. 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 Pipexus. Patients who have
experienced somnolence and/or an episode of sudden sleep onset must refrain from
driving or operating machines. Furthermore a reduction of the dose 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 sections 4.5, 4.7 and section 4.8).
Impulse control disorders
Patients should be regularly monitored for the development of impulse control
disorders. Patients and carers should be made aware that behavioural symptoms of
impulse control disorders including pathological gambling, increased libido,
hypersexuality, compulsive spending or buying, binge eating and compulsive eating
can occur in patients treated with dopamine agonists including Pipexus. Dose
reduction/tapered discontinuation should be considered if such symptoms develop.
Mania and delirium
Patients should be regularly monitored for the development of mania and delirium.
Patients and carers should be made aware that mania and delirium can occur in
patients treated with pramipexole. Dose reduction/tapered discontinuation should be
considered if such symptoms develop.

Patients with psychotic disorders
Patients with psychotic disorders should only be treated with dopamine agonists if the
potential benefits outweigh the risks. Co-administration 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).


Interaction with other medicinal products and other forms of interaction
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
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 Pipexus.

Combination with levodopa

When Pipexus is given in combination with levodopa, it is recommended that the
dose of levodopa is reduced and the dose of other anti-parkinsonian medicinal
products is kept constant while increasing the dose of Pipexus.
Because of possible additive effects, caution should be advised when patients are
taking other sedating medicinal products or alcohol in combination with pramipexole
(see sections 4.4, 4.7 and 4.8).
Antipsychotic medicinal products
Co-administration of antipsychotic medicinal products with pramipexole should be
avoided (see section 4.4), e.g. if antagonistic effects can be expected.


Fertility, pregnancy and lactation
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). Pipexus should not be used during pregnancy
unless clearly necessary, i.e. if the potential benefit justifies the potential risk to the
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, Pipexus should not be used during breast-feeding.
However, if its use is unavoidable, breast-feeding should be discontinued.
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.


Effects on ability to drive and use machines
Pipexus can have a major influence on the ability to drive and use machines.
Hallucinations or somnolence can occur.
Patients being treated with Pipexus 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).


Undesirable effects
Expected adverse reactions
The following adverse reactions are expected under the use of Pipexus: abnormal
dreams, amnesia, behavioural symptoms of impulse control disorders and
compulsions such as binge eating, compulsive shopping, hypersexuality and
pathological gambling; cardiac failure, confusion, constipation, delirium, delusion,
dizziness, dyskinesia, dyspnoea, fatigue, hallucinations, headache, hiccups,
hyperkinesia, hyperphagia, hypotension, inappropriate antidiuretic hormone secretion,
insomnia, libido disorders, mania, 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 1,778
Parkinson's disease patients on pramipexole and 1,297 patients on placebo, adverse
drug reactions were frequently reported for both groups. 67% of patients on
pramipexole and 54% of patients on placebo reported at least one adverse drug
The adverse drug reactions reported in the table below 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. The majority of adverse drug 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 to < 1/10);
uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (<
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 pramipexole salt per day (see section 4.2). A 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.

System Organ Class

Adverse Drug Reaction

Infections and infestations



Endocrine disorders

inappropriate antidiuretic hormone secretion1

Psychiatric disorders

abnormal dreams, behavioural symptoms of impulse control
disorders and compulsions; confusion, hallucinations,


binge eating1, compulsive shopping, delusion, hyperphagia1,
hypersexuality, libido disorder, paranoia, pathological
gambling, restlessness, delirium



Nervous system disorders

dizziness, dyskinesia, somnolence




amnesia, hyperkinesia, sudden onset of sleep, syncope

Eye disorders

visual impairment including diplopia, vision blurred and
visual acuity reduced

Cardiac disorders

cardiac failure1

Vascular disorders


Respiratory, thoracic, and mediastinal disorders

dyspnoea, hiccups

Gastrointestinal disorders



constipation, vomiting

Skin and subcutaneous tissue disorders

hypersensitivity, pruritus, rash

General disorders and administration site conditions

fatigue, peripheral oedema




weight decrease including decreased appetite


weight increase

This side effect has been observed in post-marketing experience. With 95 %
certainty, the frequency category is not greater than uncommon, but might be lower.
A precise frequency estimation is not possible as the side effect did not occur in a

clinical trial database of 2,762 patients with Parkinson's Disease treated with
Pramipexole is commonly associated with somnolence and has been associated
uncommonly with excessive daytime somnolence and sudden sleep onset episodes
(see also section 4.4).
Libido disorders
Pramipexole may uncommonly be associated with libido disorders (increased or
Impulse control disorders
Pathological gambling, increased libido, hypersexuality, compulsive spending or
buying, binge eating and compulsive eating can occur in patients treated with
dopamine agonists including pramipexole. (See section 4.4).
In a cross-sectional, retrospective screening and case-control study including 3,090
Parkinson's disease patients, 13.6% of all patients receiving dopaminergic or nondopaminergic 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.
Cardiac failure
In clinical studies and post-marketing experience cardiac failure has been reported in
patients with
pramipexole. In a pharmacoepidemiological study pramipexole use was associated
with an increased risk of
cardiac failure compared with non-use of pramipexole (observed risk ratio 1.86; 95%
CI, 1.21-2.85).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at:


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.




Pharmacodynamic properties
Pharmacotherapeutic group: anti-Parkinson drugs, dopamine agonists, ATC code:
Mechanism of action
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 D3
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.
Pharmacodynamic effects
In human volunteers, a dose-dependent decrease in prolactin was observed. In a
clinical trial with healthy volunteers, where pramipexole prolonged-release tablets
were titrated faster (every 3 days) than recommended up to 3.15 mg pramipexole base
(4.5 mg of salt) per day, an increase in blood pressure and heart rate was observed.
Such effect was not observed in patient studies.
Clinical efficacy and safety in Parkinson’s disease
In patients pramipexole alleviates signs and symptoms of idiopathic Parkinson's
disease. Placebo-controlled clinical trials included approximately 1,800 patients of
Hoehn and Yahr stages I – V treated with pramipexole. Out of these, approximately
1,000 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 controlled
clinical trials was maintained for approximately six months. In open continuation
trials lasting for more than three years there were no signs of decreasing efficacy.

In a controlled double blind clinical trial of 2 year duration, initial treatment with
pramipexole significantly delayed the onset of motor complications, and reduced their
occurrence compared to initial treatment with levodopa. This delay in motor
complications with pramipexole should be balanced against a greater improvement in
motor function with levodopa (as measured by the mean change in UPDRS-score).
The overall incidence of hallucinations and somnolence was generally higher in the
escalation phase with the pramipexole group. However, there was no significant
difference during the maintenance phase. These points should be considered when
initiating pramipexole treatment in patients with Parkinson's disease.
The safety and efficacy of pramipexole prolonged-release tablets in the treatment of
Parkinson's disease was evaluated in a multinational drug development program
consisting of three randomised, controlled trials. Two trials were conducted in
patients with early Parkinson's disease and one trial was conducted in patients with
advanced Parkinson's disease.
Superiority of pramipexole prolonged-release tablets over placebo was demonstrated
after 18 weeks of treatment on both the primary (UPDRS Parts II+III score) and the
key secondary (CGI-I and PGI-I responder rates) efficacy endpoints in a double-blind
placebo-controlled trial including a total of 539 patients with early Parkinson's
disease. Maintenance of efficacy was shown in patients treated for 33 weeks.
Pramipexole prolonged-release tablets were non-inferior to pramipexole immediate
release tablets as assessed on the UPDRS Parts II+III score at week 33.
In a double-blind placebo-controlled trial including a total of 517 patients with
advanced Parkinson's disease who were on concomitant levodopa therapy superiority
of pramipexole prolonged-release tablets over placebo was demonstrated after 18
weeks of treatment on both the primary (UPDRS Parts II+III score) and the key
secondary (off-time) efficacy endpoints.
The efficacy and tolerability of an overnight switch from pramipexole tablets to
pramipexole prolonged-release tablets at the same daily dose were evaluated in a
double-blind clinical study in patients with early Parkinson's disease.
Efficacy was maintained in 87 of 103 patients switched to pramipexole prolongedrelease tablets. Out of these 87 patients, 82.8% did not change their dose, 13.8%
increased and 3.4% decreased their dose.
In half of the 16 patients who did not meet the criterion for maintained efficacy on
UPDRS Part II+III score, the change from baseline was considered not clinically
Only one patient switched to pramipexole prolonged-release tablets experienced a
drug-related adverse event leading to withdrawal.
Paediatric population

The European Medicines Agency has waived the obligation to submit the results of
studies with pramipexole in all subsets of the paediatric population in Parkinson's
Disease (see section 4.2 for information on paediatric use).


Pharmacokinetic properties
Pramipexole is completely absorbed following oral administration. The absolute
bioavailability is greater than 90%.
In a Phase I trial, where pramipexole immediate release and prolonged-release tablets
were assessed in fasted state, the minimum and peak plasma concentration (Cmin,
Cmax) and exposure (AUC) of the same daily dose of pramipexole prolonged-release
tablets given once daily and pramipexole tablets given three times a day were
The once daily administration of pramipexole prolonged-release tablets causes less
frequent fluctuations in the pramipexole plasma concentration over 24 hours
compared to the three times daily administration of pramipexole immediate release
The maximum plasma concentrations occur at about 6 hours after administration of
pramipexole prolonged-release tablets once daily. Steady state of exposure is reached
at the latest after 5 days of continuous dosing.
Concomitant administration with food does generally not affect the bioavailability of
pramipexole. Intake of a high fat meal induced an increase in peak concentration
(Cmax) of about 24% after a single dose administration and about 20% after multiple
dose administrations and a delay of about 2 hours in time to reach peak concentration
in healthy volunteers. Total exposure (AUC) was not affected by concomitant food
intake. The increase in Cmax is not considered clinically relevant. In the Phase III
studies that established safety and efficacy of pramipexole prolonged-release tablets,
patients were instructed to take study medication without regard to food intake.
While body weight has no impact on the AUC, it was found to influence the volume
of distribution and therefore the peak concentrations Cmax. A decreased body weight
by 30 kg results in an increase in Cmax of 45%. However, in Phase III trials in
Parkinson's disease patients no clinically meaningful influence of body weight on the
therapeutic effect and tolerability of pramipexole prolonged-release tablets was
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 14C-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.


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
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.




List of excipients
Calcium hydrogen phosphate, anhydrous
Magnesium stearate
Silica, colloidal anhydrous


Not applicable.


Shelf life


Special precautions for storage
This medicinal product does not require any special storage conditions.


Nature and contents of container
Blister Al/OPA-Al-PVC: 10, 30 and 100 prolonged-release tablets.
Not all pack sizes may be marketed.


Special precautions for disposal
No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.


Ethypharm UK Ltd.
Goldvale House,
27-41 Church Street West,
Woking, Surrey,
GU21 6DH United Kingdom


PL 42623/0054





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Source: Medicines and Healthcare Products Regulatory Agency

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