Pipexus 3,15 mg Depottablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

22-04-2018

Produktens egenskaper Produktens egenskaper (SPC)

22-04-2018

Aktiva substanser:
pramipexoldihydrokloridmonohydrat
Tillgänglig från:
Ethypharm
ATC-kod:
N04BC05
INN (International namn):
dihydrochloride monohydrate
Dos:
3,15 mg
Läkemedelsform:
Depottablett
Sammansättning:
pramipexoldihydrokloridmonohydrat 4,5 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 10 tabletter; Blister, 30 tabletter; Blister, 100 tabletter
Bemyndigande status:
Avregistrerad
Godkännandenummer:
53466
Tillstånd datum:
2016-09-08

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

28-01-2020

Produktens egenskaper Produktens egenskaper - engelska

21-12-2017

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

08-09-2016

Läs hela dokumentet

Package leaflet: Information for the user

Pipexus 0.26 mg prolonged-release tablets

Pipexus 0.52 mg prolonged-release tablets

Pipexus 1.05 mg prolonged-release tablets

Pipexus 1.57 mg prolonged-release tablets

Pipexus 2.1 mg prolonged-release tablets

Pipexus 2.62 mg prolonged-release tablets

Pipexus 3.15 mg prolonged-release tablets

pramipexole

Read all of this leaflet carefully before you start taking this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor, pharmacist or nurse .

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if

their signs of illness are the same as yours.

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side

effects not listed in this leaflet. See section 4

What is in this leaflet

What Pipexus is and what it is used for

What you need to know before you take Pipexus

How to take Pipexus

Possible side effects

How to store Pipexus

Contents of the pack and other information

1.

What Pipexus

is and what it is used for

Pipexus contains the active substance pramipexole and belongs to a group of medicines known as dopamine

agonists, which stimulate dopamine receptors in the brain. Stimulation of the dopamine receptors triggers

nerve impulses in the brain that help to control body movements.

Pipexus is used to treat the symptoms of primary Parkinson’s disease in adults. It can be used alone or in

combination with levodopa (another medicine for Parkinson’s disease).

2.

What you need to know before you take Pipexus

Do not take Pipexus

if you are allergic to pramipexole or to any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Talk to your doctor before taking Pipexus. Tell your doctor if you have (had) or develop any medical

conditions or symptoms, especially any of the following:

Kidney disease.

Hallucinations (seeing, hearing or feeling things that are not there). Most hallucinations are visual.

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 up-titration of Pipexus.

Dystonia (inability of keeping your body and neck straight and upright (axial dystonia)). In particular,

you may experience forward flexion of the head and neck (also called antecollis), forward bending of the

lower back (also called camptocormia) or sidewards bending of the back (also called pleurothotonus or

Pisa Syndrome). If this happens, your doctor may want to change your medication.

Sleepiness and episodes of suddenly falling asleep.

Psychosis (e.g. comparable with symptoms of schizophrenia).

Vision impairment. You should have regular eye examinations during treatment with Pipexus.

Severe heart or blood vessels disease. You will need to have your blood pressure checked regularly,

especially at the beginning of treatment. This is to avoid postural hypotension (a fall in blood pressure on

standing up).

Tell your doctor if you or your family/carer notices that you are developing urges or cravings to behave in

ways that are unusual for you and you cannot resist the impulse, drive or temptation to carry out certain

activities that could harm yourself or others. These are called impulse control disorders and can include

behaviours such as addictive gambling, excessive eating or spending, an abnormally high sex drive or

preoccupation with an increase in sexual thoughts or feelings. Your doctor may need to adjust or stop your

dose.

Tell your doctor if you or your family/carer notices that you are developing mania (agitation, feeling elated

or over-excited) or delirium (decreased awareness, confusion, loss of reality). Your doctor may need to

adjust or stop your dose.

Tell your doctor if you experience symptoms such as depression, apathy, anxiety, fatigue, sweating or pain

after stopping or reducing your Pipexus treatment. If the problems persist more than a few weeks, your

doctor may need to adjust your treatment.

Pipexus prolonged-release tablets is a specially designed tablet from which the active ingredient is gradually

released, once the tablet has been ingested. Parts of tablets may occasionally be passed and seen in the stool

(faeces) and may look like whole tablets. Inform your doctor if you find tablet pieces in your faeces.

Children and adolescents

Pipexus is not recommended for use in children or adolescents under 18 years.

Other medicines and Pipexus

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This

includes

medicines,

herbal

remedies,

health

foods

supplements

that

have

obtained

without

prescription.

You should avoid taking Pipexus together with antipsychotic medicines.

Take care if you are taking the following medicines:

cimetidine (to treat excess stomach acid and stomach ulcers);

amantadine (which can be used to treat Parkinson’s disease);

mexiletine (to treat irregular heartbeats, a condition known as ventricular arrhythmia);

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).

If you are taking levodopa, the dose of levodopa is recommended to be reduced when you start treatment

with Pipexus.

Take care if you are using any medicines that calm you down (have a sedative effect) or if you are drinking

alcohol. In these cases Pipexus may affect your ability to drive and operate machinery.

Pipexus with food, drink and alcohol

You should be cautious while drinking alcohol during treatment with Pipexus.

Pipexus can be taken with or without food.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your

doctor or pharmacist for advice before taking this medicine. Your doctor will then discuss with you if you

should continue to take Pipexus.

The effect of Pipexus on the unborn child is not known. Therefore, do not take Pipexus if you are pregnant

unless your doctor tells you to do so.

Pipexus should not be used during breast-feeding. Pipexus can reduce the production of breast milk. Also, it

can pass into the breast milk and can reach your baby. If use of Pipexus is unavoidable, breast-feeding

should be stopped.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Pipexus can cause hallucinations (seeing, hearing or feeling things that are not there). If affected, do not

drive or use machines.

Pipexus has been associated with sleepiness and episodes of suddenly falling asleep, particularly in patients

with Parkinson’s disease. If you experience these side effects, you must not drive or operate machinery. You

should tell your doctor if this occurs.

3.

How to take Pipexus

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or

pharmacist if you are not sure. The doctor will advise you on the right dosing.

Take Pipexus prolonged-release tablets only once a day and each day at about the same time.

You can take Pipexus with or without food. Swallow the tablets whole with water.

Do not chew, divide or crush the prolonged-release tablets.

If you do, there is a danger you could overdose, because

the medicine may be released into your body too quickly.

During the first week, the usual daily dose is 0.26 mg pramipexole. The dose will be increased every 5-7

days as directed by your doctor until your symptoms are controlled (maintenance dose).

Ascending dose schedule of Pipexus prolonged-release tablets

Week

Daily dose (mg)

Number of tablets

0.26

One Pipexus 0.26 mg prolonged-release tablet.

0.52

One Pipexus 0.52 mg prolonged-release tablet,

two Pipexus 0.26 mg prolonged-release tablets.

1.05

One Pipexus 1.05 mg prolonged-release tablet,

two Pipexus 0.52 mg prolonged-release tablets,

four Pipexus 0.26 mg prolonged-release tablets.

The usual maintenance dose is 1.05 mg per day. However, your dose may have to be increased even further.

If necessary, your doctor may increase your dose up to a maximum of 3.15 mg of pramipexole a day. A

lower maintenance dose of one Pipexus 0.26 mg prolonged-release tablet a day is also possible.

Patients with kidney disease

If you have kidney disease, your doctor may advise you to take the usual starting dose of 0.26 mg prolonged-

release tablets only every other day for the first week. After that, your doctor may increase the dosing

frequency to one 0.26 mg prolonged-release tablet every day. If a further dose increase is necessary, your

doctor may adjust it in steps of 0.26 mg pramipexole.

If you have serious kidney problems, your doctor may need to switch you to a different pramipexole

medicine. If during treatment your kidney problems get worse, you should contact your doctor as soon as

possible.

If you are switching from

pramipexole (immediate release) tablets

Your doctor will base your dose of pramipexole prolonged-release tablets on the dose of pramipexole

(immediate release) tablets you were taking.

Take your pramipexole (immediate release) tablets as normal the day before you switch. Then take your

pramipexole prolonged-release tablets next morning and do not take any more pramipexole (immediate

release) tablets.

If you take more Pipexus than you should

If you accidentally take too many tablets,

Contact your doctor or nearest hospital casualty department immediately for advice.

You may experience vomiting, restlessness, or any of the side effects as described in Section 4 “Possible

side effects”.

If you forget to take Pipexus

If you forget to take a dose of Pipexus, but remember within 12 hours of your usual time, take your tablet

straight away and then take your next tablet at the usual time.

If you forget for more than 12 hours, simply take the next single dose at the usual time. Do not take a double

dose to make up for a forgotten tablet dose.

If you stop taking Pipexus

Do not stop taking Pipexus without first talking to your doctor. If you have to stop taking this medicine, your

doctor will reduce the dose gradually. This reduces the risk of worsening symptoms.

If you suffer from Parkinson’s disease you should not stop treatment with Pipexus abruptly. A sudden stop

could cause you to develop a medical condition called neuroleptic malignant syndrome which may represent

a major health risk. The symptoms include:

akinesia (loss of muscle movement),

rigid muscles,

fever,

unstable blood pressure,

tachycardia (increased heart rate),

confusion,

depressed level of consciousness (e.g. coma).

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Evaluation of

these side effects is based on the following frequencies:

Very common

may affect more than 1 in 10 people

Common

may affect up to 1 in 10 people

Uncommon

may affect up to 1 in 100 people

Rare

may affect up to 1 in 1,000 people

Very rare

may affect up to 1 in 10,000 people

Not known

Frequency cannot be estimated from the available data

You may experience the following side effects:

Very common:

Dyskinesia (e.g. abnormal, uncontrolled movements 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 of 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 suddenly falling asleep

Amnesia (memory disturbance)

Hyperkinesia (increased movements and inability to keep still)

Weight increase

Allergic reactions (e.g. rash, itching, hypersensitivity)

Fainting

Cardiac failure (heart problems which can cause shortness of breath or ankle swelling)*

Inappropriate antidiuretic hormone secretion*

Restlessness

Dyspnoea (difficulties to breathe)

Hiccups

Pneumonia (infection of the lungs)

Inability to resist the impulse, drive or temptation to perform an action that could be harmful to you or

others, which may include:

Strong impulse to gamble excessively despite serious personal or family consequences.

Altered or increased sexual interest and behaviour of significant concern to you or to others, for

example, an increased sexual drive.

Uncontrollable excessive shopping or spending

Binge eating (eating large amounts of food in a short time period) or compulsive eating (eating more

food than normal and more than is needed to satisfy your hunger)*

Delirium (decreased awareness, confusion, loss of reality)

Rare:

Mania (agitation, feeling elated or over-excited)

Not known:

- After stopping or reducing your Pipexus treatment: Depression, apathy, anxiety, fatigue, sweating or pain

may occur (called dopamine agonist withdrawal syndrome or DAWS).

Tell your doctor if you experience any of these behaviours; he will discuss ways of managing or

reducing the symptoms.

For the side effects marked with * a precise frequency estimation is not possible, since these side effects

were not observed in clinical studies among 2,762 patients treated with pramipexole. The frequency category

is probably not greater than “uncommon”.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects

not listed in this leaflet.

You can also report side effects directly via the national reporting system listed in [To be completed

nationally]. By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Pipexus

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister and carton after EXP. The expiry

date refers to the last day of that month.

This medicine does not require any special temperature storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw

away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Pipexus prolonged-release tablets contains

The active substance is pramipexole.

Each tablet contains 0.26 mg, 0.52 mg, 1.05 mg, 1.57 mg, 2.1 mg, 2.62 mg, or 3.15 mg pramipexole as 0.375

mg, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg, or 4.5 mg pramipexole dihydrochloride monohydrate,

respectively.

The other excipient(s) are hypromellose, anhydrous calcium hydrogen phosphate, magnesium stearate and

colloidal anhydrous silica.

What Pipexus prolonged-release tablets looks like and contents of the pack

Pipexus 0.26 mg prolonged-release tablets: The round tablets of 9 mm diameter are white or nearly white,

have a flat surface with bevelled edges and are marked with 026 on one side

Pipexus 0.52 mg prolonged-release tablets: The round tablets of 10 mm diameter are white or nearly white,

biconvex and are marked with 052 on one side

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

Pipexus 1.57 mg prolonged-release tablets: The round tablets of 10 mm diameter are white or nearly white,

biconvex and are marked with 157 on one side

Pipexus 2.1 mg prolonged-release tablets: The round tablets of 10 mm diameter are white or nearly white,

biconvex and are marked with 210 on one side

Pipexus 2.62 mg prolonged-release tablets: The round tablets of 10 mm diameter are white or nearly white,

biconvex and are marked with 262 on one side

Pipexus 3.15 mg prolonged-release tablets: The round tablets of 11 mm diameter are white or nearly white,

have a flat surface with bevelled edges and are marked with 315 on one side

Pipexus is available in packs containing 10, 30 and 100 prolonged-release tablets in aluminium blisters.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

[To be completed nationally]

This medicinal product is authorised in the Member States of the EEA under the following names:

[To be completed nationally]

This leaflet was last revised in 19 December 2019

[To be completed nationally]

Läs hela dokumentet

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Pipexus 0.26 mg prolonged-release tablets

Pipexus 0.52 mg prolonged-release tablets

Pipexus 1.05 mg prolonged-release tablets

Pipexus 1.57 mg prolonged-release tablets

Pipexus 2.1 mg prolonged-release tablets

Pipexus 2.62 mg prolonged-release tablets

Pipexus 3.15 mg prolonged-release tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Pipexus 0.26 mg prolonged-release tablets

Each prolonged-release tablet contains 0.375 mg pramipexole dihydrochloride monohydrate equivalent to

0.26 mg pramipexole.

Pipexus 0.52 mg prolonged-release tablets

Each prolonged-release tablet contains 0.75 mg pramipexole dihydrochloride monohydrate equivalent to

0.52 mg pramipexole.

Pipexus 1.05 mg prolonged-release tablets

Each prolonged-release tablet contains 1.5 mg pramipexole dihydrochloride monohydrate equivalent to 1.05

mg pramipexole.

Pipexus 1.57 mg prolonged-release tablets

Each prolonged-release tablet contains 2.25 mg pramipexole dihydrochloride monohydrate equivalent to

1.57 mg pramipexole.

Pipexus 2.10 mg prolonged-release tablets

Each prolonged-release tablet contains 3 mg pramipexole dihydrochloride monohydrate equivalent to 2.1 mg

pramipexole.

Pipexus 2.62 mg prolonged-release tablets

Each prolonged-release tablet contains 3.75 mg pramipexole dihydrochloride monohydrate equivalent to

2.62 mg pramipexole.

Pipexus 3.15 mg prolonged-release tablets

Each prolonged-release tablet contains 4.5 mg pramipexole dihydrochloride monohydrate equivalent to 3.15

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.

3.

PHARMACEUTICAL FORM

Prolonged-release tablet.

Pipexus 0.26 mg prolonged-release tablets

The round tablets of 9 mm diameter are white or nearly white, have a flat surface with bevelled edges and

are marked with 026 on one side

Pipexus 0.52 mg prolonged-release tablets

The round tablets of 10 mm diameter are white or nearly white, biconvex and are marked with 052 on one

side

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

Pipexus 1.57 mg prolonged-release tablets

The round tablets of 10 mm diameter are white or nearly white, biconvex and are marked with 157 on one

side

Pipexus 2.10 mg prolonged-release tablets

The round tablets of 10 mm diameter are white or nearly white, biconvex and are marked with 210 on one

side

Pipexus 2.62 mg prolonged-release tablets

The round tablets of 10 mm diameter are white or nearly white, biconvex and are marked with 262 on one

side

Pipexus 3.15 mg prolonged-release tablets

The round tablets of 11 mm diameter are white or nearly white, have a flat surface with bevelled edges and

are marked with 315 on one side

4.

CLINICAL PARTICULARS

4.1

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).

4.2

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

Week

Daily dose (mg of base)

Daily dose (mg of salt)

0.26

0.375

0.52

0.75

1.05

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 prolonged-release 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).

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.

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 investigated.

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 for the indication of 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.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4

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

Hallucinations are known as a side effect 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, 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

athological 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).

Dopamine agonist withdrawal syndrome

To discontinue treatment in patients with Parkinson’s disease, pramipexole should be tapered off (see

section 4.2). Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists

including pramipexole. Symptoms include apathy, anxiety, depression, fatigue, sweating and pain, which

may be severe. Patients should be informed about this before tapering the dopamine agonist and monitored

regularly thereafter. In case of persistent symptoms, it may be necessary to increase the pramipexole dose

temporarily (see section 4.8).

Remnants in stool

Some patients have reported the occurrence of remnants in faeces which may resemble intact pramipexole

prolonged-release tablets. If patients report such an observation, the physician should reassess patient’s

response to therapy.

4.5

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 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 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.

4.6

Fertility, pregnancy and lactation

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). Pipexus

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, Pipexus

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.

4.7

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).

4.8

Undesirable effects

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 reaction.

The majority of adverse drug reactions usually start early in therapy and most tended to disappear even as

therapy is 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 (<

1/10,000); not known (cannot be estimated from the available data).

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

Uncommon

pneumonia

Endocrine disorders

Uncommon

inappropriate antidiuretic hormone secretion

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, delirium

Rare

mania

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

Cardiac disorders

Uncommon

cardiac failure

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

Not Known

dopamine agonist withdrawal syndrome including apathy, anxiety,

depression, fatigue, sweating and pain.

Investigations

Common

weight decrease including decreased appetite

Uncommon

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.

Description of selected adverse reactions

Somnolence

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 decreased).

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 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.

Dopamine agonist withdrawal syndrome

Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists including

pramipexole. Symptoms include apathy, anxiety, depression, fatigue, sweating and pain (see section

4.4).

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 national reporting system listed in [to be completed

nationally]

4.9

Overdose

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.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: anti-Parkinson drugs, dopamine agonists, ATC code: N04BC05.

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 prolonged-release 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 relevant.

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).

5.2

Pharmacokinetic properties

Absorption

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 (C

) 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 equivalent.

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 tablets.

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 (C

) 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 C

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 C

. A decreased body weight by 30 kg results in an increase in C

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 detected.

Pramipexole shows linear kinetics and a small inter-patient variation of plasma levels.

Distribution

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).

Biotransformation

Pramipexole is metabolised in man only to a small extent.

Elimination

Renal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of

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.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Hypromellose

Calcium hydrogen phosphate, anhydrous

Magnesium stearate

Silica, colloidal anhydrous

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years

6.4

Special precautions for storage

This medicinal product does not require any special temperature storage conditions.

6.5

Nature and contents of container

Blister Al/OPA-Al-PVC: 10, 30 and 100 prolonged-release tablets.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7.

MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8.

MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: {DD month YYYY}>

[To be completed nationally]

10.

DATE OF REVISION OF THE TEXT

21 December 2017

Detailed information on this medicinal product is available on the website of {name of MS/Agency}

Liknande Produkter

Sök varningar relaterade till denna produkt

Visa dokumenthistorik

Dela den här informationen