Pipexus 1.05mg modified-release tablets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Pramipexole dihydrochloride monohydrate
Available from:
Ethypharm UK Ltd
ATC code:
N04BC05
INN (International Name):
Pramipexole dihydrochloride monohydrate
Dosage:
1.05mg
Pharmaceutical form:
Modified-release tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 04090100; GTIN: 5060078670029
Authorization number:
PL 42623/0052; PL 42623/0053; PL 42623/0054; PL 42623/0055; PL 42623/0056; PL 42623/0057; PL 42623/0058

Read the complete document

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

2. What you need to know before you take Pipexus

3. How to take Pipexus

4. Possible side effects

5. How to store Pipexus

6. 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.

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 or supplements that you have obtained

without a 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.

INFORMATION FOR THE USER

Continued over page

Pipexus

®

0.26 mg prolonged-release tablets

Pipexus

®

1.05 mg prolonged-release tablets

Pipexus

®

2.1 mg prolonged-release tablets

Pipexus

®

3.15 mg prolonged-release tablets

Pipexus

®

0.52 mg prolonged-release tablets

Pipexus

®

1.57 mg prolonged-release tablets

Pipexus

®

2.62 mg prolonged-release tablet

pramipexole

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 Yellow Card Scheme

at www.mhra.gov.uk/yellowcard. 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

Ethypharm UK Ltd. Goldvale House, 27-41 Church Street West,

Woking, Surrey, GU21 6DH, United Kingdom

Telephone: (01483) 726929 Fax: (01483) 720307

Email: enquiries@medinformation.co.uk

Manufacturer

Ferrer Internacional, S.A. Joan Buscallà,

1-9 Sant Cugat del Vallès, 08173, Spain

Laboratorios Normon, S.A. Ronda de Valdecarrizo, 6,

Tres Cantos, Madrid 28760, Spain

This leaflet was last revised in September 2017

Pipexus (pramipexole) PIL - UK

Dimensions: 170mm x 330mm

Proof Date: 13/09/17

4-ET1-PRPR2GB/2

Read the complete document

Object 1

Pipexus prolonged-release tablets

Summary of Product Characteristics Updated 28-Dec-2017 | Ethypharm UK Ltd

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 2.10 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

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).

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 tend 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 Yellow Card Scheme at

www.mhra.gov.uk/yellowcard.

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

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

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

3years

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 and other handling

No special requirements.

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

requirements.

7. Marketing authorisation holder

Ethypharm UK Ltd.

Goldvale House,

27-41 Church Street West,

Woking, Surrey,

GU21 6DH

United Kingdom

Telephone: (01483) 726929

Fax: (01483) 720307

Email: [email

protected]

8. Marketing authorisation number(s)

Pipexus 0.26 mg prolonged-release tablets

PL 42623/0052

Pipexus 0.52 mg prolonged-release tablets

PL 42623/0053

Pipexus 1.05 mg prolonged-release tablets

PL 42623/0054

Pipexus 1.57 mg prolonged-release tablets

PL 42623/0055

Pipexus 2.10 mg prolonged-release tablets

PL 42623/0056

Pipexus 2.62 mg prolonged-release tablets

PL 42623/0057

Pipexus 3.15 mg prolonged-release tablets

PL 42623/0058

9. Date of first authorisation/renewal of the authorisation

18/07/2016

10. Date of revision of the text

November 2017

Company Contact Details

Ethypharm UK Ltd

Address

Building A2, Glory Park Avenue, Wooburn Green, High Wycombe, Buckinghamshire, HP10 0DF, UK

Telephone

+44 (0) 1277 266 600

http://ethypharm.co.uk/

Medical Information e-mail

[email

protected]

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