Levodopa/Carbidopa/Entacapone Mylan 150 mg/37,5 mg/200 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

21-04-2018

Produktens egenskaper Produktens egenskaper (SPC)

21-04-2018

Aktiva substanser:
entakapon; karbidopa (vattenfri); levodopa
Tillgänglig från:
Mylan AB
ATC-kod:
N04BA03
INN (International namn):
entacapone; carbidopa (anhydrous); levodopa
Dos:
150 mg/37,5 mg/200 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
karbidopa (vattenfri) 37,5 mg Aktiv substans; levodopa 150 mg Aktiv substans; entakapon 200 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 30 tabletter (Al); Blister, 100 tabletter (Al); Blister, 30 tabletter (plast/Al); Blister, 100 tabletter (plast/Al); Burk, 30 tabletter; Burk, 175 tabletter; Burk, 100 tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
53651
Tillstånd datum:
2017-02-13

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

06-11-2020

Produktens egenskaper Produktens egenskaper - engelska

13-12-2016

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

20-02-2017

Läs hela dokumentet

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PACKAGE LEAFLET

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Package leaflet: Information for the patient

Levodopa/Carbidopa/Entacapone Mylan50 mg/12.5 mg/200 mg film-coated tablets

Levodopa/Carbidopa/Entacapone Mylan 75 mg/18.75 mg/200 mg film-coated tablets

Levodopa/Carbidopa/Entacapone Mylan 100 mg/25 mg/200 mg film-coated tablets

Levodopa/Carbidopa/Entacapone Mylan 125 mg/31.25 mg/200 mg film-coated tablets

Levodopa/Carbidopa/Entacapone Mylan 150 mg/37.5 mg/200 mg film-coated tablets

Levodopa/Carbidopa/Entacapone Mylan 200 mg/50 mg/200 mg film-coated tablets

levodopa/carbidopa/entacapone

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 or pharmacist.

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 or pharmacist. This includes any possible side effects

not listed in this leaflet. See section 4.

What is in this leaflet

What Levodopa/Carbidopa/Entacapone Mylan is and what it is used for

What you need to know before you take Levodopa/Carbidopa/Entacapone Mylan

How to take Levodopa/Carbidopa/Entacapone Mylan

Possible side effects

How to store Levodopa/Carbidopa/Entacapone Mylan

Contents of the pack and other information

1.

What Levodopa/Carbidopa/Entacapone Mylan is and what it is used for

Levodopa/Carbidopa/Entacapone Mylan contains three active substances (levodopa, carbidopa and

entacapone) in one film-coated tablet. Levodopa/Carbidopa/Entacapone Mylan is used for the treatment

of Parkinson’s disease.

Parkinson’s disease is caused by low levels of a substance called dopamine in the brain. Levodopa

increases the amount of dopamine and hence reduces the symptoms of Parkinson’s disease. Carbidopa

and entacapone improve the antiparkinson effects of levodopa.

2.

What you need to know before you take Levodopa/Carbidopa/Entacapone Mylan

Do not take Levodopa/Carbidopa/Entacapone Mylan if you

are allergic to levodopa, carbidopa or entacapone, or any of the other ingredients of this medicine

(listed in section 6)

have narrow-angle glaucoma (an eye disorder)

have a tumour of the adrenal gland

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are taking certain medicines for treating depression (combinations of selective MAO-A and MAO-B

inhibitors, or non-selective MAO-inhibitors)

have ever had neuroleptic malignant syndrome (NMS – this is a rare reaction to medicines used to

treat severe mental disorders)

have ever had non-traumatic rhabdomyolysis (a rare muscle disorder)

have a severe liver disease.

Warnings and precautions

Talk to your doctor or pharmacist before taking Levodopa/Carbidopa/Entacapone Mylan if you have or

have ever had:

a heart attack or any other diseases of the heart including cardiac arrhythmias, or of the blood vessels

asthma or any other disease of the lungs

a liver problem, because your dose may need to be adjusted

kidney or hormone-related diseases

stomach ulcers or convulsions

if you experience prolonged diarrhoea consult your doctor as it may be a sign of inflammation of the

colon

any form of severe mental disorder like psychosis

chronic wide-angle glaucoma, because your dose may need to be adjusted and the pressure in your

eyes may need to be monitored.

Consult your doctor if you are currently taking:

antipsychotics (medicines used to treat psychosis)

a medicine which may cause low blood pressure when rising from a chair or bed. You should be

aware that Levodopa/Carbidopa/Entacapone Mylan

may make these reactions worse.

Consult your doctor if during the treatment with Levodopa/Carbidopa/Entacapone Mylan you:

notice that your muscles get very rigid or jerk violently, or if you get tremors, agitation, confusion,

fever, rapid pulse, or wide fluctuations in your blood pressure. If any of this happens,

contact your

doctor immediately

feel depressed, have suicidal thoughts, or notice unusual changes in your behaviour

find yourself suddenly falling asleep, or if you feel very drowsy. If this happens, you should not

drive or use any tools or machines (see also section ‘Driving and using machines’)

notice that uncontrolled movements begin or get worse after you started to take

Levodopa/Carbidopa/Entacapone Mylan. If this happens, your doctor may need to change the dose

of your antiparkinson medicine

experience diarrhoea: monitoring of your weight is recommended in order to avoid potentially

excessive weight loss

experience progressive loss of appetite, asthenia (weakness, exhaustion) and weight decrease within

a relatively short period of time. If this happens, a general medical evaluation including liver

function should be considered

feel the need to stop taking Levodopa/Carbidopa/Entacapone Mylan, see section “If you stop taking

Levodopa/Carbidopa/Entacapone Mylan”.

Tell your doctor if you or your family/carer notices you are developing addiction-like symptoms leading

to craving for large doses of Levodopa/Carbidopa/Entacapone Mylan and other medicines used to treat

Parkinson’s disease.

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

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

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

can include addictive gambling, excessive eating or spending, an abnormally high sex drive or a

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

treatments.

Your doctor may take some regular blood or urine tests during a long term treatment with

Levodopa/Carbidopa/Entacapone Mylan.

If you for some other reason have a urine test, tell your doctor or nurse that you are taking

Levodopa/Carbidopa/Entacapone Mylan, as this medicine may affect the results in the test.

If you must undergo surgery, tell your doctor that you are taking Levodopa/Carbidopa/Entacapone Mylan.

Levodopa/Carbidopa/Entacapone Mylan is not recommended to be used for treatment of extrapyramidal

symptoms (e.g. involuntary movements, shaking, muscle rigidity and muscle contractions) caused by

other medicines.

Children and adolescents

Experience with levodopa/carbidopa/entacapone in patients under 18 years is limited. Therefore, the use

of Levodopa/Carbidopa/Entacapone Mylan in children is not recommended.

Other medicines and Levodopa/Carbidopa/Entacapone Mylan

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

Do not take Levodopa/Carbidopa/Entacapone Mylan if you are taking certain medicines for treating

depression (combinations of selective MAO-A and MAO-B inhibitors, or non-selective MAO inhibitors).

Levodopa/Carbidopa/Entacapone Mylan may increase the effects and side effects of certain medicines.

These include:

medicines used to treat depression such as moclobemide, amitriptyline, desipramine, maprotiline,

venlafaxine and paroxetine

rimiterol and isoprenaline, used to treat respiratory diseases

adrenaline, used for severe allergic reactions

noradrenaline, dopamine and dobutamine, used to treat heart diseases and low blood pressure

warfarin, used to prevent blood clots

medicines used to treat high blood pressure such as alpha-methyldopa

apomorphine, which is used to treat Parkinson’s disease.

The effects of Levodopa/Carbidopa/Entacapone Mylan may be weakened by certain medicines. These

include:

dopamine antagonists used to treat mental disorders, nausea and vomiting

phenytoin, used to prevent convulsions

papaverine used to relax the muscles.

Levodopa/Carbidopa/Entacapone Mylan may make it harder for you to digest iron. Therefore, do not take

Levodopa/Carbidopa/Entacapone Mylan and iron supplements at the same time. After taking one of them,

wait at least 2 to 3 hours before taking the other.

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Levodopa/Carbidopa/Entacapone Mylan with food and drink

Levodopa/Carbidopa/Entacapone Mylan may be taken with or without food. For some patients,

Levodopa/Carbidopa/Entacapone Mylan may not be well absorbed if it is taken with, or shortly after

eating protein-rich food (such as meats, fish, dairy products, seeds and nuts). Consult your doctor if you

think this applies to you.

Pregnancy, breast-feeding and fertility

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.

You should not breast-feed during treatment with Levodopa/Carbidopa/Entacapone Mylan.

Driving and using machines

Levodopa/Carbidopa/Entacapone Mylan may lower your blood pressure, which may make you feel light-

headed or dizzy. Therefore, be particularly careful when you drive or when you use any tools or

machines.

If you feel very drowsy, or if you sometimes find yourself suddenly falling asleep, wait until you feel

fully awake again before driving or doing anything else that requires you to be alert. Otherwise, you may

put yourself and others at risk of serious injury or death.

Levodopa/Carbidopa/Entacapone Mylan contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-

free’.

3.

How to take Levodopa/Carbidopa/Entacapone Mylan

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

pharmacist if you are not sure.

For adults and elderly people:

Your doctor will tell you exactly how many tablets of Levodopa/Carbidopa/Entacapone Mylan to

take each day.

The tablets are not intended to be split or broken into smaller pieces.

You should take only one tablet each time. You can take the tablet with or without food.

Depending on how you respond to treatment, your doctor may suggest a higher or lower dose.

If you are taking Levodopa/Carbidopa/Entacapone Mylan 50 mg/12.5 mg/200 mg, 75 mg/18.75

mg/200 mg, 100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg or 150 mg/37.5 mg/200 mg tablets,

do not take more than 10 tablets per day.

If you are taking Levodopa/Carbidopa/Entacapone Mylan 200 mg/50 mg/200 mg tablets, do not take

more than 7 tablets per day.

Talk to your doctor or pharmacist if you think the effect of Levodopa/Carbidopa/Entacapone Mylan

is too

strong or too weak, or if you experience possible side effects.

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[For member states where 75 mg/18.75 mg/200 mg, 125 mg/31.25 mg/200 mg or 200 mg/50 mg/200 mg

strengths are not registered:]

<Other strengths may be more appropriate from other levodopa/carbidopa/entacapone products.>

If you take more Levodopa/Carbidopa/Entacapone Mylan than you should

If you have accidentally taken more Levodopa/Carbidopa/Entacapone Mylan

tablets than you should, talk

to your doctor or pharmacist immediately. In case of an overdose you may feel confused or agitated, your

heart rate may be slower or faster than normal or the colour of your skin, tongue, eyes or urine may

change, your breathing may become abnormal or you may lose consciousness.

If you forget to take Levodopa/Carbidopa/Entacapone Mylan

Do not take a double dose to make up for a forgotten tablet.

If it is more than 1 hour until your next dose:

Take one tablet as soon as you remember, and the next tablet at the normal time.

If it is less than 1 hour until your next dose:

Take a tablet as soon as you remember, wait 1 hour, then take another tablet. After that carry on as

normal.

Always leave at least an hour between Levodopa/Carbidopa/Entacapone Mylan

tablets, to avoid possible

side effects.

If you stop taking Levodopa/Carbidopa/Entacapone Mylan

Do not stop taking Levodopa/Carbidopa/Entacapone Mylan

unless your doctor tells you to. In such a case

your doctor may need to adjust your other antiparkinson medicines, especially levodopa, to give sufficient

control of your symptoms. If you suddenly stop taking Levodopa/Carbidopa/Entacapone Mylan

and other

antiparkinsonian medicines it may result in unwanted side effects.

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

4.

Possible side effects

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

side effects can be relieved by adjusting the dose.

If you during the treatment with Levodopa/Carbidopa/Entacapone Mylan

experience the following

symptoms,

contact your doctor immediately or go to your nearest hospital emergency department

Uncommon (may affect up to 1 in 100 people)

A sudden chest pain with chest tightness and shortness of breath which may move to the neck or

arm. These may be signs of a heart attack.

Rare (may affect up to 1 in 1,000 people)

Convulsions/fits.

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Allergic reaction, the signs may include hives (nettle rash), itching, rash, swelling of your face, lips,

tongue or throat. This may cause difficulties in breathing or swallowing.

Not known (cannot be estimated from the available data)

Suicidal behaviour.

Your muscles get very rigid or jerk violently, you get tremors, agitation, confusion, fever, rapid

pulse, or wide fluctuations in your blood pressure. These can be symptoms of neuroleptic malignant

syndrome (NMS, a rare severe reaction to medicines used to treat disorders of the central nervous

system) or rhabdomyolysis (a rare severe muscle disorder).

Other possible side effects include:

Very common (may affect more than 1 in 10 people)

uncontrolled movements (dyskinesia)

feeling sick (nausea)

harmless reddish-brown discolouration of urine

muscle pain

diarrhoea

Common (may affect up to 1 in 10 people)

light-headedness or fainting due to low blood pressure especially when standing up from sitting or

lying down, high blood pressure

worsening of Parkinson`s symptoms, problems walking, dizziness, drowsiness

changes in your ability to move (on and off phenomenon) which may be caused by changes in the

effect of the medicine

vomiting, abdominal pain and discomfort, heartburn, dry mouth, constipation

inability to sleep, hallucinations, confusion, abnormal dreams (including nightmares), tiredness

mental changes – including problems with memory, anxiety and depression (possibly with thoughts

of suicide)

heart or artery disease events (e.g. chest pain), irregular heart rate or rhythm

more frequent falling

shortness of breath

increased sweating, rash

muscle spasms, swelling of the arms and legs

blurred vision

anaemia

decreased appetite, decreased weight

headache, joint pain

urinary tract infection

weakness

Uncommon (may affect up to 1 in 100 people)

inability to urinate. If serious, contact a doctor or hospital emergency department immediately

bleeding in the gut. You may have pain in the stomach with blood in your stools or dark tar-like

stools

changes in the blood cell count which may result in bleeding, abnormal liver function tests

feeling agitated

psychotic symptoms

colitis (inflammation of the colon)

discolourations other than urine (e.g. skin, nail, hair, sweat)

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swallowing difficulties

general feeling of being unwell

Not known (cannot be estimated from the available data)

feeling sick (nausea), being sick (vomiting), loss of appetite, fever, itchy skin, yellowing of the skin

or whites of the eyes, light coloured stools. These may be signs of serious problems with your liver

itching

craving for large doses of Levodopa/Carbidopa/Entacapone Mylan in excess of that required to

control motor symptoms, known as dopamine dysregulation syndrome. Some patients experience

severe abnormal involuntary movements (dyskinesias), mood swings or other side effects after

taking large doses of levodopa/carbidopa/entacapone.

You may also experience the following side effects:

Inability to resist the impulse to perform an action that could be harmful, 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).

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

reducing the symptoms.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. 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

Appendix V. By reporting side effects you can help provide more information on the safety of this

medicine.

5.

How to store Levodopa/Carbidopa/Entacapone Mylan

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 carton, label and blister after EXP.

The expiry date refers to the last day of that month.

Do not store above 25

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 Levodopa/Carbidopa/Entacapone Mylan contains

The active substances are levodopa, carbidopa and entacapone.

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Each Levodopa/Carbidopa/Entacapone Mylan 50 mg/12.5 mg/200 mg film-coated tablet

contains 50 mg of levodopa, 12.5 mg of carbidopa and 200 mg of entacapone.

Each Levodopa/Carbidopa/Entacapone Mylan 75 mg/18.75 mg/200 mg film-coated tablet

contains 75 mg of levodopa, 18.75 mg of carbidopa and 200 mg of entacapone.

Each Levodopa/Carbidopa/Entacapone Mylan 100 mg/25 mg/200 mg film-coated tablet

contains 100 mg of levodopa, 25 mg of carbidopa and 200 mg of entacapone.

Each Levodopa/Carbidopa/Entacapone Mylan 125 mg/31.25 mg/200 mg film-coated tablet

contains 125 mg of levodopa, 31.25 mg of carbidopa and 200 mg of entacapone.

Each Levodopa/Carbidopa/Entacapone Mylan 150 mg/37.5 mg/200 mg film-coated tablet

contains 150 mg of levodopa, 37.5 mg of carbidopa and 200 mg of entacapone.

Each Levodopa/Carbidopa/Entacapone Mylan 200 mg/50 mg/200 mg film-coated tablet

contains 200 mg of levodopa, 50 mg of carbidopa and 200 mg of entacapone.

The other ingredients are:

Tablet core: cellulose microcrystalline, povidone, magnesium stearate, croscarmellose sodium.

Film-coating: polydextrose, titanium dioxide (E171), hypromellose (E464), macrogol (E1521), iron

oxide red (E172), indigo carmine aluminium lake (E132).

What Levodopa/Carbidopa/Entacapone Mylan looks like and contents of the pack

Levodopa/Carbidopa/Entacapone Mylan 50 mg/12.5 mg/200 mg

A grey-purple film coated, round

shaped, biconvex, bevelled edge tablet debossed with ‘M’ on one side of the tablet and ‘LCE1’ on the

other side.

Levodopa/Carbidopa/Entacapone Mylan 75 mg/18.75 mg/200 mg: A brown-pink film coated, round

shaped, biconvex, bevelled edge tablet debossed with ‘M’ on one side of the tablet and ‘LCE2’ on the

other side.

Levodopa/Carbidopa/Entacapone Mylan 100 mg/25 mg/200 mg: A grey-purple film coated, round

shaped, biconvex, bevelled edge tablet debossed with ‘M’ on one side of the tablet and ‘LCE3’ on the

other side.

Levodopa/Carbidopa/Entacapone Mylan 125 mg/31.25 mg/200 mg: A brown-pink film coated, round

shaped, biconvex, bevelled edge tablet debossed with ‘M’ on one side of the tablet and ‘LCE4’ on the

other side.

Levodopa/Carbidopa/Entacapone Mylan 150 mg/37.5 mg/200 mg: A grey-purple film coated, round

shaped, biconvex, bevelled edge tablet debossed with ‘M’ on one side of the tablet and ‘LCE5’ on the

other side.

Levodopa/Carbidopa/Entacapone Mylan 200 mg/50 mg/200 mg: A grey-purple film coated, round

shaped, biconvex, bevelled edge tablet debossed with ‘M’ on one side of the tablet and ‘LCE7’ on the

other side.

Levodopa/Carbidopa/Entacapone Mylan is available in blister packs of 30 or 100 film-coated tablets.

Levodopa/Carbidopa/Entacapone Mylan is available in bottles with a plastic cap and desiccant of 30, 100

or 175 film-coated tablets. Do not eat the desiccant.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

[To be completed nationally]

Manufacturers

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McDermott Laboratories Limited T/A Gerard Laboratories T/A Mylan Dublin, Unit 35/36 Baldoyle

Industrial Estate, Grange Road, Dublin 13, Ireland.

Mylan Hungary Kft., H-2900 Komarom, Mylan utca 1, Hungary.

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 {MM/YYYY}

[To be completed nationally]30 October 2020

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Levodopa/Carbidopa/Entacapone Mylan 50 mg/12.5 mg/200 mg film-coated tablets

Levodopa/Carbidopa/Entacapone Mylan 75 mg/18.75 mg/200 mg film-coated tablets

Levodopa/Carbidopa/Entacapone Mylan 100 mg/25 mg/200 mg film-coated tablets

Levodopa/Carbidopa/Entacapone Mylan 125 mg/31.25 mg/200 mg film-coated tablets

Levodopa/Carbidopa/Entacapone Mylan 150 mg/37.5 mg/200 mg film-coated tablets

Levodopa/Carbidopa/Entacapone Mylan 200 mg/50 mg/200 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 50 mg of levodopa, 12.5 mg of carbidopa and 200 mg of entacapone.

Each film-coated tablet contains 75 mg of levodopa, 18.75 mg of carbidopa and 200 mg of entacapone.

Each film-coated tablet contains 100 mg of levodopa, 25 mg of carbidopa and 200 mg of entacapone.

Each film-coated tablet contains 125 mg of levodopa, 31.25 mg of carbidopa and 200 mg of entacapone.

Each film-coated tablet contains 150 mg of levodopa, 37.5 mg of carbidopa and 200 mg of entacapone.

Each film-coated tablet contains 200 mg of levodopa, 50 mg of carbidopa and 200 mg of entacapone.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet

A grey-purple film-coated, round shaped, biconvex, bevelled edge tablet debossed with ‘M’ on one side

of the tablet and ‘LCE1’ on the other side, approximately 10.7 mm in diameter.

A brown-pink film-coated, round shaped, biconvex, bevelled edge tablet debossed with ‘M’ on one side

of the tablet and ‘LCE2’ on the other side, approximately 11.1 mm in diameter.

A grey-purple film-coated, round shaped, biconvex, bevelled edge tablet debossed with ‘M’ on one side

of the tablet and ‘LCE3’ on the other side, approximately 11.5 mm in diameter.

A brown-pink film-coated, round shaped, biconvex, bevelled edge tablet debossed with ‘M’ on one side

of the tablet and ‘LCE4’ on the other side, approximately 11.9 mm in diameter.

A grey-purple film-coated, round shaped, biconvex, bevelled edge tablet debossed with ‘M’ on one side

of the tablet and ‘LCE5’ on the other side, approximately 12.4 mm in diameter.

A grey-purple film-coated, round shaped, biconvex, bevelled edge tablet debossed with ‘M’ on one side

of the tablet and ‘LCE7’ on the other side, approximately 12.8 mm in diameter.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Levodopa/Carbidopa/Entacapone Mylan is indicated for the treatment of adult patients with Parkinson’s

disease and end-of-dose motor fluctuations not stabilised on levodopa/dopa decarboxylase (DDC)

inhibitor treatment.

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4.2

Posology and method of administration

[For member states where 75 mg/18.75 mg/200 mg, 125 mg/31.25 mg/200 mg or 200 mg/50 mg/200 mg

strengths are not registered:]

<There is no marketing authorisation for Levodopa/Carbidopa/Entacapone 75 mg/18.75 mg/200 mg, 125

mg/31.25 mg/200 mg or 200 mg/50 mg/200 mg tablets, these presentations may be available from other

levodopa/carbidopa/entacapone products.>

Posology

The optimum daily dose must be determined by careful titration of levodopa in each patient. The daily

dose should be preferably optimised using one of the available tablet strengths (50 mg/12.5 mg/200 mg,

75 mg/18.75 mg/200 mg, 100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg, 150 mg/37.5 mg/200 mg, or

200 mg/50 mg/200 mg levodopa/carbidopa/entacapone).

Patients should be instructed to take only one Levodopa/Carbidopa/Entacapone Mylan tablet per dose

administration. Patients receiving less than 70-100 mg carbidopa a day are more likely to experience

nausea and vomiting. While the experience with total daily dose greater than 200 mg carbidopa is limited,

the maximum recommended daily dose of entacapone is 2,000 mg and therefore the maximum dose is

10 tablets per day for the Levodopa/Carbidopa/Entacapone Mylan strengths of 50 mg/12.5 mg/200 mg,

75 mg/18.75 mg/200 mg, 100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg and 150 mg/37.5 mg/200 mg.

Ten tablets of Levodopa/Carbidopa/Entacapone Mylan 150 mg/37.5 mg/200 mg equals 375 mg of

carbidopa a day. According to this daily carbidopa dose, the maximum recommended daily dose of

Levodopa/Carbidopa/Entacapone Mylan 200 mg/50 mg/200 mg dose is 7 tablets per day.

Usually Levodopa/Carbidopa/Entacapone Mylan is to be used in patients who are currently treated with

corresponding doses of standard release levodopa/DDC inhibitor and entacapone.

How to transfer patients taking levodopa/DDC inhibitor (carbidopa or benserazide) preparations and

entacapone tablets to Levodopa/Carbidopa/Entacapone Mylan

a

. Patients who are currently treated with entacapone and with standard release levodopa/carbidopa in

doses equal to Levodopa/Carbidopa/Entacapone Mylan tablet strengths can be directly transferred to

corresponding Levodopa/Carbidopa/Entacapone Mylan tablets.

For example, a patient taking one tablet of 50 mg/12.5 mg of levodopa/carbidopa with one tablet of

entacapone 200 mg four times daily can take one 50 mg/12.5 mg/200 mg

Levodopa/Carbidopa/Entacapone Mylan tablet four times daily in place of their usual levodopa/carbidopa

and entacapone doses.

b.

When initiating Levodopa/Carbidopa/Entacapone Mylan therapy for patients currently treated with

entacapone and levodopa/carbidopa in doses not equal to Levodopa/Carbidopa/Entacapone Mylan

50 mg/12.5 mg/200 mg (or 75 mg/18.75 mg/200 mg or 100 mg/25 mg/200 mg or

125 mg/31.25 mg/200 mg or 150 mg/37.5 mg/200 mg or 200 mg/50 mg/200 mg) tablets,

Levodopa/Carbidopa/Entacapone Mylan dosing should be carefully titrated for optimal clinical response.

At the initiation, Levodopa/Carbidopa/Entacapone Mylan should be adjusted to correspond as closely as

possible to the total daily dose of levodopa currently used.

c.

When initiating Levodopa/Carbidopa/Entacapone Mylan in patients currently treated with entacapone

and levodopa/benserazide in a standard release formulation, the dosing of levodopa/benserazide should be

discontinued in the previous night, and Levodopa/Carbidopa/Entacapone Mylan should be started in the

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next morning. The starting dose of Levodopa/Carbidopa/Entacapone Mylan should provide either the

same amount of levodopa or slightly (5-10%) more.

How to transfer patients not currently treated with entacapone to Levodopa/Carbidopa/Entacapone

Mylan

Initiation of Levodopa/Carbidopa/Entacapone Mylan may be considered at corresponding doses to current

treatment in some patients with Parkinson's disease and end-of-dose motor fluctuations, who are not

stabilised on their current standard release levodopa/DDC inhibitor treatment. However, a direct switch

from levodopa/DDC inhibitor to Levodopa/Carbidopa/Entacapone Mylan is not recommended for

patients who have dyskinesias or whose daily levodopa dose is above 800 mg. In such patients it is

advisable to introduce entacapone treatment as a separate treatment (entacapone tablets) and adjust the

levodopa dose if necessary, before switching to Levodopa/Carbidopa/Entacapone Mylan.

Entacapone enhances the effects of levodopa. It may therefore be necessary, particularly in patients with

dyskinesia, to reduce levodopa dose by 10-30% within the first days to first weeks after initiating

Levodopa/Carbidopa/Entacapone Mylan treatment. The daily dose of levodopa can be reduced by

extending the dosing intervals and/or by reducing the amount of levodopa per dose, according to the

clinical condition of the patient.

Dose adjustment during the course of the treatment

When more levodopa is required, an increase in the frequency of doses and/or the use of an alternative

strength of Levodopa/Carbidopa/Entacapone Mylan should be considered, within the dose

recommendations.

When less levodopa is required, the total daily dose of Levodopa/Carbidopa/Entacapone Mylan should be

reduced either by decreasing the frequency of administration by extending the time between doses, or by

decreasing the strength of Levodopa/Carbidopa/Entacapone Mylan at an administration.

If other levodopa products are used concomitantly with a Levodopa/Carbidopa/Entacapone Mylan tablet,

the maximum dose recommendations should be followed.

Discontinuation of Levodopa/Carbidopa/Entacapone Mylan therapy:

If Levodopa/Carbidopa/Entacapone

Mylan treatment (levodopa/carbidopa/entacapone) is discontinued and the patient is transferred to

levodopa/DDC inhibitor therapy without entacapone, it is necessary to adjust the dosing of other

antiparkinsonian treatments, especially levodopa, to achieve a sufficient level of control of the

parkinsonian symptoms.

Paediatric population:

The safety and efficacy of Levodopa/Carbidopa/Entacapone Mylan in children

aged below 18 years have not been established. No data are available.

Elderly:

No dose adjustment of Levodopa/Carbidopa/Entacapone Mylan is required for elderly people.

Hepatic impairment:

It is advised that Levodopa/Carbidopa/Entacapone Mylan should be administered

cautiously to patients with mild to moderate hepatic impairment. Dose reduction may be needed (see

section 5.2).

For severe hepatic impairment see section 4.3.

Renal impairment:

Renal impairment does not affect the pharmacokinetics of entacapone.

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No particular studies are reported on the pharmacokinetics of levodopa and carbidopa in patients with

renal insufficiency, therefore Levodopa/Carbidopa/Entacapone Mylan therapy should be administered

cautiously to patients in severe renal impairment including those receiving dialysis therapy (see section

5.2).

Method of administration

Each tablet is to be taken orally either with or without food (see section 5.2). One tablet contains one

treatment dose and the tablet may only be administered as whole tablets.

4.3

Contraindications

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

Severe hepatic impairment.

Narrow-angle glaucoma.

Pheochromocytoma.

Coadministration of Levodopa/Carbidopa/Entacapone Mylan with non-selective monoamine oxidase

(MAO-A and MAO-B) inhibitors (e.g. phenelzine, tranylcypromine).

Coadministration with a selective MAO-A inhibitor and a selective MAO-B inhibitor (see section

4.5).

A previous history of Neuroleptic Malignant Syndrome (NMS) and/or non-traumatic rhabdomyolysis.

4.4

Special warnings and precautions for use

Levodopa/Carbidopa/Entacapone Mylan is not recommended for the treatment of drug-induced

extrapyramidal reactions

Levodopa/Carbidopa/Entacapone Mylan therapy should be administered cautiously to patients with

ischemic heart disease, severe cardiovascular or pulmonary disease, bronchial asthma, renal or

endocrine disease, history of peptic ulcer disease or history of convulsions.

In patients with a history of myocardial infarction who have residual atrial nodal or ventricular

arrhythmias; cardiac function should be monitored with particular care during the period of initial

dose adjustments.

All patients treated with Levodopa/Carbidopa/Entacapone Mylan should be monitored carefully for

the development of mental changes, depression with suicidal tendencies, and other serious antisocial

behaviour. Patients with past or current psychosis should be treated with caution.

Concomitant administration of antipsychotics with dopamine receptor-blocking properties,

particularly D

receptor antagonists should be carried out with caution, and the patient carefully

observed for loss of antiparkinsonian effect or worsening of parkinsonian symptoms.

Patients with chronic wide-angle glaucoma may be treated with Levodopa/Carbidopa/Entacapone

Mylan with caution, provided the intra-ocular pressure is well controlled and the patient is monitored

carefully for changes in intra-ocular pressure.

Levodopa/Carbidopa/Entacapone Mylan may induce orthostatic hypotension. Therefore

Levodopa/Carbidopa/Entacapone Mylan should be given cautiously to patients who are taking other

medicinal products which may cause orthostatic hypotension.

Entacapone in association with levodopa has been associated with somnolence and episodes of

sudden sleep onset in patients with Parkinson’s disease and caution should therefore be exercised

when driving or operating machines (see section 4.7).

In clinical studies, dopaminergic adverse reactions, e.g. dyskinesia, were more common in patients

who received entacapone and dopamine agonists (such as bromocriptine), selegiline or amantadine

compared to those who received placebo with this combination. The doses of other antiparkinsonian

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medicinal products may need to be adjusted when Levodopa/Carbidopa/Entacapone Mylan treatment

is substituted for a patient currently not treated with entacapone.

Rhabdomyolysis secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS) has been

observed rarely in patients with Parkinson’s disease. Therefore, any abrupt dose reduction or

withdrawal of levodopa should be carefully observed, particularly in patients who are also receiving

neuroleptics. NMS, including rhabdomyolysis and hyperthermia, is characterised by motor symptoms

(rigidity, myoclonus, tremor), mental status changes (e.g., agitation, confusion, coma), hyperthermia,

autonomic dysfunction (tachycardia, labile blood pressure) and elevated serum creatine

phosphokinase. In individual cases, only some of these symptoms and/or findings may be evident.

The early diagnosis is important for the appropriate management of NMS. A syndrome resembling

the neuroleptic malignant syndrome including muscular rigidity, elevated body temperature, mental

changes and increased serum creatine phosphokinase has been reported with the abrupt withdrawal of

antiparkinsonian agents. Neither NMS nor rhabdomyolysis have been reported in association with

entacapone treatment from controlled trials in which entacapone was discontinued abruptly. Since the

introduction of entacapone into the market, isolated cases of NMS have been reported, especially

following abrupt reduction or discontinuation of entacapone and other concomitant dopaminergic

medicinal products. When considered necessary, the replacement of Levodopa/Carbidopa/Entacapone

Mylan with levodopa and DDC inhibitor without entacapone or other dopaminergic treatment should

proceed slowly and an increase in levodopa dose may be necessary.

If general anaesthesia is required, therapy with Levodopa/Carbidopa/Entacapone Mylan may be

continued for as long as the patient is permitted to take fluids and medicinal products by mouth. If

therapy has to be stopped temporarily, Levodopa/Carbidopa/Entacapone Mylan may be restarted as

soon as oral medicinal products can be taken at the same daily dose as before.

Periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function is recommended

during extended therapy with Levodopa/Carbidopa/Entacapone Mylan.

For patients experiencing diarrhoea, a follow-up of weight is recommended in order to avoid potential

excessive weight decrease. Prolonged or persistent diarrhoea appearing during use of entacapone may

be a sign of colitis. In the event of prolonged or persistent diarrhoea, the drug should be discontinued

and appropriate medical therapy and investigations considered.

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 and/or other

dopaminergic treatments containing levodopa including Levodopa/Carbidopa/Entacapone Mylan.

Review of treatment is recommended if such symptoms develop.

For patients who experience progressive anorexia, asthenia and weight decrease within a relatively

short period of time, a general medical evaluation including liver function should be considered.

Levodopa/carbidopa may cause false positive result when a dipstick is used to test for urinary ketone

and this reaction is not altered by boiling the urine sample. The use of glucose oxidase methods may

give false negative results for glycosuria.

4.5

Interaction with other medicinal products and other forms of interaction

Other antiparkinsonian medicinal products

: To date there has been no indication of interactions that

would preclude concurrent use of standard antiparkinsonian medicinal products with

Levodopa/Carbidopa/Entacapone Mylan therapy. Entacapone in high doses may affect the absorption of

carbidopa. However, no interaction with carbidopa has been observed with the recommended treatment

schedule (200 mg of entacapone up to 10 times daily). Interactions between entacapone and selegiline

have been investigated in repeated dose studies in Parkinson's disease patients treated with levodopa/DDC

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inhibitor and no interaction was observed. When used with Levodopa/Carbidopa/Entacapone Mylan, the

daily dose of selegiline should not exceed 10 mg.

Caution should be exercised when the following active substances are administered concomitantly with

levodopa therapy.

Antihypertensives

: Symptomatic postural hypotension may occur when levodopa is added to the treatment

of patients already receiving antihypertensives. Dose adjustment of the antihypertensive agent may be

required.

Antidepressants:

Rarely, reactions including hypertension and dyskinesia have been reported with the

concomitant use of tricyclic antidepressants and levodopa/carbidopa. Interactions between entacapone

and imipramine and between entacapone and moclobemide have been investigated in single dose studies

in healthy volunteers. No pharmacodynamic interactions were observed. A significant number of

Parkinson's disease patients have been treated with the combination of levodopa, carbidopa and

entacapone with several active substances including MAO-A inhibitors, tricyclic antidepressants,

noradrenaline reuptake inhibitors such as desipramine, maprotiline and venlafaxine and medicinal

products that are metabolised by COMT (e.g. catechol-structured compounds, paroxetine). No

pharmacodynamic interactions have been observed. However, caution should be exercised when these

medicinal products are used concomitantly with Levodopa/Carbidopa/Entacapone Mylan (see sections 4.3

and 4.4).

Other active substances:

Dopamine receptor antagonists (e.g. some antipsychotics and antiemetics),

phenytoin and papaverine may reduce the therapeutic effect of levodopa. Patients taking these medicinal

products with Levodopa/Carbidopa/Entacapone Mylan should be carefully observed for loss of

therapeutic response.

Due to entacapone's affinity to cytochrome P450 2C9

in vitro

(see section 5.2),

Levodopa/Carbidopa/Entacapone Mylan may potentially interfere with active substances whose

metabolism is dependent on this isoenzyme, such as S-warfarin. However, in an interaction study with

healthy volunteers, entacapone did not change the plasma levels of S-warfarin, while the AUC for R-

warfarin increased on average by 18% [CI90 11-26%]. The INR values increased on average by 13%

[CI90 6-19%]. Thus, a control of INR is recommended when Levodopa/Carbidopa/Entacapone Mylan is

initiated for patients receiving warfarin.

Other forms of interactions:

Since levodopa competes with certain amino acids, the absorption of

Levodopa/Carbidopa/Entacapone Mylan may be impaired in some patients on high protein diet.

Levodopa and entacapone may form chelates with iron in the gastrointestinal tract. Therefore,

Levodopa/Carbidopa/Entacapone Mylan and iron preparations should be taken at least 2-3 hours apart

(see section 4.8).

In vitro data:

Entacapone binds to human albumin binding site II which also binds several other

medicinal products, including diazepam and ibuprofen. According to

in vitro

studies, significant

displacement is not anticipated at therapeutic concentrations of the medicinal products. Accordingly, to

date there has been no indication of such interactions.

4.6

Fertility, pregnancy and lactation

Pregnancy

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There are no adequate data from the use of the combination of levodopa/carbidopa/entacapone in

pregnant women. Studies in animals have shown reproductive toxicity of the separate compounds (see

section 5.3). The potential risk for humans is unknown. Levodopa/Carbidopa/Entacapone Mylan should

not be used during pregnancy unless the benefits for the mother outweigh the possible risks to the foetus.

Breast-feeding

Levodopa is excreted in human breast milk. There is evidence that breast-feeding is suppressed during

treatment with levodopa. Carbidopa and entacapone were excreted in milk in animals but is not known

whether they are excreted in human breast milk. The safety of levodopa, carbidopa or entacapone in the

infant is not known. Women should not breast-feed during treatment with

Levodopa/Carbidopa/Entacapone Mylan.

Fertility

No adverse reactions on fertility were observed in preclinical studies with entacapone, carbidopa or

levodopa alone. Fertility studies in animals have not been conducted with the combination of entacapone,

levodopa and carbidopa.

4.7

Effects on ability to drive and use machines

Levodopa/Carbidopa/Entacapone Mylan may have a major influence on the ability to drive and use

machines.

Levodopa,

carbidopa

entacapone

together

cause

dizziness

symptomatic

orthostatism. Therefore, caution should be exercised when driving or using machines.

Patients being treated with Levodopa/Carbidopa/Entacapone Mylan and presenting with somnolence

and/or sudden sleep onset episodes must be instructed 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 have resolved (see section 4.4).

4.8

Undesirable effects

a.

Summary of the safety profile

The most frequently reported adverse reactions with levodopa/carbidopa/entacapone are dyskinesias

occurring in approximately 19% of patients; gastrointestinal symptoms including nausea and diarrhoea

occurring in approximately 15% and 12% of patients, respectively; muscle, musculoskeletal and

connective tissue pain occurring in approximately 12% of patients; and harmless reddish-brown

discolouration of urine (chromaturia) occurring in approximately 10% of patients. Serious events of

gastrointestinal haemorrhage (uncommon) and angioedema (rare) have been identified from the clinical

trials with levodopa/carbidopa/entacapone or entacapone combined with levodopa/DDC inhibitor. Serious

hepatitis with mainly cholestatic features, rhabdomyolysis and neuroleptic malignant syndrome may

occur with levodopa/carbidopa/entacapone although no cases have been identified from the clinical trial

data.

b.

Tabulated list of adverse reactions

The following adverse reactions, listed in Table 1, have been accumulated both from a pooled data of

eleven double-blind clinical trials consisting of 3230 patients (1810 treated with

levodopa/carbidopa/entacapone or entacapone combined with levodopa/DDC inhibitor, and 1420 treated

with placebo combined with levodopa/DDC inhibitor or cabergoline combined with levodopa/ DDC

inhibitor), and from the post-marketing data since the introduction of entacapone into the market for the

combination use of entacapone with levodopa/DDC inhibitor.

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Adverse reactions are ranked under headings of frequency, the most frequent first, using the following

convention: 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,

since no valid estimate can be derived from clinical trials or epidemiological studies).

Table 1.

Adverse reactions

Blood and lymphatic system disorders

Common:

Anaemia

Uncommon:

Thrombocytopenia

Metabolism and nutrition disorders

Common:

Weight decreased*, decreased appetite*

Psychiatric disorders

Common:

Depression, hallucination, confusional state*, abnormal dreams*, anxiety, insomnia

Uncommon:

Psychosis, agitation*

Not known:

Suicidal behaviour

Nervous system disorders

Very common:

Dyskinesia*

Common:

Parkinsonism aggravated (e.g. bradykinesia)*, tremor, on and off phenomenon, dystonia,

mental impairment (e.g. memory impairment, dementia), somnolence, dizziness*,

headache

Not known:

Neuroleptic malignant syndrome*

Eye disorders

Common:

Blurred vision

Cardiac disorders

Common:

Ischemic heart disease events other than myocardial infarction (e.g. angina pectoris)**,

irregular heart rhythm

Uncommon:

Myocardial infarction**

Vascular disorders:

Common:

Orthostatic hypotension, hypertension

Uncommon:

Gastrointestinal haemorrhage

Respiratory, thoracic and mediastinal disorders

Common:

Dyspnoea

Gastrointestinal disorders

Very common: Diarrhoea*, nausea*

Common:

Constipation*, vomiting*, dyspepsia, abdominal pain and discomfort*, dry mouth*

Uncommon:

Colitis*, dysphagia

Hepatobiliary disorders

Uncommon:

Hepatic function test abnormal*

Not known:

Hepatitis with mainly cholestatic features (see section 4.4)*

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Skin and subcutaneous tissue disorders

Common:

Rash*, hyperhidrosis

Uncommon:

Discolourations other than urine (e.g. skin, nail, hair, sweat)*

Rare:

Angioedema

Not known:

Urticaria*

Musculoskeletal and connective tissue disorders

Very common: Muscle, musculoskeletal and connective tissue pain*

Common:

Muscle spasms, arthralgia

Not known:

Rhabdomyolysis*

Renal and urinary disorders

Very common: Chromaturia*

Common:

Urinary tract infection

Uncommon:

Urinary retention

General disorders and administration site conditions

Common:

Chest pain, peripheral oedema, fall, gait disturbance, asthenia, fatigue

Uncommon:

Malaise

*Adverse reactions that are mainly attributable to entacapone or are more frequent (by the frequency

difference of at least 1% in the clinical trial data) with entacapone than levodopa/DDC inhibitor alone.

See section c.

**The incidence rates of myocardial infarction and other ischemic heart disease events (0.43% and

1.54%, respectively) are derived from an analysis of 13 double-blind studies involving 2082 patients with

end-of-dose motor fluctuations receiving entacapone.

c.

Description of selected adverse reactions

Adverse reactions that are mainly attributable to entacapone or are more frequent with entacapone than

levodopa/DDC inhibitor alone are indicated with an asterisk in Table 1, section 4.8b. Some of these

adverse reactions relate to the increased dopaminergic activity (e.g. dyskinesia, nausea and vomiting) and

occur most commonly at the beginning of the treatment. Reduction of levodopa dose decreases the

severity and frequency of these dopaminergic reactions. Few adverse reactions are known to be directly

attributable to the active substance entacapone including diarrhoea and reddish-brown discolouration of

urine. Entacapone may in some cases cause also discolouration of e.g. skin, nail, hair and sweat. Other

adverse reactions with an asterisk in Table 1, section 4.8b are marked based on either their more frequent

occurring (by the frequency difference of at least 1%) in the clinical trial data with entacapone than

levodopa/DDCI alone or the individual case safety reports received after the introduction of entacapone

into the market.

Convulsions have occurred rarely with levodopa/carbidopa; however a causal relationship to

levodopa/carbidopa therapy has not been established.

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 and/or

other dopaminergic treatments containing levodopa including Levodopa/Carbidopa/Entacapone Mylan

(see section 4.4).

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Entacapone in association with levodopa has been associated with isolated cases of excessive daytime

somnolence and sudden sleep onset episodes.

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 Appendix V.

4.9

Overdose

The post-marketing data includes isolated cases of overdose in which the reported highest daily doses of

levodopa and entacapone have been at least 10,000 mg and 40,000 mg, respectively. The acute symptoms

and signs in these cases of overdose included agitation, confusional state, coma, bradycardia, ventricular

tachycardia, Cheyne-Stokes respiration, discolourations of skin, tongue and conjunctiva, and chromaturia.

Management of acute overdose with Levodopa/Carbidopa/Entacapone Mylan therapy is similar to acute

overdose with levodopa. Pyridoxine, however, is not effective in reversing the actions of

levodopa/carbidopa/entacapone . Hospitalisation is advised and general supportive measures should be

employed with immediate gastric lavage and repeated doses of charcoal over time. This may hasten the

elimination of entacapone in particular by decreasing its absorption/reabsorption from the GI tract. The

adequacy of the respiratory, circulatory and renal systems should be carefully monitored and appropriate

supportive measures employed. ECG monitoring should be started and the patient carefully monitored for

the possible development of arrhythmias. If required, appropriate anti-arrhythmic therapy should be

given. The possibility that the patient has taken other active substances in addition to

levodopa/carbidopa/entacapone should be taken into consideration. The value of dialysis in the treatment

of overdose is not known.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Anti-parkinson drugs, dopa and dopa derivatives, ATC code: N04BA03.

According to the current understanding, the symptoms of Parkinson’s disease are related to depletion of

dopamine in the corpus striatum. Dopamine does not cross the blood-brain barrier. Levodopa, the

precursor of dopamine, crosses the blood brain barrier and relieves the symptoms of the disease. As

levodopa is extensively metabolised in the periphery, only a small portion of a given dose reaches the

central nervous system when levodopa is administered without metabolic enzyme inhibitors.

Carbidopa and benserazide are peripheral DDC inhibitors which reduce the peripheral metabolism of

levodopa to dopamine, and thus, more levodopa is available to the brain. When decarboxylation of

levodopa is reduced with the co-administration of a DDC inhibitor, a lower dose of levodopa can be used

and the incidence of adverse reactions such as nausea is reduced.

With inhibition of the decarboxylase by a DDC inhibitor, catechol-

O

-methyltransferase (COMT) becomes

the major peripheral metabolic pathway catalyzing the conversion of levodopa to 3-O-methyldopa (3-

OMD), a potentially harmful metabolite of levodopa. Entacapone is a reversible, specific and mainly

peripherally acting COMT inhibitor designed for concomitant administration with levodopa. Entacapone

slows the clearance of levodopa from the bloodstream resulting in an increased area under the curve

(AUC) in the pharmacokinetic profile of levodopa. Consequently the clinical response to each dose of

levodopa is enhanced and prolonged.

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The evidence of the therapeutic effects of levodopa/carbidopa/entacapone is based on two phase III

double-blind studies, in which 376 Parkinson’s disease patients with end-of-dose motor fluctuations

received either entacapone or placebo with each levodopa/DDC inhibitor dose. Daily ON time with and

without entacapone was recorded in home-diaries by patients. In the first study, entacapone increased the

mean daily ON time by 1 h 20 min (CI

45 min, 1 h 56 min) from baseline. This corresponded to an

8.3% increase in the proportion of daily ON time. Correspondingly, the decrease in daily OFF time was

24% in the entacapone group and 0% in the placebo group. In the second study, the mean proportion of

daily ON time increased by 4.5% (CI

0.93%, 7.97%) from baseline. This is translated to a mean

increase of 35 min in the daily ON time. Correspondingly, the daily OFF time decreased by 18% on

entacapone and by 5% on placebo. Because the effects of levodopa/carbidopa/entacapone tablets are

equivalent with entacapone 200 mg tablet administered concomitantly with the commercially available

standard release carbidopa/levodopa preparations in corresponding doses these results are applicable to

describe the effects of Levodopa/Carbidopa/Entacapone Mylan as well.

5.2

Pharmacokinetic properties

General characteristics of the active substances

Absorption/distribution:

There are substantial inter- and intra-individual variations in the absorption of

levodopa, carbidopa and entacapone. Both levodopa and entacapone are rapidly absorbed and eliminated.

Carbidopa is absorbed and eliminated slightly slower compared with levodopa. When given separately

without the two other active substances, the bioavailability for levodopa is 15-33%, for carbidopa 40-70%

and for entacapone 35% after a 200 mg oral dose. Meals rich in large neutral amino acids may delay and

reduce the absorption of levodopa. Food does not significantly affect the absorption of entacapone. The

distribution volume of both levodopa (Vd 0.36-1.6 l/kg) and entacapone (Vd

0.27 l/kg) is moderately

small while no data for carbidopa are available.

Levodopa is bound to plasma protein only to a minor extent of about 10-30% and carbidopa is bound

approximately 36%, while entacapone is extensively bound to plasma proteins (about 98%) – mainly to

serum albumin. At therapeutic concentrations, entacapone does not displace other extensively bound

active substances (e.g. warfarin, salicylic acid, phenylbutazone, or diazepam), nor is it displaced to any

significant extent by any of these substances at therapeutic or higher concentrations.

Biotransformation and elimination:

Levodopa is extensively metabolised to various metabolites:

decarboxylation by dopa decarboxylase (DDC) and O-methylation by catechol-O-methyltransferase

(COMT) being the most important pathways.

Carbidopa is metabolized to two main metabolites which are excreted in the urine as glucuronides and

unconjugated compounds. Unchanged carbidopa accounts for 30% of the total urinary excretion.

Entacapone is almost completely metabolized prior to excretion via urine (10 to 20%) and bile/faeces (80

to 90%). The main metabolic pathway is glucuronidation of entacapone and its active metabolite, the cis-

isomer, which accounts for about 5% of plasma total amount.

Total clearance for levodopa is in the range of 0.55-1.38 l/kg/h and for entacapone is in the range of 0.70

l/kg/h. The elimination-half life is (t1/2) is 0.6-1.3 hours for levodopa, 2-3 hours for carbidopa and 0.4-

0.7 hours for entacapone, each given separately.

Due to short elimination half-lives, no true accumulation of levodopa or entacapone occurs on repeated

administration.

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Data from

in vitro

studies using human liver microsomal preparations indicate that entacapone inhibits

cytochrome P450 2C9 (IC50 ~ 4 μM). Entacapone showed little or no inhibition of other types of P450

isoenzymes (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19); see section 4.5.

Characteristics in patients

Elderly

: When given without carbidopa and entacapone, the absorption of levodopa is greater and

elimination is slower in older people than in young people. However, after combination of carbidopa with

levodopa, the absorption of levodopa is similar between the elderly people and the young people, but the

AUC is still 1.5 fold greater in the elderly people due to decreased DDC activity and lower clearance by

aging. There are no significant differences in the AUC of carbidopa or entacapone between younger (45–

64 years) and elderly people (65–75 years).

Gender:

Bioavailability of levodopa is significantly higher in women than in men. In the pharmacokinetic

studies with levodopa/carbidopa/entacapone the bioavailability of levodopa is higher in women than in

men, primarily due to the difference in body weight, while there is no gender difference with carbidopa

and entacapone.

Hepatic impairment:

The metabolism of entacapone is slowed in patients with mild to moderate hepatic

impairment (Child-Pugh Class A and B) leading to an increased plasma concentration of entacapone both

in the absorption and elimination phases (see sections 4.2 and 4.3). No particular studies on the

pharmacokinetics of carbidopa and levodopa in patients with hepatic impairment are reported, however, it

is advised that Levodopa/Carbidopa/Entacapone Mylan should be administered cautiously to patients with

mild or moderate hepatic impairment.

Renal impairment

: Renal impairment does not affect the pharmacokinetics of entacapone. No particular

studies are reported on the pharmacokinetics of levodopa and carbidopa in patients with renal impairment.

However, a longer dosing interval of Levodopa/Carbidopa/Entacapone Mylan may be considered for

patients who are receiving dialysis therapy (see section 4.2).

5.3

Preclinical safety data

Preclinical data of levodopa, carbidopa and entacapone, tested alone or in combination, revealed no

special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity,

genotoxicity, and carcinogenic potential. In repeated dose toxicity studies with entacapone, anaemia most

likely due to iron chelating properties of entacapone was observed. Regarding reproduction toxicity of

entacapone, decreased foetal weight and a slightly delayed bone development were noticed in rabbits

treated at systemic exposure levels in the therapeutic range. Both levodopa and combinations of carbidopa

and levodopa have caused visceral and skeletal malformations in rabbits.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core:

Cellulose, microcrystalline

Povidone

Magnesium stearate

Croscarmellose sodium

Page

13

14

Film-coating:

Polydextrose

Titanium dioxide (E171)

Hypromellose (E464)

Macrogol (E1521)

Iron oxide, red (E172)

Indigo carmine aluminium lake (E132)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

PVC/Aclar-Al blister pack: 18 months

OPA/Al/PVC-Al blister pack: 2 years

HDPE bottle pack: 2 years

6.4

Special precautions for storage

Do not store above 25

6.5

Nature and contents of container

PVC/Aclar-Al blister pack containing 30 and 100 tablets.

OPA/Al/PVC-Al blister pack containing 30 and 100 tablets.

HDPE bottle pack with a polypropylene cap with aluminium induction liner sealing wad along with

desiccant containing 30, 100 or 175 tablets.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

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

Page

14

14

Date of first authorisation:

[To be completed nationally]

10.

DATE OF REVISION OF THE TEXT

13 December 2016

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