STALEVO 5012.5200 MG

STAL CTAB PL SH 290920

STAL CTAB PL SH 290920

PATIENT PACKAGE INSERT

IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS

)PREPARATIONS( – 1986

The medicine is dispensed with a

doctor’s prescription only

Stalevo

®

50/12.5/200 mg

Film-coated tablets

Stalevo

®

75/18.75/200 mg

Film-coated tablets

Stalevo

®

100/25/200 mg

Film-coated tablets

Stalevo

®

125/31.25/200 mg

Film-coated tablets

Stalevo

®

150/37.5/200 mg

Film-coated tablets

Stalevo

®

200/50/200 mg

Film-coated tablets

Active ingredients

Stalevo 50/12.5/200 mg

Each

tablet

contains

levodopa/

carbidopa/entacapone

50/12.5/200 mg

Stalevo 75/18.75/200 mg

Each

tablet

contains

levodopa/

carbidopa/entacapone

75/18.75/200 mg

Stalevo 100/25/200 mg

Each

tablet

contains

levodopa/

carbidopa/entacapone

100/25/200 mg

Stalevo 125/31.25/200 mg

Each

tablet

contains

levodopa/

carbidopa/entacapone

125/31.25/200 mg

Stalevo 150/37.5/200 mg

Each

tablet

contains

levodopa/

carbidopa/entacapone

150/37.5/200 mg

Stalevo 200/50/200 mg

Each

tablet

contains

levodopa/

carbidopa/entacapone

200/50/200 mg

Inactive ingredients

See section 6 ‘Further Information’ and

section 2 ‘Before using the medicine’

in section ‘Important information

about some of the ingredients of the

medicine’.

Read the leaflet carefully in its

entirety before using the medicine.

This leaflet contains concise information

about the medicine. If you have further

questions, refer to the doctor or

pharmacist.

This medicine has been prescribed

to treat your ailment. Do not pass it

on to others. It may harm them even

if it seems to you that their ailment is

similar.

1. WHAT

IS

THE

MEDICINE

INTENDED FOR?

For treatment of Parkinson’s disease.

Therapeutic group: Anti-Parkinson

medicines, dopa and dopa derivatives.

Stalevo contains 3 active ingredients

)levodopa, carbidopa and entacapone(

in one film-coated tablet. Parkinson’s

disease is caused by low brain levels

of a substance called dopamine.

Levodopa

increases

amount

of dopamine, thereby reducing the

symptoms of Parkinson’s disease.

Carbidopa and entacapone improve the

anti-Parkinsonian effects of levodopa.

2. BEFORE USING THE MEDICINE

Do not use the medicine if:

- You are allergic )hypersensitive( to

levodopa, carbidopa, entacapone or

to any of the additional ingredients

of the medicine, listed in section 6

‘Further Information’.

- You have narrow-angle glaucoma )a

type of eye disease(.

- You have a tumor of the adrenal

gland )pheochromocytoma(.

- You are taking certain medicines

to treat depression )a combination

of selective MAO-A and MAO-B

inhibitors, or non-selective MAO

inhibitors(.

- You have ever had neuroleptic

malignant syndrome )NMS; this is

a rare reaction to medicines used

to treat severe mental disorders(.

- You have ever had non-traumatic

rhabdomyolysis )a rare muscle

disorder(.

- You have a severe liver disease.

- You are breastfeeding.

Special warnings regarding use of

the medicine:

Before taking Stalevo, talk to the

doctor or pharmacist if you have or

have ever had:

- A heart attack, or any other heart

disease, including heart rhythm or

blood vessel disturbances

- Asthma or any other lung disease

- A liver problem, because the dosage

may have to be adjusted

- A kidney or hormone-related disease

- Stomach ulcers or convulsions

- If you are experiencing prolonged

diarrhea, consult with your doctor as

it may be a sign of inflammation of the

bowel

- Any type of severe mental disorder,

such as psychosis

- Chronic

wide-angle

glaucoma,

as it may be necessary to adjust

your dosage and to monitor your

intraocular pressure

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 Stalevo may make these effects

worse.

Consult the doctor if during the

treatment with Stalevo you:

- Notice that your muscles get very

rigid or jerk forcefully, or if you get

tremors, shaking, confusion, fever,

rapid pulse, or wide fluctuations in

your blood pressure. If any of these

happen to you, contact the doctor

immediately

- Feel

depressed,

have

suicidal

thoughts, or notice unusual changes

in your behavior

- Find

yourself

suddenly

falling

asleep, or if you feel very sleepy. If

this happens, do not drive and do

not use any tools or machinery )see

also section ‘Driving and operating

machinery’(

- Notice that uncontrolled movements

begin or get worse after you started

to take Stalevo. If this happens,

the doctor may need to change

the dosage of your anti-Parkinson

medicines

- You have diarrhea: monitoring of your

weight is recommended in order to

avoid potentially excessive weight

loss

- You experience advanced anorexia,

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 using Stalevo;

see section ‘Stopping treatment’.

Tell the doctor if you or your family or

your carer notices you are developing

addiction-like symptoms leading to

craving for large doses of Stalevo

and other medicines used to treat

Parkinson’s disease.

Tell the doctor if you or your family or

your 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 activities that could harm you

or others. These behaviors 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.

The doctor may need to review your

treatments.

If you are due to undergo surgery,

please tell your doctor that you are

using Stalevo.

Stalevo 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.

Tests and follow-up

The doctor may perform some routine

laboratory tests during long-term

treatment with Stalevo.

Periodic

evaluation

hepatic,

hematopoietic, cardiovascular and

renal function is recommended during

extended treatment with Stalevo.

All patients treated with Stalevo

should be monitored carefully for

the development of mental changes

)e.g., hallucinations and psychoses(,

depression with suicidal tendencies,

and serious antisocial behavior. In case

any of these changes occur, refer to the

doctor immediately.

Children and adolescents

Experience with use of Stalevo in

children and adolescents under 18

years of age is limited; therefore,

the medicine is not intended for this

population.

Elderly patients

Dosage adjustment is not necessary

for the elderly.

Drug interactions

If you are taking, or have recently

taken, other medicines, including

non-prescription medicines and

nutritional supplements, tell the

doctor or pharmacist. Especially if

you are taking:

take

Stalevo

taking certain medicines for treating

depression )combination of selective

MAO-A and MAO-B inhibitors, or

non-selective MAO inhibitors(.

Stalevo may increase the effects and

side effects of certain medicines,

including:

- Medicines used to treat depression

such as moclobemide, amitriptyline,

desipramine, maprotiline, venlafaxine

and paroxetine

- Rimiterol and isoprenaline, used to

treat lung diseases

- Adrenaline, used to treat severe

allergic reactions

- Noradrenaline,

dopamine

dobutamine, used to treat heart

diseases and low blood pressure

- Alpha-methyldopa, used to treat high

blood pressure

- Apomorphine,

used

treat

Parkinson’s disease

The effects of Stalevo may be weakened

by certain medicines. These include:

- Dopamine antagonists used to treat

mental disturbances, nausea and

vomiting

Phenytoin, used to prevent convulsions

- Papaverine, used to relax the muscles.

Stalevo may make it harder to digest

iron. Therefore, do not take Stalevo and

iron supplements at the same time.

After taking one of them, wait at least

two to three hours before taking the

other.

Use of Stalevo and food

Stalevo may be taken with or without

food.

For some patients, Stalevo may not

be well absorbed if it is taken with, or

shortly, after a protein-rich meal )such

as meat, fish, dairy products, seeds and

nuts(. Consult the doctor if you think this

applies to you.

Pregnancy

If you are pregnant or breastfeeding,

if you think you are pregnant, or are

planning to have a baby, consult the

doctor or pharmacist before taking the

medicine.

Do not use Stalevo during pregnancy,

unless the benefit to the mother

outweighs the possible risks to the

unborn baby.

Breastfeeding

Do not breastfeed during treatment

with Stalevo. Levodopa is secreted into

breast milk.

Driving and operating machinery

Stalevo may lower your blood pressure,

which may make you feel dizzy.

Therefore, be particularly careful when

you drive or when you operate any tools

or machinery.

If you feel very sleepy, or if you

sometimes find yourself suddenly

falling asleep, you must avoid driving

or engaging in any other activity that

requires alertness )operating tools or

machinery(. Otherwise, you put yourself

and others at risk of serious injury or

death.

Wait until you feel fully alert before

driving or engaging in anything that

requires alertness.

Important information about some

of the ingredients of the medicine

The tablets contain sucrose.

If the doctor has told you that you have

an intolerance to certain sugars, refer to

the doctor before taking Stalevo.

3. HOW SHOULD YOU USE THE

MEDICINE?

Always use the preparation according

to the doctor’s instructions. Check with

the doctor or pharmacist if you are

uncertain regarding the dosage and

treatment regimen of the preparation.

Dosage

The dosage and treatment regimen will

be determined by the doctor only.

Adults and elderly:

- The doctor will tell you exactly how

many Stalevo tablets to take each day.

- Do not split or break the tablet into

smaller pieces.

- Take only one tablet each time.

- Depending on how you respond to

treatment, the doctor will suggest a

higher or lower dosage.

- At dosages of 50/12.5/200 mg,

75/18.75/200 mg, 100/25/200 mg,

125/31.25/200 mg, 150/37.5/200 mg:

do not take more than 10 tablets each

day.

- At a dosage of 200/50/200 mg: do not

take more than 7 tablets each day.

Do not exceed the recommended

dose.

Consult the doctor or pharmacist if you

think the effect of the medicine is too

strong or too weak, or if you experience

side effects.

To open the bottle for the first time:

open the cover, and then press with

your thumb on the seal until it breaks

)see picture 1(.

Picture 1

Taking more Stalevo than required

If you took an overdose or if a child has

accidentally swallowed the medicine,

immediately refer to a doctor or proceed

to a hospital emergency room and bring

the package of the medicine with you.

In case of an overdose, you may feel

confused or agitated, your heart rate

may be slower or faster than normal or

the color of your skin, tongue, eyes or

urine may change.

If you forget to take Stalevo

take

double

dose

compensate for a forgotten tablet.

If it is more than 1 hour until the next

dose: Take one tablet as soon as you

remember, and the next tablet at the

usual time.

If it is less than 1 hour until your next

dose: Take one tablet as soon as you

remember, wait one hour, and then take

another tablet. After that, return to the

usual times.

To avoid possible side effects, always

wait at least one hour between taking

one Stalevo tablet and the next.

Adhere to the treatment regimen as

recommended by the doctor.

Stopping treatment

Even if there is an improvement in your

health condition, do not stop treatment

with the medicine without consulting

the doctor.

In case of discontinuation of treatment,

the doctor may need to readjust your

other

anti-Parkinson

medicines,

especially levodopa, so there will be

sufficient control of your symptoms.

Sudden discontinuation of Stalevo and

other anti-Parkinson medicines may

result in unwanted side effects.

Do not take medicines in the dark!

Check the label and the dose

each time you take a medicine.

Wear glasses if you need them.

If you have further questions

regarding use of the medicine,

consult the doctor or pharmacist.

4. SIDE EFFECTS

As with any medicine, use of Stalevo

may cause side effects in some users.

Do not be alarmed when reading the list

of side effects. You may not suffer from

any of them.

Many of the side effects can be relieved

by adjusting the dosage.

If during the treatment with Stalevo you

experience the following symptoms,

refer to a doctor immediately:

Your muscles get very rigid or jerk

forcefully, you get tremors, shaking,

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 disturbances of the central

nervous system( or rhabdomyolysis

)a rare severe muscle disorder(.

Allergic reaction; the signs may

include

urticaria,

itching,

rash,

swelling of the face, lips, tongue or

throat. This may cause difficulties in

breathing or swallowing.

Very common )may affect more than

1 in 10 patients(

Involuntary movements )dyskinesias(

Nausea

Harmless reddish-brown discoloration

of urine

Muscle pain

Diarrhea

Common )may affect up to 1 in 10

patients(

Light-headedness or fainting due

to low blood pressure; high blood

pressure

Worsening of Parkinson’s symptoms,

dizziness; drowsiness

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 suicidal thoughts(

Heart or artery disease events )e.g.,

chest pain(; irregular heart rhythm

More frequent falling

Shortness of breath

Increased sweating; rashes

Muscle cramps; swelling of legs

Blurred vision

Anemia

Decreased appetite; decreased

weight

Headache; joint pain

Urinary tract infection

Uncommon )may affect up to 1 in

100 patients(

Heart attack

Bleeding in the gut

Changes in the blood cell count which

may result in bleeding; abnormal liver

function test results

Restlessness

Psychotic symptoms

Inflammation of the colon )colitis(

Discolorations other than urine )e.g.,

skin, nails, hair, and sweat(

Swallowing difficulties

Inability to urinate

Certain side effects may be rare or

very rare

Convulsions

Unknown frequency )cannot be

estimated from the available data(

Craving for large dosages of Stalevo

beyond that required to control motor

symptoms,

known

dopamine

dysregulation syndrome )DDS(. Some

patients experience severe abnormal

involuntary movements )dyskinesias(,

mood swings or other side effects after

taking a large dosage of Stalevo.

The following side effects have also

been reported:

Hepatitis )inflammation of the liver(

Itching

You may experience the following side

effects:

Inability to resist the impulse to

perform an action that could be

harmful, which may include:

- Strong

impulse

gamble

excessively,

despite

serious

personal or family consequences

- Altered or increased sexual interest

and behavior 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(.

Refer to a doctor if you experience

any of these behaviors; the doctor will

advise you as to how to manage or

reduce the symptoms.

If a side effect occurs, if one of the

side effects worsens, or if you suffer

from a side effect not mentioned in

the leaflet, consult with the doctor.

Side effects can be reported to the

Ministry of Health by clicking on the

link “Report Side Effects of Drug

Treatment” found on the Ministry of

Health homepage )www.health.gov.il(

that directs you to the online form for

reporting side effects, or by entering

the link:

https://sideeffects.health.gov.il

5. HOW SHOULD THE MEDICINE BE

STORED?

Avoid poisoning! This medicine, and

any other medicine, should be kept in

a safe place out of the reach and sight

of children and/or infants in order to

avoid poisoning. Do not induce vomiting

unless explicitly instructed to do so by

the doctor.

Do not use the medicine after the expiry

date )exp. date( that appears on the

package. The expiry date refers to the

last day of that month.

Storage conditions:

Store below 25°C.

After first opening the bottle, use within

6 months.

Do not discard medicines in wastewater

or a household waste bin. Ask your

pharmacist how to dispose of medicines

that you no longer use. These measures

will help protect the environment.

6. FURTHER INFORMATION

In addition to the active ingredients, the

medicine also contains:

Tablet:

Mannitol, maize starch, povidone,

croscarmellose sodium, magnesium

stearate

Tablet coating:

Hypromellose,

titanium

dioxide,

sucrose, magnesium stearate, glycerol

85%, red iron oxide, polysorbate 80,

yellow iron oxide

Yellow iron oxide is not found in tablets

of the following dosages:

75/18.75/200 mg, 125/31.25/200 mg,

200/50/200 mg

The amount of sucrose )in mg( per

tablet:

200/50/200 – 2.26 mg

150/37.5/200 – 1.91 mg

125/31.25/200 – 1.62 mg

100/25/200 – 1.55 mg

75/18.75/200 – 1.35 mg

50/12.5/200 – 1.18 mg

What the medicine looks like and the

contents of the package

Stalevo 50/12.5/200 mg:

A brownish-red to grayish-red colored,

round, convex, unscored tablet, marked

with LCE 50 on one side.

Stalevo 75/18.75/200 mg:

A light brownish-red colored, oval,

unscored tablet, marked with LCE 75

on one side.

Stalevo 100/25/200 mg:

A brownish-red to grayish-red colored,

oval, unscored tablet, marked with LCE

100 on one side.

Stalevo 125/31.25/200 mg:

A light brownish-red colored, oval,

unscored tablet, marked with LCE 125

on one side.

Stalevo 150/37.5/200 mg:

A brownish-red to grayish-red colored,

elongated-ellipse, unscored tablet,

marked with LCE 150 on one side.

Stalevo 200/50/200 mg:

A dark brownish-red colored, oval,

unscored tablet, marked with LCE 200

on one side.

Package sizes: A bottle that contains 10

or 30 or 100 tablets.

Not all package sizes are marketed.

License

holder

and

address:

Inovamed Pharma Ltd., P.O.B. 2349,

Bnei Brak 5112202.

Manufacturer and address: Orion

Corporation, Espoo, Finland.

Edited in May 2020.

Registration number of the medicine

in the National Drug Registry of the

Ministry of Health:

Stalevo 50/12.5/200 mg:

132 34 31105

Stalevo 75/18.75/200 mg:

144 30 32962

Stalevo 100/25/200 mg:

132 35 31106

Stalevo 125/31.25/200 mg:

144 31 32963

Stalevo 150/37.5/200 mg:

132 36 31107

Stalevo 200/50/200 mg:

141 94 31768

،غلم 100/25/200 ،غلم 75/18.75/200 150/37.5/200 ،غلم 125/31.25/200 يف صارقأ 10 نم رثكأ لوانت زوجي لا :غلم .مويلا لوانت زوجي لا :غلم 200/50/200 رايع نم

.مويلا يف صارقأ 7 نم رثكأ .هب ىصوملا يئاودلا رادقملا زواجت زوجي لا نأ كل ادب لاح يف يلديصلا وأ بيبطلا رشتسإ اذإ وأ ،مزلالا نم فعضأ وأ ىوقأ ءاودلا ريثأت .ةيبناج ضارعأب رعشت تنك طغضاو ءاطغلا حتفإ :ىلولأا ةرملل ةنينقلا حتفل رظنأ( .رسكني ىتح متخلا ىلع ماهبلإا ةطساوب .)1 ةروصلا يف 1 ةروصلا بولطملا نم رثكأ وڤيلاتس لوانت لفط علب اذإ وأ

اطرفم

ايئاود

ارادقم تلوانت اذإ ةفرغل وأ بيبطلا ىلإ

لااح هجوت ،ءاودلا نم أطخلاب .ءاودلا ةبلع كعم رضحأو ىفشتسملا يف ئراوطلا رعشت دقف ةطرفم ةيئاود ةعرج لوانت لاح يف كيدل بلقلا مظن نوكي دق ،جئاه وأ كبترم كنأب ،دلجلا نول ريغتي دق وأ داتعملا نم عرسأ وأ أطبأ .كيدل لوبلا وأ نينيعلا ،ناسللا وڤيلاتس لوانت تيسن اذإ ضيوعتلل ةفعاضم ةيئاود ةعرج لوانت زوجي لا .يسنملا صرقلا نع ةيئاودلا ةعرجلا ىتح ةعاس نم رثكأ ىقبت اذإ لوانتو ،كركذت لاح دحاو صرق لوانتب مق :ةمداقلا .يدايتعلإا نمزلا يف يلاتلا صرقلا :ةمداقلا ةيئاودلا ةعرجلا ىتح ةعاس نم لقأ ىقبت اذإ ةعاس رظتنإ ،كركذت لاح دحاو صرق لوانتب مق ةدوعلا بجي اهدعب .يفاضإ صرق لوانت مث ةدحاو .ةيدايتعلإا ديعاوملا ىلإ لوانت نيب ةعاس لقلأا ىلع راظتنلإا

امئاد بجي ضارعأ بنجتل كلذو ،رخآو وڤيلاتس نم دحاو صرق .ةلمتحم ةيبناج .بيبطلا ةيصوت بسح جلاعلا ىلع ةبظاوملا بجي جلاعلا نع فقوتلا زوجي لا ،يحصلا كعضو ىلع نسحت أرط ول ىتح .بيبطلا ةراشتسإ نود ءاودلاب جلاعلا نع فقوتلا جاتحي نأ زئاجلا نم ،جلاعلا نع فقوتلا لاح يف ىرخلأا ةيودلأل يئاودلا رادقملا ةمءلامل بيبطلا ،اپودوڤيل

ةصاخ ،ديدج نم نوسنكراپلل ةداضملا .كيدل ضارعلأا ىلع ةيفاك ةرطيس كانه نوكت يكل كلذكو وڤيلاتس لامعتسإ نع ئجافملا فقوتلا نإ يدؤي نأ نكمي ،نوسنكراپلل ةداضم ىرخأ ةيودأ .ةبوغرم ريغ ةيبناج ضارعأ ثودح ىلإ صيخشت بجي !ةمتعلا يف ةيودأ لوانت زوجي لا يئاودلا رادقملا نم دكأتلاو ءاودلا عباط تاراظنلا عض .ءاود اهيف لوانتت ةرم لك يف .كلذ رملأا مزل اذإ ةيبطلا لامعتسإ لوح ةيفاضإ ةلئسأ كيدل ترفوت اذإ .يلديصلا وأ بيبطلا رشتسإ ،ءاودلا اذه ةيبناجلا ضارعلأا )4

اضارعأ ببسي دق وڤيلاتس لامعتسإ نإ ،ءاود لكب امك ةمئاق نم شهدنت لا .نيلمعتسملا ضعب دنع ةيبناج .اهنم

ايأ يناعت لاأ زئاجلا نم .ةيبناجلا ضارعلأا ةطساوب ةيبناجلا ضارعلأا بلغأ فيفخت ناكملإاب .يئاودلا رادقملا ةمءلام ضارعلأاب وڤيلاتس ـب جلاعلا للاخ ترعش اذإ :بيبطلا ىلإ ا

ً

روف هجوتلا بجي ،ةيلاتلا ،ةدشب جنشتت وأ

ادج ةبلص كتلاضع تحبصأ اذإ

ضبن ،ةنوخس ،كابترإ ،شاعترإ ،فاجترإ كيدل .كيدل مدلا طغض يف ةعساو تابلقت وأ عيرس ةمزلاتم ضارعأ نوكت نأ روملأا هذهل نكمي ريطخ لعف در

NMS( ةثيبخلا ناهذلا تاداضم زاهجلا تابارطضإ جلاعل لمعتس

ت ةيودلأ ردانو ةططخملا تلاضعلا للاحنإ وأ )يزكرملا يبصعلا .)ردانو ريطخ يلضع ضرم( ،ىرش لمشت دق تاملاعلا ،يسسحت لعف در وأ ناسللا ،نيتفشلا ،هجولا خافتنإ ،حفط ،ةكح تابوعص ببسي نأ نكمي رملأا اذه .ةرجنحلا .علبلا وأ سفنتلا يف جلاعتم نم رثكأ ىلع رثؤت دق( ا

ً

دج ةعئاش )نيجلاعتم 10 نيب نم دحاو )dyskinesias( ةيدارإ لا تاكرح

نايثغ

لئاملا -ينبلا ىلإ لوبلا نول يف راض ريغ ريغت

رارمحلإا ىلإ تلاضعلا يف ملأ

لاهسإ

10 نيب نم دحاو ىتح ىلع رثؤت دق( ةعئاش )نيجلاعتم ;ضفخنم مد طغضل ةجيتن ءامغإ وأ ةفيفخ ةخود عفترم مد طغض ساعن ؛راود ،نوسن

كراپلا ضارعأ يف مقافت

؛ناقرح ؛نطبلا يف جاعزنإو نطبلا يف ملأ ؛ؤيقت كاسمإ ؛مفلا يف فافج ملاحأ ؛كابترإ ؛ةسوله ؛مونلا ىلع ةردقلا مدع قاهرإ ؛ )ةيليل سيباوك لمشت( ةيداع ريغ ؛ةركاذلا يف لكاشم كلذ يف امب - ةيسفن تاريغت راكفأب قفارتت نأ زئاجلا نم( بائتكإو قلق )ةيراحتنا يف ملأ

لاثم( نييارشلا وأ بلقلل ةيضرم ثداوح

مظتنم ريغ بلق مظن ؛ )ردصلا

ارتاوت رثكأ تاطوقس

سفنتلا يف قيض

حفط ؛قرعتلا ةدايز

نيلجرلا خافتنإ ؛ةيلضع تاصلقت

ةيؤرلا يف شوشت

مد رقف

نزولا ضافخنإ ؛ماعطلل ةيهشلا ضافخنإ

لصافم ملأ ؛عادص

ةيلوبلا كلاسملا يف باهتلإ

نيب نم دحاو ىتح ىلع رثؤت دق( ةعئاش ريغ )جلاعتم 100 ةيبلق ةبون

ءاعملأا يف فزن

ببست دق يتلاو مدلا ايلاخ دادعت يف تاريغت

دبكلا فئاظو صوحفل ةذاش جئاتن ؛فزنلا ءوده مدع

ةيناهذ ضارعأ

)colitis( نولوقلا باهتلإ

،دلجلا

لاثم( لوبلا ادع ام نوللا يف تارييغت )قرعلاو رعشلا ،رفاظلأا علبلا يف تابوعص لوبتلا ىلع ةردقلا مدع وأ ةردان نوكت دق ةنيعم ةيبناج ضارعأ

ً

ادج ةردان تاجلاتخإ

نم اهريدقت نكمي لا( فورعم ريغ اهعويش )ةرفوتملا تامولعملا وه امم رثكأ وڤيلاتس نم ربكأ يئاود رادقمل قوشتلا فورعملا ،ةكرحلا ضارعأ ىلع ةرطيسلل بولطم dopamine( نيماپودلا ميظنت للخ ةمزلاتمك

)dysregulation syndrome

ةذاش ةيدارإ لا تاكرحب نيجلاعتملا ضعب رعشي جازملا يف تابلقت ،)dyskinesias( ةديدشو يئاود رادقم لوانت دعب ىرخأ ةيبناج ضارعأ وأ .وڤيلاتس نم

لاع :ةيلاتلا ةيبناجلا ضارعلأا نع

ً

اضيأ غلب )دبكلا باهتلإ( ناقري

ةكح

:ةيلاتلا ةيبناجلا ضارعلأاب رعشت نأ زئاجلا نم يذلا لمعب مايقلل عفاد ةمواقم ىلع ةردقلا مدع

:لمشت دق ثيح ،

ارضم نوكي نأ هنأش نم دوجو مغر طرفم لكشب ةرماقملل يوق عفاد

ةيلئاع وأ ةيصخش ،ةيدج بقاوع ناذللا دئاز وأ فلتخم يسنج كولسو مامتهإ

لاثم ،نيرخلآل وأ كل يدج قلق ناببسي ةيسنجلا ةبغرلا ةدايز نع ةجراخو لاملل طرفم ريذبت وأ تايرتشم

ةرطيسلا ماعطلا نم ةريبك تايمك لكأ( لكلأا يف ةغلابم

لكأ( يرهق لكأ وأ )ةريصق ةينمز ةرتف للاخ بولطملا نم رثكأو داتعملا نم رثكأ ماعط .)عوجلا عابشلإ هذه ىدحإ نم يساقت تنك اذإ بيبطلا ىلإ هجوت ةقيرطلا صوصخب بيبطلا حصنيس ،تافرصتلا .اهليلقت وأ ضارعلأا ىلع ةرطيسلل ىدحإ تمقافت اذإ ،يبناج ضرع رهظ اذإ ضرع نم يناعت امدنع وأ ةيبناجلا ضارعلأا ةراشتسإ كيلع ،ةرشنلا هذه يف ركذي مل يبناج .بيبطلا ةرازول ةيبناج ضارعأ نع غيلبتلا ناكملإاب نع غيلبت« طبارلا ىلع طغضلا ةطساوب ةحصلا دوجوملا »يئاود جلاع بقع ةيبناج ضارعأ ةحصلا ةرازو عقومل ةيسيئرلا ةحفصلا ىلع ىلإ كهجوي يذلا )www.health.gov.il( وأ ،ةيبناج ضارعأ نع غيلبتلل رشابملا جذومنلا :طبارلا حفصت قيرط نع

https://sideeffects.health.gov.il

؟ءاودلا نيزخت ةيفيك )5 ءاود لكو ءاودلا اذه ظفح بجي !ممستلا بنجت لاجمو يديأ لوانتم نع

اديعب قلغم ناكم يف رخآ مهتباصإ يدافتل كلذو ،عضرلا وأ/و لافطلأا ةيؤر ةحيرص تاميلعت نودب ؤيقتلا ببست لا .ممستلاب .بيبطلا نم خيرات ءاضقنإ دعب ءاودلا لامعتسإ زوجي لا رهظ ىلع رهظي يذلا )

exp.date

( ةيحلاصلا ريخلأا مويلا ىلإ ةيحلاصلا خيرات ريشي .ةبلعلا .رهشلا سفن نم :نيزختلا طورش .ةيوئم ةجرد 25 نود نيزختلا بجي للاخ لامعتسلإا بجي ،ةرم لولأ ةنينقلا حتف دعب .رهشأ 6 ةمامقلل وأ يراجملا ىلإ ةيودلأا يمر زوجي لا نم صلختلا ةيفيك نع يلديصلا لأسإ .ةيلزنملا .لامعتسلإا ديق دعت مل ةيودأ .ةئيبلا ىلع ظافحلا يف دعاست لئاسولا هذه ةيفاضإ تامولعم )6 :ىلع

اضيأ ةلاعفلا تابكرملل ةفاضلإاب ءاودلا يوتحي :صرقلا

Mannitol, maize starch, povidone,

croscarmellose sodium, magnesium

stearate

:صرقلا ءلاط

Hypromellose, titanium dioxide,

sucrose, magnesium stearate,

glycerol 85%, red iron oxide,

polysorbate 80, yellow iron oxide

يف

ادوجوم سيل yellow iron oxide بكرملا :تارايعلا تاذ صارقلأا 125/31.25/200 ،غلم 75/18.75/200 غلم 200/50/200 ،غلم :صرق لك يف )غلم ـب( زوركسلا ةيمك غلم 2.26 – 200/50/200 غلم 1.91 – 150/37.5/200 غلم 1.62 – 125/31.25/200 غلم 1.55 – 100/25/200 غلم 1.35 – 75/18.75/200 غلم 1.18 – 50/12.5/200 ةبلعلا ىوتحم وه امو ءاودلا ودبي فيك :غلم 50/12.5/ 200 وڤيلاتس ىلإ براض-رمحأ ىتح ينب

رمحأ نولب صرق عم ،رطشلا طخ نودب ،بدحم ،ريدتسم ،يدامرلا .دحاو بناج يف LCE 50 ةملاعلا :غلم 75/18.75/200 وڤيلاتس طخ نودب ،يوضيب ،حتاف ينب

رمحأ نولب صرق .دحاو بناج يف LCE 75 ةملاعلا عم ،رطشلا :غلم 100/25/200 وڤيلاتس ىلإ براض

رمحأ ىتح ينب

رمحأ نولب صرق ةملاعلا عم ،رطشلا طخ نودب ،يوضيب ،يدامرلا .دحاو بناج يف LCE 100 :غلم 125/31.25/200 وڤيلاتس طخ نودب ،يوضيب ،حتاف ينب

رمحأ نولب صرق .دحاو بناج يف LCE 125 ةملاعلا عم ،رطشلا :غلم 150/37.5/200 وڤيلاتس ىلإ براض

رمحأ ىتح ينب

رمحأ نولب صرق عم ،رطشلا طخ نودب ،لواطم

يوضيب ،يدامرلا .دحاو بناج يف LCE 150 ةملاعلا :غلم 200/50/200 وڤيلاتس طخ نودب ،يوضيب ،قماغ ينب

رمحأ نولب صرق .دحاو بناج يف LCE 200 ةملاعلا عم ،رطشلا 30 وأ صارقأ 10 ىلع يوتحت ةنينق :بلعلا مجح

اصرق 100 وأ

اصرق .بلعلا ماجحأ ةفاك ق

وست لا .ض.م امراف دماڤونيإ :هناونعو زايتملإا بحاص .5112202 كارب ينب

2349 ب.ص .ادنلنف ،وپسإ ،نويروأ ةكرش :هناونعو جتنملا مسإ .2020 رايأ يف هدادعإ مت يف يموكحلا ةيودلأا لجس يف ءاودلا لجس مقر :ةحصلا ةرازو :غلم 50/12.5/200 وڤيلاتس

132 34 31105

:غلم 75/18.75/200 وڤيلاتس

144 30 32962

:غلم 100/25/200 وڤيلاتس

132 35 31106

:غلم 125/31.25/200 وڤيلاتس

144 31 32963

:غلم 150/37.5/200 وڤيلاتس

132 36 31107

:غلم 200/50/200 وڤيلاتس

141 94 31768

هذه ةغايص تمت ،ةءارقلا نيوهتو ةلوهس لجأ نم نإف ،كلذ نم مغرلا ىلع .ركذملا ةغيصب ةرشنلا .نيسنجلا لاكل صصخم ءاودلا

Page 1

EU SmPC Sep.2019

Prescribing Information

1.

NAME OF THE MEDICINAL PRODUCT

Stalevo 50 mg/12.5 mg/200 mg film-coated tablets

Stalevo 75 mg/18.75 mg/200 mg film-coated tablets

Stalevo 100 mg/25 mg/200 mg film-coated tablets

Stalevo 125 mg/31.25 mg/200 mg film-coated tablets

Stalevo 150 mg/37.5 mg/200 mg film-coated tablets

Stalevo 200 mg/50 mg/200 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Stalevo 50 mg/12.5 mg/200 mg: each tablet contains 50 mg of levodopa, 12.5 mg of carbidopa and

200 mg of entacapone.

Excipient with known effect:

Each tablet contains 1.18 mg of sucrose.

Stalevo 75 mg/18.75 mg/200 mg: each tablet contains 75 mg of levodopa, 18.75 mg of carbidopa and

200 mg of entacapone.

Excipient with known effect:

Each tablet contains 1.35 mg of sucrose.

Stalevo 100 mg/25 mg/200 mg: each tablet contains 100 mg of levodopa, 25 mg of carbidopa and 200 mg

of entacapone.

Excipient with known effect:

Each tablet contains 1.55 mg of sucrose.

Stalevo 125 mg/31.25 mg/200 mg: each tablet contains 125 mg of levodopa, 31.25 mg of carbidopa and

200 mg of entacapone.

Excipient with known effect:

Each tablet contains 1.62 mg of sucrose.

Stalevo 150 mg/37.5 mg/200 mg: each tablet contains 150 mg of levodopa, 37.5 mg of carbidopa and

200 mg of entacapone.

Excipient with known effect:

Each tablet contains 1.91 mg of sucrose.

Stalevo 200 mg/50 mg/200 mg: each tablet contains 200 mg of levodopa, 50 mg of carbidopa and 200 mg

of entacapone.

Excipient with known effect:

Each tablet contains 2.26 mg of sucrose.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablets.

Stalevo 50 mg/12.5 mg/200 mg: brownish- or greyish-red, round, convex, unscored film coated

tablets marked with ‘LCE 50’ on one side.

Stalevo 75 mg/18.75 mg/200 mg: light brownish red, oval-shaped, unscored film-coated tablets

marked with ‘LCE 75’ on one side.

Stalevo 100 mg/25 mg/200 mg: brownish- or greyish-red, oval-shaped, unscored film-coated tablets

Page 2

EU SmPC Sep.2019

marked with ‘LCE 100’ on one side.

Stalevo 125 mg/31.25 mg/200 mg: light brownish red, oval-shaped, unscored film-coated tablets

marked with ‘LCE 125’ on one side

Stalevo 150 mg/37.5 mg/200 mg: brownish- or greyish-red, elongated-ellipse shaped, unscored film-

coated tablets marked with ‘LCE 150’ on one side.

Stalevo 200 mg/50 mg/200 mg: dark brownish red, oval-shaped, unscored film-coated tablets

marked with ‘LCE 200’ on one side.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Stalevo is indicated for the treatment of patients with Parkinson’s disease and end-of-dose motor

fluctuations not stabilised on levodopa/dopa decarboxylase (DDC) inhibitor treatment.

4.2

Posology and method of administration

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

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

75/18.75/200 mg, 100/25/200 mg, 125/31.25/200 mg, 150/37.5/200 mg or 200/50/200 mg

levodopa/carbidopa/entacapone).

Patients should be instructed to take only one Stalevo 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 dosage greater than 200 mg carbidopa is limited, the maximum recommended

daily dose of entacapone is 2000 mg and therefore the maximum Stalevo dose, for the Stalevo strengths

of 50/12.5/200 mg, 75/18.75/200 mg, 100/25/200 mg, 125/31.25/200 mg, and 150/37.5/200 mg, is 10

tablets per day. Ten (10) tablets of Stalevo 150/37.5/200 mg equal 375 mg of carbidopa a day. Therefore,

using a maximum recommended daily dose of 375 mg of carbidopa, the maximum daily dose of Stalevo

200/50/200 mg is 7 tablets per day.

The maximum total daily levodopa dose administered in the form of Stalevo should not exceed 1500 mg.

Starting Stalevo therapy

Patients with Parkinson’s disease with end-of-dose motor fluctuations not stabilised on

levodopa/dopa decarboxylase (DDC) inhibitor treatment

Switching from levodopa/ DDC inhibitor (carbidopa or benserazide) preparations and entacapone

to Stalevo

Usually Stalevo is intended for use in patients already receiving treatment with corresponding doses of

standard-release levodopa/DDC inhibitor and entacapone.

As with levodopa/carbidopa, non-selective monoamine oxidase (MAO) inhibitors are contraindicated for

use with Stalevo. These inhibitors must be discontinued at least two weeks prior to initiating therapy with

Stalevo. Stalevo may be administered concomitantly with the manufacturer’s recommended dose of MAO

inhibitors with selectivity for MAO type B (e.g., selegiline HCl).

a

. Patients who are currently receiving treatment with entacapone and standard-release

levodopa/carbidopa in doses equal to Stalevo tablet strengths can be directly switched to the

corresponding Stalevo tablets, for example:

Levodopa/Carbidopa

Entacapone

Equivalent Stalevo

50/12.5 mg

200 mg

50/12.5/200 mg

100/25 mg

200 mg

100/25/200 mg

Page 3

EU SmPC Sep.2019

150/37.5 mg

200 mg

150/37.5/200 mg

200/50 mg

200 mg

200/50/200 mg

b.

When initiating Stalevo therapy in patients currently receiving treatment with entacapone and

levodopa/carbidopa in doses not equal to the available Stalevo tablet strengths (50/12.5/200 mg,

75/18.75/200 mg, 100/25/200 mg, 125/31.25/200 mg, 150/37.5/200 mg, or 200/50/200 mg), Stalevo

dosing should be carefully titrated for optimal clinical response. At the start of therapy, Stalevo should be

adjusted to correspond as closely as possible to the total daily dose of levodopa currently used.

c.

When initiating Stalevo in patients currently treated with entacapone and levodopa/benserazide in a

standard-release formulation, treatment should be stopped for one night and Stalevo therapy started the

next morning. The therapy should begin with a dosage of Stalevo that will provide either the same

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

Switching in patients not currently treated with entacapone to Stalevo

As with levodopa/carbidopa, non-selective monoamine oxidase (MAO) inhibitors are contraindicated for

use with Stalevo. These inhibitors must be discontinued at least two weeks prior to initiating therapy with

Stalevo. Stalevo may be administered concomitantly with the manufacturer’s recommended dose of MAO

inhibitors with selectivity for MAO type B (e.g., selegiline HCl).

Initiation of Stalevo at a dosage corresponding to current treatment may be considered 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 Stalevo 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 medication (entacapone tablets) and adjust the levodopa

dose if necessary, before switching to Stalevo.

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

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

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.

Dosage 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 Stalevo should be considered, within the dosage recommendations.

When less levodopa is required, the total daily dosage of Stalevo should be reduced either by decreasing

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

Stalevo at an administration.

If other levodopa products are used concomitantly with a Stalevo tablet, the maximum dosage

recommendations should be followed.

Discontinuation of Stalevo therapy

If Stalevo treatment (levodopa/carbidopa/entacapone) is discontinued and the patient is switched 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. (See section 4.4).

Children and adolescents

The safety and efficacy of Stalevo in children aged below 18 years have not been established. No data are

available. Stalevo is not indicated for children and adolescents below 18 years of age.

Elderly

No adjustment of Stalevo dosage is necessary in elderly patients.

Page 4

EU SmPC Sep.2019

Hepatic impairment

Caution is recommended when administering Stalevo to patients with mild to moderate hepatic

impairment. Dose reduction may be necessary (see Section 5.2).

Renal impairment

Renal impairment does not affect the pharmacokinetics of entacapone. No specific studies are reported on

the pharmacokinetics of levodopa and carbidopa in patients with renal impairment, and Stalevo should

therefore be administered with caution in patients with 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.

Co-administraton of Stalevo with non-selective monoamine oxidase (MAO-A and MAO-B)

inhibitors (e.g. phenelzine, tranylcypromine).

Co-administration 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

Stalevo is not recommended for the treatment of drug-induced extrapyramidal reactions.

Stalevo 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 Stalevo 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 Stalevo with caution, provided

the intra-ocular pressure is well controlled and the patient is monitored carefully for changes in

intra-ocular pressure.

Stalevo may induce orthostatic hypotension. Therefore Stalevo 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 medicinal products may need to be adjusted when Stalevo treatment is

Page 5

EU SmPC Sep.2019

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 Stalevo 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 Stalevo 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, Stalevo 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 Stalevo.

For patients experiencing diarrhea, 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 Stalevo. Review of

treatment is recommended if such symptoms develop.

Dopamine Dysregulation Syndrome (DDS) is an addictive disorder resulting in excessive use of

the product seen in some patients treated with carbidopa/levodopa. Before initiation of treatment,

patients and caregivers should be warned of the potential risk of developing DDS (see also

section 4.8).

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.

Stalevo contains sucrose, and therefore patients with rare hereditary problems of fructose

intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take

this medicine.

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

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EU SmPC Sep.2019

antiparkinsonian medicinal products with Stalevo 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 inhibitor and no interaction was observed. When used with Stalevo, 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

Stalevo (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 Stalevo should be

carefully observed for loss of therapeutic response.

Due to entacapone's affinity to cytochrome P450 2C9

in vitro

(see section 5.2), Stalevo 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% [CI

11-26 %]. The INR values

increased on average by 13% [CI

6-19%]. Thus, a control of INR is recommended when Stalevo is

initiated for patients receiving warfarin.

Other forms of interactions

Since levodopa competes with certain amino acids, the absorption of Stalevo may be impaired in some

patients on high protein diet.

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

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

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EU SmPC Sep.2019

section 5.3). The potential risk for humans is unknown. Stalevo 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 it 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 Stalevo.

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

Stalevo may have a major influence on the ability to drive and use machines. Levodopa, carbidopa and

entacapone together may cause dizziness and symptomatic orthostatism. Therefore, caution should be

exercised when driving or using machines.

Patients being treated with Stalevo 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 Stalevo 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

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 Stalevo or entacapone combined

with levodopa/DDC inhibitor. Serious hepatitis with mainly cholestatic features, rhabdomyolysis and

neuroleptic malignant syndrome may occur with Stalevo 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 Stalevo 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.

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

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EU SmPC Sep.2019

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, Dopamine dysregulation syndrome

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)*

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

Page 9

EU SmPC Sep.2019

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 occuring (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

causal

relationship

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 Stalevo (see section 4.4).

Dopamine Dysregulation Syndrome (DDS) is an addictive disorder seen in some patients treated with

carbidopa/levodopa. Affected patients show a compulsive pattern of dopaminergic drug misuse above doses

adequate to control motor symptoms, which may in some cases result in severe dyskinesias (see also section

4.4).

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.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form: https://sideeffects.health.gov.il

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 Stalevo therapy is similar to acute overdose with levodopa.

Pyridoxine, however, is not effective in reversing the actions of Stalevo. 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 gastrointestinal 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

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EU SmPC Sep.2019

arrhythmias. If required, appropriate anti-arrhythmic therapy should be given. The possibility that the

patient has taken other active substances in addition to Stalevo 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.

The evidence of the therapeutic effects of Stalevo 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

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

translated

mean

increase

daily

time.

Correspondingly, the daily OFF time decreased by 18% on entacapone and by 5% on placebo. Because the

effects of Stalevo 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 Stalevo 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 of 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 (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

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EU SmPC Sep.2019

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 (t

) 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.

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 elderly than in young people. However, after combination of carbidopa with levodopa, the

absorption of levodopa is similar between the elderly and the young people, but the AUC is still 1.5 fold

greater in the elderly due to decreased DDC activity and lower clearance caused by aging. There are no

significant differences in the AUC of carbidopa or entacapone between younger (45–64 years) and elderly

subjects (65–75 years).

Gender

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

with Stalevo 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

Stalevo 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 on the

pharmacokinetics of levodopa and carbidopa in patients with renal impairment. However, a longer dosing

interval of Stalevo 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

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EU SmPC Sep.2019

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: mannitol, maize starch, povidone, croscarmellose sodium, magnesium stearate

Film-coating: Hypromellose, titanium dioxide, sucrose, magnesium stearate, polysorbate 80, glycerol

85%, red iron oxide, yellow iron oxide, (Note: yellow iron oxide not used in 75/18.75/200 mg,

125/31.25/200 mg and 200/50/200 mg tablets).

6.2

Incompatibilities

Not applicable

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials.

6.4

Special precautions for storage

Store below 25°C.

After first opening of the bottle, use within 6 months.

6.5

Nature and content of container

HDPE bottles with polypropylene closure.

Pack sizes: 10, 30 and 100 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.

MANUFACTURER

Orion Corporation, Espoo, Finland

REGISTRATION HOLDER

Inovamed Pharma Ltd. P.O.B. 2349 Bnei Brak 5112202

Revised in May 2020.