Consumer medicine information

Stalevo

Levodopa; Carbidopa; Entacapone

BRAND INFORMATION

Brand name

Stalevo

Active ingredient

Levodopa; Carbidopa; Entacapone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Stalevo.

What is in this leaflet

This leaflet answers some common questions about Stalevo.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. You can also download the most up to date leaflet from www.novartis.com.au. Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will provide.

If you have any concerns about this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Stalevo is used for

Stalevo is used to treat the symptoms of Parkinson's disease.

Parkinson's disease is a disorder of the nervous system. It is caused by a lack of dopamine, a natural substance that is produced in the brain. Dopamine relays messages in the part of the brain that controls muscle movement. When too little dopamine is produced, problems with movement result.

Stalevo contains three active ingredients: levodopa, carbidopa anhydrous and entacapone. Levodopa is a chemical closely related to dopamine, which allows the body to make its own dopamine. Levodopa works by increasing the level of dopamine in the brain. Carbidopa makes sure that enough levodopa gets to the brain where it is needed, and entacapone makes the effect of levodopa last longer.

Stalevo helps to relieve symptoms such as shaking of the limbs, stiffness and slowness of movement, which make it difficult to perform normal daily activities. Other medicines can also be added to help treat this condition.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another purpose.

This medicine is only available with a doctor's prescription. It is not habit-forming.

There is not enough information to recommend this medicine for children under 18 years of age.

Before you take Stalevo

When you must not take it

Do not take Stalevo if you have ever had an allergy to any medicines containing levodopa, carbidopa or entacapone (the active ingredients in Stalevo) or to any of the other ingredients listed at the end of this leaflet. Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

Do not take Stalevo if you are taking a medicine called a monoamine oxidase inhibitor (MAOI) such as phenelzine and tranylcypromine. Taking Stalevo together with some, but not all, MAOI medicines may cause a serious reaction with a sudden increase in body temperature, extremely high blood pressure and severe convulsions. Your doctor will know whether or not the MAOI medicine you are taking can be safely taken with Stalevo.

Ask your doctor or pharmacist if you are not sure if you have been taking one of these medicines.

Do not take Stalevo if you are pregnant. There is not enough information to recommend its use during pregnancy.

Do not breast-feed while you are taking Stalevo. It is not known if the active ingredient in Stalevo passes into breast milk and could affect your baby.

Do not take Stalevo if you have any of the following health problems / medical conditions:

  • a problem with your liver
  • a tumour of the adrenal gland (called phaeochromocytoma), which could cause your blood pressure to rise to a dangerous level
  • you have ever had a serious condition called neuroleptic malignant syndrome (NMS), with symptoms such as a sudden increase in body temperature, sweating, fast heart beat, muscle stiffness and fluctuating blood pressure
  • you have ever had a condition called rhabdomyolysis, with symptoms of severe muscle weakness that was not due to an injury.
  • unusual skin lumps or moles which have not been examined by your doctor, or if you have ever had skin cancer or melanoma.
  • have a type of glaucoma called narrow-angle glaucoma.

If you are not sure whether any of the above conditions apply to you, your doctor can advise you.

Tell your doctor if you have an intolerance to sucrose.

This medicine contains sucrose.

Do not take Stalevo after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. In that case, return it to your pharmacist.

Before you start to take it

Tell your doctor if you are pregnant or intend to become pregnant. Your doctor will discuss the possible risks and benefits of using Stalevo during pregnancy.

Tell your doctor if you have, or have ever had any medical condition, especially the following:

  • depression, mental disturbances, or you recognise anti-social behaviour
  • heart disease, including irregular heart beat, also known as arrhythmia
  • kidney problems
  • lung problems including asthma
  • hormonal problems
  • convulsions or fits
  • a type of glaucoma called wide-angle glaucoma
  • stomach ulcers
  • problems with your gall bladder
  • inflammatory bowel disease

Your doctor may need to adjust the dose of Stalevo in some of these cases.

Tell your doctor if you have allergies to any other medicines, foods, dyes or preservatives. Your doctor will want to know if you are prone to allergies.

Taking other medicines

Tell your doctor if you are taking a medicine called a monoamine oxidase inhibitor (MAOI) such as phenelzine and tranylcypromine. Taking Stalevo together with some, but not all, MAOI medicines may cause a serious reaction with a sudden increase in body temperature, extremely high blood pressure and severe convulsions. Your doctor will know whether or not the MAOI medicine you are taking can be safely taken with Stalevo.

Ask your doctor or pharmacist if you are not sure if you have been taking one of these medicines.

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines and Stalevo may interfere with each other. These include:

  • some antibiotics such as erythromycin, rifampicin, ampicillin and chloramphenicol
  • apomorphine, a medicine used in Parkinson's Disease
  • adrenaline, a medicine used in some local anaesthetics and in emergency treatment of allergic reactions
  • cholestyramine, a medicine used to reduce high levels of cholesterol in the blood
  • papaverine, a medicine used to expand blood vessels to treat men with erectile dysfunction
  • probenecid, a medicine used to prevent gout
  • some medicines used to treat high blood pressure
  • other medicines for Parkinson's disease
  • some medicines for depression
  • some medicines for psychiatric disorders
  • methyldopa, a medicine for high blood pressure
  • isoniazid, a medicine used to treat tuberculosis
  • some medicines for nausea and vomiting
  • phenytoin, a medicine used to treat convulsions
  • medicines containing iron, such as iron tablets or multiple vitamins
  • warfarin, a medicine used to prevent blood clots

You may need to take different amounts of your medicines or to take different medicines while you are taking Stalevo. Your doctor and pharmacist have more information.

If you have not told your doctor about any of these things, tell him/her before you start taking this medicine.

How to take Stalevo

Follow all directions given to you by your doctor and pharmacist carefully. These directions may differ from the information contained in this leaflet.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

How much to take

People with moderate to severe Parkinson's disease usually take from 3 to 7 tablets of Stalevo each day.

For Stalevo 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, the maximum dose is 10 tablets each day.

For Stalevo 200/50/200 mg: The maximum dose is 7 tablets each day.

Take only one STALEVO tablet at each dose.

Do not take 2 or more STALEVO tablets at a time.

Do not break the tablets into halves.

How to take it

Take the tablet with a full glass of water.

If your stomach is upset after taking the tablet, take it with a meal or after a snack. It does not matter if you take Stalevo with or without food but avoid a high protein meal.

If you are taking any medicines containing iron, take them at least 2 or 3 hours before or after a dose of Stalevo. If you take the two medicines at the same time, your body may absorb less iron than usual.

How long to take it

Do not stop taking this medicine without first checking with your doctor. You may need to take Stalevo for a long time to control your symptoms. If you stop taking it, the dose of your other medicines for Parkinson's disease may have to be increased to prevent your symptoms from getting worse.

If you forget to take it

If it is almost time for your next dose (say, within an hour of the next dose), skip the dose you missed and take your next dose when you are meant to.

If you forget to take a tablet of Stalevo, you should take it as soon as you notice that you have forgotten to take your medication.

Do not take a double dose to make up for forgotten individual doses. This may increase the chance of you getting an unwanted side effect.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Center (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much Stalevo. Do this even if there are no signs of discomfort or poisoning. Keep the telephone numbers for these places handy.

While you are taking Stalevo

Things you must do

If you experience times where Stalevo does not appear to be working as well as it did previously, tell your doctor.

If you become pregnant, tell your doctor immediately. You should not take this medicine while you are pregnant.

Before having any surgery or other hospital treatment, tell the anaesthetist or the doctor in charge that you are taking Stalevo. It may cause unwanted side effects if you take it at the same time as some medicines that are used in hospital.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Stalevo.

Tell any other doctor, dentist or pharmacist who treats you that you are taking Stalevo.

Be sure to keep all of your doctor's appointments so that your progress can be checked. Your doctor may also want to take some tests from time to time to help prevent unwanted side effects.

Tell your doctor if you or your family/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 (known as dopamine dysregulation syndrome).

Tell your doctor if you or your family/caregiver 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 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.

Things you must not do

Do not give this medicine to anyone else, even if their condition seems similar to yours.

Do not use it to treat any other complaints unless your doctor tells you to.

Do not reduce the dose or stop treatment abruptly without consulting your doctor. It may be necessary to reduce the dose of Stalevo gradually in order to prevent side effects.

Things to be careful of

Be careful driving, operating machinery or doing jobs that require you to be alert while you are taking Stalevo until you know how it affects you. This medicine may increase the dizziness, light-headedness or sleepiness that sometimes happens when you take levodopa. Very rarely it can cause extreme sleepiness and sudden onset of sleep in the middle of daytime activities, sometimes without warning. If you have any of these symptoms, do not drive or do anything else that could be dangerous.

If this medicine makes you feel light-headed, dizzy or faint, be careful when getting up from a sitting or lying position. These symptoms may be a sign of low blood pressure. You can usually prevent them by getting up slowly and flexing leg muscles and toes to get the blood flowing. When getting out of bed, dangle your legs over the side for a minute or two before standing up.

Be careful not to eat a diet high in protein. The amount of levodopa absorbed by the body may be impaired if you eat a diet high in protein. Ask your doctor, pharmacist or dietician to check your diet.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Stalevo. All medicines can have side effects. Sometimes they are serious, but most of the time they are not. You may need medical treatment if you get some of the side effects.

Some of the side effects listed below are more common at the beginning of treatment and may disappear as treatment continues.

Do not be alarmed by these lists of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following side effects and they worry you:

  • nausea (feeling sick) or vomiting
  • indigestion
  • diarrhoea
  • pain in the stomach
  • constipation
  • dry mouth
  • dizziness or light-headedness
  • unsteadiness when walking, or a lack of coordination in your movements or speech
  • spinning sensation (vertigo)
  • tiredness or sleepiness
  • shakiness
  • aches and pains
  • muscle cramps and pain or joint pain
  • headache
  • increased sweating
  • difficulty sleeping or unusual dreams
  • feeling depressed or agitated
  • a reddish-brown colour to the urine (this is harmless)
  • weight gain or loss (these are less common side effects)
  • blurred vision
  • seeing double
  • strong urge to urinate that cannot be delayed, which is followed by a sharp pain or burning sensation in the urethra when the urine is released (urinary tract infection).

Tell your doctor immediately if you notice any of the following side effects:

  • rash, itching or hives on the skin
  • unusual and uncontrolled movements of the body such as twisting, jerking or writhing movements
  • symptoms of neuroleptic malignant syndrome, such as a sudden increase in body temperature, sweating, fast heart beat, muscle stiffness and fluctuating blood pressure
  • extreme sleepiness or sudden onset of sleep in the middle of daytime activities
  • worsening of your symptoms of Parkinson's disease
  • craving for large doses of Stalevo in excess of that required to control motor symptoms, known as dopamine dysregulation syndrome. Some patients experience severe uncontrolled movements (dyskinesias), mood swings, or other side effects after taking large doses of Stalevo.
  • inability to resist the impulse to perform an action that could be harmful, which may include:
    - strong impulse to gamble excessively despite serious or personal 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).
    - medicine use or repetitive purposeless activities.

Tell your doctor if you experience any of these behaviours.

Your doctor will discuss ways of managing or reducing the symptoms.

  • confusion or hallucinations (seeing, hearing or feeling things that are not there)
  • difficulty breathing, congestion in the chest, chest pain
  • signs of possible anaemia (low amount of iron in your blood) such as tiredness, headaches, shortness of breath when exercising, dizziness and looking pale
  • signs of possible liver problems such as loss of appetite, feeling generally unwell, fever, itching, yellow colour to the skin and eyes
  • temporary paralysis or weakness of muscles
  • gastrointestinal bleeding (coughing up blood or blood in the stools)
  • diarrhoea, usually with blood and mucus, stomach pain, fever

Tell your doctor if you notice anything else that is making you feel unwell. Some people may have other side effects not yet known or mentioned in this leaflet.

After using Stalevo

Storage

  • Keep your medicine in the original container until it is time to take it.
  • Store it in a cool dry place.
  • Do not store Stalevo or any other medicine in the bathroom or near a sink.
  • Do not leave it in the car or on windowsills.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking Stalevo or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

There are six strengths of Stalevo available and they each look different from one another.

  • Stalevo 50/12.5/200 are round-shaped tablets marked with 'LCE 50' on one side
  • Stalevo 75/18.75/200 are oval-shaped tablets marked with 'LCE 75' on one side
  • Stalevo 100/25/200 are oval-shaped tablets marked with 'LCE 100' on one side
  • Stalevo 125/31.25/200 are oval-shaped tablets marked with 'LCE 125' on one side
  • Stalevo 150/37.5/200 are ellipse-shaped tablets marked with 'LCE 150' on one side.
  • Stalevo 200/50/200 are oval-shaped tablets marked with 'LCE 200' on one side.

Stalevo 50/12.5/200 mg, 100/25/200 mg and 150/37.5/200 mg are brownish- or greyish-red; 200/50/200 mg is a dark brownish-red; and 75/18.75/200 mg and 125/31.25/200 mg are light brownish red film-coated tablets

All six strengths of Stalevo are available in bottles of 30 tablets (sample pack) and 100 tablets (commercial pack).

Ingredients

Stalevo is supplied in 6 strengths:

  • Stalevo 50/12.5/200 containing 12.5 mg carbidopa anhydrous, 50 mg levodopa, and 200 mg entacapone
  • Stalevo 75/18.75/200 containing 18.75 mg carbidopa anhydrous, 75 mg levodopa, and 200 mg entacapone
  • Stalevo 100/25/200 containing 25 mg carbidopa anhydrous, 100 mg levodopa, and 200 mg entacapone
  • Stalevo 125/31.25/200 containing 31.25 mg carbidopa anhydrous, 125 mg levodopa, and 200 mg entacapone
  • Stalevo 150/37.5/200 containing 37.5 mg carbidopa anhydrous, 150 mg levodopa, and 200 mg entacapone
  • Stalevo 200/50/200 containing 50 mg carbidopa anhydrous, 200 mg levodopa, and 200 mg entacapone

Apart from the active ingredients, levodopa, carbidopa anhydrous and entacapone, Stalevo tablets contain the following inactive ingredients.

  • croscarmellose sodium
  • magnesium stearate
  • starch - maize
  • mannitol
  • povidone
  • glycerol
  • hypromellose
  • magnesium stearate
  • polysorbate 80
  • iron oxide red CI77491
  • sucrose
  • titanium dioxide
  • iron oxide yellow CI77492.

Stalevo does not contain gluten, tartrazine or any other azo dyes.

Sponsor

Stalevo is supplied in Australia by:

NOVARTIS Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
North Ryde NSW 2113
Telephone 1 800 671 203

®= Registered Trademark

This leaflet was prepared in August 2019.

Australian Registration Number.

Stalevo (50/12.5/200) tablet
AUST R 96372

Stalevo (75/18.75/200) tablet
AUST R 160686

Stalevo (100/25/200) tablet
AUST R 96395

Stalevo (125/31.25/200) tablet
AUST R 160687

Stalevo (150/37.5/200) tablet
AUST R 96396

Stalevo (200/50/200) tablet
AUST R 146890

(sta010819c.doc) based on PI (sta010819i.doc)

Published by MIMS October 2019

BRAND INFORMATION

Brand name

Stalevo

Active ingredient

Levodopa; Carbidopa; Entacapone

Schedule

S4

 

1 Name of Medicine

Levodopa/carbidopa anhydrous/entacapone.

6.7 Physicochemical Properties

Levodopa and carbidopa are white crystalline compounds, slightly soluble in water. Entacapone is a yellow or greenish yellow crystalline powder. The (E)-isomer is the main product and less than 0.5% of the (Z)-isomer occurs in the raw material.

Levodopa.

Chemical name: (2S)-2-amino-3- (3,4-dihydroxyphenyl)propanoic acid. Molecular formula: C9H11NO4. Molecular weight: 197.19.

Carbidopa (anhydrous).

Chemical name: (2S)-3-(3,4-dihydroxyphenyl)- 2-hydrazino-2-methylpropanoic acid, monohydrate. Molecular formula: C10H14N2O4. Molecular weight: 226.2.

Entacapone.

Chemical name: (E)-2-cyano-3- (3,4-dihydroxy-5-nitrophenyl)- N,N-diethyl-2-propenamide. Molecular formula: C14H15N3O5. Molecular weight: 305.28.

Chemical structure.


CAS number.

Levodopa: 59-92-7.
Carbidopa anhydrous: 31823-41-3.
Entacapone: 130929-57-6.

2 Qualitative and Quantitative Composition

Stalevo film-coated tablets are available in six strengths, each containing a 4:1 ratio of levodopa to carbidopa anhydrous combined with 200 mg of entacapone in a standard release formulation: 50/12.5/200 mg, 75/18.75/200 mg, 100/25/200 mg, 125/31.25/200 mg, 150/37.5/200 mg and 200/50/200 mg.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Stalevo 50 mg/12.5 mg/200 are round, biconvex tablets marked with 'LCE 50' on one side.
Stalevo 75/18.75/200 are oval tablets marked with 'LCE 75' on one side.
Stalevo 100/25/200 are oval tablets marked with 'LCE 100' on one side.
Stalevo 125/31.25/200 are oval tablets marked with 'LCE 125' on one side.
Stalevo 150/37.5/200 are elongated-ellipse shaped tablets marked with 'LCE 150' on one side.
Stalevo 200/50/200 are oval tablets marked with 'LCE 200' on one side.
Stalevo strengths 50/12.5/200 mg, 100/25/200 mg and 150/37.5/200 mg are brownish- or greyish-red, film-coated tablets. Stalevo strength 200/50/200 mg is a dark brownish-red film-coated tablet. Stalevo strengths 75/18.75/200 mg and 125/31.25/200 mg are light brownish red, film-coated tablets.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The symptoms of Parkinson's disease are thought to be 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 dopa decarboxylase (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 coadministration of a DDC inhibitor, a lower dose of levodopa can be used and the incidence of adverse effects such as nausea is reduced.
With inhibition of the decarboxylase by a DDC inhibitor, COMT becomes the major peripheral metabolic pathway catalysing 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 reversibility of COMT inhibition with entacapone has been demonstrated in bioassays of COMT activity in red blood cells; red blood cell COMT inhibition tightly correlates with plasma concentrations of the drug.

Clinical trials.

Each Stalevo tablet, provided in six single dose strengths, contains carbidopa anhydrous and levodopa in a 1:4 ratio and a 200 mg dose of entacapone. Four Stalevo strengths 50/12.5/200 mg, 100/25/200 mg, 150/37.5/200 mg and 200/50/200 mg have been shown to be bioequivalent to the corresponding doses of standard release levodopa/carbidopa anhydrous 100/25 mg tablets and entacapone 200 mg tablets. Hence, the results from previous trials of entacapone 200 mg administered concomitantly with standard levodopa/carbidopa preparations are applicable to the effects of Stalevo as well.
The anticipated therapeutic effects of Stalevo are based on the results of two pivotal phase III studies in 376 Parkinson's disease patients with end of dose motor fluctuations receiving entacapone or placebo with each levodopa/DDC inhibitor dose.
The two pivotal phase III studies, entitled NOMECOMT and SEESAW, were prospective, randomised, double blind, placebo controlled, parallel group trials, each conducted over a 6 month period. In the two studies, a total of 188 patients in the entacapone group and 188 patients in the placebo group were included in the intention to treat analysis. The mean duration of Parkinson's disease in subjects prior to trial entry was 10-11 years and the duration of fluctuations in motor performance was > 4 years. A tablet of entacapone 200 mg or placebo was administered in combination with each patient's usual scheduled dose of levodopa/DDC inhibitor (4 to 10 doses daily). The primary efficacy parameter was the increase in mean daily 'on' time or proportion of 'on' time (from the home diaries) compared to placebo. In the NOMECOMT study, the duration of 'on' time following the first daily dose of levodopa was also a primary parameter. Of secondary importance were evaluations of 'off' time, the UPDRS, global score, daily fluctuations and daily levodopa dosage.
In both studies, entacapone had a significant positive effect on the primary, and most of the secondary efficacy parameters. In the NOMECOMT study, the mean daily 'on' time was 1.3 hours (approximately 14%) longer in the entacapone group relative to placebo (p < 0.001). The percent of 'on' time while awake increased significantly (p < 0.001) and the duration of 'on' time after the first daily dose was also significantly longer (p < 0.05). In the SEESAW study, although the increase in daily 'on' time of 0.6 hours did not reach statistical significance, the 'on' time expressed as a percent of time awake was significantly improved (p < 0.05). The UPDRS objective disease rating (total, activities of daily living, motor parts) and the global evaluation by the investigator were significantly in favour of entacapone in both studies, and the daily dose of levodopa required decreased by approximately 100 mg per day (p < 0.001). At the end of the active treatment period, a well defined withdrawal effect of entacapone was demonstrated, with the outcome for all variables showing a significant deterioration in the patients' condition. The average daily 'on' time decreased by 1.5 hours (p < 0.001) and the motor score of the UPDRS deteriorated significantly (p < 0.01) in both studies.

5.2 Pharmacokinetic Properties

Absorption and distribution.

There are substantial inter- and intraindividual 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 ingredients, the bioavailability for levodopa is 15-33%, for carbidopa 40-70% and for entacapone 29-36% (35% after the 200 mg oral dose). High protein 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 effect of food on Stalevo tablets has not been evaluated.

Levodopa.

The pharmacokinetic characteristics of levodopa following the administration of single dose Stalevo tablets are summarised in Table 3.
Levodopa is bound to plasma protein only to a minor extent of about 10-30%.

Carbidopa.

Following administration of Stalevo as a single dose to healthy male and female subjects, the peak concentration of carbidopa was reached within 2.5 to 3.4 hours on average. The mean Cmax ranged from about 40 to 125 nanogram/mL and the mean AUC from 170 to 700 nanogram.hour/mL, with different Stalevo strengths providing 12.5 mg, 25 mg or 37.5 mg of carbidopa anhydrous. Carbidopa is bound approximately 36% to plasma protein.

Entacapone.

Following administration of Stalevo as a single dose to healthy male and female subjects, the peak concentration of entacapone in plasma was reached within 1.0 to 1.2 hours on average. The mean Cmax of entacapone was about 1,200 nanogram/mL and the AUC 1,250 to 1,450 nanogram.hour/mL after administration of different Stalevo strengths all providing 200 mg entacapone. Entacapone is extensively bound to plasma proteins (about 98%), mainly to serum albumin.
The distribution volumes of both levodopa (0.36-1.6 L/kg) and entacapone (0.27 L/kg) are moderately small while no data for carbidopa are available.

Metabolism and excretion.

Data from in vitro studies using human liver microsomal preparations indicate that entacapone inhibits cytochrome P450 2C9 (IC50 ≈ 4 microM). Entacapone showed little or no inhibition of other types of P450 isoenzymes (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Levodopa.

The elimination half-life (t1/2el) is 0.6-1.3 hours for levodopa. 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.

The elimination half-life (t1/2el) is 2-3 hours for carbidopa. Carbidopa is metabolised to two main metabolites (α-methyl-3-methoxy-4- hydroxyphenylpropionic acid and α-methyl-3,4- dihydroxyphenylpropionic acid) which are excreted in the urine as glucuronides and unconjugated compounds. Unchanged carbidopa accounts for 30% of the total urinary excretion.

Entacapone.

The elimination half-life (t1/2el) is 0.4-0.7 hours for entacapone. Entacapone is almost completely metabolised prior to excretion; only about 0.2% is excreted unchanged in urine. The main metabolic pathway is glucuronidation of entacapone and its active metabolite, the cis-isomer, which accounts for about 5% of plasma total amount. Ten percent of an entacapone dose is excreted in urine, and 90% in faeces by biliary excretion. Of entacapone metabolites found in urine only about 1% have been formed through oxidation. Total plasma clearance for levodopa is in the range of 0.55-1.38 L/kg/hour and for entacapone is in the range of 0.70 L/kg/hour.
Due to short elimination half-lives, no true accumulation of levodopa or entacapone occurs when they are administered repeatedly.

Pharmacokinetics in patients with liver impairment.

Stalevo should be administered cautiously to patients with biliary obstruction or hepatic disease. There are no studies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic impairment, but biliary excretion appears to be the major route of excretion of entacapone.

Entacapone.

Hepatic impairment had a significant effect on the pharmacokinetics of entacapone when 200 mg entacapone was administered alone. A single 200 mg dose of entacapone, without levodopa/DDC inhibitor coadministration, showed approximately twofold higher AUC and Cmax values in patients with a history of alcoholism and hepatic impairment (n = 10) compared to normal subjects (n = 10). All patients had biopsy proven liver cirrhosis caused by alcohol. According to Child-Pugh grading 7 patients with liver disease had mild hepatic impairment and 3 patients had moderate hepatic impairment. As only about 10% of the entacapone dose is excreted in urine, as parent compound and conjugated glucuronide, biliary excretion appears to be the major route of excretion of this drug. Consequently, Stalevo should be administered with care to patients with biliary obstruction or hepatic disease.

Pharmacokinetics in patients with renal impairment.

Stalevo should be administered cautiously to patients with severe renal disease (see Section 4.2 Dose and Method of Administration). There are no 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.

Entacapone.

No important effects of renal function on the pharmacokinetics of entacapone were found. The pharmacokinetics of entacapone have been investigated after a single 200 mg entacapone dose, without levodopa/ dopa decarboxylase inhibitor coadministration, in a specific renal impairment study. There were three groups: normal subjects (n = 7; creatinine clearance > 1.12 mL/second/1.73 m2), moderate impairment (n = 10; creatinine clearance ranging from 0.60-0.89 mL/second/1.73 m2), and severe impairment (n = 7; creatinine clearance ranging from 0.20-0.44 mL/second/1.73 m2).

Pharmacokinetics in the elderly.

Stalevo tablets have not been studied in Parkinson's disease patients or in healthy volunteers older than 75 years old. In the pharmacokinetics studies conducted in healthy volunteers following single dose of carbidopa/ levodopa/ entacapone (as Stalevo or as separate carbidopa/ levodopa and Comtan tablets):

Levodopa.

The AUC of levodopa is significantly (on average 10-20%) higher in elderly (60-75 years) than younger subjects (45-60 years). There is no significant difference in the Cmax of levodopa between younger (45-60 years) and elderly subjects (60-75 years).

Carbidopa.

There is no significant difference in the Cmax and AUC of carbidopa, between younger (45-60 years) and elderly subjects (60-75 years).

Entacapone.

The AUC of entacapone is significantly (on average, 15%) higher in elderly (60-75 years) than younger subjects (45-60 years). There is no significant difference in the Cmax of entacapone between younger (45-60 years) and elderly subjects (60-75 years).

Gender differences in pharmacokinetics.

The bioavailability of levodopa is significantly higher in females when given with or without carbidopa and/or entacapone. In the pharmacokinetic studies with Stalevo, the bioavailability of levodopa is higher in women than in men, primarily due to the difference in bodyweight, while there is no gender difference with carbidopa and entacapone. Following a single dose of carbidopa, levodopa and entacapone together, either as Stalevo or as separate carbidopa/ levodopa and Comtan tablets in healthy volunteers (age range 45-74 years).

Levodopa.

The plasma exposure (AUC and Cmax) of levodopa is significantly higher in females than males (on average, 40% for AUC and 30% for Cmax). These differences are primarily explained by bodyweight. Other published literature showed significant gender effect (higher concentrations in females) even after correction for bodyweight.

Carbidopa.

There is no gender difference in the pharmacokinetics of carbidopa.

Entacapone.

There is no gender difference in the pharmacokinetics of entacapone.

5.3 Preclinical Safety Data

Genotoxicity.

Entacapone was not genotoxic in a bacterial gene mutation assay, but positive results were obtained in a mammalian gene mutation assay and an in vitro assay for clastogenicity. Entacapone was negative in an in vivo assay for clastogenicity and assays for DNA damage. Carbidopa was positive in bacterial and mammalian gene mutation assays, but negative in an in vivo assay for clastogenicity. A combination of levodopa, carbidopa and entacapone was negative in a bacterial gene mutation assay and two in vivo assays for clastogenicity.

Carcinogenicity.

Two year carcinogenicity studies were conducted in mice and rats dosed orally with entacapone daily. No carcinogenic effects were found in the rodents at exposures (plasma AUC) of at least 6 times the maximal clinical exposure, except for an increased incidence of renal tubule tumours in male rats at the highest dose. The tumours were induced by a disturbance in the renal hydrolysis of a protein (α2u-globulin) specific to male rats, and are thought not to constitute a hazard for clinical use.

4 Clinical Particulars

4.1 Therapeutic Indications

Stalevo is indicated for the management of patients with Parkinson's disease who are experiencing motor fluctuations.

4.3 Contraindications

Known hypersensitivity to the active substances or to any of the excipients.
Pregnancy and breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in lactation).
Severe liver impairment (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in patients with liver impairment).
Patients with narrow angle glaucoma.
Patients with phaeochromocytoma due to the increased risk of hypertensive crisis.
Coadministration of Stalevo with nonselective monoamine oxidase (MAO-A and MAO-B) inhibitors (e.g. phenelzine, tranylcypromine) is contraindicated. Similarly, coadministration of a selective MAO-A inhibitor plus a selective MAO-B inhibitor and Stalevo is contraindicated.
A previous history of neuroleptic malignant syndrome and/or nontraumatic rhabdomyolysis (see Section 4.4 Special Warnings and Precautions for Use, Neuroleptic malignant syndrome and rhabdomyolysis).
Because levodopa may activate malignant melanoma, Stalevo should not be used in patients with suspicious undiagnosed skin lesions or a history of malignant melanoma.

4.4 Special Warnings and Precautions for Use

Precautions relating to levodopa component of Stalevo.

Stalevo is not recommended for the treatment of drug induced extrapyramidal reactions.
Stalevo should be administered cautiously to patients with ischaemic heart disease, severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease, or history of peptic ulcer disease or 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 dosage adjustments.
All patients treated with levodopa 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 antipsychotic drugs with dopamine receptor blocking properties particular D2-receptor antagonists should be carried out with caution and the patient carefully observed for loss of antiparkinsonian effect or worsening of antiparkinsonian symptoms.
Patients with chronic wide angle glaucoma may be treated with Stalevo with caution, provided the intraocular pressure is well controlled and the patient is monitored carefully for changes in intraocular 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 Effects on Ability to Drive and Use Machines).

Neuroleptic malignant syndrome and rhabdomyolysis.

Neuroleptic malignant syndrome (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. 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. Isolated cases of NMS have been reported, especially following abrupt reduction or discontinuation of entacapone (see Section 4.2 Dose and Method of Administration, Discontinuation of Stalevo therapy). Rhabdomyolysis secondary to severe dyskinesias or NMS has been observed rarely in patients with Parkinson's disease. Isolated cases of rhabdomyolysis have been reported with entacapone treatment. When considered necessary, withdrawal of Stalevo and other dopaminergic treatment should proceed slowly, and if signs and/or symptoms occur despite a slow withdrawal of Stalevo, an increase in levodopa dosage may be necessary.
Prescribers should exercise caution when switching patients from Stalevo to levodopa/DDC inhibitor therapy without entacapone. When considered necessary, the replacement of Stalevo with levodopa and DDC inhibitor without entacapone should proceed slowly and an increase in levodopa dosage may be necessary.

Diarrhoea, anorexia, asthenia and weight loss.

For patients experiencing diarrhoea, a follow-up of weight is recommended in order to avoid potential excessive weight decrease. Prolonged or persistent diarrhoea suspected to be related to Stalevo 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.
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.

Dopamine dysregulation syndrome (DDS).

Dopamine dysregulation syndrome (DDS) is an addictive disorder resulting in excessive use of the product seen in some patients treated with levodopa/carbidopa. Before initiation of treatment, patients and caregivers should be warned of the potential risk of developing DDS (see Section 4.8 Adverse Effects (Undesirable Effects)).

Impulse control disorders.

Patients should be regularly monitored for the development of impulse control disorders. Patients and caregivers 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, medication use and punding (repetitive purposeless activity) 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.

Hallucinations.

Dopaminergic therapy in Parkinson's disease patients has been associated with hallucinations. In clinical trials of entacapone, hallucinations developed in approximately 4.0% of patients treated with 200 mg entacapone or placebo in combination with levodopa/ dopa decarboxylase inhibitor. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 0.8% and 0% of patients treated with 200 mg entacapone and placebo, respectively. Hallucinations led to hospitalisation in 1.0% and 0.3% of patients in the 200 mg entacapone and placebo groups, respectively.

Dyskinesia.

Entacapone may potentiate the dopaminergic side effects of levodopa and may therefore cause and/or exacerbate pre-existing dyskinesia. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled trials continued to experience frequent dyskinesias despite a reduction in their dose of levodopa. The rates were 1.5% and 0.8% for 200 mg entacapone and placebo, respectively.

Fibrotic complications.

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion and pleural thickening have been reported in some patients treated with ergot derived dopaminergic agents. These complications may resolve when the drug is discontinued, but complete resolution does not always occur. Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other nonergot derived drugs (e.g. entacapone, levodopa) that increase dopaminergic activity can cause them is unknown. It should be noted that the expected incidence of fibrotic complications is so low that even if entacapone caused these complications at rates similar to those attributable to other dopaminergic therapies, it is unlikely that it would have been detected in a cohort of the size exposed to entacapone. Four cases of pulmonary fibrosis were reported during clinical development of entacapone; three of these patients were also treated with pergolide and one with bromocriptine. The duration of treatment with entacapone ranged from 7-17 months.

General anaesthesia.

If general anaesthesia is required, therapy with Stalevo may be continued for as long as the patient is permitted to take fluids and medication by mouth. If therapy has to be stopped temporarily, Stalevo may be restarted as soon as oral medication can be taken at the same daily dosage as before.

Patient monitoring.

As with levodopa, periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function is recommended during extended therapy with Stalevo.

Concurrent diseases.

Stalevo should be administered cautiously to patients with biliary obstruction, hepatic disease, severe cardiovascular or pulmonary disease, bronchial asthma, renal, or endocrine disease.

Use in combination with other antiparkinsonian medications.

In clinical studies, undesirable dopaminergic effects (e.g. dyskinesia) were more common in patients who received entacapone and dopamine agonists (such as bromocriptine), selegiline or amantadine compared to patients who received placebo in combination with any of these medications. The doses of other antiparkinsonian medications may require adjustment when Stalevo is being substituted in patients not currently taking entacapone.

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Elderly patients; Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in the elderly for further information.

Paediatric use (age < 18).

Stalevo is not recommended for use in children below age 18 due to lack of data on safety and efficacy.

Effects on laboratory tests.

Laboratory abnormalities have been reported with levodopa/carbidopa treatment and entacapone, see Section 4.8 Adverse Effects (Undesirable Effects), Adverse effects in laboratory tests for further information.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Caution should be exercised when the following drugs are administered concomitantly with Stalevo therapy.

Antihypertensive drugs.

Symptomatic postural hypotension may occur when levodopa is added to the treatment of patients already receiving antihypertensive drugs. Dosage 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 (see Section 4.2 Dose and Method of Administration). No interactions were observed between entacapone and imipramine and between entacapone and moclobemide in single dose studies in healthy volunteers.

MAO inhibitors.

For patients receiving nonselective MAO inhibitors see Section 4.3 Contraindications.

Selegiline.

No interactions were observed between entacapone and selegiline in repeated dose studies in patients with Parkinson's disease. Entacapone may be used in combination with selegiline (a selective MAO-B inhibitor), but the daily dose should not exceed 10 mg.

Warfarin.

Due to entacapone's affinity to cytochrome P450 2C9 in vitro (see Section 5.2 Pharmacokinetic Properties, Metabolism and excretion), Stalevo may potentially interfere with drugs 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 International Normalised Ratio (INR) values increased on average by 13% (CI90 6-19%). Thus, control of INR is recommended when Stalevo is initiated for patients receiving warfarin.

Dopamine D2-receptor antagonists.

Dopamine D2-receptor antagonists (e.g. phenothiazines, butyrophenones, risperidone and isoniazid) may reduce the therapeutic effects of levodopa.

Phenytoin and papaverine.

Phenytoin and papaverine may reduce the therapeutic effect of levodopa. Patients taking these drugs with Stalevo should be carefully observed for loss of therapeutic response.

Metoclopramide.

Although metoclopramide may increase the bioavailability of levodopa by increasing the gastric emptying, metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic properties.

Pyridoxine.

Stalevo can be given to patients receiving supplemental pyridoxine. Oral coadministration of 10-25 mg of pyridoxine hydrochloride (vitamin B6) with levodopa may reverse the effects of levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa inhibits this action of pyridoxine; therefore, Stalevo can be given to patients receiving supplemental pyridoxine.

Drugs metabolised by COMT.

Because of its mechanism of action, entacapone may interfere with the metabolism of drugs containing a catechol group and potentiate their action. Thus, entacapone should be administered cautiously to patients being treated with drugs metabolised by COMT (e.g. isoprenaline, adrenaline, noradrenaline, dopamine, dobutamine, alpha-methyldopa and apomorphine, paroxetine). Patients should be carefully monitored if entacapone is administered in combination with any of these drugs.
When a single 400 mg dose of entacapone was given together with intravenous isoprenaline and adrenaline without coadministered levodopa/dopa decarboxylase inhibitor, the overall mean maximal changes in heart rate during infusion were about 50% and 80% higher than with placebo, for isoprenaline and adrenaline, respectively. Therefore, drugs known to be metabolised by COMT, such as isoprenaline, adrenaline, noradrenaline, dopamine, dobutamine, methyldopa and apomorphine should be administered with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as their interaction may result in increased heart rates, possibly arrhythmias and excessive changes in blood pressure.

Food.

Levodopa competes with certain amino acids, and so its absorption from Stalevo may be impaired in some patients on a high protein diet.

Other forms of interactions.

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 Adverse Effects (Undesirable Effects)).
In pharmacokinetic studies at therapeutic concentrations, entacapone does not displace other extensively bound drugs (e.g. warfarin, salicylic acid, phenylbutazone and diazepam), nor is it displaced to any significant extent by any of these drugs at therapeutic or higher concentrations. However, entacapone binds to human albumin binding site II, which also binds several other medicinal products, including diazepam and ibuprofen. Clinical interaction studies with diazepam and nonsteroidal anti-inflammatory drugs have not been carried out.
As most entacapone excretion is via the bile, caution should be exercised when drugs known to interfere with biliary excretion, glucuronidation and intestinal beta-glucuronidase are given concurrently with entacapone. These include probenecid, cholestyramine and some antibiotics (e.g. erythromycin, rifampicin, ampicillin and chloramphenicol).

Sucrose.

Stalevo tablets contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take Stalevo tablets.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Oral administration of entacapone to male and female rats prior to and during mating did not affect reproductive parameters at exposures (plasma AUC) up to 26 times the maximal clinical exposure.
(Category B3)
There are no adequate data from the use of combination levodopa/carbidopa/entacapone in pregnant women. In rats and rabbits, coadministration of levodopa, carbidopa and entacapone during the period of organogenesis at oral doses of less than (levodopa, carbidopa) and twice (entacapone) the intakes on a mg/m2 basis at the recommended human dose of Stalevo, was not teratogenic. Levodopa and combinations of carbidopa and levodopa have caused visceral and skeletal malformations in rabbits. No teratogenicity was observed following administration of entacapone to pregnant rats and rabbits during the period of organogenesis at oral doses producing respective maternal exposures (plasma AUC) of 40 times, and marginally greater than, the maximal clinical exposure. In pregnant rabbits, fetotoxicity and abortions occurred at maternal exposures less than the maximal clinical exposure. The extent of placental transfer of entacapone and its metabolites in animals and humans is unknown, and there is no experience of the use of entacapone in pregnant women. Hence, the use of Stalevo during pregnancy is contraindicated.
In animal studies, carbidopa and entacapone were excreted in milk. Oral administration of entacapone to rats from early pregnancy to weaning reduced offspring bodyweight at maternal exposure (plasma AUC) of 26 times the maximal clinical exposure, but not at an exposure of six times the maximal clinical exposure. It is not known whether levodopa, carbidopa or entacapone is excreted in human milk. Therefore, Stalevo is contraindicated for nursing mothers.

4.8 Adverse Effects (Undesirable Effects)

Stalevo combines levodopa/carbidopa and entacapone in one product. The following section describes the undesirable effects reported for levodopa/carbidopa and for entacapone used in combination with levodopa/DDC inhibitor.

Levodopa/carbidopa.

Adverse effects that occur frequently with levodopa/carbidopa are those due to the central neuropharmacological activity of dopamine. These reactions can usually be diminished by levodopa dosage reduction.

More common reactions.

The most common adverse effects are dyskinesias including choreiform, dystonic and other involuntary movements. Muscle twitching and blepharospasm may be taken as early signs to consider levodopa dosage reduction. Nausea is also related to enhanced central dopaminergic activity, is a common adverse effect of levodopa/carbidopa.
Other adverse effects associated with levodopa/carbidopa therapy are mental changes, including paranoid ideation and psychotic episodes; depression, with or without development of suicidal tendencies; cognitive dysfunction; and dopamine dysregulation syndrome. Adding entacapone to levodopa/DDC inhibitor therapy (carbidopa or benserazide), e.g. initiation of Stalevo treatment in an entacapone naive patient may affect the occurrence of some of these mental changes (see Table 2, Psychiatric disorders).

Less common reactions.

Less frequent adverse effects of levodopa/carbidopa therapy are cardiac irregularities and/or palpitations, orthostatic hypotensive episodes, bradykinetic episodes (the 'on-off' phenomenon), anorexia, vomiting, dizziness and somnolence.
Gastrointestinal bleeding, development of duodenal ulcer, hypertension, phlebitis, leucopenia, haemolytic and nonhaemolytic anaemia, thrombocytopenia, agranulocytosis, chest pain, dyspnoea and paraesthesia have occurred rarely with levodopa/carbidopa.
Convulsions have occurred rarely with levodopa/carbidopa; however a causal relationship to levodopa/carbidopa therapy has not been established.
Dopamine dysregulation syndrome (DDS) is an addictive disorder seen in some patients treated with levodopa/carbidopa. 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 Section 4.4 Special Warnings and Precautions for Use).

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 Special Warnings and Precautions for Use, Impulse control disorders).
Other adverse effects that have been reported with levodopa and may, therefore, be potential adverse effects of Stalevo as well, include:

Neurological.

Ataxia, numbness, increased hand tremor, muscle twitching, muscle cramp, trismus, activation of latent Horner's syndrome, falling, gait abnormalities.

Psychiatric events.

Confusion, insomnia, nightmares, hallucinations, delusions, agitation, anxiety, euphoria.

Gastrointestinal.

Dry mouth, bitter taste, sialorrhoea, dysphagia, bruxism, hiccups, abdominal pain, constipation, diarrhoea, flatulence, burning sensation of the tongue.

Metabolic.

Weight gain or loss, oedema.

Skin and subcutaneous tissue.

Flushing, increased sweating, dark sweat, rash, hair loss.

Genitourinary.

Urinary retention, urinary incontinence, dark urine, priapism.

Metabolic.

Weight gain or loss, oedema.

Skin and subcutaneous tissue.

Flushing, increased sweating, dark sweat, rash, hair loss.

Genitourinary.

Urinary retention, urinary incontinence, dark urine, priapism.

Eye.

Diplopia, blurred vision, dilated pupils, oculogyric crises.

Miscellaneous.

Weakness, faintness, fatigue, headache, hoarseness, malaise, hot flushes, sense of stimulation, bizarre breathing patterns, neuroleptic malignant syndrome (see Section 4.3 Contraindications), malignant melanoma.

Entacapone.

The most frequent adverse reactions caused by entacapone relate to the increased dopaminergic activity and occur most commonly at the beginning of the treatment. Reduction of levodopa dosage usually decreases the severity and frequency of the reactions. The other major class of adverse reactions are gastrointestinal symptoms, including nausea, vomiting, abdominal pain, constipation and diarrhoea. Urine may be discoloured reddish brown by entacapone but this is a harmless phenomenon.
Usually the adverse reactions caused by entacapone in combination with levodopa/DDC inhibitor are mild to moderate. In clinical studies the most common adverse reactions leading to discontinuation of entacapone treatment have been gastrointestinal symptoms (e.g. diarrhoea) and increased dopaminergic adverse reactions of levodopa (e.g. dyskinesias).
Entacapone in association with levodopa has been associated with isolated episodes of excessive daytime somnolence and sudden sleep onset.
Isolated cases of neuroleptic malignant syndrome (NMS) have been reported especially following abrupt reduction or discontinuation of entacapone and other dopaminergic medications.
Isolated cases of rhabdomyolysis have been reported.
Dyskinesias, nausea, diarrhoea, abdominal pain and dry mouth were reported significantly more often with entacapone than with placebo (Table 2), based on pooled data from clinical studies involving 603 patients taking levodopa/DDC inhibitor and entacapone and 400 patients taking levodopa/DDC inhibitor therapy and placebo. Other common adverse events (incidence < 3%) included sleep disturbances and paroniria. Serious adverse events (incidence > 0.3% and ≥ placebo) that do not appear in Table 2 included chest pain, pneumonia, confusion and dyspnoea.
Some of the adverse reactions, such as dyskinesia, nausea and abdominal pain, may be more common with higher doses of entacapone (1,400 to 2,000 mg per day) than with lower doses of entacapone.

Incidence rates of myocardial infarction and other ischemic heart disease events in a meta-analysis.

Myocardial infarction and other ischemic heart disease events have been reported with the use of entacapone in combination with carbidopa/ levodopa. A meta-analysis of 13 controlled, double blind studies in patients with end of dose motor fluctuations ('wearing off') was conducted. In 2082 patients treated with entacapone, the results of the meta-analysis showed incidence rates of 0.43% (95% CI: 0.20%-0.82%) and 1.54% (95% CI: 1.05%-2.16%) for myocardial infarction and other ischemic heart disease events, respectively. Based on the risk difference, there was an estimated 2 (95% CI: -2 to 6) per 1000 more entacapone patients than placebo (carbidopa/ levodopa) patients who experienced myocardial infarction in the double blind wearing off studies.

Adverse reactions from postmarketing reports.

The following are additional adverse drug reactions that have been reported since the introduction of entacapone for combination use with levodopa/DDC inhibitor. Adverse reactions are ranked under headings of frequency using the following convention: very common (≥ 10%); common (≥ 1% to < 10%); uncommon (≥ 0.1% to < 1%); rare (≥ 0.01% to < 0.1%); very rare (< 0.01% including isolated reports).

Body as a whole.

Very rare: weight decrease.

Dermatological disorders.

Rare: erythematous or maculopapular rash.
Very rare: urticaria, skin, hair, beard and nail discolourations.

Gastrointestinal disorders.

Very rare: anorexia, colitis.

Hepatic disorders.

Very rare: hepatitis with cholestatic features.

Psychiatric disorders.

Very rare: agitation.
Isolated cases of neuroleptic malignant syndrome (NMS) have been reported, especially following abrupt reduction or discontinuation of entacapone and other dopaminergic medications.
Isolated cases of rhabdomyolysis have been reported.
Isolated cases of angiodema have been reported after initiation of Stalevo.

Other.

The following adverse reactions have also been observed.

Gastrointestinal disorders.

Common: dyspepsia.

Musculoskeletal and connective tissue disorders.

Very common: muscle, musculoskeletal and connective tissue pain.
Common: arthralgia.

Renal and urinary disorders.

Common: urinary tract infection.

Adverse effects in laboratory tests.

The following laboratory abnormalities have been reported with levodopa/carbidopa treatment and entacapone.
Abnormalities include elevated values of blood urea, AST (SGOT), ALT (SGPT), LDH, bilirubin and alkaline phosphatase. Commonly, levels of blood urea nitrogen and uric acid are lower during administration of levodopa/carbidopa than with levodopa alone. Decreased haemoglobin, haematocrit, elevated serum glucose and white blood cells, bacteria and blood in the urine have been reported. Positive Coombs' tests have been reported, both for levodopa/carbidopa and for levodopa alone, but haemolytic anaemia is extremely rare.
Levodopa/carbidopa may cause false positive results 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.
Slight decreases in haemoglobin, erythrocyte count and haematocrit have been reported during entacapone treatment. The underlying mechanism may involve decreased absorption of iron from the gastrointestinal tract. During long-term (6 months) treatment with entacapone, a clinically significant decrease in haemoglobin has been observed in 1.8% of patients. A small number of reports of clinically significant increases in liver enzymes have been received.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

The optimum daily dosage of Stalevo must be determined by careful titration 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 anhydrous/entacapone).
Patients should be instructed to take only one Stalevo tablet per dose administration. The experience with total daily dosage greater than 200 mg carbidopa anhydrous is limited, whereas patients receiving less than 70-100 mg carbidopa anhydrous a day are more likely to experience nausea and vomiting. The maximum recommended daily dose of entacapone is 2,000 mg, therefore the maximum Stalevo dose must not exceed 10 tablets per day, 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. Ten (10) tablets of Stalevo 150/37.5/200 mg equals 375 mg of carbidopa anhydrous a day. Therefore, using a maximum recommended daily dose of 375 mg of carbidopa anhydrous, 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 1,500 mg.
Generally speaking, Stalevo 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 Stalevo.

a. Patients who are currently treated with entacapone and with standard release levodopa/carbidopa in doses equal to Stalevo tablet strengths can be directly transferred to corresponding Stalevo tablets. For example, a patient taking one tablet of 100/25 mg of levodopa/carbidopa with one tablet of entacapone 200 mg four times daily can take one 100/25/200 mg Stalevo tablet four times daily in place of their usual levodopa/carbidopa and entacapone doses.
b. When initiating Stalevo therapy for patients currently treated with entacapone and levodopa/carbidopa in doses not equal to one of the available Stalevo tablet strengths, Stalevo dosing should be carefully titrated for optimal clinical response. At the initiation, 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, discontinue dosing of levodopa/ benserazide the previous night and start Stalevo the next morning. Begin with a dosage of Stalevo that will provide either the same amount of levodopa or slightly (5-10%) more.

How to transfer patients taking levodopa/DDC inhibitor preparations not currently taking entacapone to Stalevo.

Initiation of Stalevo 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 Stalevo is not recommended for patients who have dyskinesias and whose daily levodopa dose is above 800 mg (see Table 1). 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.
There are no data on transferring patients from controlled release formulations of levodopa/carbidopa to Stalevo.

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 described in the above section. 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 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 anhydrous/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 (see Section 4.4 Special Warnings and Precautions for Use, Neuroleptic malignant syndrome and rhabdomyolysis).

Children and adolescents.

Stalevo is not recommended for use in children below age 18 due to lack of data on safety and efficacy.

Elderly patients.

No dosage adjustment of Stalevo is required for elderly patients (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in the elderly).

Hepatic impairment.

It is advised that Stalevo should be administered cautiously to patients with mild to moderate hepatic impairment. Dose reduction may be needed (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in patients with liver impairment).

Renal impairment.

Renal insufficiency does not affect the pharmacokinetics of entacapone. No particular studies are reported on the pharmacokinetics of levodopa and carbidopa in patients with renal insufficiency, therefore Stalevo therapy should be administered cautiously to patients with severe renal impairment including those receiving dialysis therapy (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in patients with renal impairment).

Method of administration.

Each tablet is to be taken orally either with or without food (see Section 5.2 Pharmacokinetic Properties). One tablet contains one treatment dose and the tablet may only be administered as whole tablets.

4.7 Effects on Ability to Drive and Use Machines

Stalevo may cause dizziness, somnolence and episodes of sudden sleep onset, and symptomatic orthostatic hypotension. Therefore, caution should be exercised when driving or using machines. The ability of patients with Parkinson's disease to drive or operate machinery should be evaluated by the treating physician.
Stalevo may have a major influence on the ability to drive and use machines. Patients being treated with Stalevo 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 Special Warnings and Precautions for Use).

4.9 Overdose

The postmarketing 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 overdosage with Stalevo therapy is similar to acute overdosage with levodopa. Pyridoxine, however, is not effective in reversing the actions of Stalevo. Hospitalisation is advised and general supportive measures should be employed with repeated doses of activated 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. Intravenous fluids should be administered judiciously and an adequate airway maintained. ECG monitoring should be started and the patient carefully monitored for the possible development of arrhythmia. If required, appropriate, antiarrhythmic therapy should be given. The possibility that the patient has taken other drugs in addition to Stalevo should be taken into consideration. The value of dialysis in the treatment of overdosage is not known.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each strength of Stalevo tablets contains the following excipients: croscarmellose sodium, magnesium stearate, starch - maize, mannitol, povidone, glycerol, hypromellose, polysorbate 80, iron oxide red CI77491, sucrose, titanium dioxide, iron oxide yellow CI77492. Iron oxide yellow CI77492 is not present in the 75/18.75/200 mg, 125/31.25/200 mg, 200/50/200 mg tablets.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Keep out of the reach of children.

6.5 Nature and Contents of Container

All strengths are registered in bottles of 10, 30, 100 and 250* tablets.
* Stalevo 75/18.75/200 mg and 125/31.25/200 mg and 200/50/200 mg tablets are not available in bottles of 250 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes