Consumer medicine information

Tridopa

Levodopa; Carbidopa; Entacapone

BRAND INFORMATION

Brand name

Tridopa

Active ingredient

Levodopa; Carbidopa; Entacapone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tridopa.

SUMMARY CMI

TRIDOPA™

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using TRIDOPA?

TRIDOPA contains the active ingredients levodopa, carbidopa and entacapone. TRIDOPA is used to treat the symptoms of Parkinson's disease.

For more information, see Section 1. Why am I using TRIDOPA? in the full CMI.

2. What should I know before I take TRIDOPA?

Do not take if you have ever had an allergic reaction to TRIDOPA or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I take TRIDOPA? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with TRIDOPA and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take TRIDOPA?

  • People with moderate to severe Parkinson's disease usually take from 3 to 7 tablets of TRIDOPA each day.
  • Take only one TRIDOPA tablet at each dose. Swallow the tablets whole with a full glass of water.

More instructions can be found in Section 4. How do I take TRIDOPA? in the full CMI.

5. What should I know while taking TRIDOPA?

Things you should do
  • Tell your doctor straight away if you become pregnant.
  • Remind any doctor, surgeon, dentist or pharmacist you visit that you are using TRIDOPA.
  • Visit your doctor regularly so they can check on your progress.
Things you should not do
  • Do not stop using this medicine without talking to your doctor.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how TRIDOPA affects you.
Looking after your medicine
  • Store below 25°C.

For more information, see Section 5. What should I know while taking TRIDOPA? in the full CMI.

6. Are there any side effects?

Some of the most common side effects of TRIDOPA are nausea, vomiting, diarrhoea, stomach pains, constipation, dizziness or light-headedness, extreme sleepiness and sudden onset of sleep and unusual and uncontrollable twitching, jerking or writhing movements, muscle and/or joint pain.

Serious side effects may include feeling depressed, compulsive behaviours, confusion, paranoia, chest pain/tightness, shortness of breath or difficulty breathing and fast or irregular heartbeats.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

TRIDOPA™

Active ingredient(s): levodopa/carbidopa/entacapone

Consumer Medicine Information (CMI)

This leaflet provides important information about using TRIDOPA. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using TRIDOPA.

Where to find information in this leaflet:

1. Why am I using TRIDOPA?
2. What should I know before I take TRIDOPA?
3. What if I am taking other medicines?
4. How do I take TRIDOPA?
5. What should I know while taking TRIDOPA?
6. Are there any side effects?
7. Product details

1. Why am I using TRIDOPA?

TRIDOPA contains three active ingredients: levodopa, carbidopa and entacapone. TRIDOPA is an anti-Parkinson medicine containing dopaminergic agents that work together to raise the dopamine levels in the brain.

TRIDOPA is used to treat the symptoms of Parkinson's disease, such as shaking of the limbs, stiffness and slowness of movement, which make it difficult to perform normal daily activities.

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.

2. What should I know before I take TRIDOPA?

Warnings

Do not use TRIDOPA if:

  • you are allergic to levodopa, carbidopa, entacapone, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • you have liver problems
  • you have narrow-angle glaucoma
  • you have a rare tumour of the adrenal gland, which sits near the kidney (called phaeochromocytoma)
  • you have ever had a reaction to some medicines with a sudden increase in body temperature, extremely high blood pressure and severe convulsion (called neuroleptic malignant syndrome)
  • you have ever had temporary paralysis or weakness of muscles (called rhabdomyolysis)
  • you have unusual skin lumps or moles which have not been examined by your doctor, or if you have ever had skin cancer or melanoma.

Check with your doctor if:

You have or have had, any of the following medical conditions:

  • depression, mental disturbances or you recognise anti-social behaviour
  • heart disease, including irregular heartbeats
  • 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
  • trehalase insufficiency.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Do not take TRIDOPA if you are pregnant. Tell your doctor immediately if you become pregnant. There is not enough information to recommend using TRIDOPA during pregnancy.

Do not take TRIDOPA if you are breastfeeding. It is not known if the active ingredients in TRIDOPA passes into breast milk and could affect your baby. Talk to your doctor if you are breastfeeding or intend to breastfeed.

Use in children

TRIDOPA should not be used in children under the age of 18 years. The safety of TRIDOPA and how well it works has not be studied in children younger than 18 years of age.

3. What if I am taking other medicines?

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

Some medicines may interfere with TRIDOPA and affect how well each works. These include:

  • phenelzine and tranylcypromine, medicines called monoamine oxidase inhibitor (MAOI) used to treat depression. TRIDOPA and MAOIs must not be taken together.
  • 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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect TRIDOPA.

4. How do I take TRIDOPA?

How much to take

  • People with moderate to severe Parkinson's disease usually take from 3 to 7 tablets of TRIDOPA each day.
  • The maximum dose of TRIDOPA 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 each day.
  • The maximum dose of TRIDOPA 200/50/200 mg is 7 tablets each day.
  • Take only one TRIDOPA tablet at each dose.
  • Swallow the tablet whole with a full glass of water. Do not break the tablet into halves.
  • Follow the instructions provided and keep taking TRIDOPA until your doctor tells you to stop.

When to take TRIDOPA

  • It does not matter if you take TRIDOPA with or without food but avoid a high protein meal.
  • If your stomach is upset after taking the tablet, take it with a meal or after a snack.
  • If you are taking any medicines containing iron, take them at least 2 to 3 hours before or after a dose of TRIDOPA.

If you forget to take TRIDOPA

TRIDOPA should be used regularly at the same times each day. If you miss your dose at the usual time, you should take it as soon as you noticed that you have forgotten to take your medicine.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you take too much TRIDOPA

If you think that you have taken too much TRIDOPA, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking TRIDOPA?

Things you should do

  • Visit your doctor regularly so they can check on your progress. Your doctor may also carry out tests to check your blood, liver, heart and kidney functions.
  • If your symptoms appear to worsen, tell your doctor.
  • If you plan to have surgery, including dental surgery, tell your doctor or dentist that you are taking TRIDOPA.
  • Remind any doctor, dentist or pharmacist you visit that you are using TRIDOPA.

Things you should not do

  • Do not stop taking this medicine or change the dose unless your doctor tells you to.

Dietary considerations

Be careful not to eat a high protein diet. If you are unsure, ask your doctor, pharmacist or dietician to check your diet.

Behavioural changes

Tell your doctor if you or your family/care giver notices you are developing:

  • addiction-like symptoms leading to craving for larger doses of TRIDOPA and other medicines used to treat Parkinson's disease (known as dopamine dysregulation syndrome).
  • urges or craving to behave in ways that are unusual for your 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.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how TRIDOPA affects you.

TRIDOPA may cause drowsiness, dizziness or lightheadedness. It can cause extreme sleepiness and sudden onset of sleep in the middle of daytime activities, sometimes without warning.

Looking after your medicine

  • Store below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Stomach, bowel or urinary related:
  • nausea (feeling sick) or vomiting
  • stomach pains
  • diarrhoea
  • constipation
  • a reddish-brown colour to the urine (this is harmless)
  • urinary tract infection
Motion or movement related:
  • dizziness or light-headedness
  • unusual and uncontrollable twitching, jerking or writhing movements
  • muscle and/or joint pain
Mental states or behaviour related:
  • feeling depressed with suicidal thoughts
  • urge to gamble or increased sexual desires, uncontrollable shopping, binge eating, medicine use or repetitive purposeless activities
  • confusion, paranoia or hallucinations (seeing, hearing or feeling things that are not there)
  • inability to concentrate or solve problems
  • extreme sleepiness and sudden onset of sleep
Eye related:
  • difficulty in opening the eye
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Heart or blood pressure related
  • chest pain/tightness, shortness of breath or difficulty breathing
  • fast or irregular heartbeats
Other:
  • sudden increase in body temperature, extremely high blood pressure and severe convulsion
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What TRIDOPA contains

Active ingredients
(main ingredients)		levodopa, carbidopa, entacapone
Other ingredients
(inactive ingredients)		Croscarmellose sodium, hyprolose, trehalose dihydrate, powdered cellulose, sodium sulphate, microcrystalline cellulose, magnesium stearate, Opadry II complete film coating 85G35208 RED (ARTG 108033)

Do not take this medicine if you are allergic to any of these ingredients.

What TRIDOPA looks like

TRIDOPA comes in 6 strengths of tablets:

  • TRIDOPA 50/12.5/200 mg – oval biconvex red tablet marked “50” on one side and “LEC” on the other side. (AUST R 195188)
  • TRIDOPA 75/18.75/200 mg – oval biconvex red tablet marked “75” on one side and “LEC” on the other side. (AUST R 195184)
  • TRIDOPA 100/25/200 mg – oval biconvex red tablet marked “100” on one side and “LEC” on the other side. (AUST R 195187)
  • TRIDOPA 125/31.25/200 mg – oval biconvex red tablet marked “125” on one side and “LEC” on the other side. (AUST R 195185)
  • TRIDOPA 150/37.5/200 mg – oval biconvex red tablet marked “150” on one side and “LEC” on the other side. (AUST R 195197)
  • TRIDOPA 200/50/200 mg – oval biconvex red tablet marked “200” on one side and “LEC” on the other side. (AUST R 195190)

Each pack contains 100 tablets. Not all strengths may be available.

Who distributes TRIDOPA

Stada Pharmaceuticals Australia Pty Ltd
Level 3, Suite 204, 26 Rodborough Road
Frenchs Forest NSW 2086

This leaflet was prepared in June 2021.

Published by MIMS August 2021

BRAND INFORMATION

Brand name

Tridopa

Active ingredient

Levodopa; Carbidopa; Entacapone

Schedule

S4

 

1 Name of Medicine

Levodopa, carbidopa and entacapone.

2 Qualitative and Quantitative Composition

Tridopa tablets come in six strengths each containing a 4:1 ratio of levodopa to carbidopa anhydrous combined with entacapone 200 mg in an immediate release formulation. Containing levodopa, carbidopa anhydrous, entacapone, the strengths are 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

Tridopa 50/12.5/200.

Levodopa/carbidopa/entacapone 50 mg/12.5 mg/200 mg film-coated tablet; red, oval, biconvex coated tablet with '50' on one side and 'LEC' on the other side.

Tridopa 75/18.75/200.

Levodopa/carbidopa/entacapone 75 mg/18.75 mg/200 mg film-coated tablet; red, oval, biconvex coated tablet with '75' on one side and 'LEC' on the other side.

Tridopa 100/25/200.

Levodopa/carbidopa/entacapone 100 mg/25 mg/200 mg film-coated tablet; red, oval, biconvex coated tablet with '100' on one side and 'LEC' on the other side.

Tridopa 125/31.25/200.

Levodopa/carbidopa/entacapone 125 mg/31.25 mg/200 mg film-coated tablet; red, oval, biconvex coated tablet with '125' on one side and 'LEC' on the other side.

Tridopa 150/37.5/200.

Levodopa/carbidopa/entacapone 150 mg/37.5 mg/200 mg film-coated tablet; red, oval, biconvex coated tablet with '150' on one side and 'LEC' on the other side.

Tridopa 200/50/200.

Levodopa/carbidopa/entacapone 200 mg/50 mg/200 mg film-coated tablet; red, oval, biconvex coated tablet with '200' on one side and 'LEC' on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of Administration

Each Tridopa 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.
The optimum daily dosage of Tridopa 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/entacapone).
Patients should be instructed to take only one Tridopa tablet per dose administration. The experience with total daily dosage greater than 200 mg carbidopa is limited, whereas patients receiving less than 70-100 mg carbidopa a day are more likely to experience nausea and vomiting. The maximum recommended daily dose of entacapone is 2000 mg, therefore the maximum levodopa/carbidopa/entacapone dose must not exceed 10 tablets per day, for the levodopa/carbidopa/entacapone 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 Tridopa 150/37.5/200 mg equals 375 mg of carbidopa a day.
Therefore, using a maximum recommended daily dose of 375 mg of carbidopa, the maximum daily dose of Tridopa 200/50/200 mg is 7 tablets per day.
The maximum total daily levodopa dose administered in the form of Tridopa should not exceed 1500 mg.
Generally speaking, Tridopa is to be used in patients who are currently treated with corresponding doses of standard release levodopa/DDC inhibitor and entacapone.

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

a. Patients who are currently treated with entacapone and with standard release levodopa/carbidopa in doses equal to Tridopa tablet strengths can be directly transferred to corresponding Tridopa 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 Tridopa tablet four times daily in place of their usual levodopa/carbidopa and entacapone doses.
b. When initiating Tridopa therapy for patients currently treated with entacapone and levodopa/carbidopa in doses not equal to one of the available levodopa/carbidopa/entacapone tablet strengths, Tridopa dosing should be carefully titrated for optimal clinical response. At the initiation, Tridopa should be adjusted to correspond as closely as possible to the total daily dose of levodopa currently used.
c. When initiating Tridopa in patients currently treated with entacapone and levodopa/benserazide in a standard release formulation, discontinue dosing of levodopa/benserazide the previous night and start Tridopa the next morning. Begin with a dosage of levodopa/carbidopa/entacapone 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 Tridopa.

Initiation of Tridopa 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 stabilized on their current standard release levodopa/DDC inhibitor treatment. However, a direct switch from levodopa/DDC inhibitor to Tridopa 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 levodopa/carbidopa/entacapone.
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 Tridopa 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 Tridopa.

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 Tridopa should be considered, within the dosage recommendations described in the above section. When less levodopa is required, the total daily dosage of Tridopa should be reduced either by decreasing the frequency of administration, by extending the time between doses, or by decreasing the strength of Tridopa at administration. If other levodopa products are used concomitantly with a Tridopa tablet, the maximum dosage recommendations should be followed.

Discontinuation of Tridopa therapy.

If Tridopa treatment (levodopa/carbidopa/entacapone) is discontinued and the patient is transferred to levodopa/DDC inhibitor therapy without entacapone, it is necessary to adjust the dosing of other antiparkinsonian treatments, especially levodopa, to achieve a sufficient level of control of the parkinsonian symptoms (see Section 4.4 Special Warnings and Precautions for Use, Neuroleptic malignant syndrome and rhabdomyolysis).

Children and adolescents.

Tridopa 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 Tridopa is required for elderly patients (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in the elderly).

Hepatic impairment.

It is advised that Tridopa 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 Tridopa therapy should be administered cautiously to patients with severe renal impairments including those receiving dialysis therapy (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in patients with renal impairment).

4.3 Contraindications

Tridopa is contraindicated in the following:
Known hypersensitivity to the active substances or to any of the excipients.
Pregnancy and breast feeding (see Section 4.6 Fertility, Pregnancy and 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.
Concomitant use of Tridopa with non-selective monoamine oxidase (MAO-A and MAO-B) inhibitors (e.g. phenelzine, tranylcypromine) is contraindicated. Similarly, concomitant use of a selective MAO-A inhibitor plus a selective MAO-B inhibitor and Tridopa is contraindicated.
A previous history of neuroleptic malignant syndrome and/or non-traumatic rhabdomyolysis (see Section 4.4 Special Warnings and Precautions for Use, Neuroleptic malignant syndrome and rhabdomyolysis).
Because levodopa may activate malignant melanoma, Tridopa 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 Tridopa.

Tridopa is not recommended for the treatment of drug-induced extrapyramidal reactions.
Tridopa should be administered cautiously to patients with ischemic 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 levodopa/carbidopa/entacapone with caution, provided the intra-ocular pressure is well controlled and the patient is monitored carefully for changes in intra-ocular pressure.
Tridopa may induce orthostatic hypotension. Therefore, it 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 creatinine 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 Tridopa 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 Tridopa and other dopaminergic treatment should proceed slowly, and if signs and/or symptoms occur despite a slow withdrawal of Tridopa, an increase in levodopa dosage may be necessary.
Prescribers should exercise caution when switching patients from Tridopa to levodopa/DDC inhibitor therapy without entacapone. When considered necessary, the replacement of levodopa/carbidopa/entacapone 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 levodopa/carbidopa/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.
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 Tridopa. Prescribers, patients and caregivers should be alert to the possibility of such behaviour, which may have serious financial and social consequences. 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 non-ergot 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 Tridopa 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, Tridopa 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 levodopa/carbidopa/entacapone.

Concurrent diseases.

Tridopa 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 Tridopa is being substituted in patients not currently taking entacapone.

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration, Hepatic impairment; Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in patients with liver impairment.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration, Renal impairment; Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in patients with renal impairment.

Use in the elderly.

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

Paediatric use.

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

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Adverse effects in laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Caution should be exercised when the following drugs are administered concomitantly with Tridopa 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), levodopa/carbidopa/entacapone 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 Tridopa 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 Tridopa 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.

Tridopa 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, Tridopa 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 (epinephrine), noradrenaline (norepinephrine), 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 (epinephrine) 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 (epinephrine) respectively. Therefore, drugs known to be metabolised by COMT, such as isoprenaline, adrenaline (epinephrine), noradrenaline (norepinephrine), 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 levodopa/carbidopa/entacapone maybe 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, Tridopa 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 non-steroidal 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).

Trehalose.

Tridopa tablets contain trehalose dihydrate. Patients with rare problems of trehalose insufficiency (primary or secondary) should not take Tridopa 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)1
There are no adequate data from the use of combination levodopa/carbidopa/entacapone in pregnant women. In rats and rabbits, co-administration 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 levodopa/carbidopa/entacapone, 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, foetotoxicity 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 levodopa/carbidopa/entacapone during pregnancy is contraindicated.
1 Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed.
Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.
 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, levodopa/carbidopa/entacapone is contraindicated for nursing mothers.

4.7 Effects on Ability to Drive and Use Machines

Tridopa 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.
Tridopa may have a major influence on the ability to drive and use machines. Patients being treated with levodopa/carbidopa/entacapone 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).

4.8 Adverse Effects (Undesirable Effects)

Tridopa 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 levodopa/carbidopa/entacapone 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 non-haemolytic 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 Tridopa (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 levodopa/carbidopa/entacapone 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.

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 1 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 post-marketing 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 levodopa/carbidopa/entacapone.

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.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
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 overdosage with levodopa/carbidopa/entacapone therapy is similar to acute overdosage with levodopa. Pyridoxine, however, is not effective in reversing the actions of levodopa/carbidopa/entacapone tablets. 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 Tridopa should be taken into consideration. The value of dialysis in the treatment of overdosage is not known.

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 co-administration 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 levodopa/carbidopa/entacapone tablet, provided in six single-dose strengths, contains carbidopa and levodopa in a 1:4 ratio and a 200 mg dose of entacapone. Four 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 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 levodopa/carbidopa/entacapone, as well.
The anticipated therapeutic effects of levodopa/carbidopa/entacapone 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 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 ingredients, the bioavailability for levodopa is 15 - 33%, for carbidopa 40 -70% and for entacapone 29 - 36% (35% after a 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 the tablets has not been evaluated.

Levodopa.

The pharmacokinetic characteristics of levodopa following the administration of single-dose levodopa/carbidopa/entacapone 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 the levodopa/carbidopa/entacapone tablets 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.h/mL, with different tablet strengths providing 12.5 mg, 25 mg or 37.5 mg of carbidopa. Carbidopa is bound approximately 36% bound to plasma protein.

Entacapone.

Following administration of the levodopa/carbidopa/entacapone tablets 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 1200 nanogram/mL and the AUC 1250 to 1450 nanogram.h/mL after administration of different levodopa/carbidopa/entacapone tablet 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 (t½el) 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 (t½el) 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 is (t½el) 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 the total amount in plasma. 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/h and for entacapone is in the range of 0.70 L/kg/h.
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.

Levodopa/carbidopa/entacapone 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/DDI inhibitor co-administration, 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, levodopa/carbidopa/entacapone should be administered with care to patients with biliary obstruction or hepatic disease.

Pharmacokinetics in patients with renal impairment.

Levodopa/carbidopa/entacapone 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 levodopa/carbidopa/entacapone 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 co-administration, in a specific renal impairment study. There were three groups: normal subjects (n=7; creatinine clearance > 1.12 mL/sec/1.73 m2), moderate impairment (n=10; creatinine clearance ranging from 0.60 - 0.89 mL/sec/1.73 m2), and severe impairment (n=7; creatinine clearance ranging from 0.20 - 0.44 mL/sec/1.73 m2).

Pharmacokinetics in the elderly.

Levodopa/carbidopa/entacapone 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 levodopa/carbidopa/entacapone or as separate carbidopa/levodopa and entacapone 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 levodopa/carbidopa/entacapone, the bioavailability of levodopa is higher in women than in men, primarily due to the difference in body weight, while there is no gender difference with carbidopa and entacapone. Following a single dose of carbidopa, levodopa and entacapone together, either as levodopa/carbidopa/entacapone or as separate carbidopa/levodopa and entacapone 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 body weight. Other published literature showed significant gender effect (higher concentrations in females) even after correction for body weight.

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 (α2 mu-globulin) specific to male rats, and are thought not to constitute a hazard for clinical use.

6 Pharmaceutical Particulars

6.1 List of Excipients

The tablets also contain croscarmellose sodium, hyprolose, trehalose dihydrate, powdered cellulose, sodium sulfate, microcrystalline cellulose, magnesium stearate and Opadry II complete film coating system 85G35208 Red (ARTG 108033).
The tablets are gluten free.

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).

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Bottles (consisting of HDPE container with PP closure) of 100 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Levodopa.


Carbidopa.


Entacapone.


CAS number.

Levodopa.

59-92-7.

Carbidopa.

38821-49-7.

Entacapone.

130929-57-6.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicines - S4.

Summary Table of Changes