Consumer medicine information

Comtan

Entacapone

BRAND INFORMATION

Brand name

Comtan

Active ingredient

Entacapone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Comtan.

What is in this leaflet

This leaflet answers some common questions about Comtan.

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 Comtan is used for

Comtan is used to treat the symptoms of Parkinson's disease in people who are already taking a medicine called levodopa. When levodopa on its own does not control the symptoms, Comtan can be added.

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.

Comtan is always used together with levodopa. Levodopa works by increasing the level of dopamine in the brain and Comtan works by making the effect of levodopa last longer. Together, Comtan and levodopa help 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 Comtan

When you must not take it

Do not take Comtan if you have ever had an allergy to entacapone (the active ingredient in Comtan) 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 Comtan if you are pregnant. There is not enough information to recommend its use during pregnancy.

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

Do not take Comtan if you have or ever had 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
  • 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
  • a condition called rhabdomyolysis, with symptoms of severe muscle weakness, that was not due to an injury.

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

Do not take Comtan 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 have or ever had any of the following health problems / medical conditions:

  • severe kidney disease that requires dialysis treatment.
    Your doctor may need to adjust the dose of Comtan in this case.
  • heart attack or any other diseases of the heart.

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.

Tell your doctor if you have an intolerance to sucrose. This medicine contains sucrose.

Taking other medicines

Tell your doctor if you are taking a medicine called a monoamine-oxidase inhibitor (MAOI). Taking Comtan together with some, but not all, MAOI medicines may cause serious side effects. Your doctor will know whether or not the MAOI medicine you are taking can be safely taken with Comtan.

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 Comtan may interfere with each other. These include:

  • other medicines for Parkinson's disease
  • some medicines for depression
  • methyldopa, a medicine for high blood pressure
  • 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 Comtan. 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 Comtan

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

Take one tablet (200 mg) of Comtan each time you take a dose of levodopa.

People with moderate to severe Parkinson's disease usually take from 4 to 7 tablets of Comtan each day. The maximum dose is 10 tablets each day.

Because Comtan increases the action of levodopa, it can also increase some of its side effects, especially at the start of treatment. To prevent this from happening, your doctor may lower your usual dose of levodopa for a few days or weeks. However, it is still important that you take a tablet of Comtan each time you take a dose of levodopa.

How to take it

Take the tablet with a full glass of water at the same time as you take a dose of levodopa.

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 Comtan with or without food but avoid fatty meals.

If you are taking any medicines containing iron, take them at least 2 or 3 hours before or after a dose of Comtan. 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 Comtan 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 you forget to take a tablet of Comtan with your dose of levodopa, wait until the next dose of levodopa is due and start taking Comtan again at that time.

Do not take a double dose to make up for the one that you missed. 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 Centre (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 Comtan. Do this even if there are no signs of discomfort or poisoning. Keep the telephone numbers for these places handy.

While you are taking Comtan

Things you must do

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 Comtan. 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 Comtan.

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

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.

Things to be careful of

Be careful driving, operating machinery or doing jobs that require you to be alert while you are taking Comtan 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.

Tell your doctor if you experience:

  • temporary paralysis or severe weakness of the muscles
  • prolonged diarrhoea. Your doctor may follow-up on your weight in order to prevent potential excessive weight loss
  • 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.
  • progressive anorexia, asthenia (weakness, exhaustion) and weight decrease within a relatively short period of time. Your doctor may decide to conduct a general medical evaluation including liver function
  • symptoms such as sudden increase in body temperature, more rapid heart beat, extremely high blood pressure or severe convulsions.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Comtan.

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
  • diarrhoea
  • pain in the stomach
  • constipation
  • dry mouth
  • dizziness or lightheadedness
  • spinning sensation (vertigo)
  • tiredness
  • shakiness
  • aches and pains
  • leg cramps
  • headache
  • increased sweating
  • difficulty sleeping or unusual dreams
  • feeling depressed, confused or agitated
  • a reddish-brown colour to the urine (this is harmless)
  • discolouration of hair, beard, skin or nails
  • 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 increase sexual interest and behaviour of significant concern to you or to others, for example, an increased sexual drive,
    - uncontrollable excessive shopping or spending,
    - binge eating (eating large amounts of food in a short time period) or compulsive eating (eating more food than normal and more than is needed to satisfy your hunger).

Tell your doctor if you experience any of these behaviours. Your doctor will discuss ways of managing or reducing the symptoms.

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
  • 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
  • weight loss, often in association with diarrhoea and loss of appetite
  • 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 Comtan

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 Comtan or any other medicine in the bathroom or near a sink.
  • Do not leave it in the car or on window sills.

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 Comtan 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

Comtan tablets are oval, brownish-orange tablets, marked COMTAN on one side; packs of 100 tablets.

Ingredients

Comtan tablets contain 200 mg of entacapone as the active ingredient.

The tablets also contain:

  • microcrystalline cellulose
  • mannitol
  • croscarmellose sodium
  • hydrogenated vegetable oil
  • hypromellose
  • polysorbate 80
  • glycerol 85%
  • sucrose
  • magnesium stearate
  • iron oxide yellow CI77492
  • iron oxide red CI77491
  • titanium dioxide.

Comtan contains sucrose and sorbates.

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

Sponsor

Comtan is supplied in Australia by:

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Tel: 1800 726 369

® = Registered Trademark

This leaflet was prepared in December 2020.

Australian Registration Number.
200 mg tablet AUST R 68463

Published by MIMS March 2021

BRAND INFORMATION

Brand name

Comtan

Active ingredient

Entacapone

Schedule

S4

 

1 Name of Medicine

Entacapone.

2 Qualitative and Quantitative Composition

Each tablet contains 200 mg entacapone.
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Comtan is a brownish-orange film-coated tablets, length 17.2-17.5 mm, breadth 8-8.2 mm, marked with the word "Comtan".

4 Clinical Particulars

4.1 Therapeutic Indications

Comtan is indicated in the management of Parkinson's disease as an adjunct to levodopa/dopa decarboxylase inhibitor therapy in patients who are experiencing motor fluctuations (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Comtan is used in combination with levodopa preparations, either levodopa/carbidopa or levodopa/benserazide. It can be used with both standard and sustained release preparations of levodopa. Other antiparkinsonian drugs may be used simultaneously.
Entacapone enhances the effects of levodopa. Hence, to reduce levodopa related dopaminergic adverse reactions (e.g. dyskinesias, nausea, vomiting and hallucinations) it is often necessary to adjust levodopa dosage within the first few days to first few weeks after initiating treatment with Comtan. The daily dose of levodopa should be reduced by about 10 to 30% by extending the dosing intervals and/or by reducing the amount of levodopa per dose.
Entacapone increases the bioavailability of levodopa from standard levodopa/benserazide preparations slightly more (5-10%) than from standard levodopa/carbidopa preparations. Hence, patients who are taking standard levodopa/benserazide preparations may need a larger reduction in their levodopa dose when Comtan is initiated.
If Comtan treatment is discontinued, it is necessary to adjust the dosing of other antiparkinsonian treatments, especially levodopa, to achieve a sufficient level of control of the parkinsonian symptoms.

Comtan dosage regimen.

Starting dose.

One 200 mg tablet is taken with each levodopa/dopa decarboxylase inhibitor dose. On average 4 to 7 doses daily are used in patients with moderate or severe Parkinson's disease. The same dosage is used in all adults, including elderly patients. Comtan may be taken with or without food. The effects of a high fat meal on absorption have not been formally evaluated.

Maintenance dose.

The maintenance dose of Comtan is the same as the starting dose.

Maximum recommended dose.

2,000 mg (i.e. 10 doses) daily.

Patients with renal dysfunction.

Renal insufficiency does not affect the pharmacokinetics of entacapone and there is no need for dose adjustment. However, patients who are receiving dialysis therapy should be closely monitored and the possible need for a longer dosing interval should be kept in mind.

4.3 Contraindications

Known hypersensitivity to entacapone or any other components of the formulation.
Pregnancy and breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation).
Hepatic impairment (see Section 5.2 Pharmacokinetic Properties).
Patients with phaeochromocytoma due to the increased risk of hypertensive crisis.
Concomitant use of Comtan with nonselective 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 Comtan is contraindicated.
A previous history of neuroleptic malignant syndrome (NMS) and/or nontraumatic rhabdomyolysis.

4.4 Special Warnings and Precautions for Use

Neuroleptic malignant syndrome and rhabdomyolysis.

Rhabdomyolysis secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS) has been observed rarely in patients with Parkinson's disease. Isolated cases of rhabdomyolysis have been reported with entacapone treatment.
NMS, including rhabdomyolysis and hyperthermia, is characterised by motor symptoms (rigidity, myoclonus, tremor), changes in mental status (e.g. agitation, confusion, coma), hyperthermia, autonomic dysfunction (tachycardia, labile blood pressure) and elevated serum creatine phosphokinase (CPK). In individual cases, only some of these symptoms and/or findings may be evident.
Isolated cases of NMS have been reported, especially following abrupt reduction or discontinuation of Comtan and other dopaminergic medications. When considered necessary, withdrawal of Comtan and other dopaminergic treatment should proceed slowly and, if signs and/or symptoms occur despite a slow withdrawal of Comtan, an increase in levodopa dosage may be necessary.

Ischaemic heart disease.

Entacapone therapy should be administered with caution to patients with ischaemic heart disease.

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 entacapone may be a sign of colitis. In the event of prolonged or persistent diarrhoea, entacapone 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.

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 can occur in patients treated with dopamine agonists and/or other dopaminergic treatments such as entacapone in association with levodopa. Review of treatment is recommended if such symptoms develop.

Use in combination with levodopa.

Comtan is always given as an adjunct to levodopa treatment. Hence, the precautions applicable to levodopa treatment should also be taken into account for Comtan treatment.
Entacapone may aggravate levodopa induced orthostatic hypotension. Comtan should be given cautiously to patients who are taking other medications that may cause orthostatic hypotension.
Comtan in association with levodopa has been associated with somnolence and episodes of sudden sleep onset in patients with Parkinson's disease. Therefore, caution should be exercised when driving or operating machinery (see Section 4.7 Effects on Ability to Drive and Use Machines).

Use in combination with other antiparkinsonian medications.

In clinical studies, undesirable dopaminergic effects (e.g. dyskinesia) were more common in patients who received Comtan 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 Comtan treatment is initiated.

Use in the elderly.

See Section 5.2 Pharmacokinetic Properties.

Paediatric use.

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

Effects on laboratory tests.

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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Entacapone increases the bioavailability of levodopa from standard levodopa/benserazide preparations 5-10% more than from standard levodopa/carbidopa preparations. Consequently, undesirable dopaminergic effects may be more frequent when Comtan is added to levodopa/benserazide treatment. To reduce levodopa related dopaminergic adverse reactions, it is often necessary to adjust levodopa dosage within the first days to weeks after initiating Comtan treatment, according to the clinical condition of the patient (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).
High single doses (≥ 400 mg) of entacapone may decrease the bioavailability of carbidopa. However, no interaction of entacapone with carbidopa has been observed with the recommended dosage schedule. Pharmacokinetic interaction with benserazide has not been studied.
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.
Due to its inhibitory effect on cytochrome P450 2C9 activity (see Section 5.2 Pharmacokinetic Properties, Metabolism), entacapone may potentially interfere with drugs whose metabolism is dependent on this isoenzyme, such as warfarin, which is commercially available as a racemic mixture of the S(-) and R(+) enantiomers of the sodium salt. In an interaction study in 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 entacapone treatment is initiated for patients receiving warfarin.
In single dose studies in healthy volunteers, no interactions were observed between entacapone and imipramine, or between entacapone and moclobemide. Similarly, no interactions were observed between entacapone and selegiline in repeated dose studies in patients with Parkinson's disease. Comtan may be used in combination with selegiline (a selective MAO-B inhibitor), but the daily dose of selegiline should not exceed 10 mg.
However, experience of the clinical use of entacapone with several drugs, including MAO-A inhibitors (see Section 4.3 Contraindications), tricyclic antidepressants, noradrenaline reuptake inhibitors such as desipramine and venlafaxine, and drugs containing a catechol group that are metabolised by COMT (see below), is still limited. Concomitant use of Comtan with these drugs is not recommended.
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 Comtan is administered in combination with any of these drugs.
Entacapone may form chelates with iron in the gastrointestinal tract. Comtan and iron preparations should be taken at least 2-3 hours apart (see Section 4.8 Adverse Effects (Undesirable Effects)).

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)
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 Comtan in pregnant women. The use of this drug during pregnancy is not recommended.
In lactating rats, entacapone and/or its metabolites are excreted into 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 6 times the maximal clinical exposure. It is not known whether entacapone is excreted in human milk and Comtan is, therefore, not recommended for nursing mothers.

4.7 Effects on Ability to Drive and Use Machines

Comtan on its own is not expected to impair the ability to drive or to operate machinery. However, it may increase some side effects of levodopa, such as 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.
Comtan in association with levodopa may have major influence on the ability to drive and use machines. Patients being treated with Comtan in association with levodopa and presenting with somnolence and/or sudden sleep onset episodes must be instructed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes have resolved (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.8 Adverse Effects (Undesirable Effects)

The most frequent adverse events caused by entacapone relate to the increased dopaminergic activity and occur most commonly at the beginning of treatment. Reduction of levodopa dosage may decrease the severity and frequency of these events. The other major class of adverse events are gastrointestinal symptoms, including nausea, vomiting, abdominal pains, constipation and diarrhoea. Due to the presence of a nitrocatecholamine group in the molecule, urine may be discoloured reddish brown by entacapone, but this is a harmless phenomenon.
Usually adverse events caused by entacapone are mild to moderate. Most commonly the adverse events leading to discontinuation of entacapone treatment have been gastrointestinal symptoms (e.g. diarrhoea) and dopaminergic symptoms (e.g. dyskinesias).
Comtan in association with levodopa has been associated with isolated episodes of excessive daytime somnolence and sudden sleep onset.
Isolated cases of neuromalignant syndrome (NMS) have been reported especially following abrupt reduction or discontinuation of Comtan and other dopaminergic medications.
Isolated cases of rhabdomyolysis have been reported.

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 such as entacapone in association with levodopa (see Section 4.4 Special Warnings and Precautions for Use, Impulse control disorders).
Dyskinesias, nausea, diarrhoea, abdominal pain and dry mouth were reported significantly more often with entacapone than with placebo (see Table 1). 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 events, such as dyskinesia, nausea, and abdominal pains, may be more common with the higher doses (1,400 to 2,000 mg per day) than with the lower doses of entacapone.

Adverse effects in laboratory tests.

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.

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.

Postmarketing reports.

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.

Rare: hepatic function tests abnormal.
Very rare: hepatitis with cholestatic features.

Psychiatric disorders.

Common: confusion, nightmares.
Very rare: agitation.

Cardiac disorders.

Common: ischaemic heart disease events other than myocardial infarction (e.g. angina pectoris).
Uncommon: myocardial infarction.

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

The postmarketing data includes isolated cases of overdose in which the reported highest daily dose of entacapone has been 16,000 mg. The acute symptoms and signs in these cases of overdose included confusion, decreased activity, somnolence, hypotonia, skin discolouration and urticaria.
Management of acute overdose is symptomatic.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Entacapone belongs to a new therapeutic class, the catechol-O-methyl transferase (COMT) inhibitors. It is a reversible, specific, and mainly peripherally acting COMT inhibitor designed for concomitant administration with levodopa preparations. Entacapone decreases the metabolic loss of levodopa to 3-O-methyldopa (3-OMD) by inhibiting the enzyme COMT. This leads to a more sustained plasma concentration of levodopa with no delay in the time to reach the peak concentration. The amount of levodopa available to the brain is increased and more dopamine is formed in the central nervous system. Entacapone thus prolongs the clinical response to levodopa.
Entacapone inhibits the enzyme COMT mainly in peripheral tissues. COMT inhibition in red blood cells closely follows the plasma concentration of entacapone, thus clearly indicating the reversible nature of COMT inhibition. The antiparkinsonian effects of entacapone, i.e. the effects of entacapone on levodopa pharmacokinetics, have nearly disappeared 24 hours after stopping drug intake.

Clinical trials.

The use of Comtan in the treatment of patients with Parkinson's disease was supported by the results of one pivotal phase II and two pivotal phase III studies. The majority of patients also suffered from fluctuations in motor performance. All patients were treated concomitantly with a levodopa/dopa decarboxylase (DDC) inhibitor and the patients were also permitted to use other antiparkinsonian drugs.
The pivotal efficacy studies recruited only patients with motor fluctuations. To avoid any confounding factors in the use of controlled release levodopa, patients were switched to immediate release preparations. Although clinical pharmacology studies have shown that entacapone increases the bioavailability of levodopa from controlled release formulations, efficacy in patients has not been proven. Although patients without motor fluctuations have not been systematically evaluated for efficacy, they have been included in the placebo controlled and open label safety studies.
A pivotal double blind phase II study was completed in 23 patients with advanced Parkinson's disease. Subjects received 4 weeks of treatment with Comtan and 4 weeks of placebo in a crossover format. A tablet of Comtan 200 mg or placebo was administered with each scheduled dose of levodopa/DDC inhibitor four to ten times daily during each treatment period. The primary efficacy parameter was the change in the duration of motor response ('ON' time), as scored on the modified motor part of the UPDRS (Unified Parkinson's Disease Rating Scale). Using measurements taken every 30 minutes for 4 to 6 hours at the end of the treatment periods, Comtan was found to increase the mean 'ON' time significantly relative to placebo (p < 0.01). The mean total daily levodopa dosage required by the patients was decreased by 140 mg in the Comtan group relative to placebo (p < 0.01).
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 Comtan 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 Comtan 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, Comtan 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 Comtan 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 Comtan 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 Comtan 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.
Additional data on the safety of entacapone has been obtained from approximately 800 patients treated for 1 year and about 400 patients treated for at least 2 years.

5.2 Pharmacokinetic Properties

There are large intra- and interindividual variations in the pharmacokinetics of entacapone.

Absorption.

The peak concentration (Cmax) of entacapone in plasma is usually reached about one hour after ingestion of a 200 mg tablet of Comtan. The drug is subject to extensive first-pass metabolism. The bioavailability of entacapone is about 35% after an oral dose. Food does not affect the absorption of entacapone to any significant extent, but the effects of a fatty meal on its absorption have not been studied.

Distribution.

After absorption from the gastrointestinal tract, entacapone is rapidly distributed to the peripheral tissues, with a distribution volume at steady state of 20 L. Entacapone is extensively bound to plasma proteins, mainly to albumin. Within the range of therapeutic concentrations, the unbound fraction in human plasma is about 2.0%.

Metabolism.

A small amount of entacapone, the (E)-isomer, is converted to its (Z)-isomer. The (E)-isomer accounts for 95% of the AUC of entacapone. The (Z)-isomer and traces of other metabolites account for the remaining 5% of AUC.
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).

Excretion.

The elimination of entacapone occurs mainly by nonrenal metabolic routes. Entacapone is metabolised in the liver primarily by conjugation with glucuronic acid. The elimination of entacapone occurs mainly by biliary excretion. About 10% of the dose is excreted in the urine. Only traces of entacapone are found as unchanged drug in urine. The major part (95%) of the drug excreted in urine is conjugated with glucuronic acid. Of the metabolites found in urine, only about 1% have been formed through oxidation.
Approximately 92% of the dose is eliminated during the β-phase with a short elimination half-life of 30 minutes. The total plasma clearance of entacapone is about 800 mL/minute. There is no evidence of polymorphic metabolism of entacapone.

Pharmacokinetics in the elderly.

The pharmacokinetic properties of entacapone are similar in both young and elderly adults.

Pharmacokinetics in patients with hepatic dysfunction.

The metabolism of entacapone is slowed in patients with mild to moderate liver impairment (Child-Pugh class A and B), which leads to an increased plasma concentration of entacapone, both in the absorption and elimination phases (see Section 4.3 Contraindications).

Pharmacokinetics in patients with renal dysfunction.

Renal impairment does not affect the pharmacokinetics of entacapone and there is no need for dose adjustment. However, the possible need for a longer dosing interval should be kept in mind in the treatment of patients receiving dialysis therapy (see Section 4.2 Dose and Method of Administration).

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. An in vivo assay for clastogenicity and assays for DNA damage were negative.

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 (α2mu-globulin) specific to male rats, and are thought not to constitute a hazard for clinical use.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, mannitol, croscarmellose sodium, hydrogenated vegetable oil, hypromellose, polysorbate 80, glycerol, sucrose, magnesium stearate, iron oxide yellow, iron oxide red and titanium dioxide.

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 25°C.

6.5 Nature and Contents of Container

Comtan tablets are supplied in glass coloured bottles or HDPE bottles with PP child resistant closures in pack sizes of 30, 60 or 100 tablets.
Not all pack sizes marketed.

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

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.

Chemical structure.


Chemical name: (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl -2-propenamide.
Molecular formula: C14H15N3O5.
Molecular weight: 305.26.

CAS number.

130929-57-6.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes