Consumer medicine information

Madopar

Levodopa; Benserazide hydrochloride

BRAND INFORMATION

Brand name

Madopar

Active ingredient

Levodopa; Benserazide hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Madopar.

What is in this leaflet

This leaflet answers some common questions about Madopar tablets and capsules.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

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

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

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

What Madopar is used for

The name of your medicine is Madopar. It contains two active ingredients called levodopa and benserazide.

Madopar belongs to a group of medicines called antiparkinsonian agents and is used for the treatment of Parkinson's disease.

Antiparkinsonian agents work on the central nervous system. The symptoms of Parkinson's disease are caused by a deficiency of a natural substance in the brain called dopamine. Madopar helps to replace this substance. By improving muscle control, Madopar allows more normal movements of the body.

The symptoms of patients suffering from Parkinson's disease can be reduced by taking this medicine. Madopar does not, however, cure the disease, since the cause of the dopamine deficiency within the brain is not removed.

Your doctor, however, may have prescribed Madopar for another purpose.

Ask your doctor if you have any questions about why Madopar has been prescribed for you.

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

Before you take Madopar

Do not take Madopar if:

Do not take Madopar if you have an allergy to:

  • any medicine containing levodopa or benserazide
  • any of the 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 Madopar if:

  • you have taken a non-selective monoamine oxidase inhibitor (MAO-I) medicine such as tranylcypromine or phenelzine within the last 2 weeks
  • you have taken a combination of a selective MAO-A inhibitor such as moclobemide with a selective MAO-B inhibitor such as selegiline or rasagiline
  • you have untreated heart, liver, kidney, lung, blood or endocrine (hormonal) disease
  • you have narrow (closed) angle glaucoma (high pressure in the eye)
  • you are being treated for severe mental illness (active psychosis or serious psychoneurosis)
  • you have melanoma or suspected melanoma
  • you are under the age of 30
  • you are being treated for Huntington's chorea or intention tremor

Do not take Madopar after the expiry date (EXP) printed on the pack or if the packaging is torn or shows signs of tampering. If you take this medicine after the expiry date has passed, it may not work as well.

If you are not sure if you should be taking Madopar, talk to your doctor.

You must tell your doctor if:

  1. you are allergic to any other medicines, foods, dyes or preservatives
  2. you have any other health problems including:
  • convulsions (fits)
  • diabetes
  • stomach ulcers
  • feeling down (depression) or other psychological disorders
  • osteoporosis or osteomalacia
  • irregular heart beat
  • wide-angle glaucoma (high pressure in the eye)
  • any compulsive behaviour disorder
  • onset of sudden sleep disorder
  • other illnesses
  1. you plan to have surgery
  2. you are pregnant or plan to become pregnant.
Madopar should not be taken during pregnancy. You should use effective contraception to avoid becoming pregnant while you are being treated with Madopar.
  1. you are breast-feeding or plan to breast-feed.
Your doctor will discuss the risks and benefits of taking Madopar when breast-feeding.

If you have not told your doctor about any of the above, tell them before you start taking Madopar.

When taken with certain foods

Madopar may not work as well as usual when taken with a protein rich meal (e.g. meat).

Taking other medicines

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

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

  • sympathomimetics such as cough and cold medicines containing ephedrine or pseudoephedrine, adrenaline, noradrenaline, isoprenaline, dexamphetamine, asthma preparations, epi-pens
  • blood pressure lowering medications such as metoprolol, atenolol
  • other antiparkinsonian medications such as anticholinergics, amantadine, selegiline, bromocriptine and dopamine agonists
  • medicines containing iron
  • medicines for relief of nausea such as metoclopramide
  • some medications used to treat mental illness, particularly the phenothiazines, tricyclic antidepressants and butyrophenone derivatives such as chlorpromazine, fluphenazine, prochlorperazine, thioridazine, trifluoperazine or haloperidol
  • general anaesthetics (medicines that put you to sleep before an operation), particularly cyclopropane and halothane. If you know you are going to have an operation, you should stop Madopar 2-3 days beforehand. You should discuss this with your doctor first.
  • opioids such as morphine, pethidine, methadone and codeine (may be present in some cough and cold or pain relieving medicines)
  • antacids (medicines for heartburn, indigestion) should not be taken at the same time as Madopar HBS, as they interfere with the controlled release characteristics of Madopar HBS. Antacids can be taken at other times of the day.

These medicines may be affected by Madopar or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor or pharmacist has more information on the medicines to be careful with or to avoid while taking Madopar.

If you have not told your doctor about any of the above, tell them before you start taking Madopar.

Ask your doctor or pharmacist if you are not sure about any of the medicines on this list.

How to take Madopar

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

How much to take

Your doctor will tell you how many Madopar tablets or capsules to take each day.

The dose depends on your individual symptoms and your response to the medicine. The dose of Madopar has to be carefully adjusted for each person. If you take too little Madopar your symptoms may not be controlled. If you take too much Madopar, you may experience unwanted effects. It may take several weeks before the best dose for you is reached.

Remember this is just a guide. This guide can be used for Madopar capsules or tablets.

Treatment with Madopar is usually started with lower doses. This may be increased each week until you have reached your required dose. Your doctor will decide which dose is best for you.

Do not stop taking Madopar without first discussing with your doctor.

Madopar HBS (slow release) Capsules
Madopar HBS is different to other Madopar products. It takes longer to start working but its effects last longer.

If you change from normal Madopar to Madopar HBS, you start on the same number of capsules or tablets, but this is gradually increased by your doctor.

Some people who change to Madopar HBS capsules might feel a little worse at first. This should only be temporary, but speak to your doctor if anything worries you.

When you take Madopar HBS, your doctor may tell you to take a Madopar capsule or Madopar Rapid (dispersible) tablet in the morning to help maintain better control of your symptoms.

How to take it

Madopar Capsules
Madopar capsules or tablets should be swallowed whole with a glass of water or non-alcoholic drink.

Madopar HBS Capsules
Madopar HBS capsules should be swallowed whole and not chewed, opened or dissolved in liquid.

Madopar Rapid (dispersible) Tablets
Madopar Rapid tablets are for people who have difficulty swallowing whole tablets or who require the medicine to work quickly. They should be mixed with a quarter of a glass (at least 25-50mL) of water. The tablets will disperse into granules to give a milky-looking liquid which you should drink within 30 minutes. Remember to stir the liquid immediately before taking because the granules can settle at the bottom. The tablets do not completely dissolve.

Madopar Tablets
Madopar tablets can be broken across the score line. Any tablets which do not break cleanly along the line should not be taken.

Do not chew capsules or tablets.

When to take it

If possible, Madopar should be taken either 30 minutes before a meal or one hour after a meal. However, some patients may prefer to take Madopar with food.

If you have stomach upsets which can occur in the early stages of treatment with Madopar, try taking Madopar with a small snack (e.g. a biscuit) or liquid. Tell your doctor if anything worries you.

How long to take Madopar

When you start Madopar you will need to take it long term. You may need at least 6 months before deciding if Madopar is working for you.

Continue taking Madopar until your doctor tells you to stop.

If you forget to take Madopar

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

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for one you have missed. This may increase the chance of you getting an unwanted side effect.

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

If you are not sure what to do, ask your doctor or pharmacist.

In case of an overdose

If you think that you or anyone else may have taken too much Madopar, immediately telephone your doctor or Poisons Information Centre (Australia telephone 13 11 26; New Zealand telephone 0800 764 766) for advice or go to Accident and Emergency at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Keep telephone numbers for these places handy.

If you take an overdose of Madopar, you will experience some or all of the symptoms described under Side Effects, but these symptoms may be more severe.

While you are taking Madopar

Things you must do

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

Tell any other doctors, dentists and pharmacists who are treating you that you are taking Madopar.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

Tell your doctor if you become pregnant whilst taking Madopar. Madopar should not be taken during pregnancy. You should use effective contraception to avoid becoming pregnant while you are being treated with Madopar.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Tell your doctor if you feel that Madopar is not helping your condition.

Tell your doctor if you suffer from sleepiness or sudden onset of sleep during daily activities.

Be sure to keep all of your appointments with your doctor so that your progress can be checked. Your doctor may perform regular tests while you are taking Madopar.

Things you must not do

Do not stop taking Madopar or change the dose without first checking with your doctor.

Do not let yourself run out of medicine over the weekend or on holidays.

Do not give Madopar to anyone else even if they have the same condition as you.

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

Do not take any other medicines whether they require a prescription or not without first talking to your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how Madopar affects you.

Madopar is associated with excessive drowsiness and very rarely with excessive daytime drowsiness and sudden sleep onset episodes.

Tell your doctor if you experience these effects and do not drive or operate machinery until this has been resolved.

Side Effects

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

Madopar helps most people with Parkinson's Disease but it may have unwanted side effects in some people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following list of 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 and they worry you:

  • abnormal involuntary jerking movements of the body. These are usually caused if your dose is too high and will lessen or disappear when your dose is reduced
  • mental changes including paranoia, depression, mania, agitation and hallucinations (seeing, feeling or hearing things that are not there)
  • fluctuations in the effect of Madopar known as freezing episodes. These can usually be helped by asking your doctor to adjust your dose
  • nausea and vomiting
  • loss of appetite
  • weight gain
  • constipation
  • skin rash or itching
  • confusion, tiredness, sleeplessness, or sudden onset of sleep episodes
  • poor muscle tone, hiccups
  • restlessness
  • water retention, cramps

The above side effects are common, especially if you have just started Madopar.

  • changes in sex drive or hypersexuality
  • signs of compulsive behaviour (performing a repetitive purposeless activity)
  • loss of taste
  • your urine, mouth, saliva, tongue and teeth may be darker with a red tinge
  • bleeding or bruising more easily
  • frequent infections such as fever, severe chills
  • sore throat or mouth ulcers

Tell your doctor as soon as possible if you notice any of the following:

  • palpitations or changes in the rhythm or rate of the heartbeat, chest pain, dizziness on standing up
  • diarrhoea
  • confusion

These may be serious side effects and your doctor may need to change your Madopar dose.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Ask your doctor or pharmacist if you don't understand anything on this list.

Do not be alarmed by this list of side effects. You may not experience any of them.

After taking Madopar

Storage

Keep your capsules or tablets in the bottle, with the cap tightly closed, until it is time to take them. If you take the capsules or tablets out of the bottle, or the cap is loose, they may not keep as well.

Keep Madopar capsules and tablets in a cool dry place where the temperature stays below 25°C.

Do not store it, or any other medicine, in a bathroom or near a sink.

Do not leave it in the car or on window sills. Heat and dampness can destroy this medicine.

Keep Madopar where young 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 Madopar, or the tablets/capsules have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product Description

What Madopar looks like

There are eight Madopar products available to meet individual needs:

  • Madopar 62.5 capsules are light grey at one end and powder blue at the other end, with 'ROCHE' printed on both ends.
  • Madopar 125 capsules are flesh coloured at one end and powder blue at the other end, with 'ROCHE' printed on both ends.
  • Madopar 250 capsules are caramel coloured at one end and powder blue at the other end, with 'ROCHE' printed on both ends.
  • Madopar HBS 125 (slow-release) capsules are light blue at one end and dark green at the other end, with 'ROCHE' printed in red ink on both ends.
  • Madopar 125 tablets# are pale red in colour, cross-scored on both sides.
  • Madopar 250 tablets# are pale red in colour, imprinted on both sides with 'ROCHE and a hexagon on one side crossed-scored on both sides.
  • Madopar Rapid 62.5 (dispersible) tablets are off-white in colour, scored on one side and printed with 'ROCHE 62.5' on the other.
  • Madopar Rapid 125# (dispersible) tablets are off-white in colour, scored on one side and printed with 'ROCHE 125' on the other.

All Madopar capsules and tablets come in bottles of 100.

(#Not available in New Zealand)

Ingredients

Active ingredients:

Madopar Capsules:

Madopar 62.5 capsules contain levodopa 50 mg and benserazide 12.5 mg.

Madopar 125 capsules contain levodopa 100 mg and benserazide 25 mg.

Madopar 250 capsules contain levodopa 200 mg and benserazide 50 mg.

Madopar HBS 125 (slow-release) capsules contain levodopa 100 mg and benserazide 25 mg.

Madopar Tablets

Madopar 125 tablets contain levodopa 100 mg and benserazide 25 mg.

Madopar 250 tablets contain levodopa 200 mg and benserazide 50 mg.

Madopar Rapid (dispersible) Tablets:

Madopar Rapid 62.5 tablets contain levodopa 50 mg and benserazide 12.5 mg.

Madopar Rapid 125 tablets contain levodopa 100 mg and benserazide 25 mg.

Inactive ingredients:

Madopar Capsules:

Madopar 62.5, 125 and 250 capsules all contain:

microcrystalline cellulose, talc, povidone, magnesium stearate, indigo carmine (132), titanium dioxide (171), iron oxide (red, yellow or black - 172) and gelatin.

Madopar 62.5 capsules also contain mannitol.

Madopar HBS (slow-release) capsules contain:

mannitol, talc, povidone, magnesium stearate, calcium hydrogen phosphate, hypromellose, hydrogenated vegetable oil, indigo carmine (132), iron oxide yellow (172), titanium dioxide (171) and gelatin and TEKPRINT SW-1102 Red Ink used as a printing ink.

Madopar Tablets:

Madopar 125 and 250 tablets contain:

mannitol, microcrystalline cellulose, crospovidone, magnesium stearate, pregelatinised maize starch, ethylcellulose, anhydrous calcium hydrogen phosphate, colloidal anhydrous silica, docusate sodium and iron oxide red (172).

Madopar Rapid (dispersible) Tablets:

Madopar Rapid 62.5 and Rapid 125 tablets contain:

citric acid, starch- maize, microcrystalline cellulose and magnesium stearate.

Manufacturer

Madopar is distributed in Australia by:

Roche Products Pty Limited
ABN 70 000 132 865
Level 8, 30-34 Hickson Road
Sydney NSW 2000

Medical enquiries: 1800 233 950

Distributed in New Zealand by:

Roche Products (New Zealand) Limited
PO Box 109113
Newmarket, Auckland 1149

Medical enquiries: 0800 276 243

Please check with your pharmacist for the latest Consumer Medicine Information.

Australian Registration Numbers

Madopar Capsules:

  • Madopar 62.5 - AUST R 13744
  • Madopar 125 - AUST R 13746
  • Madopar 250 - AUST R 13742
  • Madopar HBS - AUST R 13743

Madopar Tablets:

  • Madopar 125 - AUST R 43517
  • Madopar 250 - AUST R 13745

Madopar Rapid Tablets:

  • Madopar Rapid 62.5 - AUST R 59577
  • MADOPAR Rapid 125 - AUST R 59576

This leaflet was prepared on 18 July 2019

Published by MIMS October 2019

BRAND INFORMATION

Brand name

Madopar

Active ingredient

Levodopa; Benserazide hydrochloride

Schedule

S4

 

1 Name of Medicine

Levodopa and benserazide hydrochloride.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

Benserazide: 322 35 0.
Levodopa: 59 92 7.

2 Qualitative and Quantitative Composition

Each Madopar 62.5 capsule contains 50 mg levodopa and 14.25 mg benserazide (equivalent to 12.5 mg of the base).
Each Madopar 125 capsule contains 100 mg levodopa and 28.5 mg benserazide (equivalent to 25 mg of the base).
Each Madopar 250 capsule contains 200 mg levodopa and 57 mg benserazide (equivalent to 50 mg of the base).
Each Madopar HBS 125 capsule contains 100 mg levodopa and 28.5 mg benserazide (equivalent to 25 mg of the base).
Each Madopar 125 tablet contains 100 mg levodopa and 28.5 mg benserazide (equivalent to 25 mg of the base).
Each Madopar 250 tablet contains 200 mg levodopa and 57 mg benserazide (equivalent to 50 mg of the base).
Each Madopar Rapid 62.5 dispersible tablet contains 50 mg levodopa and 14.25 mg benserazide (equivalent to 12.5 mg of the base).
Each Madopar Rapid 125 dispersible tablet contains 100 mg levodopa and 28.5 mg benserazide (equivalent to 25 mg of the base).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Madopar 62.5 capsules have a light grey opaque body with powder blue opaque cap, imprinted with 'ROCHE' on both ends.
Madopar 125 capsules have a flesh coloured opaque body and powder blue opaque cap, imprinted with 'ROCHE' on both ends.
Madopar 250 capsules have a caramel coloured opaque body and powder-blue opaque cap, imprinted with 'ROCHE' on both ends.
Madopar HBS (Hydrodynamically Balanced System) 125 capsules have a light blue opaque body and dark green opaque cap imprinted with 'ROCHE' in red ink on both ends.
Madopar 125 tablets are cylindrical, biconvex, pale red tablets, cross-scored on both sides.
Madopar 250 tablets are cylindrical, biconvex, pale red tablets, imprinted with 'ROCHE' and a hexagon on one side, cross-scored on both sides.
Madopar Rapid 62.5 dispersible tablets are off-white, cylindrical, bi-planar tablets with bevelled edges, imprinted with 'ROCHE 62.5' on one side and a break-bar on the other.
Madopar Rapid 125 dispersible tablets are off-white, cylindrical, bi-planar tablets with bevelled edges, imprinted with 'ROCHE 125' on one side and a break-bar on the other.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Anti-parkinson drugs, ATC code: N04BA02.

Mechanism of action.

Levodopa is the metabolic precursor of dopamine. The latter is severely depleted in the striatum pallidum and substantia nigra of Parkinsonian patients and it is considered that the administration of levodopa raises the level of available dopamine in these centres. The major portion of a levodopa dose, however, is decarboxylated in tissues outside the brain. As a consequence the full therapeutic effect may not be obtained and side effects may occur.
The decarboxylase inhibitor, benserazide, at the recommended therapeutic dose does not cross the blood-brain barrier to any significant degree, although at very high doses it may enter the central nervous system.
Administration of benserazide makes it possible to inhibit the peripheral decarboxylation of levodopa without significantly affecting its metabolism in the brain. Combined therapy with levodopa and benserazide reduces the amount of levodopa required for optimal therapeutic benefit and permits an earlier response to therapy.
The HBS form (Hydrodynamically Balanced System) provides prolonged release of the active ingredients in the stomach where the capsule remains for several hours. It ensures therapeutic levodopa plasma levels for several hours and a significant reduction of the concentration peaks.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Direct methods to measure benserazide are lacking, however, studies using radiolabelled benserazide have shown that 70% of the oral dose is absorbed from the intestine reaching peak plasma levels in about an hour. Measurements of the total radioactivity of the plasma levels indicate at least two metabolites with different half- lives. The metabolites in humans have not been clearly identified but probably include serine and trihydroxy-benzyl-hydrazine.
After a single oral dose of benserazide alone about 60% of the total radioactivity appears in the urine, most of it (85%) during the first 12 hours. 30% of the dose appears in the faeces. The presence of levodopa causes a somewhat higher absorption and excretion of the benserazide.
Levodopa is almost completely absorbed from conventional Madopar tablets and capsules giving peak levels in 1-2 hours. In the presence of benserazide the levels reached by 200 mg levodopa approximate those of 1000 mg levodopa alone. The duration of action of a dose of levodopa is variable according to the stage of the disease. 78% is excreted in the urine in 48 hours, with only about 0.2% in the faeces. Metabolites include homovanillic acid (24%) and mandelic acid.
The pharmacokinetic profile of levodopa following administration of Madopar Rapid is very similar to that following Madopar Standard in healthy volunteers and in Parkinsonian patients, but the time to peak concentrations tends to be shorter after Madopar Rapid.
The pharmacokinetic properties of the Madopar HBS form differ from those of the conventional capsules and tablets. The active ingredients are released slowly in the stomach. The maximum plasma concentration, which is lower than for the standard dosage forms, is reached approximately 3 hours after ingestion. The plasma concentration curve shows a longer "half-duration" (time span where plasma concentrations are equal to or higher than the half maximum concentration) than that of the conventional forms which indicates pronounced controlled-release properties.
The bioavailability of Madopar HBS is about 60% of the conventional capsules or tablets. The bioavailability is reduced by antacids but not by food.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

4 Clinical Particulars

4.1 Therapeutic Indications

Parkinson's disease and parkinsonian symptoms including post-encephalitic and toxic forms, but excluding drug induced parkinsonism.
Madopar HBS is indicated for patients presenting with all types of fluctuations in response (i.e. "peak dose dyskinesia" and "end of dose deterioration") and for better control of nocturnal symptoms.

4.3 Contraindications

As with levodopa, patients in whom sympathomimetic amines are contraindicated should not receive Madopar. Monoamine oxidase inhibitors should not be given concomitantly and should be withdrawn at least two weeks prior to initiating Madopar therapy.
Madopar must not be given in conjunction with non-selective monoamine oxidase (MAO) inhibitors due to the risk of hypertensive crisis (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). However, selective monoamine oxidase B (MAO-B) inhibitors, such as selegiline and rasagiline, and selective monoamine oxidase A (MAO-A) inhibitors, such as moclobemide are not contraindicated. Combination of MAO-A and MAO-B inhibitors is equivalent to non-selective MAO inhibition and hence they should not be given concomitantly with Madopar.
Madopar should not be administered to patients with clinical or laboratory evidence of uncompensated cardiovascular, endocrine, renal, hepatic, haematological or pulmonary disease, or in patients with narrow angle glaucoma, or with active psychosis or serious psychoneurosis. Because levodopa may activate a malignant melanoma, Madopar should not be used in patients with suspicious, undiagnosed lesions or a history of melanoma. Madopar is contraindicated in the management of intention tremor and Huntington's chorea.
Madopar must not be given to patients under 30 years of age.
Madopar is contraindicated in those patients who may be hypersensitive to levodopa, benserazide or any of the excipients.

4.4 Special Warnings and Precautions for Use

Hypersensitivity reactions may occur in susceptible individuals.
All patients should be carefully observed for signs of depression with suicidal tendencies or other serious behavioural changes. Extreme caution should be used in treating patients with a history of psychotic disorders or who are receiving psychotherapeutic agents such as phenothiazines or tricyclic anti-depressants.
Care should be exercised in administering Madopar to patients with a history of myocardial infarction or who have atrial, nodal or ventricular arrhythmias. Patients with cardiac abnormalities should have their treatment with Madopar initiated in a facility with adequate monitoring equipment and provision for intensive care.

General.

Regular assessment of cardiovascular, hepatic, haematopoietic and renal function should be performed in all patients during extended therapy.

Diabetes.

Patients with diabetes should undergo frequent blood sugar tests, and the dosage of antidiabetic agents should be adjusted to blood sugar levels.
Patients with a history of convulsive disorders should be treated cautiously if Madopar is incorporated into their regimen. The possibility of upper gastro-intestinal haemorrhage occurring in patients with a history of peptic ulcer must be borne in mind when treating them with Madopar.

Use in patients with osteoporosis and osteomalacia.

The effects of Madopar on human bone during prolonged administration is not known. It should be remembered that elderly people have a considerable incidence of subclinical osteoporosis and osteomalacia. In animal studies in rats, skeletal abnormalities resulting from disturbance of the growth of the epiphyseal plates, prior to closure, have occurred.

Physical activity.

Patients with severe parkinsonism who improve on Madopar therapy should be advised to resume normal activities gradually and with caution as rapid mobilisation may increase the risk of injury.

Use in patients with wide-angle glaucoma.

Patients with chronic wide-angle glaucoma can be treated cautiously with Madopar, provided the intra-ocular pressure is well controlled and monitored carefully during therapy. Rarely pupillary dilatation and activation of latent Horner's syndrome have been reported during levodopa treatment.

Psychoactive drugs.

If concomitant administration of psychoactive drugs are necessary, they should be administered with great caution. Patients should be carefully observed for unusual, untoward drug effect (see Section 4.3 Contraindications). Phenothiazines and butyrophenone derivatives may antagonise Madopar and in general should not be used.

Anaesthesia.

If general anaesthesia is required, Madopar should, if possible be discontinued 2 or 3 days beforehand. On resumption of medication the dosage should be gradually stepped up again to the pre-operative level. Anaesthesia with cyclopropane or halothane should be avoided in emergency surgery. The patient must be closely supervised during the operation.

Somnolence.

Madopar has been associated with somnolence and episodes of sudden sleep onset. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported very rarely. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with Madopar (see Section 4.7 Effects on Ability to Drive and Use Machines). A reduction of dosage or termination of therapy may be considered.

Dopaminergic drugs.

Compulsive behaviour such as gambling, hypersexuality, shopping, eating, medication use and punding (repetitive purposeless activity) has been reported in patients taking dopamine agonists for Parkinson's Disease, especially at high doses. There is no established causal relationship between benserazide, which is not a dopamine agonist, and these events. However, caution is advised as levodopa is a dopaminergic drug. Prescribers, patients and caregivers should be alert to the possibility of such behaviour, which may have serious financial and social consequences.

Withdrawal of Madopar.

Madopar must not be withdrawn abruptly. Abrupt withdrawal of the preparation may result in a neuroleptic malignant-like syndrome (hyperpyrexia, muscular rigidity, possibly psychological changes and elevated serum creatinine phosphokinase) which may be life-threatening. Should a combination of such symptoms and signs occur then the patient should be kept under surveillance by a physician (if necessary hospitalised) and rapid and appropriate symptomatic treatment given. This may include re-introduction of Madopar after appropriate evaluation.

Potential for drug dependence or abuse.

Dopamine dysregulation syndrome (DDS).

A small number of patients suffer from cognitive and behavioural disturbances that can be directly attributed to taking increasing quantities of medication against medical advice and well beyond the doses required to treat their motor disabilities.

Effect on laboratory tests.

Madopar therapy may increase urinary catecholamines and metabolites and may therefore interfere with interpretation of urinary assays, e.g. diagnosis of adrenal tumours. False positive urine test results for ketone bodies have been reported.
Coombs' test may give false positive results in patients on Madopar therapy.
"T" wave increase was observed in 27% of patients in one study. Rarely, "PR" intervals may increase.
Uric acid, creatinine and glucose estimation may be interfered with by levodopa.
For reported biochemical disturbances see Section 4.8 Adverse Effects (Undesirable Effects).

Use in the elderly.

No data available.

Paediatric use.

Madopar is contraindicated in patients less than 30 years old (see Section 4.3 Contraindications).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Cardiovascular drugs.

Postural hypotensive episodes have been reported; therefore, Madopar should be administered cautiously and blood pressure monitored in patients on antihypertensive medication. Furthermore, special care is required with alpha methyldopa which is a substrate for the enzyme dopa decarboxylase.
The effect of Madopar is not impaired by multivitamin preparations containing vitamin B6. The absorption of levodopa from the gastrointestinal tract may be impaired by a protein-rich meal taken at the same time.

Pharmacokinetic interactions.

Coadministration of antacids with Madopar HBS reduces the extent of levodopa absorption by 32%. The HBS formulation showed a different pharmacokinetic profile when compared with Madopar when they were given with antacids. The rate of absorption of HBS was reduced and peak levels were lower. There was a tendency to produce a plateau, which lasted 2-4 hours, as the drug was being absorbed and eliminated at the same rate.
Ferrous sulphate decreases the maximum plasma concentration and the AUC of levodopa by 30-50%. This difference may result in a reduction of the effectiveness of Madopar.
Metoclopramide may increase the rate of levodopa absorption. The effect on the HBS formulation has not been examined.
Coadministration of domperidone with levodopa significantly increased the bioavailability of levodopa compared to levodopa given alone. Domperidone significantly increased the maximum plasma concentration of levodopa and the AUC from 0-3 hours by 1.5-fold and 1.3-fold respectively. Domperidone may increase the bioavailability of levodopa by stimulation of gastric emptying.

Pharmacodynamic interactions.

The action of Madopar is inhibited by neuroleptics and opioids.
Madopar should not be administered concomitantly with irreversible non-selective MAO inhibitors; there should be an interval of at least two weeks between stopping the MAO inhibitor and starting Madopar therapy. Otherwise unwanted side effects such as hypertensive crises are likely to occur. However, selective MAO-B inhibitors, such as selegiline, rasagiline and selective MAO-A inhibitors, such as moclobemide can be prescribed to patients on Madopar therapy and it may be necessary to adjust the patient's levodopa dose.
Combination of MAO-A and MAO-B inhibitors is equivalent to non-selective MAO inhibition and hence they should not be given concomitantly with Madopar (see Section 4.3 Contraindications).
Madopar should not be administered concomitantly with sympathomimetic agents (adrenaline, noradrenaline, isoprenaline or dexamphetamine) as their effect may be potentiated by levodopa. If concomitant administration is necessary, monitoring of the cardiovascular system is essential, and the dose of the sympathomimetic agent may need to be reduced.
Combination with other anti-parkinsonian agents (anticholinergics, amantadine, selegiline, bromocriptine and dopamine agonists) is permissible, though such combination may intensify both the desired and the undesired effects. Dosage adjustment of Madopar or the other substance may be required. When initiating adjuvant treatment with a COMT inhibitor, a reduction of the dosage of Madopar may be necessary. Anticholinergics should not be withdrawn abruptly if therapy with Madopar is initiated.
Concomitant administration of antipsychotics with dopamine-receptor blocking properties, particularly D2-receptor antagonists, might antagonise the antiparkinsonian effects of Madopar. Levodopa may reduce antipsychotic effects of these drugs. These drugs should be co-administered with caution.

4.6 Fertility, Pregnancy and Lactation

(Category B3)
Madopar should not be taken during pregnancy or by women of childbearing potential in the absence of adequate contraception because of possible damage to foetal skeletal development.

Madopar should not be given to nursing mothers as levodopa and benserazide may appear in the mother's milk; furthermore, levodopa may inhibit lactation and there is a possibility that the skeletal changes found in rats may be relevant to growing bones in humans.

Effects on fertility.

No data available.

4.8 Adverse Effects (Undesirable Effects)

Psychiatric disorders.

Depression can be part of the clinical picture in patients with Parkinson's disease and may also occur in patients treated with Madopar. Agitation, anxiety, insomnia, hallucinations, delusions and temporal disorientation may occur particularly in elderly patients and in patients with a history of such disorders. Mania, confusion and fainting have also been reported. Dopamine dysregulation syndrome (DDS) has been reported.

Nervous system disorders.

Abnormal involuntary movements (lips, head, tongue, cheeks, extremities), dyskinesia, hyperkinesia and involuntary jerks (muscle twitch and blepharospasm may be taken as early signs to consider dosage reduction), hiccups, nocturnal excitation, diurnal excitation, dizziness. Isolated cases of ageusia or dysgeusia have been reported. At later stages of the treatment, dyskinesia (e.g. choreiform or athetotic) may occur. With prolonged treatment, fluctuations in therapeutic response may also be encountered. They include freezing episodes, end-of-dose deterioration and the "on-off" effect. Madopar is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes.

Cardiac disorders.

Cardiac arrhythmias, palpitations and angina pectoris have also been reported.

Respiratory disorders.

Dyspnoea.

Vascular disorders.

Orthostatic hypotension may occur occasionally. Orthostatic disorders commonly improve following reduction of the Madopar dosage.

Gastrointestinal disorders.

Nausea and vomiting (although these occur significantly less often with Madopar than with levodopa alone) and diarrhoea, sialorrhoea and constipation have been reported with Madopar.

Skin and subcutaneous tissue disorders.

Allergic skin reactions such as pruritus and rash may occur in rare cases.

Musculoskeletal disorders.

Muscle cramps, hypotonia, leg pain, torsion dystonia.

Reproductive disorders (male and female).

Changes in libido.

Body as a whole.

Weight gain, oedema, lassitude.

Investigations.

Transient rises in AST, ALT and alkaline phosphatase are common. Increased gamma-glutamyltransferase has been reported. Serum urea and creatinine levels may fall early in treatment and then revert to normal after some months. Serum protein-bound-iodine (PBI) levels may rise. Transient rise in bromsulphalein (BSP) retention. Prothrombin levels may rise. Transient fall in platelet and eosinophil count may occur. Urine may be altered in colour, usually red tinged and turns dark on standing. Other body fluids or tissues may also be discoloured or stained including saliva, the tongue, teeth or oral mucosa.

Post-marketing.

Blood and lymphatic system disorders.

Haemolytic anaemia, transient leukopenia and thrombocytopenia have been reported in rare cases. Therefore, as in any long-term levodopa-containing treatment, blood cell count and liver and kidney function should be monitored periodically.

Metabolic and nutritional disorders.

Anorexia has been reported.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage.

In order to reduce the incidence of adverse reactions and achieve maximal benefit, Madopar therapy must be individualised and drug administration must be continuously matched to the patient's needs and tolerance. Dosage must be carefully titrated in the elderly. Combined therapy with Madopar has a narrower therapeutic range than with levodopa alone because of its greater milligram potency. Therefore, titration and adjustment of dosage should be made in small steps and the dosage ranges recommended should usually not be exceeded. The appearance of involuntary movements should be regarded as a sign of levodopa toxicity and as an indication of overdosage requiring dose reduction. Treatment should, therefore, aim at maximal benefit without dyskinesias.
The following schemes may be taken as a guide.

Initial treatment.

The initial dosage schedule recommended is 1 capsule, tablet Madopar 125 or 125 mg dispersible tablet three times daily. The daily dosage is then increased by 1 capsule, tablet Madopar 125 or 125 mg dispersible tablet at weekly intervals until the individual therapeutic dosage is reached; when the patient can be followed very frequently the rate of dosage increase can be faster, e.g. twice a week. Thus the effective dose may be reached in as little as four days.
The effective dosage is generally between 4 and 8 capsules, tablets Madopar 125 or 125 mg dispersible tablets daily, divided into three or four doses; it is rarely necessary to administer more than 10 capsules, tablets Madopar 125 or 125 mg dispersible tablets daily.

Maintenance treatment.

Madopar capsules or tablets can be used if the optimum therapeutic dosage amounts to more than 5 capsules or, tablets Madopar 125 or 125 mg dispersible tablets daily, since it is advisable to divide the daily dosage into at least three doses.
The average maintenance dosage is 1 capsule or tablet Madopar three times daily, however, since the improvement may fluctuate, division of the daily dosage (regarding both the number of individual doses and their distribution through the day) must be adapted to individual requirements. If a patient begins to experience marked fluctuations in response in the course of the day (e.g. 'on-off' phenomena) the situation can often be noticeably improved by using Madopar 62.5, or, preferably by using Madopar HBS as recommended below.
If using Madopar 62.5 capsules or Madopar Rapid 62.5 tablets the total daily dosage is in principle not changed, but some (or all, if necessary) of the capsules or dispersible tablets of Madopar 125 or Madopar are replaced by capsules or dispersible tablets of Madopar 62.5, taken at shorter intervals.

Use of Madopar HBS.

The switch to Madopar HBS is preferably made from one day to the next while keeping the same daily dose and the same frequency of intake. After two to three days, the dosage should be gradually increased by about 50%, because of the lower bioavailability of this special dosage form. Patients should be informed that their condition may deteriorate for a while.
Due to the pharmacokinetic properties of Madopar HBS, the onset of action is approximately three hours. If desired, effective plasma levels may be achieved more rapidly by administering Madopar HBS together with conventional capsules or tablets. This may prove especially useful for the first morning dose, which should preferably be somewhat higher than the subsequent daily doses.
The individual titration for Madopar HBS must be carried out slowly and carefully, in intervals of at least 2 to 3 days between each change of dosage.
In case of poor response to Madopar HBS even at daily doses corresponding to 1500 mg of levodopa, or after six weeks treatment it is preferable to resume the previous treatment with the conventional capsules, tablets or dispersible tablets.
Over-responsiveness may be controlled by increasing the length of the intervals between administrations rather than by reducing the single doses.
In patients with nocturnal disability, positive effects have been reported after gradually increasing the last evening dose up to three Madopar HBS capsules at bedtime. Patients should be carefully observed for possible psychic side effects.
Dosage must be carefully titrated in every individual, including in elderly patients.

Use of Madopar Rapid.

Madopar Rapid 62.5 and Rapid 125 tablets are particularly suitable for patients with dysphagia (difficulties in swallowing) or in situations where a more rapid onset of action is required e.g. patients suffering from early morning and afternoon akinesia, or in patients who exhibit "delayed on" or "wearing off" phenomenon.

Conversion from levodopa alone to Madopar.

Gradually reduce the dosage of levodopa until parkinsonian symptoms reappear or become marked; when this point has been reached replace each 500 mg levodopa then being administered by 1 capsule, tablet Madopar 125 or 125 mg dispersible tablet, since the efficacy of 1 capsule, tablet Madopar 125 or 125 mg dispersible tablet is approximately equal to that of 500 mg levodopa.
Observe the patient closely for one week, and then if necessary, begin to increase the dosage of Madopar until a satisfactory improvement is obtained (the dosage schedule is identical with that for patients not previously treated with levodopa); this dosage increase can be commenced earlier if there is a deterioration in the patient's clinical condition.

General remarks.

In the rare cases in which intolerable side effects occur during the initial phase of treatment, incrementation of the dosage is stopped, or dosage is reduced. Withdrawal of the drug is seldom necessary. Once the side effects disappear or become tolerable, the daily dosage is again increased but more slowly, e.g. by 1 capsule, tablet Madopar 125 or 125 mg dispersible tablet every two or three weeks.
The interval between dosage increases is longer when the average dosage (6 capsules, tablets Madopar 125 or 125 mg dispersible tablets) has been exceeded, because a long period of time may elapse before the full effect of the product is observed.

Special populations.

Renal impairment.

No dose reduction is considered necessary in case of mild or moderate renal insufficiency (see Section 4.3 Contraindications).

Hepatic impairment.

The safety and efficacy of Madopar have not been established in patients with hepatic impairment (see Section 4.3 Contraindications).

Method of administration.

Madopar capsules must always be swallowed whole. They must never be opened or dissolved in fluid.
Madopar tablets can be broken across the score line. Tablets which break incorrectly (i.e. away from the score line) should be discarded.
Madopar Rapid 62.5 and Rapid 125 tablets should be dispersed in a quarter of a glass of water (approx. 25-50 mL). The tablets completely disperse within a few minutes to give a milky white dispersion. Due to rapid sedimentation, it is advisable to stir the dispersion immediately before drinking. Madopar Rapid 62.5 and Rapid 125 tablets should be taken within half an hour of dispersing the tablets.
Where possible, Madopar should be taken either at least 30 minutes before or 1 hour after meals, so that the competitive effect of dietary protein on levodopa uptake can be avoided and to facilitate a more rapid onset of action. However some patients find that Madopar is better tolerated if it is taken with food.
Like all replacement therapy, treatment with Madopar is permanent. Therapy with Madopar should be continued for at least six months before it is presumed to be ineffective.
The above dosage recommendations are based on the capsule dosage forms. However, the same doses may be achieved using the tablets which are cross-scored to facilitate titration of the dose to suit the patient's individual requirements.

4.7 Effects on Ability to Drive and Use Machines

Madopar may have a major influence on the ability to drive and use machines. Patients being treated with Madopar and presenting with somnolence and/or sudden sleep episodes must be informed 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 and somnolence have resolved.

4.9 Overdose

Symptoms and signs.

Symptoms and signs of overdose are qualitatively similar to the side effects of Madopar in therapeutic doses but may be of greater severity. Overdose may lead to: cardiovascular side effects (e.g. cardiac arrhythmias), psychiatric disturbances (e.g. confusion and insomnia), gastrointestinal effects (e.g. nausea and vomiting) and abnormal involuntary movements.
If a patient has taken an overdose of a controlled release form of Madopar (e.g. Madopar HBS capsules), occurrence of symptoms and signs may be delayed due to delayed absorption of the active substances from the stomach.

Treatment.

Monitor the patient's vital signs and institute supportive measures as indicated by the patient's clinical state. In particular, patients may require symptomatic treatment for cardiovascular effects (e.g. antiarrhythmics) or central nervous system effects (e.g. respiratory stimulants, neuroleptics).
In addition, for the controlled release formulations further absorption should be prevented using an appropriate method.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Madopar 125 and Madopar 250 tablets.

Mannitol, microcrystalline cellulose, crospovidone, magnesium stearate, pregelatinised maize starch, ethylcellulose, anhydrous calcium hydrogen phosphate, colloidal anhydrous silica, docusate sodium, iron oxide red.

Madopar Rapid 62.5 and Madopar Rapid 125 tablets.

Citric acid, starch- maize, microcrystalline cellulose, magnesium stearate.

Madopar 62.5, Madopar 125 and Madopar 250 capsules.

Microcrystalline cellulose, talc, povidone, magnesium stearate, indigo carmine, titanium dioxide, iron oxide (red, yellow or black), gelatin.
Madopar 62.5 capsules also contains mannitol.

Madopar HBS (hydrodynamically balanced system) capsules.

Mannitol, talc, povidone, magnesium stearate, calcium hydrogen phosphate, hypromellose, hydrogenated vegetable oil, indigo carmine, iron oxide yellow, titanium dioxide, gelatin, Tekprint SW-1102 Red Ink used as a printing ink.

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

Madopar 62.5, 125, 250 capsules.

Store below 30°C. Keep the bottle tightly closed.

Madopar HBS 125 capsules.

Store below 30°C. Keep the bottle tightly closed.

Madopar 125 tablets.

Store below 30°C. Keep the bottle tightly closed.

Madopar 250 tablets.

Store below 25°C. Keep the bottle tightly closed.

Madopar Rapid 62.5 tablets.

Store below 25°C. Protect from moisture.

6.5 Nature and Contents of Container

Madopar 62.5, Madopar 125 and Madopar 250 capsules are supplied in amber glass bottles with HDPE cap with integral desiccant (bottle contains 100 capsules).
Madopar HBS 125 capsules are supplied in amber glass bottles with HDPE cap with integral desiccant (bottle contains 100 capsules).
Madopar 125 and Madopar 250 tablets are supplied in amber glass bottles with HDPE cap with integral desiccant (bottle contains 100 tablets).
Madopar Rapid 62.5 and Madopar Rapid 125 dispersible tablets are supplied in amber glass bottles with HDPE cap with integral desiccant (bottle contains 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.

Summary Table of Changes