Consumer medicine information

Sinemet CR

Levodopa; Carbidopa

BRAND INFORMATION

Brand name

Sinemet CR

Active ingredient

Levodopa; Carbidopa

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Sinemet CR.

What is in this leaflet

This leaflet answers some common questions about SINEMET CR. 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 SINEMET CR 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 SINEMET CR is used for

SINEMET CR is used to treat some of the symptoms of Parkinson's disease. This is a disease of the nervous system that mainly affects body movement. The three main symptoms are shaking (tremor), muscle stiffness and slow and unsteady movement. People with Parkinson's disease often walk with a shuffle as they have difficulty in initiating movement. If untreated, Parkinson's disease can cause difficulty in performing normal daily activities.

SINEMET CR is most helpful in improving slow movement and muscle stiffness. It is also frequently helpful in treating shaking, difficulty in swallowing and drooling.

The symptoms of Parkinson's disease are caused by a lack of dopamine, a naturally occurring chemical produced by certain brain cells. Dopamine relays messages in the part of the brain that controls muscle movement.

When too little dopamine is produced slowness of movement results.

SINEMET CR contains two active ingredients, levodopa and carbidopa. Levodopa is a chemical closely related to dopamine which allows the body to make its own dopamine. Carbidopa makes sure that enough levodopa gets to the brain where it is needed. SINEMET CR is formulated to slowly release the levodopa and carbidopa. This keeps the amount of levodopa in your brain as even as possible. In many patients, SINEMET CR reduces some of the symptoms of Parkinson's disease.

Your doctor may have prescribed SINEMET CR for another reason. Ask your doctor if you have any questions about why SINEMET CR has been prescribed for you.

Before you take SINEMET CR

When you must not take it

Do not take SINEMET CR if:

  • you have an allergy to SINEMET CR or any of the ingredients listed at the end of this leaflet
  • you have any unusual skin lumps or moles which have not been examined by your doctor, or if you have ever had skin cancer or melanoma
  • you have a type of glaucoma called narrow-angle glaucoma
  • are being treated for depression with certain medicines called monoamine oxidase (MAO) inhibitors.
    Ask your doctor or pharmacist if you are not sure whether you are taking one of these medicines.
  • you are breast-feeding or plan to breast-feed.
    It has been shown that one of the active ingredients of SINEMET CR passes into breast milk. Therefore, because of the potential harm to the baby, SINEMET CR should not be used during breast-feeding.
  • the packaging is torn or shows signs of tampering
  • the expiry date on the pack has passed.
    If you take this medicine after the expiry date has passed, it may not work.

If you are not sure whether you should start taking SINEMET CR, talk to your doctor.

Do not give SINEMET CR to a child or teenager below the age of 18, unless advised by the child's doctor. The safety and effectiveness of SINEMET CR in children and teenagers under 18 years of age has not been established.

Before you start to take it

Tell your doctor if:

  1. you are pregnant or intend to become pregnant.
    Your doctor will discuss the possible risks and benefits of using SINEMET CR during pregnancy.
  2. you have or have had any medical conditions, especially the following:
  • depression or mental disturbances
  • heart disease, including irregular heartbeat, also known as arrhythmia
  • lung disease, including asthma
  • kidney, liver or hormonal problems
  • convulsions or fits
  • glaucoma
  • peptic ulcer disease
  1. you or your family member/caregiver notices you are developing urges to gamble, increased sexual urges, excessive eating or spending, medicine use or repetitive purposeless activities with other medicines for Parkinson's Disease, and/or other intense urges that could harm yourself or others. These behaviours are called impulse control disorders. Your doctor may need to review your treatments.
  2. you have previously been or are currently being treated with levodopa.
  3. you have any allergies to any other medicines or any other substances such as foods, preservatives or dyes.

If you have not told your doctor about any of the above, tell them before you take any SINEMET CR.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop. Some medicines and SINEMET CR may interfere with each other. These include:-

  • some medicines used to treat high blood pressure
  • some medicines used to treat depression
  • some medicines used to treat psychiatric problems
  • some medicines used to treat diseases related to involuntary movements
  • some medicines used to treat muscle spasms
  • phenytoin, a medicine used to treat convulsions
  • isoniazid, a medicine used to treat tuberculosis
  • selegiline, another medicine used to treat Parkinson's disease
  • iron supplements and multivitamins containing iron.

These medicines may be affected by SINEMET CR, or may affect how well the tablets work. You may need different amounts of your medicine, or you may need to take different medicines.

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

How to take SINEMET CR

How much to take

Take SINEMET CR only when prescribed by your doctor. Your doctor will tell you how many tablets to take each day. This depends on the severity of your condition, your response to treatment and whether you are taking other medicines. The dose varies considerably from patient to patient. Most patients need 2-8 tablets per day, taken in divided doses.

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

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

How to take it

Swallow SINEMET CR whole, with a glass of water.

Do not chew or crush the tablets. If the tablets are crushed or chewed, they will no longer have their slow-release properties.

How long to take it

SINEMET CR helps control some of your symptoms of Parkinson's disease, but does not cure it. Therefore SINEMET CR must be taken every day. Continue taking SINEMET CR for as long as your doctor prescribes.

Do not stop taking SINEMET CR, or lower the dosage, without checking with your doctor. Your doctor may want you to gradually reduce the amount of SINEMET CR you are using before stopping completely. This may help reduce the possibility of withdrawal symptoms such as muscle stiffness, fever and mental changes.

If you forget to take it

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 tablet(s) as you would normally.

If you are not sure whether to skip the dose, talk to your doctor or pharmacist.

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

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

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26), or go to accident and emergency at your nearest hospital, if you think that you or anyone else may have taken too much SINEMET CR. Do this even if there are no signs of discomfort or poisoning.

While you are using SINEMET CR

Things you must do

If you feel light-headed, dizzy or faint, get up slowly when getting out of bed or standing up. Although rare, you may feel light-headed or dizzy while taking SINEMET CR. This is because your blood pressure is falling suddenly.

Standing up slowly, especially when you get up from the bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, tell your doctor.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking SINEMET CR.

If you experience times where SINEMET CR does not appear to be working as well as it did previously, tell your doctor. After taking this medicine for long periods of time, such as a year or more, some people suddenly lose the ability to move. This loss of movement may last from a few minutes to several hours. The person is then able to move as before. This condition may unexpectedly occur again and again. This problem is called the "on-off" effect. Your doctor may prescribe you a stronger dose of SINEMET CR or may ask you to take it more frequently. Your doctor may need to prescribe you a different medicine.

Have blood tests when your doctor says to make sure SINEMET CR is not causing any problems with your blood, liver, kidneys or heart.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking SINEMET CR.

If you become pregnant while taking SINEMET CR, tell your doctor.

Things you must not do

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

Things to be careful of

Be careful when driving or operating machinery until you know how SINEMET CR affects you. SINEMET CR may cause dizziness or light-headedness in some people. Make sure you know how you react to SINEMET CR before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If you drink alcohol, dizziness or light-headedness may be worse.

In addition, in very rare cases, SINEMET CR may cause excessive sleepiness and sudden onset of sleep. If you experience these effects, do not drive or operate machinery until these effects have resolved.

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

If you are diabetic, check with your doctor or pharmacist before using urine sugar tests. SINEMET CR may cause false test results with some urine sugar tests.

Side Effects

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

SINEMET CR helps most people with Parkinson's disease, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time, they are not. You may need medical treatment if you get some of the side effects.

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 uncontrolled movements, which may or may not resemble your Parkinson's symptoms
  • feeling sick (nausea), vomiting, loss of appetite
  • dizziness, light-headedness when standing quickly
  • dry mouth
  • discolouration of urine, sweat and/or saliva
  • dream abnormalities, sleeping difficulty
  • sleepiness or sudden onset of sleep
  • hallucinations
  • weakness
  • confusion
  • flushing
  • hair loss

Tell your doctor if you experience any of these behaviours:

You may experience an inability to resist the impulse to perform an action that could be harmful, which may include:

  • strong impulses to gamble
  • increased sexual drive
  • uncontrollable excessive shopping or spending
  • binge/compulsive eating
  • taking medicines and repetitive purposeless activities
  • and/or other urges

Most of these are the more common side effects of SINEMET CR. For the most part, these have been mild.

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

  • difficult or painful urination
  • changes in mood such as depression
  • forgetfulness
  • signs of anaemia, such as tiredness, being short of breath, and looking pale
  • signs of frequent or worrying infections such as fever, severe chills, sore throat or mouth ulcers
  • bruising or bleeding more easily than normal, nose bleeds
  • fainting
  • skin rash, itchiness
  • pinkish, itchy swellings on the skin, also called hives or nettle rash
  • numbness or tingling in the hands or feet
  • signs of melanoma, such as new skin spots or changes to the size, shape, colour or edges of an existing skin spot, freckle or mole.

These are serious side effects. You may need urgent medical attention. Serious side effects are generally rare.

Tell your doctor immediately or go to accident and emergency at your nearest hospital if you notice any of the following:

  • swelling of the face, lips, mouth, throat or tongue which may cause difficulty in swallowing or breathing
  • vomiting blood or material that looks like coffee grounds
  • bleeding from the back passage, black sticky bowel motions (stools) or bloody diarrhoea
  • chest pain
  • fast or irregular heartbeats, also called palpitations
  • it becomes impossible to empty your bladder (urinary retention)
  • mental changes such as feeling very fearful or paranoid, hallucinations
  • muscle stiffness accompanied by fever
  • shortness of breath, difficulty breathing.

These are all serious side effects that need urgent medical attention. Serious side effects are generally rare.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice any other effects.

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

After using SINEMET CR

Storage

Keep your tablets in the bottle until it is time to take them. If you take the tablets out of the bottle, they may not keep well.

Keep SINEMET CR in a cool dry place where the temperature stays below 30°C. Do not store it or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills. Heat and dampness can damage some medicines.

Keep it 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 SINEMET CR or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

SINEMET CR AUST R NUMBER: 171694

What it looks like

SINEMET CR comes as a dappled purple coloured, oval-shaped tablet plain on one side with '521' on the other.

A bottle of SINEMET CR contains 100 tablets.

Ingredients

Active ingredients:

  • SINEMET CR - 50 mg carbidopa and 200 mg levodopa per tablet.

Inactive ingredients:

  • hyprolose
  • magnesium stearate
  • hypromellose
  • Indigo Carmine
  • Allura Red AC

SINEMET CR tablets do not contain lactose, gluten, sucrose, tartrazine or any other azo dyes.

Supplier

SINEMET CR is supplied in Australia by:

Merck Sharp & Dohme (Australia) Pty Limited
Level 1, Building A,
26 Talavera Road
MACQUARIE PARK
NSW 2113

This leaflet was prepared in September 2019.

S-WPPI-MK0295B-CR-082013

Published by MIMS November 2019

BRAND INFORMATION

Brand name

Sinemet CR

Active ingredient

Levodopa; Carbidopa

Schedule

S4

 

1 Name of Medicine

Levodopa and carbidopa.

6.7 Physicochemical Properties

Carbidopa.

The empirical formula is C10H14N2O4 with a molecular weight of 244.3. It is designed chemically as (-)-L-alpha-hydrazino-alpha-methyl-beta-(3,4-dihydroxy-benzene) propanoic acid monohydrate. Tablet content is expressed in terms of anhydrous carbidopa, which has a molecular weight of 226.3.

Levodopa.

The empirical formula is C9H11NO4 with a molecular weight of 197.2. It is designated chemically as (-)L-alpha-amino-beta- (3,4-dihydroxybenzene) propanoic acid.

Chemical structure.


CAS number.

Carbidopa: 28860-95-9.
Levodopa: 59-92-7.

2 Qualitative and Quantitative Composition

Carbidopa.

Carbidopa, an inhibitor of aromatic amino acid decarboxylase, is a white, crystalline compound, slightly soluble in water.

Levodopa.

Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Sinemet CR 200/50 (levodopa 200 mg and carbidopa 50 mg) is supplied as tablets for oral administration. Sinemet CR is a controlled-release formulation of levodopa, and carbidopa, in a ratio of 4:1. The tablet contains a polymer-based drug delivery system which controls the release of levodopa and carbidopa as it slowly erodes.
Sinemet CR 200/50 is a dappled, purple, oval tablet, plain on one side with 521 on the other.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action

Parkinson's disease is a degenerative neurological disorder characterised by the progressive loss of dopaminergic nigrostriatal neurons. The signs and symptoms, including rigidity, tremor, bradykinesia, postural changes, and gait disturbances, are usually treated adequately with drugs that mimic or replace depleted dopamine. Sinemet CR, which combines the dopamine precursor, levodopa, and the peripheral levodopa/decarboxylase inhibitor, carbidopa, is effective in providing dopamine to the brain. Carbidopa, which does not cross the blood brain barrier, increased both plasma levels and plasma half-life of levodopa by inhibiting extracerebral levodopa/decarboxylation, principally in the intestinal mucosa.
Patients with Parkinson's disease treated with preparations containing levodopa may develop motor fluctuations characterised by end of dose failure, peak dose dyskinesia, and akinesia.
The advanced form of motor fluctuations (on-off phenomenon) is characterised by unpredictable swings from mobility to immobility. Although the causes of the motor fluctuations are not completely understood, it has been demonstrated that they can be attenuated by treatment regimens that produce steady plasma levels of levodopa.
Sinemet CR contains 200 mg of levodopa and 50 mg of carbidopa in a controlled release dosage form designed to release these ingredients over a 4 to 6 hour period. With this formulation there is less variation in plasma levodopa levels than with conventional Sinemet.

Clinical trials.

In clinical trials, patients with moderate to severe motor fluctuations who received Sinemet CR experienced reduced off time when compared with Sinemet. Global ratings of improvement and activities of daily living in the on and off state, as assessed by both patient and physician, were better during therapy with Sinemet CR than with Sinemet. Patients considered Sinemet CR to be more helpful for their motor fluctuations, and preferred it over Sinemet. In patients without motor fluctuations, Sinemet CR, under controlled conditions, provided the same therapeutic benefit with less frequent dosing when compared with Sinemet.

5.2 Pharmacokinetic Properties

Carbidopa.

Absorption.

Following an oral dose of radioactive labelled carbidopa to healthy subjects and to patients with Parkinson's disease, maximum plasma levels of radioactivity were reached in two to four hours in the normal subjects and in one and one-half to five hours in the patients.

Metabolism and excretion.

Following an oral dose of radioactive labelled carbidopa to healthy subjects and to patients with Parkinson's disease, approximately equal quantities were excreted in the urine and the faeces by both groups. Comparison of urinary metabolites in healthy subjects and patients indicated that the drug is metabolised to the same degree in both. Urinary excretion of unchanged drug was essentially complete in seven hours and represented 35 percent of the total urinary radioactivity. Only metabolites were present thereafter.
Among the metabolites excreted by man are alpha-methyl-3-methoxy-4- hydroxy-phenylpropionic acid and alpha-methyl-3,4- dihydroxyphenylpropionic acid. These accounted for approximately 14 and 10 percent, respectively, of the radioactive metabolites excreted. Two minor metabolites were found. One was identified as 3,4-dihydroxy- phenyl-acetone and the other tentatively identified as N-methyl-carbidopa. They each accounted for less than five percent of the urinary metabolites. Unchanged carbidopa was also present in the urine. No conjugates were found.

Levodopa.

Absorption.

Levodopa is absorbed rapidly from the gastrointestinal tract.

Metabolism and excretion.

Levodopa is extensively metabolised. Although more than 30 metabolites may be formed, it is converted mainly to dopamine, epinephrine and norepinephrine, and eventually to dihydroxyphenylacetic acid, homovanillic acid and vanillylmandelic acid. 3-0-methyldopa appears in the plasma and cerebrospinal fluid. Its significance is not known.
When single test doses of radioactive levodopa are given to fasting patients with Parkinson's disease, plasma levels of radioactivity reach a peak level in one-half to two hours and remain measurable for four to six hours. At peak levels, about 30% of radioactivity appears as catecholamines, 15% as dopamine, and 10% as dopa.
Radioactive compounds are excreted rapidly in the urine, one-third of the dose appearing in two hours. Eighty to ninety percent of urinary metabolites are phenylcarboxylic acids, principally homovanillic acid. Over 24 hours, one or two percent of recovered radioactivity is dopamine, and less than one percent is epinephrine, norepinephrine and unchanged levodopa.

Effect of carbidopa on levodopa metabolism.

In healthy subjects, carbidopa increased plasma levels of levodopa consistently by statistically significant amounts, measured against placebo. This has been demonstrated when carbidopa was given before levodopa and when the two drugs were given simultaneously. In one study, pretreatment with carbidopa increased plasma levels of a single dose of levodopa about five times and extended the duration of measurable plasma concentrations of levodopa from four hours to eight hours. When the two drugs were given simultaneously in other studies, similar results were obtained.
In a study in which a single dose of stem labelled levodopa was given to patients with Parkinson's disease who had been pretreated with carbidopa, there was an increase in the half-life of total plasma radioactivity derived from the levodopa, from 3 hours to 15 hours. The proportion of radioactivity remaining as unmetabolised levodopa was increased at least three times by carbidopa. Plasma and urinary dopamine and homovanillic acid were both decreased by carbidopa pretreatment.

Pharmacokinetics of Sinemet CR.

The pharmacokinetics of levodopa following administration of Sinemet CR were studied in young and elderly healthy volunteers. The mean time to peak plasma levodopa level after Sinemet CR was approximately two hours compared to 0.75 hours with Sinemet. The mean peak plasma levodopa levels were 60 percent lower with Sinemet CR than with Sinemet. The in vivo absorption of levodopa following administration of Sinemet CR was continuous for 4 to 6 hours. In these studies, as with patients, plasma levodopa concentrations fluctuated in a narrower range than with Sinemet. Because the bioavailability of levodopa from Sinemet CR, relative to Sinemet, is approximately 70 percent, the daily dosage of levodopa in the controlled release formulation will usually be higher than with conventional formulations. There was no evidence that Sinemet CR released its ingredients in a rapid or uncontrolled fashion.

5.3 Preclinical Safety Data

Genotoxicity.

Please see Carcinogenicity subsection below.

Carcinogenicity.

In a two-year bioassay with levodopa and carbidopa, no evidence of carcinogenicity was found in rats receiving doses of approximately two times the maximum daily human dose of carbidopa and four times the maximum daily human dose of levodopa.

4 Clinical Particulars

4.1 Therapeutic Indications

Idiopathic parkinsonism, where standard formulations containing levodopa/carbidopa have produced inadequate control. Experience is limited with Sinemet CR in patients who have not been treated with levodopa before.

4.3 Contraindications

Monoamine oxidase inhibitors and Sinemet CR should not be given concomitantly. These inhibitors must be discontinued at least two weeks prior to initiating therapy with Sinemet CR. Sinemet CR may be administered concomitantly with the manufacturer's recommended dose of a MAO inhibitor with selectivity for MAO type B, e.g. selegiline (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Other drugs).
Sinemet CR is contraindicated in patients with known hypersensitivity and in patients with narrow angle glaucoma.
Because levodopa may activate a malignant melanoma, Sinemet CR should not be used in patients with suspicious undiagnosed skin lesions or a history of melanoma.

4.4 Special Warnings and Precautions for Use

When patients are receiving levodopa monotherapy, levodopa must be discontinued at least 8 hours before therapy with Sinemet CR is started (at least 12 hours if slow release plain levodopa has been administered).
Dyskinesias may occur in patients previously treated with levodopa alone because carbidopa permits more levodopa to reach the brain, and thus more dopamine to be formed. The occurrence of dyskinesias may require dosage reduction.
As with levodopa, Sinemet CR may cause involuntary movements and mental disturbances. These reactions are thought to be due to increased brain dopamine following administration of levodopa. Dosage reduction may be required. All patients should be observed carefully for the development of depression with concomitant suicidal tendencies. Patients with past or current psychoses should be treated with caution.
Levodopa 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 levodopa. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore, a reduction of dosage or termination of therapy may be considered.
Sinemet CR should be administered cautiously to patients with severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease, or a history of peptic ulcer disease or of convulsions.
Care should be exercised in administering Sinemet CR to patients with a history of recent myocardial infarction who have residual atrial, nodal or ventricular arrhythmia. In such patients, cardiac function should be monitored with particular care during the period of initial dosage administration and titration.
Patients with chronic wide angle glaucoma may be treated cautiously with Sinemet CR, provided the intraocular pressure is well controlled and the patient monitored carefully for changes in intraocular pressure during therapy.
A symptom complex resembling the neuroleptic malignant syndrome, including muscular rigidity, elevated body temperature, mental changes and increased serum creatine phosphokinase, has been reported when antiparkinsonian agents were withdrawn abruptly. Therefore, patients should be observed carefully when the dosage of levodopa/carbidopa combinations is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.
Sinemet CR is not recommended for the treatment of drug induced extrapyramidal reactions.
Periodic evaluations of hepatic, haematopoietic, cardiovascular and renal function are recommended during extended therapy.

Melanoma.

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2 to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease is unclear.
For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Sinemet CR for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g. dermatologists).

Compulsive behaviour.

Patient 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 (such as pathological gambling, hypersexuality, increased libido, compulsive spending/buying, and binge/compulsive eating, medication use and punding (repetitive purposeless activity)) have been reported in patients treated with dopamine agonists and/or other dopaminergic treatment for Parkinson's disease, especially at high doses. Review of treatment is recommended if such symptoms develop. Prescribers, patients and caregivers should be alert to the possibility of such behaviour, which may have serious financial and social consequences.

Use in hepatic impairment.

Sinemet CR should be administered cautiously to patients with severe hepatic disease. Periodic evaluation of hepatic function is recommended during extended therapy.

Use in renal impairment.

Sinemet CR should be administered cautiously to patients with severe renal disease. Periodic evaluation of renal function is recommended during extended therapy.

Use in the elderly.

There is wide experience in the use of levodopa and carbidopa in elderly patients. The recommendations set out above reflect the clinical data derived from this experience (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Paediatric use.

Safety and effectiveness of Sinemet CR in infants and children have not been established, and its use in patients below the age of 18 is not recommended.

Effects on laboratory tests.

Laboratory tests which have been reported to be abnormal are creatinine, uric acid, alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, bilirubin, blood urea nitrogen, and Coombs' test.
Decreased haemoglobin and haematocrit; elevated serum glucose and white blood cells, bacteria and blood in the urine have been reported.
Carbidopa/levodopa preparations may cause a false positive reaction for urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction will not be altered by boiling the urine specimen. False negative tests may result with the use of glucose oxidase methods of testing for glycosuria.
In some patients in clinical studies a minor elevation of blood glucose (not above 5% range) was noted. This may be the effect of high dose levodopa on glucose tolerance and may not have clinical significance.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Caution should be exercised when the following drugs are administered concomitantly with Sinemet CR:

Antihypertensive agents.

Symptomatic postural hypotension has occurred when levodopa/decarboxylase inhibitor combinations were added to the treatment of patients receiving some antihypertensive drugs. Therefore, when therapy with Sinemet CR is started, dosage adjustment of the antihypertensive drug may be required.

Antidepressants.

There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa/levodopa preparations.
For patients receiving monoamine oxidase inhibitors, see Section 4.3 Contraindications.

Iron.

Studies demonstrate a decrease in the bioavailability of carbidopa and/or levodopa when it is ingested with ferrous sulfate or ferrous gluconate.

Other drugs.

Dopamine D2-receptor antagonists (e.g. phenothiazines, butyrophenones and risperidone) and isoniazid may reduce the therapeutic effects of levodopa. The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin and papaverine. Patients taking these drugs with Sinemet CR should be observed carefully for loss of therapeutic response.
Use of Sinemet CR with dopamine depleting agents (e.g. reserpine and tetrabenazine) or other drugs known to deplete monoamine stores is not recommended.
Concomitant therapy with selegiline and carbidopa/levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa/levodopa alone (see Section 4.3 Contraindications).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In reproduction studies with levodopa and carbidopa, no effects on fertility were found in rats receiving doses of approximately two times the maximum daily human dose of carbidopa and four times the maximum daily human dose of levodopa.
Therefore, the use of Sinemet CR in women of childbearing potential requires that the anticipated benefits of the drug be weighed against possible hazards should pregnancy occur.
(Category B3)
Although the effects of Sinemet CR on human pregnancy are unknown, both levodopa and combinations of levodopa and carbidopa have caused visceral and skeletal malformations in rabbits. Therefore, use of Sinemet CR in women of childbearing potential requires that the anticipated benefits of the drug be weighed against possible hazards should pregnancy occur.
It is not known whether carbidopa is excreted in human milk. In a study of one nursing mother with Parkinson's disease, excretion of levodopa in human breast milk was reported. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in infants, Sinemet CR should not be used by nursing mothers. A decision should be made either to discontinue nursing or to discontinue Sinemet CR.

4.8 Adverse Effects (Undesirable Effects)

In controlled clinical trials in patients with moderate to severe motor fluctuations, Sinemet CR did not produce side effects which were unique to the controlled release formulation.
The side effect reported most frequently was dyskinesia (a form of abnormal involuntary movements). A somewhat greater incidence of dyskinesias was seen with Sinemet CR than with Sinemet possibly due to the replacement of off time (which is reduced with Sinemet CR) by on time (which is sometimes accompanied by dyskinesias). Patients with motor fluctuations receiving Sinemet CR may develop dyskinesias more often at higher doses (over 1500 mg of levodopa daily) in association with a decrease in off time.
Other side effects that also were reported frequently (above 2%) were nausea, hallucinations, confusion, dizziness, chorea and dry mouth.
Side effects occurring less frequently (1-2%) were dream abnormalities, dystonia, somnolence, insomnia, depression, asthenia, vomiting and anorexia.
Other side effects reported in postmarketing experience or observed rarely (0.5-1%) in clinical trials include:

Body as a whole.

Chest pain, syncope.

Cardiovascular.

Palpitation, orthostatic effects including hypotensive episodes.

Gastrointestinal.

Constipation, diarrhoea, dyspepsia, gastrointestinal pain, dark saliva.

Hypersensitivity.

Angioedema, urticaria, pruritus.

Investigations.

Weight gain, weight loss.

Metabolism and nutrition disorders.

Anorexia.

Nervous system/psychiatric.

Neuroleptic malignant syndrome, (see Section 4.4 Special Warnings and Precautions for Use), agitation, anxiety, decreased mental acuity, paraesthesia, disorientation, fatigue, headache, extrapyramidal and movement disorders, falling, gait abnormalities, muscle cramps, on-off phenomenon, peripheral neuropathy, psychotic episodes including delusions and paranoid ideation.
Levodopa is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes.
In postmarketing use, pathological (compulsive) gambling, increased libido, hypersexuality, compulsive spending/buying, and binge/compulsive eating have been reported with dopamine agonists and/or other dopaminergic treatments, and in patients treated with levodopa including Sinemet CR (see Section 4.4 Special Warnings and Precautions for Use).

Respiratory.

Dyspnoea.

Skin.

Flushing, alopecia, rash, dark sweat.

Special senses.

Blurred vision.

Urogenital.

Dark urine.
Other side effects that have been reported with levodopa or levodopa/carbidopa combinations and may be potential side effects with Sinemet CR are listed below:

Cardiovascular.

Cardiac irregularities, hypertension, phlebitis.

Gastrointestinal.

Bitter taste, sialorrhoea, dysphagia, bruxism, hiccups, gastrointestinal bleeding, flatulence, burning sensation of tongue, development of duodenal ulcer.

Haematologic.

Leucopenia, haemolytic and nonhaemolytic anaemia, thrombocytopenia, agranulocytosis.

Nervous system/psychiatric.

Ataxia, numbness, increased hand tremor, muscle twitching, blepharospasm, trismus, activation of latent Horner's syndrome, sleepiness, euphoria and dementia, depression with suicidal tendencies.

Skin.

Increased sweating.

Special senses.

Diplopia, dilated pupils, oculogyric crises.

Urogenital.

Urinary retention, urinary incontinence, priapism.

Miscellaneous.

Oedema, weakness, faintness, hoarseness, malaise, hot flushes, sense of stimulation, bizarre breathing patterns, malignant melanoma (see Section 4.3 Contraindications), Henoch-Schönlein purpura.
Convulsions have occurred; however, a causal relationship with levodopa or levodopa/carbidopa combinations has not been established.

Reporting of suspected adverse effects.

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

4.2 Dose and Method of Administration

Sinemet CR tablets contain a 4:1 ratio of levodopa to carbidopa (levodopa 200 mg/carbidopa 50 mg per tablet). The daily dosage of Sinemet CR must be determined by careful titration. Patients should be monitored closely during the dose adjustment period, particularly with regard to appearance or worsening of nausea or abnormal involuntary movements, including dyskinesias, chorea and dystonia.
Sinemet CR should only be administered as whole tablets. So that the controlled release properties of the product can be maintained, tablets should not be chewed or crushed.
Standard antiparkinson drugs, other than levodopa alone, may be continued while Sinemet CR is being administered, although their dosage may have to be adjusted.
Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine, Sinemet CR can be given to patients receiving supplemental pyridoxine (vitamin B6).

Initial dosage.

Patients currently treated with conventional levodopa/decarboxylase inhibitor combinations.

Dosage with Sinemet CR should be substituted at an amount that provides approximately 10% more levodopa per day, although this may need to be increased to a dosage that provides up to 30% more levodopa per day depending on clinical response (see Titration). The interval between doses of Sinemet CR should be 4-8 hours during the waking day. (See Section 5.2 Pharmacokinetic Properties.)
A guide for substitution of Sinemet CR treatment for conventional levodopa/decarboxylase inhibitor combinations is shown in Table 1.

Patients currently treated with levodopa alone.

Levodopa must be discontinued at least eight hours before therapy with Sinemet CR is started. In patients with mild to moderate disease, the initial recommended dose is one tablet of Sinemet CR two or three times daily.

Titration.

Following initiation of therapy, doses and dosing intervals may be increased or decreased, depending upon therapeutic response. Most patients have been adequately treated with 2 to 8 tablets per day, administered as divided doses at intervals ranging from 4 to 12 hours during the waking day. Higher doses (up to 12 tablets) and shorter intervals (less than 4 hours) have been used, but are not usually recommended.
When doses of Sinemet CR are given at intervals of less than 4 hours, or if the divided doses are not equal, it is recommended that the smaller doses be given at the end of the day. In some patients the onset of effect of the first morning dose may be delayed for up to 1 hour compared with the response usually obtained from the first morning dose of Sinemet.
An interval of at least 3 days between dosage adjustments is recommended.

Maintenance.

Because Parkinson's disease is progressive, periodic clinical evaluations are recommended and adjustment of the dosage regimen of Sinemet CR may be required.

Addition of other antiparkinson medications.

Anticholinergic agents, dopamine agonists and amantadine can be given with Sinemet CR. Dosage adjustment of Sinemet CR may be necessary when these agents are added to an existing treatment regimen for Sinemet CR.
A dose of Sinemet 100/25 can be added to the dosage regimen of Sinemet CR in selected patients with advanced disease who need additional levodopa for a brief time during daytime hours.

Interruption of therapy.

Patients should be observed carefully if abrupt reduction or discontinuation of Sinemet CR is required, especially if the patient is receiving neuroleptics (see Section 4.4 Special Warnings and Precautions for Use).
If general anaesthesia is required, Sinemet CR may be continued as long as the patient is permitted to take oral medication. If therapy is interrupted temporarily, the usual dosage should be administered as soon as the patient is able to take oral medication.

4.7 Effects on Ability to Drive and Use Machines

See Section 4.4 Special Warnings and Precautions for Use.

4.9 Overdose

Management of acute overdosage with Sinemet CR is basically the same as management of acute overdosage with levodopa; however, pyridoxine is not effective in reversing the actions of Sinemet CR.
In the event of overdosage, general supportive measures should be employed. Intravenous fluids should be administered judiciously and an adequate airway maintained. Electrocardiographic monitoring should be instituted and the patient observed carefully for the development of arrhythmias; if required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have taken other drugs as well as Sinemet CR should be taken into consideration. To date, no experience has been reported with dialysis, hence its value in overdosage is not known.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

In addition to the active ingredients levodopa and carbidopa, each tablet contains the following inactive ingredients: hyprolose, magnesium stearate, hypromellose, Indigo Carmine and Allura Red AC.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C. Keep in tightly closed container, protected from light and moisture.

6.5 Nature and Contents of Container

Sinemet CR is supplied in bottles of 100 tablets - AUST R 171694.

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