Posology : מינונים

4.2   Posology and method of administration
'Sinemet CR' tablets contain a 1:4 ratio of carbidopa to levodopa ('Sinemet CR': carbidopa 50 mg/levodopa 200 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.

Route of administration: oral

'Sinemet CR' may be administered as whole or broken in half. 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 Dose

Patients currently treated with conventional levodopa/decarboxylase inhibitor combinations
Dosage with 'Sinemet CR' should be substituted initially at an amount that provides no more than approximately 10% more levodopa per day when higher dosages are given (more than 900 mg per day). The dosing interval between doses should be prolonged by 30 to 50% at intervals ranging from 4 to 12 hours. It is recommended to give the smaller dose, if divided doses are not equal, at the end of the day. The dose needs to be titrated further depending on clinical response, as indicated below under ‘Titration’. Dosages that provide up to 30% more levodopa per day may be necessary.

A guide for substitution of 'Sinemet CR' treatment for conventional levodopa/decarboxylase inhibitor combinations is shown in the table below:

Guideline for Conversion from Levodopa/decarboxylase inhibitor to 'Sinemet CR' 
Levodopa/decarboxylase inhibitor             'Sinemet CR'
Daily Dosage           Daily Dosage
Levodopa (mg)          Levodopa (mg)    Dosage Regimen
________________________________________________________
300 - 400            400              1 Tablet 2 x daily
500 - 600            600              1 Tablet 3 x daily
700 - 800            800              4 Tablets in 3 or more divided doses 900 - 1000           1000             5 Tablets in 3 or more divided doses 1100 - 1200            1200             6 Tablets in 3 or more divided doses 1300 - 1400            1400             7 Tablets in 3 or more divided doses 1500 - 1600            1600             8 Tablets in 3 or more divided doses 

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' twice daily.

Patients not receiving levodopa
In patients with mild to moderate disease, the initial recommended dose is one tablet of 'Sinemet CR' twice daily. Initial dosages should not exceed 600 mg per day of levodopa, nor be given at intervals of less than six hours.

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 two to eight tablets per day of 'Sinemet CR' administered as divided doses at intervals ranging from four to twelve hours during the waking day. Higher doses (up to 12 tablets) and shorter intervals (less than four hours) have been used, but are not usually recommended.

When doses of 'Sinemet CR' are given at intervals of less than four 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 one hour compared with the response usually obtained from the first morning dose of a conventional levodopa/decarboxylase inhibitor combination.
An interval of at least three 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 medication
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'.

Interruption of therapy
Patients should be observed carefully if abrupt reduction or discontinuation of 'Sinemet CR' is required, especially if the patient is receiving antipsychotics (see 4.4 ‘Special warnings and precautions for use’).

Use in Children
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.