Carbidopa and Levodopa (Page 4 of 5)

OVERDOSAGE

Management of acute overdosage with carbidopa and levodopa extended-release tablets is the same as with levodopa. Pyridoxine is not effective in reversing the actions of carbidopa and levodopa extended-release tablets.

General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered judiciously and an adequate airway maintained. Electrocardiographic monitoring should be instituted and the patient carefully observed 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 carbidopa and levodopa extended-release tablets should be taken into consideration. To date, no experience has been reported with dialysis; hence, its value in overdosage is not known.

Based on studies in which high doses of levodopa and/or carbidopa were administered, a significant proportion of rats and mice given single oral doses of levodopa of approximately 1500-2000 mg/kg are expected to die. A significant proportion of infant rats of both sexes are expected to die at a dose of 800 mg/kg. A significant proportion of rats are expected to die after treatment with similar doses of carbidopa. The addition of carbidopa in a 1:10 ratio with levodopa increases the dose at which a significant proportion of mice are expected to die to 3360 mg/kg.

DOSAGE AND ADMINISTRATION

Carbidopa and levodopa extended-release tablets contain carbidopa and levodopa in a 1:4 ratio as the 50 mg/200 mg tablet. The daily dosage of carbidopa and levodopa extended-release tablets must be determined by careful titration. Patients should be monitored closely during the dose adjustment period, particularly with regard to appearance or worsening of involuntary movements, dyskinesias or nausea. Carbidopa and levodopa extended-release tablets 50 mg/200 mg may be administered as whole or as half-tablets which should not be chewed or crushed. Carbidopa and levodopa extended-release tablets 25 mg/100 mg may be used in combination with carbidopa and levodopa extended-release tablets 50 mg/200 mg to titrate to the optimum dosage, or as an alternative to the 50 mg/200 mg half-tablet.

Standard drugs for Parkinson’s disease, other than levodopa without a decarboxylase inhibitor, may be used concomitantly while carbidopa and levodopa extended-release tablets are being administered, although their dosage may have to be adjusted.

Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine, carbidopa and levodopa extended-release tablets can be given to patients receiving supplemental pyridoxine (vitamin B6 ).

Initial Dosage

Patients Currently Treated With Conventional Carbidopa-Levodopa Preparations: Studies show that peripheral dopa-decarboxylase is saturated by the bioavailable carbidopa at doses of 70 mg a day and greater. Because the bioavailabilities of carbidopa and levodopa in carbidopa and levodopa tablets and carbidopa and levodopa extended-release tablets are different, appropriate adjustments should be made, as shown in Table II.

Table II Approximate Bioavailabilities at Steady State*
Tablet Amount of Levodopa (mg) in Each Tablet Approximate Bioavailability Approximate Amount of Bioavailable Levodopa (mg) in Each Tablet
*This table is only a guide to bioavailabilities since other factors such as food, drugs, and inter-patient variabilities may affect the bioavailability of carbidopa and levodopa.**The extent of availability of levodopa from carbidopa and levodopa extended-release tablets was about 70-75% relative to intravenous levodopa or standard carbidopa and levodopa tablets in the elderly.***The extent of availability of levodopa from carbidopa and levodopa was 99% relative to intravenous levodopa in the healthy elderly.
Carbidopa-Levodopa50-200Extended Release 200 0.70-0.75** 140-150
Carbidopa-Levodopa25-100 100 0.99*** 99

Dosage with carbidopa and levodopa extended-release tablets 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 DOSAGE AND ADMINISTRATION,Titration). The interval between doses of carbidopa and levodopa extended-release tablets should be 4-8 hours during the waking day (see CLINICAL PHARMACOLOGY, Pharmacodynamics).

A guideline for initiation of carbidopa and levodopa extended-release tablets is shown in Table III.

Table III Guidelines for Initial Conversion From Carbidopa and Levodopa Tablets To Carbidopa and Levodopa Extended-Release Tablets
Carbidopa and Levodopa Tablets Carbidopa and Levodopa Extended-Release Tablets
Total Daily Dose* Levodopa (mg) Suggested Dosage Regimen
*For dosing ranges not shown in the table, see DOSAGE AND ADMINISTRATION, Initial Dosage, Patients currently treated with conventional carbidopa-levodopa preparations.
300-400 200 mg b.i.d.
500-600 300 mg b.i.d.or 200 mg t.i.d.
700-800 A total of 800 mg in 3 or more divided doses (e.g., 300 mg a.m., 300 mg early p.m., and 200 mg later p.m.)
900-1000 A total of 1000 mg in 3 or more divided doses (e.g., 400 mg a.m., 400 mg early p.m., and 200 mg later p.m.)

Patients Currently Treated With Levodopa Without a Decarboxylase Inhibitor

Levodopa must be discontinued at least twelve hours before therapy with carbidopa and levodopa extended-release tablets is started. Carbidopa and levodopa extended-release tablets should be substituted at a dosage that will provide approximately 25% of the previous levodopa dosage. In patients with mild to moderate disease, the initial dose is usually 1 tablet of carbidopa and levodopa extended-release tablets 50 mg/200 mg b.i.d.

Patients Not Receiving Levodopa

In patients with mild to moderate disease, the initial recommended dose is 1 tablet of carbidopa and levodopa extended-release tablets 50 mg/200 mg b.i.d. Initial dosage should not be given at intervals of less than 6 hours.

Titration with Carbidopa and Levodopa Extended-Release Tablets

Following initiation of therapy, doses and dosing intervals may be increased or decreased depending upon therapeutic response. Most patients have been adequately treated with doses of carbidopa and levodopa extended-release tablets that provide 400 to 1600 mg of levodopa per day, administered as divided doses at intervals ranging from 4 to 8 hours during the waking day. Higher doses of carbidopa and levodopa extended-release tablets (2400 mg or more of levodopa per day) and shorter intervals (less than 4 hours) have been used, but are not usually recommended.

When doses of carbidopa and levodopa extended-release tablets are given at intervals of less than 4 hours, and/or if the divided doses are not equal, it is recommended that the smaller doses be given at the end of the day.

An interval of at least 3 days between dosage adjustments is recommended.

Maintenance

Because Parkinson’s disease is progressive, periodic clinical evaluations are recommended; adjustment of the dosage regimen of carbidopa and levodopa extended-release tablets may be required.

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