Levoxyl (Levothyroxine Sodium) - Indications and Dosage

INDICATIONS AND USAGE

SINEMET CR is indicated in the treatment of the symptoms of idiopathic Parkinson's disease (paralysis agitans), postencephalitic parkinsonism, and symptomatic parkinsonism which may follow injury to the nervous system by carbon monoxide intoxication and/or manganese intoxication.

DOSAGE AND ADMINISTRATION

SINEMET CR contains carbidopa and levodopa in a 1:4 ratio as either the 50-200 tablet or the 25-100 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 involuntary movements, dyskinesias or nausea. SINEMET CR 50-200 may be administered as whole or as half-tablets which should not be chewed or crushed. SINEMET CR 25-100 may be used in combination with SINEMET CR 50-200 to titrate to the optimum dosage, or as an alternative to the 50-200 half-tablet.

Standard drugs for Parkinson's disease, other than levodopa without a decarboxylase inhibitor, may be used concomitantly 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 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 SINEMET and SINEMET CR 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 SINEMET CR was about 70-75% relative to intravenous levodopa or standard SINEMET (Carbidopa-Levodopa) in the elderly.
†††The extent of availability of levodopa from SINEMET was 99% relative to intravenous levodopa in the healthy elderly.
SINEMET CR 50-200	200	0.70-0.75††	140-150
SINEMET 25-100	100	0.99†††	99

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 DOSAGE AND ADMINISTRATION: Titration with SINEMET CR). The interval between doses of SINEMET CR should be 4-8 hours during the waking day. (See CLINICAL PHARMACOLOGY: Pharmacodynamics.)

A guideline for initiation of SINEMET CR is shown in Table III.

Table III: Guidelines for Initial Conversion from SINEMET (Carbidopa-Levodopa) to SINEMET CR

*For dosing ranges not shown in the table see DOSAGE AND ADMINISTRATION: Initial Dosage — Patients currently treated with conventional carbidopa-levodopa preparations.
SINEMET (Carbidopa-Levodopa) Total Daily Dose* Levodopa (mg)	SINEMET CR Suggested Dosage Regimen
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 SINEMET CR is started. SINEMET CR 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 SINEMET CR 50-200 b.i.d.

Patients not receiving levodopa: In patients with mild to moderate disease, the initial recommended dose is 1 tablet of SINEMET CR 50-200 b.i.d. Initial dosage should not be given at intervals of less than 6 hours.

Titration with SINEMET CR

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 SINEMET CR 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 SINEMET CR (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 SINEMET CR 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 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.

A dose of SINEMET (Carbidopa-Levodopa) 25-100 or 10-100 (one half or a whole tablet) can be added to the dosage regimen of SINEMET CR in selected patients with advanced disease who need additional immediate-release levodopa for a brief time during daytime hours.

Interruption of Therapy

Sporadic cases of a symptom complex resembling Neuroleptic Malignant Syndrome (NMS) have been associated with dose reductions and withdrawal of SINEMET (Carbidopa-Levodopa) or SINEMET CR.

Patients should be observed carefully if abrupt reduction or discontinuation of SINEMET CR is required, especially if the patient is receiving neuroleptics. (See WARNINGS.)

If general anesthesia is required, SINEMET CR may be continued as long as the patient is permitted to take oral medication. If therapy is interrupted temporarily, the patient should be observed for symptoms resembling NMS, and the usual dosage should be administered as soon as the patient is able to take oral medication.

HOW SUPPLIED

SINEMET CR 50-200 (Carbidopa-Levodopa) Sustained-Release Tablets containing 50 mg of carbidopa and 200 mg of levodopa, are peach colored, oval, biconvex, compressed tablets, that are scored and coded "521" on one side and SINEMET CR on the other side. They are supplied as follows:

           NDC 0056-0521-68 bottles of 100
           NDC 0056-0521-85 bottles of 500.

SINEMET CR 25-100 (Carbidopa-Levodopa) Sustained-Release Tablets containing 25 mg of carbidopa and 100 mg of levodopa, are pink colored, oval, biconvex, compressed tablets, that are coded " 601 " (with bar) on one side and SINEMET CR on the other side. They are supplied as follows:

           NDC 0056-0601-68 bottles of 100.

Storage

Store below 30°C (86°F). Store in a tightly closed container.