Generic Name: levodopa

Brand Names: Larodopa, Dopar

Uses

Parkinsonian Syndrome

Symptomatic treatment of idiopathic Parkinson’s disease (paralysis agitans), parkinsonian syndrome (postencephalitic parkinsonism), and symptomatic parkinsonism resulting from carbon monoxide intoxication and/or manganese intoxication.

Levodopa is the most effective drug for relieving the symptoms of parkinsonian syndrome.

Levodopa provides symptomatic relief (e.g., akinesia, rigidity, tremor); does not alter the disease course.

Drug of choice in the management of idiopathic parkinsonian syndrome, especially in patients >70 years of age, those with cognitive impairment, and those with severe disease.

Levodopa is used in conjunction with a decarboxylase inhibitor, carbidopa. Levodopa-carbidopa can be used alone or in conjunction with other antiparkinsonian drugs (e.g. ergot- and nonergot-derivative dopamine receptor agonists, catechol-O-methyltransferase [COMT] inhibitor, and/or selegiline).

Drug-induced Extrapyramidal Effects

Not effective in the management of extrapyramidal effects† induced by antipsychotic agents (e.g., phenothiazines).

Dosage and Administration

Administration

Oral Administration

Administer extended-release tablets as whole or half tablets; do not chew or crush.

Just prior to administration of the orally disintegrating tablet, gently remove the tablet from the bottle with dry hands. Place tablet on tongue to dissolve (usually within seconds) and swallow with saliva.

Administration of orally disintegrating tablet with water is not necessary.

Do not divide the fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo^®); administer only one tablet per dosing interval.

Dosage

Dosage expressed in terms of levodopa and carbidopa.

Available in combination products containing a 1:4 or 1:10 ratio of carbidopa to levodopa. Additional carbidopa can be administered separately if a higher carbidopa dosage than is available in the combination preparations is needed. The treatment regimen can include levodopa-carbidopa extended-release tablets, conventional tablets, and orally disintegrating tablets and carbidopa tablets based on individual requirements. Levodopa no longer is commercially available in the US as a single-entity preparation.

Also available as a fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo^®); available in a 1:4 ratio of carbidopa to levodopa. Used if optimum maintenance dosage of the 3 drugs corresponds to the dosage in the combination preparation. No experience transferring patients receiving levodopa-carbidopa extended-release tablets or levodopa-carbidopa preparations containing the 1:10 ratio.

For some patients (maintenance levodopa dosage ≤600 mg daily, no dyskinesias), the fixed combination containing levodopa, carbidopa, and entacapone (Stalevo^®) can be used when initiating entacapone therapy if optimum maintenance dosage of levodopa-carbidopa corresponds to dosage in the combination preparation.

Adjust levodopa-carbidopa dosage carefully according to individual requirements, response, and tolerance.

Dosage adjustment may be needed when other antiparkinsonian drugs are added to or discontinued from the regimen.

Daily dosage of carbidopa should be at least 70–100 mg daily; patients receiving <70–100 mg daily are likely to experience nausea and vomiting.

Observe patient closely if dosage is reduced abruptly or the drug is discontinued; risk of precipitating a symptom complex resembling neuroleptic malignant syndrome (NMS). (See Neuroleptic Malignant Syndrome under Cautions.)

If general anesthesia required, continue therapy as long as patient permitted to take oral medications; resume as soon as patient is able to take oral medication. If therapy interrupted, observe for NMS. (See Neuroleptic Malignant Syndrome under Cautions.)

Adults

Parkinsonian Syndrome

Levodopa-Carbidopa Conventional Tablets or Orally Disintegrating Tablets

Oral

Initially, levodopa 100 mg/carbidopa 25 mg (as 1 tablet) 3 times daily.

Increase dosage by levodopa 100 mg/carbidopa 25 mg (1 tablet) daily or every other day until a daily dosage of levodopa 800 mg/carbidopa 200 mg is reached or adverse effects prevent further increases or necessitate discontinuance.

Alternatively, initiate with levodopa 100 mg/carbidopa 10 mg (as 1 tablet) 3 or 4 times daily; this dosage will not provide an adequate dose of carbidopa for most patients. Increase dosage by levodopa 100 mg/carbidopa 10 mg (1 tablet) daily or every other day until a daily dosage of levodopa 800 mg/carbidopa 80 mg is reached.

Levodopa-Carbidopa Extended-release Tablets

Oral

Initially, levodopa 200 mg/carbidopa 50 mg (as 1 extended-release tablet) twice daily; initial dosage should not be given at intervals <6 hours. Adjust dosage based on response and tolerance at intervals ≥3 days. Most patients are treated adequately with levodopa 400 mg to 1.6 g daily and carbidopa 100–400 mg daily, administered in divided doses at intervals ranging from 4–8 hours while awake. Higher dosages (levodopa 2.4 g/carbidopa 600 mg) and shorter intervals (<4 hours) have been used but usually are not recommended. If the dosing interval is <4 hours and/or the divided doses are not equal, the smaller doses can be given at the end of the day.

Dosage may be initiated, titrated, and stabilized initially with conventional (immediate-release) tablets.

Transfer to extended-release tablets: initial dosage should provide 10% more levodopa daily than dosage previously received as conventional tablets; levodopa dosage may need to be increased up to 30% more daily, depending on response. (See Bioavailability under Pharmacokinetics.)

Carbidopa

Carbidopa: 25 mg with first dose of levodopa/carbidopa each day for patients who need additional carbidopa; additional 12.5- or 25-mg doses may given during the day with each dose of levodopa/carbidopa.

Prescribing Limits

Adults

Parkinsonian Syndrome

Oral

Experience with carbidopa dosages >200 mg daily limited.

Cautions

Contraindications

• Concomitant use with a nonselective MAO inhibitor. (See Specific Drugs and Foods under Interactions.)
• Angle-closure glaucoma.
• Known hypersensitivity to levodopa, carbidopa, or any ingredient in the formulation.
• Malignant melanoma, history of melanoma, or suspicious undiagnosed skin lesions.

Warnings/Precautions

Warnings

Nervous System and Muscular Effects

Therapy associated with dyskinesias; dosage reduction may be needed.

Mental disturbances reported. Observe patients for depression with concomitant suicidal tendencies. Use with caution in patients with current or past psychoses.

Bradykinetic Episodes

“On-off” phenomenon: Sudden loss of effectiveness with abrupt onset of akinesia (“off” effect; persists 1–60 minutes) followed by sudden return of effectiveness (“on” effect); may recur many times daily and respond to increased dosing frequency.

Akinesia Paradoxica (“start hesitation”): Sudden hypotonic freezing (patient falls frequently while attempting to walk); may respond to decreased dosage.

Cardiovascular Effects

Risk of orthostatic hypotension; usually asymptomatic and tolerance usually develops within a few months.

Use with care in patients with a history of MI who have residual atrial, nodal, or ventricular arrhythmias; monitor cardiac function in a facility with intensive cardiac care immediately available during the initial dosage adjustment.

Use with caution in patients with severe cardiovascular disease.

Respiratory Effects

Caution in patients with pulmonary disease (e.g., emphysema) or asthma who may require use of sympathomimetics.

GI Effects

Use with caution in patients with a history of peptic ulcers; possibility of upper GI hemorrhage in these patients.

Neuroleptic Malignant Syndrome (NMS)

Symptom complex resembling NMS reported following dosage reduction or abrupt withdrawal of levodopa.

Observe closely when dosage is reduced or the drug discontinued; especially important in patients receiving concomitant therapy with an antipsychotic agent.

General Precautions

Evaluate hepatic, hematopoietic, cardiovascular, and renal function periodically.

Use of Fixed Combinations

When the fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo^®) is used, observe the usual precautions and contraindications associated with all drugs in the preparation.

Glaucoma

Can be used with caution in patients with well-controlled open-angle glaucoma; monitor IOP. (See Contraindications under Cautions.)

Endocrine Disorders

Use with caution.

Closely monitor diabetic patients; levodopa may affect glycemic control.

Phenylketonuria

Levodopa-carbidopa orally disintegrating tablets contain aspartame (NutraSweet^®), which is metabolized in the GI tract to phenylalanine.

Specific Populations

Pregnancy

Category C.

Lactation

Carbidopa is distributed into milk in rats. Not known whether levodopa-carbidopa distributes into human milk; caution advised.

Pediatric Use

Safety and efficacy not established in children <18 years of age.

Common Adverse Effects

Dyskinesias (choreiform, dystonic, other adventitious movements), nausea.

Interactions

Specific Drugs and Foods

Pharmacokinetics

Absorption

Bioavailability

Well absorbed from the GI tract; peak plasma levodopa concentrations achieved within 0.5 or 2 hours following administration of conventional tablets or extended-release tablets, respectively.

Bioavailability of levodopa from extended-release tablets 70–75% of that from conventional tablets.

Extended-release tablets result in less fluctuation in plasma concentrations between doses than conventional tablets.

Levodopa-carbodopa conventional tablets and orally disintegrating tablets begin to release the drugs within 30 minutes of administration. Pharmacokinetic values for orally disintegrating tablet are similar to those for the conventional tablet.

Food

High protein diet may interfere with absorption of levodopa.

Extended-release tablets: Food increases bioavailability and peak plasma concentrations of levodopa.

Distribution

Extent

Widely distributed.

<1% of levodopa penetrates the CNS; carbidopa does not cross the blood-brain barrier.

Plasma Protein Binding

Levodopa: 10–30%.

Carbidopa: About 36%.

Elimination

Metabolism

Levodopa is metabolized in the stomach and intestine and on first pass through the liver; absorbed levodopa decarboxylated to dopamine.

Carbidopa inhibits peripheral decarboxylation of levodopa, thus increasing availability of levodopa for distribution into the CNS.

Elimination Route

Levodopa is excreted in urine as metabolites.

Half-life

Levodopa: 1.5 hours when administered with carbidopa.

Stability

Storage

Oral

Conventional Tablets

Protect from light.

Extended-release Tablets

Tight container; avoid temperatures >30°C.

Orally Disintegrating Tablets

Tight, light-resistant container; 20–25°C (may be exposed to 15–30°C).

Actions

• Manifestations of parkinsonian syndrome related to depletion of dopamine in the corpus striatum.
• Levodopa relieves symptoms of parkinsonism presumably by increasing dopamine concentrations in the brain.

Advice to Patients

• Importance of taking levodopa/carbidopa at regular intervals as scheduled by the clinician. Importance of not altering the prescribed dosage regimen or adding other antiparkinsonian drugs.
• Advise patient not to chew or crush extended-release tablets; however, tablets may be halved.
• For patients taking orally disintegrating tablets, advise to gently remove the tablet from the bottle with dry hands just before administering a dose and then placing the tablet on the tongue to dissolve and be swallowed with saliva.
• Importance of informing patients with phenylketonuria that the orally disintegrating tablets contain aspartame.
• Advise patient to notify clinician if abnormal involuntary movements appear or get worse; dosage adjustment may be needed.
• Advise patient of expected onset and duration of effect.
• Possibility that dark color (red, brown, black) may appear in saliva, urine, or sweat; garments may be discolored.
• Advise patient that a change in diet to food high in protein may delay absorption of levodopa and reduce systemic availability. Excess acidity may delay absorption.
• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products.
• Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.
• Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

AHFS Drug Information. © Copyright, 1959-2009, Selected Revisions May 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.