Levodopa and Carbidopa

Pronunciation

(lee voe DOE pa & kar bi DOE pa)

U.S. Brand Names

Parcopa™; Sinemet®; Sinemet® CR

Synonyms

Carbidopa and Levodopa

Generic Available

Yes: Excludes orally-disintegrating tablet

Canadian Brand Names

Apo-Levocarb®; Endo®-Levodopa/Carbidopa; Novo-Levocarbidopa; Nu-Levocarb; Sinemet®; Sinemet® CR

Use

Idiopathic Parkinson's disease; postencephalitic parkinsonism; symptomatic parkinsonism

Use - Unlabeled/Investigational

Restless leg syndrome

Pregnancy Risk Factor

Pregnancy Implications

Teratogenic effects were observed with levodopa and carbidopa in animal studies. There are case reports of levodopa crossing the placenta in humans.

Lactation

Excretion in breast milk unknown/use caution

Contraindications

Hypersensitivity to levodopa, carbidopa, or any component of the formulation; narrow-angle glaucoma; use of MAO inhibitors within prior 14 days (however, may be administered concomitantly with the manufacturer's recommended dose of an MAO inhibitor with selectivity for MAO type B); history of melanoma or undiagnosed skin lesions

Warnings/Precautions

Use with caution in patients with history of cardiovascular disease (including myocardial infarction and arrhythmias); pulmonary diseases such as asthma, psychosis, wide-angle glaucoma, peptic ulcer disease; as well as in renal, hepatic, or endocrine disease. Sudden discontinuation of levodopa may cause a worsening of Parkinson's disease. Elderly may be more sensitive to CNS effects of levodopa. May cause or exacerbate dyskinesias. May cause orthostatic hypotension; Parkinson's disease patients appear to have an impaired capacity to respond to a postural challenge; use with caution in patients at risk of hypotension (such as those receiving antihypertensive drugs) or where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). Observe patients closely for development of depression with concomitant suicidal tendencies. Has been associated with a syndrome resembling neuroleptic malignant syndrome on withdrawal or significant dosage reduction after long-term use. Protein in the diet should be distributed throughout the day to avoid fluctuations in levodopa absorption.

Adverse Reactions

Frequency not defined.

Cardiovascular: Orthostatic hypotension, arrhythmia, chest pain, hypertension, syncope, palpitation, phlebitis

Central nervous system: Dizziness, anxiety, confusion, nightmares, headache, hallucinations, on-off phenomenon, decreased mental acuity, memory impairment, disorientation, delusions, euphoria, agitation, somnolence, insomnia, gait abnormalities, nervousness, ataxia, EPS, falling, psychosis, peripheral neuropathy, seizure (causal relationship not established)

Dermatologic: Rash, alopecia, malignant melanoma, hypersensitivity (angioedema, urticaria, pruritus, bullous lesions, Henoch-Schönlein purpura)

Endocrine & metabolic: Increased libido

Gastrointestinal: Anorexia, nausea, vomiting, constipation, GI bleeding, duodenal ulcer, diarrhea, dyspepsia, taste alterations, sialorrhea, heartburn

Genitourinary: Discoloration of urine, urinary frequency

Hematologic: Hemolytic anemia, agranulocytosis, thrombocytopenia, leukopenia; decreased hemoglobin and hematocrit; abnormalities in AST and ALT, LDH, bilirubin, BUN, Coombs' test

Neuromuscular & skeletal: Choreiform and involuntary movements, paresthesia, bone pain, shoulder pain, muscle cramps, weakness

Ocular: Blepharospasm, oculogyric crises (may be associated with acute dystonic reactions)

Renal: Difficult urination

Respiratory: Dyspnea, cough

Miscellaneous: Hiccups, discoloration of sweat, diaphoresis (increased)

Overdosage/Toxicology

Symptoms of overdose include palpitations, arrhythmias, spasms; may cause hypertension or hypotension. Treatment is supportive. ECG monitoring is warranted. May precipitate a variety of arrhythmias.

Drug Interactions

Antacids: Levodopa absorption may be increased; monitor

Anticholinergics: May reduce the efficacy of levodopa, possibly due to reduced gastrointestinal absorption (also see tricyclic antidepressants); limited evidence of clinical significance; monitor

Antipsychotics: May inhibit the antiparkinsonian effects of levodopa via dopamine receptor blockade; use antipsychotics with low dopamine blockade (clozapine, olanzapine, quetiapine)

Benzodiazepines: May inhibit the antiparkinsonian effects of levodopa; monitor for reduced effect

Clonidine: May reduce the efficacy of levodopa; monitor

Dextromethorphan: Toxic reactions have occurred with dextromethorphan

Furazolidone: May increase the effect/toxicity of levodopa; hypertensive episodes have been reported; monitor

Iron salts: Binds levodopa and reduces its bioavailability; separate doses of iron and levodopa

Linezolid: Due to MAO inhibition (see note on MAO inhibitors), this agent is best avoided

MAO inhibitors: Concurrent use of levodopa with nonselective MAO inhibitors may result in hypertensive reactions via an increased storage and release of dopamine, norepinephrine, or both; use with carbidopa to minimize reactions if combination is necessary, otherwise avoid combination.

L-methionine: May inhibit levodopa's antiparkinsonian effects; monitor for reduced effect

Metoclopramide: May increase the absorption/effect of levodopa; hypertensive episodes have been reported. Levodopa antagonizes metoclopramide's effects on lower esophageal sphincter pressure. Avoid use of metoclopramide for reflux, monitor response to levodopa carefully if used.

Methyldopa: May potentiate the effects of levodopa; levodopa may increase the hypotensive response to methyldopa; monitor

Papaverine: May decrease the efficacy of levodopa; includes other similar agents (ethaverine); monitor

Penicillamine: May increase serum concentrations of levodopa; monitor for increased effect

Phenytoin: May inhibit levodopa's antiparkinsonian effects; monitor for reduced effect

Pyridoxine: May inhibit levodopa's antiparkinsonian effects; monitor for reduced effect (pyridoxine in doses >10-25 mg for levodopa alone, higher doses >200 mg/day may be a problem for levodopa/carbidopa)

Spiramycin: May inhibit levodopa's antiparkinsonian effects; monitor for reduced effect

Tacrine: May inhibit the effects of levodopa via enhanced cholinergic activity; monitor for reduced effect

Tricyclic antidepressants: May decrease the absorption (bioavailability) of levodopa; rare hypertensive episodes have also been attributed to this combination

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (due to CNS depression).

Food: Avoid high protein diets and high intakes of vitamin B6.

Herb/Nutraceutical: Avoid kava kava (may decrease effects). Pyridoxine in doses >10-25 mg (for levodopa alone) or higher doses >200 mg/day (for levodopa/carbidopa) may decrease efficacy.

Stability

Store at 20°C to 25°C (68°F to 77°F); excursions are allowed between 15°C to 30°C (59°F to 86°F); protect from light and moisture

Mechanism of Action

Parkinson's symptoms are due to a lack of striatal dopamine; levodopa circulates in the plasma to the blood-brain-barrier (BBB), where it crosses, to be converted by striatal enzymes to dopamine; carbidopa inhibits the peripheral plasma breakdown of levodopa by inhibiting its decarboxylation, and thereby increases available levodopa at the BBB

Pharmacodynamics/Kinetics

Duration: Variable, 6-12 hours; longer with sustained release forms

See individual agents.

Dosage

Oral: Adults:

Parkinson's disease:

Immediate release tablet:

Initial: Carbidopa 25 mg/levodopa 100 mg 3 times/day

Dosage adjustment: Alternate tablet strengths may be substituted according to individual carbidopa/levodopa requirements. Increase by 1 tablet every other day as necessary, except when using the carbidopa 25 mg/levodopa 250 mg tablets where increases should be made using ¹ /2-1 tablet every 1-2 days. Use of more than 1 dosage strength or dosing 4 times/day may be required (maximum: 8 tablets of any strength/day or 200 mg of carbidopa and 2000 mg of levodopa)

Sustained release tablet:

Initial: Carbidopa 50 mg/levodopa 200 mg 2 times/day, at intervals not <6 hours

Dosage adjustment: May adjust every 3 days; intervals should be between 4-8 hours during the waking day (maximum: 8 tablets/day)

Restless leg syndrome (unlabeled use): Carbidopa 25 mg/levodopa 100 mg given 30-60 minutes before bedtime; may repeat dose once

Elderly: Initial: Carbidopa 25 mg/levodopa 100 mg twice daily, increase as necessary

Administration

Space doses evenly over the waking hours. Give with meals to decrease GI upset. Sustained release product should not be crushed. Orally-disintegrating tablets do not require water; the tablet should disintegrate on the tongue's surface before swallowing.

Monitoring Parameters

Blood pressure, standing and sitting/supine; symptoms of parkinsonism, dyskinesias, mental status

Test Interactions

False-positive reaction for urinary glucose with Clinitest®; false-negative reaction using Clinistix®; false-positive urine ketones with Acetest®, Ketostix®, Labstix®

Dietary Considerations

Levodopa peak serum concentrations may be decreased if taken with food. High protein diets (>2 g/kg) may decrease the efficacy of levodopa via competition with amino acids in crossing the blood-brain barrier.

Parcopa™: Contains phenylalanine 3.4 mg per 10/100 mg and 25/100 mg strengths; phenylalanine 8.4 mg in 25/250 mg strength

Patient Education

Take exactly as directed; do not change dosage or discontinue without consulting prescriber. Do not crush sustained release form. Therapeutic effects may take several weeks or months to achieve and you may need frequent monitoring during first weeks of therapy. Take with meals if GI upset occurs, before meals if dry mouth occurs, after eating if drooling or if nausea occurs. Take at the same time each day. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake; void before taking medication. Do not use alcohol and prescription or OTC sedatives or CNS depressants without consulting prescriber. Urine or perspiration may appear darker. You may experience drowsiness, dizziness, confusion, or vision changes (use caution when driving, climbing stairs, or engaging in tasks requiring alertness until response to drug is known); orthostatic hypotension (use caution when changing position - rising to standing from sitting or lying); increased susceptibility to heat stroke, decreased perspiration (use caution in hot weather - maintain adequate fluids and reduce exercise activity); constipation (increased exercise, fluids, fruit, or fiber may help); dry skin or nasal passages (consult prescriber for appropriate relief); or nausea, vomiting, loss of appetite, or stomach discomfort (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help). Report unresolved constipation or vomiting; chest pain or irregular heartbeat; respiratory difficulty; acute headache or dizziness; CNS changes (hallucination, loss of memory, nervousness, etc); painful or difficult urination; abdominal pain or blood in stool; increased muscle spasticity or rigidity; skin rash; or significant worsening of condition. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.

Additional Information

50-100 mg/day of carbidopa is needed to block the peripheral conversion of levodopa to dopamine. "On-off" (a clinical syndrome characterized by sudden periods of drug activity/inactivity), can be managed by giving smaller, more frequent doses of Sinemet® or adding a dopamine agonist or selegiline; when adding a new agent, doses of Sinemet® can usually be decreased. Protein in the diet should be distributed throughout the day to avoid fluctuations in levodopa absorption. Levodopa is the drug of choice when rigidity is the predominant presenting symptom.

Conversion from levodopa to carbidopa/levodopa: Note: Levodopa must be discontinued at least 12 hours prior to initiation of levodopa/carbidopa:

Initial dose: Levodopa portion of carbidopa/levodopa should be at least 25% of previous levodopa therapy.

Levodopa <1500 mg/day: Sinemet® or Parcopa™ (levodopa 25 mg/carbidopa 100 mg) 3-4 times/day

Levodopa 1500 mg/day: Sinemet® or Parcopa™ (levodopa 25 mg/carbidopa 250 mg) 3-4 times/day

Conversion from immediate release carbidopa/levodopa (Sinemet® or Parcopa™) to Sinemet® CR (50/200):

Sinemet® or Parcopa™ [total daily dose of levodopa]/Sinemet® CR:

Sinemet® or Parcopa™ (levodopa 300-400 mg/day): Sinemet® CR (50/200) 1 tablet twice daily

Sinemet® or Parcopa™ (levodopa 500-600 mg/day): Sinemet® CR (50/200) 1 1/2 tablets twice daily or 1 tablet 3 times/day

Sinemet® or Parcopa™ (levodopa 700-800 mg/day): Sinemet® CR (50/200) 4 tablets in 3 or more divided doses

Sinemet® or Parcopa™ (levodopa 900-1000 mg/day): Sinemet® CR (50/200) 5 tablets in 3 or more divided doses

Intervals between doses of Sinemet® CR should be 4-8 hours while awake; when divided doses are not equal, smaller doses should be given toward the end of the day,

Anesthesia and Critical Care Concerns/Other Considerations

Consider use of alternative therapies before attempting to use levodopa containing products.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation). Dopaminergic therapy in Parkinson's disease (ie, treatment with levodopa and carbidopa combination) is associated with orthostatic hypotension. Patients medicated with this drug combination should be carefully assisted from the chair and observed for signs of orthostatic hypotension.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Dosage Forms

Tablet immediate release (Sinemet®):

10/100: Carbidopa 10 mg and levodopa 100 mg

25/100: Carbidopa 25 mg and levodopa 100 mg

25/250: Carbidopa 25 mg and levodopa 250 mg

Tablet, immediate release, orally-disintegrating (Parcopa™):

10/100: Carbidopa 10 mg and levodopa 100 mg [contains phenylalanine 3.4 mg/tablet; mint flavor]

25/100: Carbidopa 25 mg and levodopa 100 mg [contains phenylalanine 3.4 mg/tablet; mint flavor]

25/250: Carbidopa 25 mg and levodopa 250 mg [contains phenylalanine 8.4 mg/tablet; mint flavor]

Tablet, sustained release (Sinemet® CR):

Carbidopa 25 mg and levodopa 100 mg

Carbidopa 50 mg and levodopa 200 mg

References

Olanow CW, Watts RL, and Koller WC, "An Algorithm (Decision Tree) for the Management of Parkinson's Disease (2001): Treatment Guidelines," Neurology , 2001, 56(11 Suppl 5):1-88.

Restless Leg Syndrome Foundation, Inc, 2001 Medical Bulletin , revised April 2001. Available at: http://www.rls.org/frames/home_frame.htm. Accessed May 1, 2002.

Stern MB, "Contemporary Approaches to the Pharmacotherapeutic Management of Parkinson's Disease: An Overview," Neurology , 1997, 49(1 Suppl 1):2-9.

Walker SW, Fina A, and Kryger MH, "L-Dopa/Carbidopa for Nocturnal Movement Disorders in Uremia," Sleep , 1996, 19(3):214-8.

International Brand Names

Apo-Levocarb® (CA); Endo®-Levodopa/Carbidopa (CA); Novo-Levocarbidopa (CA); Nu-Levocarb (CA); Sinemet® (CA); Sinemet® CR (CA)

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