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Carbidopa / Levodopa / Entacapone

Pronouncation: (CAR-bih-doe-puh/LEE-voe-DOE-puh/en-TACK-ah-pone)
Class: Antiparkinson agent

Trade Names:
Stalevo 50
- Tablets 12.5 mg carbidopa, 50 mg levodopa, 200 mg entacapone

Trade Names:
Stalevo 100
- Tablets 25 mg carbidopa, 100 mg levodopa, 200 mg entacapone

Trade Names:
Stalevo 150
- Tablets 37.5 mg carbidopa, 150 mg levodopa, 200 mg entacapone

Pharmacology

Feedback for Carbidopa/Levodopa/Entacapone

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Compare with other drugs.

Carbidopa

Inhibits peripheral decarboxylation of levodopa, making more levodopa available for transport to the brain.

Levodopa

Precursor of dopamine, which is deficient in parkinsonism patients.

Entacapone

Inhibits the enzyme that metabolizes levodopa (catechol-O-methyltransferase [COMT]), which increases and prolongs levodopa plasma levels.

Indications and Usage

Treatment of idiopathic Parkinson disease: 1) to substitute (with equivalent strength of each of the 3 immediate-release components) for the previously administered individual products, 2) to replace immediate-release carbidopa/levodopa therapy (without entacapone) when patients experience signs and symptoms of end-of-dose “wearing-off” (only for patients taking a total daily dose of levodopa of 600 mg or less and not experiencing dyskinesias).

Contraindications

Narrow-angle glaucoma; nonselective monoamine oxidase inhibitors (MAOIs) (eg, phenelzine) should be discontinued at least 2 wk prior to initiating therapy with carbidopa/levodopa/entacapone; patients with history of melanoma or suspicious undiagnosed skin lesions; hypersensitivity to any component of the product.

Dosage and Administration

Adults

PO 1 tablet should be administered at each dosing interval. The product is available in 3 strengths, each in a 1:4 ratio of carbidopa to levodopa and combined with 200 mg of entacapone. Generally, the product should be used to substitute for patients already stabilized on a given dose of carbidopa, levodopa, and entacapone. However, some patients stabilized on a given dose of carbidopa/levodopa may be treated with this product if a decision to add entacapone has been made. The optimum daily dosage must be determined by careful titration in each patient. Therapy should be individualized and adjusted according to the desired therapeutic response.

General Advice

Administer prescribed dose without regard to meals. Administer with food if GI upset occurs, however, do not administer with high-protein foods because they reduce absorption of medication.
Administer only 1 tablet at each dosing interval. If an increased dose is needed, a different tablet strength will need to be administered.

Storage/Stability

Store at controlled room temperature (59° to 86°F).

Drug Interactions

Antihypertensive agents

Symptomatic postural hypotension may occur when adding carbidopa/levodopa; therefore, be prepared to adjust antihypertensive therapy as needed.

Dopamine D2 receptor antagonists (eg, phenothiazines, risperidone), isoniazid, papaverine, phenytoin

May reduce the therapeutic effects of levodopa.

Drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta glucuronidase (eg, ampicillin, cholestyramine, chloramphenicol, erythromycin, probenecid, rifampin)

Because entacapone is excreted via the bile, drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidase should be used with caution.

Drugs metabolized by COMT (eg, alpha-methyldopa, bitolterol, dobutamine, dopamine, epinephrine, isoproterenol)

Increased heart rate, possible arrhythmia, and excessive BP changes may occur.

Iron salts

May reduce the bioavailability of levodopa; however, the clinical importance is unclear.

MAOIs

Concurrent therapy with nonselective MAOIs (eg, phenelzine) is contraindicated. Therapy with MAOIs should be discontinued 2 wk prior to starting carbidopa/levodopa/entacapone.

Metoclopramide

May increase levodopa bioavailability by increasing gastric emptying and because of its dopamine receptor antagonistic properties; metoclopramide may also adversely affect disease control.

Pyridoxine

Pyridoxine in doses of 10 to 25 mg may reverse the effects of levodopa; however, carbidopa inhibits this effect of levodopa. Therefore, supplemental pyridoxine can be given concurrently.

Tricyclic antidepressants (TCA [eg, amitriptyline])

Rare reports of adverse reactions, including hypertension and dyskinesia, have been noted with concomitant use of levodopa/carbidopa and TCA.

Laboratory Test Interactions

False-positive reactions for urinary ketone bodies may occur when a test tape is used for ketonuria determination; false-positive Coombs test results may occur; because falsely diagnosed pheochromocytoma has occurred, exercise caution when interpreting plasma and urine levels of catecholamines and their metabolites.

Adverse Reactions

Cardiovascular

Carbidopa/Levodopa

Cardiac irregularities, hypotension, orthostatic effects (including orthostatic hypotension, hypertension, syncope, phlebitis, palpitation); MI (levodopa).

Entacapone

Dyspnea (3%).

CNS

Carbidopa/Levodopa

Dyskinesias (including choreiform, dystonic, and other involuntary movements), psychotic episodes (including delusions, hallucinations, paranoid ideation), neuroleptic malignant syndrome, bradykinetic episodes (“on-off” phenomenon), confusion, agitation, dizziness, somnolence, dream abnormalities, insomnia, paresthesia, headache, depression with or without development of suicidal tendencies, dementia, increased libido, convulsions (carbidopa/levodopa); fatigue, ataxia, extrapyramidal disorder, anxiety, gait abnormalities, nervousness, decreased mental acuity, memory impairment, disorientation, euphoria, blepharospasm, trismus, increased tremor, numbness, muscle twitching, activation of latent Horner syndrome, peripheral neuropathy (levodopa).

Entacapone

Dyskinesia (25%); hyperkinesia (10%); hypokinesia (9%); agitation (1%).

Dermatologic

Carbidopa/Levodopa

Rash, increased sweating, alopecia, dark sweat; malignant melanoma, flushing (levodopa).

EENT

Levodopa

Oculogyric crisis; diplopia; blurred vision; dilated pupils.

GI

Carbidopa/Levodopa

Nausea, dark saliva, GI bleeding, duodenal ulcer, anorexia, vomiting, diarrhea, constipation, dyspepsia, dry mouth, taste alteration; GI pain, dysphagia, sialorrhea, flatulence, bruxism, burning sensation of the tongue, heartburn, hiccups (levodopa).

Entacapone

Nausea (14%); diarrhea (10%); abdominal pain (8%); constipation (6%); vomiting (4%); dry mouth (3%); dyspepsia, flatulence (2%); gastritis, nonspecific GI disorders (1%).

Genitourinary

Carbidopa/Levodopa

UTI, urinary frequency, dark urine; urinary retention, urinary incontinence, priapism (levodopa).

Entacapone

Urine discoloration (10%); renal toxicity.

Hematologic

Carbidopa/Levodopa

Agranulocytosis; hemolytic and nonhemolytic anemia; thrombocytopenia; leukopenia.

Metabolic

Levodopa

Edema; weight gain; weight loss.

Respiratory

Carbidopa/Levodopa

Dyspnea, upper respiratory tract infection; pharyngeal pain, cough (levodopa).

Entacapone

Purpura (2%).

Miscellaneous

Carbidopa/Levodopa

Chest pain, asthenia, angioedema, urticaria, pruritus, Henoch-Schönlein purpura, bullous lesions (including pemphigus-like reactions), back pain, shoulder pain, muscle cramps, decreased hemoglobin and hematocrit, abnormalities in alkaline phosphatase, ALT, AST, lactic dehydrogenase, bilirubin, BUN, and Coombs test, elevated serum glucose, bacteria, and blood in the urine (carbidopa/levodopa); abdominal pain and distress, leg pain, bizarre breathing patterns, faintness, hoarseness, malaise, hot flashes, sense of stimulation, decreased WBC, decreased serum potassium, increased serum creatinine and uric acid, protein and glucose in urine (levodopa).

Entacapone

Fatigue (6%); back pain (4%); asthenia, increased sweating (2%); bacterial infection (1%); aggravation of Parkinson disease symptoms.

Precautions

Monitor

Parkinsonian symptoms

Assess parkinsonian symptoms before and periodically during therapy.

Routine tests

Ensure that liver, cardiovascular, hematopoietic, and renal function are assessed before and periodically during therapy.

Neurological status

Assess neurological status before and during treatment. Observe for involuntary body and facial movements, depression, hallucinations, or dizziness. Inform health care provider if noted.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Hepatic Function

Use with caution; AUC and C _max of entacapone approximately doubled.

Special Risk Patients

Use with caution in patients with severe cardiovascular or pulmonary disease, bronchial asthma, biliary obstruction, renal, hepatic or endocrine disease, administer cautiously to patients with history of MI who have residual atrial, nodal, or ventricular arrhythmias and to patients with wide-angle glaucoma.

Blepharospasm

May be an early sign of excessive dosage, which may indicate the need for dosage reduction.

Dyskinesia

Entacapone may potentiate the dopaminergic side effects of levodopa; exacerbating preexisting dyskinesia; dosage reduction may be required.

Fibrotic complications

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported.

Hallucinations

Dopaminergic therapy has been associated with hallucinations.

Hormone levels

Prolactin secretion may be decreased while growth hormone levels may be increased.

Hyperpyrexia/confusion

Elevated temperature, muscular rigidity, altered consciousness, and elevated CPK have been reported with rapid dose reduction or withdrawal of other dopaminergic drugs.

Mental disturbances

Observe carefully for the development of depression with concomitant suicidal tendencies, or with past or current psychosis.

Neuroleptic malignant syndrome

A symptom complex resembling neuroleptic malignant syndrome has been reported in association with dose reductions or withdrawal of carbidopa/levodopa therapy.

Peptic ulcer

The risk of upper GI hemorrhage may be increased.

Rhabdomyolysis

Severe cases have been reported in patients receiving entacapone in combination with levodopa.

Overdosage

Symptoms

Dopaminergic overstimulation, CNS disturbances, cardiovascular disturbances (eg, hypotension, tachycardia), severe psychiatric problems, rhabdomyolysis, transient renal insufficiency, COMT inhibition.

Patient Information

Advise patient, family, or caregiver that medication is not a cure for the disease but may help reduce symptoms.
Advise patient, family, or caregiver that medication is started at a low dose and gradually increased to achieve maximum benefit.
Caution patient, family, or caregiver that only 1 tablet should be taken at each dosing interval and that no more than 8 tablets should be taken in any 24-h period.
Advise patient, family, or caregiver that medication can be taken without regard to meals but to take with food if GI upset occurs. However, caution against taking medication with high-protein foods because they reduce absorption and effectiveness of medication.
Caution patient, family, or caregiver that tablets should never be cut, split, or crushed.
Advise patient, family, or caregiver that medication should be taken as prescribed and to not stop taking or change the dose unless advised by health care provider. Emphasize that medication must be taken at regular intervals to obtain maximum benefit.
Advise patient, family, or caregiver that if a dose is missed it should be taken as soon as remembered but to never double the dose to catch up or take more than the prescribed total daily dose.
Caution patient, family, or caregiver not to take any other antiparkinsonian medications unless advised by health care provider.
Caution patient to avoid sudden position changes to prevent orthostatic hypotension (dizziness or faintness when arising suddenly from a sitting or lying position).
Advise patient that the drug may cause dizziness or other nervous system disorders and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
Advise patient, family, or caregiver that medication may cause a red, brown, or black discoloration of saliva, urine, or sweat that is not harmful but may discolor clothing or bedding.
Advise patient family or caregiver to report any of the following to health care provider: worsening of Parkinson symptoms before next dose (“wearing off” effect); persistent or frequent nausea or vomiting; involuntary body or facial movements; mood or mental changes; hallucinations; or any unexplained symptom or problem.