Carbidopa / Levodopa / Entacapone

Pronunciation: KAR-bi-DOE-pa/LEE-voe-DOE-pa/en-TAK-a-pone
Class: Antiparkinson agent

Trade Names

Stalevo 50
- Tablets carbidopa 12.5 mg/levodopa 50 mg/entacapone 200 mg

Stalevo 75
- Tablets carbidopa 18.75 mg/levodopa 75 mg/entacapone 200 mg

Stalevo 100
- Tablets carbidopa 25 mg/levodopa 100 mg/entacapone 200 mg

Stalevo 125
- Tablets carbidopa 31.25 mg/levodopa 125 mg/entacapone 200 mg

Stalevo 150
- Tablets carbidopa 37.5 mg/levodopa 150 mg/entacapone 200 mg

Stalevo 200
- Tablets carbidopa 50 mg/levodopa 200 mg/entacapone 200 mg

Pharmacology

Carbidopa

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

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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 to substitute (with equivalent strength of each of the 3 immediate-release components) for the previously administered individual products, or 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 600 mg or less and not experiencing dyskinesias).

Contraindications

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

Dosage and Administration

Adults

PO 1 tablet should be administered at each dosing interval. The product is available in 6 strengths, each in a 1:4 ratio of carbidopa to levodopa and combined with entacapone 200 mg. Generally, the product should be used to substitute for patients already stabilized on equivalent doses 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.

Transferring Patients to Carbidopa/Levodopa/Entacapone
Adults

PO There is no experience in transferring patients currently treated with standard formulations of carbidopa/levodopa other than immediate-release carbidopa/levodopa with a 1:4 ratio and entacapone to carbidopa/levodopa/entacapone. Patients who are taking entacapone 200 mg with each dose of standard-release carbidopa/levodopa can be directly switched to the corresponding strength of Stalevo containing the same amounts of levodopa and carbidopa.

Transferring Patients Not Currently Taking Entacapone
Adults

PO Patients should be titrated individually with a carbidopa/levodopa product (ratio 1:4) and an entacapone product. Then, once the patient has stabilized, transfer patient to a corresponding dose of carbidopa/levodopa/entacapone. Since entacapone prolongs and enhances the effects of levodopa, therapy should be individualized and adjusted, if necessary, 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.
  • The max recommended dose of Stalevo , defined by the max daily dose of entacapone, is 8 tablets daily, which would include a total of entacapone 1,600 mg.
  • Individualize and adjust therapy for each patient according to the desired therapeutic response.
  • When less levodopa is required, the total daily dose of carbidopa/levodopa should be reduced either by decreasing the carbidopa/levodopa/entacapone strength or by decreasing the frequency of administration.
  • When more levodopa is required, the next higher strength of carbidopa/levodopa/entacapone should be taken and/or the frequency of doses should be increased, up to a max of 8 times daily of Stalevo .
  • Standard drugs for Parkinson disease may be coadministered with carbidopa/levodopa/entacapone; however, dosage adjustments may be required.

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, butyrophenones, isoniazid, phenothiazines, risperidone), papaverine, phenytoin

May reduce the therapeutic effects of levodopa.

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

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

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

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. Discontinue therapy with MAOIs 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 (TCAs) (eg, amitriptyline)

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

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, hypertension, hypotension, orthostatic hypotension, palpitation, phlebitis, syncope.

Levodopa

MI.

CNS

Carbidopa/Levodopa

Abnormal dreams (including nightmares), agitation, asthenia, bradykinetic episodes (“on-off” phenomenon), confusion, convulsions, dementia, depression with and without suicidal tendencies, dizziness, dyskinesia, hallucinations, headache, increased libido, insomnia, NMS, paranoid ideation, paresthesia, psychotic episodes (including delusions), somnolence.

Entacapone

Dyskinesia (25%); hyperkinesia (10%); hypokinesia (9%); dizziness (8%); fatigue (6%); anxiety, asthenia, somnolence (2%); agitation (1%).

Levodopa

Abnormal gait, activation of latent Horner syndrome, anxiety, ataxia, blepharospasm, decreased mental acuity, disorientation, euphoria, extrapyramidal disorder, falling, fatigue, increased tremor, malaise, memory impairment, muscle twitching, nervousness, numbness, peripheral neuropathy, sense of stimulation, trismus.

Dermatologic

Carbidopa/Levodopa

Alopecia, dark-colored sweat, increased sweating, rash.

Entacapone

Increased sweating (2%).

Levodopa

Flushing, malignant melanoma.

EENT

Levodopa

Blurred vision, dilated pupils, diplopia, oculogyric crisis.

GI

Carbidopa/Levodopa

Anorexia, constipation, dark saliva, diarrhea, dry mouth, duodenal ulcer, dyspepsia, GI bleeding, nausea, taste alterations, vomiting.

Entacapone

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

Levodopa

Abdominal pain and distress, burning sensation of the tongue, clenching/grinding of teeth, dysphagia, flatulence, GI pain, heartburn, hiccups, sialorrhea.

Genitourinary

Carbidopa/Levodopa

Dark urine, urinary frequency, UTI.

Entacapone

Urinary discoloration (10%).

Levodopa

Priapism, urinary incontinence, urinary retention.

Hematologic-Lymphatic

Carbidopa/Levodopa

Agranulocytosis, hemolytic anemia, leukopenia, nonhemolytic anemia, thrombocytopenia.

Entacapone

Purpura (2%).

Hypersensitivity

Carbidopa/Levodopa

Angioedema, bullous lesions (including pemphigus-like reactions), Henoch-Schönlein purpura, pruritus, urticaria.

Lab Tests

Carbidopa/Levodopa

Abnormalities in alkaline phosphatase ALT, AST, bilirubin, BUN, Coombs test, and lactic dehydrogenase; decreased hemoglobin and hematocrit; elevated serum glucose; bacteria, blood, and white blood cells in the urine.

Levodopa

Decreased serum potassium and WBC; increased protein, serum creatinine, uric acid, and urine glucose.

Metabolic-Nutritional

Levodopa

Edema, weight gain, weight loss.

Musculoskeletal

Carbidopa/Levodopa

Back pain, muscle cramps, shoulder pain.

Entacapone

Back pain (4%).

Respiratory

Carbidopa/Levodopa

Dyspnea; upper respiratory tract infection.

Entacapone

Dyspnea (3%).

Levodopa

Cough, pharyngeal pain.

Miscellaneous

Carbidopa/Levodopa

Chest pain.

Entacapone

Bacterial infection (1%).

Levodopa

Bizarre breathing patterns, faintness, hoarseness, hot flashes.

Precautions

Monitor

Parkinsonian symptoms

Assess parkinsonian symptoms before and periodically during therapy.

Routine tests

Ensure that liver, CV, 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.


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 CV 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.

Anesthesia

If general anesthesia is required, carbidopa/levodopa/entacapone may be continued as long as the patient is permitted to take fluids and medication by mouth. If therapy is interrupted, observe the patient for symptoms of NMS. Resume therapy at the usual dose as soon as the patient is able to take oral medication.

Blepharospasm

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

Diarrhea

Diarrhea has been reported and may occur as early as the first week or many months after starting entacapone treatment.

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.

NMS

A symptom complex resembling NMS 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.

Syncope

Syncope has been reported and may be frequent in patients with a history of hypotension.

Overdosage

Symptoms

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

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 max benefit.
  • Caution patient, family, or caregiver that patient should take only 1 tablet at each dosing interval and not to take more than 8 tablets 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 max benefit.
  • Advise patient, family, or caregiver that if a dose is missed, to take 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 that patient should not 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 that may discolor clothing or bedding.
  • Advise patient, family, or caregiver to report any of the following to health care provider: hallucinations; involuntary body or facial movements; mood or mental changes; persistent or frequent nausea or vomiting; worsening of Parkinson symptoms before next dose (“wearing off” effect); or any unexplained symptom or problem.

Copyright © 2009 Wolters Kluwer Health.

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