Class: Catechol-O-Methyltransferase (COMT) Inhibitors
VA Class: CN500
Chemical Name: (E)-α-Cyano-N,N-diethyl-1,3,4-dihydroxy-5-nitrocinnamamide
Molecular Formula: C14H15N3O5
CAS Number: 130929-57-6
Brands: Comtan, Stalevo
Introduction
Selective, reversible inhibitor of catechol-O-methyltransferase (COMT).1 2 3 7
Uses for Entacapone
Parkinsonian Syndrome
Adjunct to levodopa-carbidopa in the symptomatic treatment of idiopathic parkinsonian syndrome in patients with manifestations of end-of-dose “wearing-off.”1 4
Not evaluated systematically in patients without manifestations of end-of-dose “wearing-off.”1
Entacapone Dosage and Administration
Administration
Oral Administration
Administer orally without regard to meals.1
Administer in conjunction with levodopa-carbidopa (conventional tablets, orally disintegrating tablets, or extended-release preparations) or as a fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo).1 8
Administer one tablet of the fixed-combination preparation (Stalevo) per dosing interval; do not divide the tablets.8
Dosage
Adults
Parkinsonian Syndrome
Oral
200 mg with each levodopa-carbidopa dose.1
May need to reduce daily levodopa dosage or administration frequency to optimize patient response.1 In clinical studies, most patients receiving ≥800 mg of levodopa daily or experiencing moderate or severe dyskinesias before initiating entacapone therapy required a reduction (average 25%) in levodopa dosage.1
Transferring to the Fixed-combination Preparation (Stalevo)
Oral
Patients receiving levodopa-carbidopa conventional tablets containing a 1:4 ratio of carbidopa to levodopa: Switch to the corresponding strength of Stalevo.8
No information on transferring patients receiving extended-release levodopa-carbidopa preparation or levodopa-carbidopa preparations containing a 1:10 ratio of carbidopa to levodopa.8
Initiating Entacapone Using the Fixed-combination Preparation (Stalevo)
Oral
Patients receiving levodopa >600 mg daily or with history of moderate or severe dyskinesias: Administer levodopa-carbidopa (1:4 ratio) and entacapone as separate preparations to determine optimum maintenance dosage and then switch to corresponding strength of Stalevo.8
Patients receiving levodopa <600 mg daily (conventional tablet, 1:4 ratio) with no dyskinesias: Switch to the strength of Stalevo that corresponds to the dosage of levodopa-carbidopa being taken.8 Further adjustment may be needed.8
Prescribing Limits
Adults
Parkinsonian Syndrome
Oral
Entacapone: Maximum of 8 doses (1.6 g) daily; clinical experience with dosages >1.6 g daily is limited.1 8
Fixed-combination preparations containing levodopa 50–150 mg, carbidopa 12.5–37.5 mg, and entacapone 200 mg (Stalevo 50, 75, 100, 125, and 150): Maximum of 8 tablets daily; clinical experience with entacapone dosages >1.6 g daily is limited.8
Fixed-combination preparation containing levodopa 200 mg, carbidopa 50 mg, and entacapone 200 mg (Stalevo 200): Maximum of 6 tablets daily; clinical experience with carbidopa dosages >300 mg daily is limited.8
Cautions for Entacapone
Contraindications
Known hypersensitivity to entacapone or any ingredient in the formulation.1
When entacapone is used in fixed combination with levodopa-carbidopa, consider the contraindications associated with levodopa-carbidopa.8
Warnings/Precautions
Warnings
Concomitant Use with MAO Inhibitors
Possible inhibition of principal pathways involved in the metabolism of catecholamines if used concomitantly with a nonselective MAO inhibitor (e.g., phenelzine, tranylcypromine); concomitant use not recommended.1 (See Specific Drugs under Interactions.)
Concomitant Use with Drugs Metabolized by Catechol-O-methyltransferase
Possible increased heart rate, arrhythmias, and excessive changes in BP when used concomitantly with drugs metabolized by catechol-O-methyltransferase (COMT).1 (See Specific Drugs under Interactions.)
Potential Risk of Prostate Cancer
Higher incidence of prostate cancer was observed in one long-term, randomized, controlled study in patients initiating levodopa therapy with levodopa, carbidopa, and entacapone (Stalevo) compared with those initiating therapy with conventional levodopa-carbidopa formulation.11 13 Increased risk of prostate cancer not observed in other shorter-term controlled studies evaluating entacapone as an adjunct to levodopa-carbidopa.11 13 FDA is continuing to review available data related to this safety concern.11
FDA advises patients receiving entacapone as an adjunct to levodopa-carbidopa (either separately or as a fixed-combination preparation) to continue taking the drugs as prescribed unless otherwise instructed by a clinician.11 Men receiving such therapy should continue to be monitored for development of prostate cancer according to current prostate cancer screening guidelines.11
Major Toxicities
Cardiovascular Effects
Enhances levodopa availability; possible increased occurrence of orthostatic hypotension or syncope when administered with levodopa-carbidopa.1
Findings from an FDA-conducted meta-analysis suggest that patients receiving combined therapy with levodopa, carbidopa, and entacapone may be at increased risk of adverse cardiovascular events (i.e., MI, stroke, cardiovascular death) compared with those receiving levodopa-carbidopa.12 However, several limitations of the meta-analysis preclude definite conclusions.12 FDA is continuing to review available data related to this safety concern.12 FDA advises patients receiving entacapone as an adjunct to levodopa-carbidopa (either separately or as a fixed-combination preparation) to continue taking the drugs as prescribed unless otherwise instructed by a clinician.12 Clinicians should monitor cardiac function regularly, particularly in patients with a history of cardiovascular disease.12
GI Effects
Possible mild to moderate diarrhea; rarely may be severe.1 Generally occurs during first 4–12 weeks of therapy; may occur as early as first week or as late as several months following initiation and resolves following discontinuance.1
Hallucinations
Possible hallucinations, sometimes resulting in hospitalization.1
Dyskinesia
May potentiate adverse dopaminergic effects of levodopa and may cause or exacerbate dyskinesias.1 3 4
Reduction of levodopa dosage may ameliorate dyskinesias; however, many patients in clinical studies continued to experience frequent dyskinesias.1 Discontinuance of therapy may be required.1
Rhabdomyolysis
Severe rhabdomyolysis reported rarely.1 4 7
Nervous System and Muscular Effects
Symptom complex resembling neuroleptic malignant syndrome (NMS) (elevated temperature, muscular rigidity, altered consciousness, elevated CPK) reported in association with abrupt withdrawal or dosage lowering of other dopaminergic agents.1 Similar episodes possible with entacapone.1 4 7 (See Withdrawal of Therapy under Cautions.)
Respiratory Effects
Retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and thickening of the pleura reported with ergot-derivative dopamine receptor agonists (e.g., bromocriptine, pergolide); possibility exists that nonergot-derived drugs that increase dopaminergic activity (e.g., entacapone) may induce similar pulmonary changes.1
General Precautions
Use of Fixed Combination
When the fixed combination containing levodopa, carbidopa, and entacapone (Stalevo) is used, observe the usual precautions and contraindications associated with all the drugs in the preparation.8
Withdrawal of Therapy
Slow withdrawal is recommended.1
If entacapone therapy is discontinued, closely monitor patient and adjust dosage of dopaminergic therapy accordingly.1
If hyperpyrexia or severe rigidity occurs, consider possibility of symptom complex resembling NMS.1
Melanoma
Epidemiologic studies indicate patients with parkinsonian syndrome have a twofold to approximately sixfold higher risk of developing melanoma than the general population.1 8 Unclear whether increased risk is due to parkinsonian syndrome or other factors (e.g., drugs used to treat the disease).1 8
Monitor for melanoma on a frequent and regular basis.1 8 Manufacturer recommends periodic skin examinations performed by appropriately qualified individuals (e.g., dermatologists).1 8
Intense Urges
Intense urges (e.g., urge to gamble, increased sexual urges, other intense urges) and inability to control these urges reported in some patients receiving antiparkinsonian agents that increase central dopaminergic tone (including entacapone).1 8 Although causal relationship not established, urges stopped in some cases when dosage was reduced or drug was discontinued.1 8
Consider reducing dosage or discontinuing entacapone if a patient develops such urges.1 8
Specific Populations
Pregnancy
Category C.1
Lactation
Distributed into milk in rats; not known whether distributed into human milk.1 Caution if used in nursing women.1
Pediatric Use
Not indicated.1
Geriatric Use
No substantial differences in safety or pharmacokinetics relative to younger adults.1 3 7
Hepatic Impairment
Use with caution.1 (See Special Populations under Pharmacokinetics.)
Biliary Obstruction
Use with caution.1
Common Adverse Effects
Dyskinesia, nausea, hyperkinesia, diarrhea, urine discoloration, hypokinesia, dizziness, abdominal pain, constipation, fatigue.1
Interactions for Entacapone
Inhibits CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A only at very high concentrations.1 Inhibition of these isoenzymes not expected during clinical use.1
Drugs Metabolized by Catechol-O-methyltransferase
Possible increased heart rate, arrhythmias, and excessive changes in BP.1
Drugs Interfering with Biliary Excretion, Glucuronidation, and Intestinal β-Glucuronidase
Decreased entacapone excretion.1 7
Protein-bound Drugs
No binding displacement between entacapone and other highly protein bound drugs (e.g., warfarin, salicylic acid, phenylbutazone, diazepam).1
Specific Drugs
Drug | Interaction | Comments |
|---|---|---|
Anti-infective agents (e.g., ampicillin, chloramphenicol, erythromycin, rifampin) | Possible decreased entacapone excretion1 7 | Use with caution1 |
Apomorphine | Possible increased heart rate, arrhythmias, and excessive changes in BP1 | |
Cholestyramine | Possible decreased entacapone excretion1 | Use with caution1 |
CNS depressants | Additive sedative effects1 | |
Imipramine | Pharmacologic interaction unlikely1 | |
Levodopa | Increased plasma levodopa concentrations, resulting in enhanced therapeutic effects1 Increased risk of levodopa-induced cardiovascular effects and dyskinesia1 | |
MAO inhibitors | Potential inhibition of catecholamine metabolism when used concomitantly with nonselective MAO inhibitors (e.g., phenelzine, tranylcypromine)1 Pharmacologic interaction unlikely with selective MAO-B inhibitors (e.g., selegiline)1 | Avoid concomitant use with nonselective MAO inhibitors1 |
Methyldopa | Possible increased heart rate, arrhythmias, and excessive changes in BP1 | |
Probenecid | Possible decreased entacapone excretion1 | Use with caution1 |
Sympathomimetic (adrenergic) agents (e.g., dobutamine, dopamine, epinephrine, isoetharine, isoproterenol, norepinephrine) | Possible increased heart rate, arrhythmias, and excessive changes in BP1 |
Entacapone Pharmacokinetics
Absorption
Bioavailability
Rapidly absorbed following oral administration, with peak plasma concentrations attained within approximately 1 hour.1
Absolute bioavailability is 35%.1 a
Food
Food does not affect pharmacokinetics.1
Special Populations
Increased peak plasma concentrations and AUC in patients with mild to moderate hepatic impairment.1
Distribution
Extent
Does not distribute widely into tissues.1
Distributed into milk in rats; not known whether distributed into human milk.1
Plasma Protein Binding
98% (mainly albumin).1
Elimination
Metabolism
Almost completely metabolized, principally by isomerization followed by glucuronidation to an inactive conjugate.1
Elimination Route
Entacapone and its metabolites are eliminated principally in feces (90%) via biliary excretion and to a lesser extent in urine (10%).1 3 4
Half-life
Approximately 2.4 hours.1 a
Stability
Storage
Oral
Tablets
25°C (may be exposed to 15–30°C).1
ActionsActions
Structurally and pharmacologically related to tolcapone;1 3 7 however, unlike tolcapone, not associated with hepatotoxicity (e.g., drug-induced hepatitis, fatal liver failure).1 3 4 7
Inhibits catechol-O-methyltransferase (COMT) enzyme in peripheral tissues;1 3 4 effects on central COMT activity in humans not studied.1
Concomitant administration with levodopa and a decarboxylase inhibitor (e.g., carbidopa) results in increased and more sustained plasma levodopa concentrations compared with administration of levodopa and a decarboxylase inhibitor.1 3 4
Lacks antiparkinsonian activity when administered alone.1
Advice to Patients
Importance of taking entacapone as prescribed and not discontinuing abruptly.1
Necessity of exercising caution when driving or operating machinery when entacapone is initiated.1 Caution when taking other CNS depressants.1
Advise that entacapone may cause brownish orange discoloration of urine; not clinically important.1
Advise that hallucinations, nausea, and increased dyskinesia can occur.1
Advise patients not to rise rapidly after prolonged sitting or lying down, especially during first few weeks of therapy.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1
Importance of asking patients whether they have developed any new or increased gambling urges, sexual urges, or other urges while receiving entacapone and of advising them of the importance of reporting such urges.1 8
Importance of frequent monitoring for melanoma and periodic dermatologic examinations by a dermatologist.1 8
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 200 mg | Comtan | Novartis |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 200 mg with Carbidopa 12.5 mg (of anhydrous carbidopa) and Levodopa 50 mg | Stalevo | Novartis |
200 mg with Carbidopa 18.75 mg (of anhydrous carbidopa) and Levodopa 75 mg | Stalevo | Novartis | ||
200 mg with Carbidopa 25 mg (of anhydrous carbidopa) and Levodopa 100 mg | Stalevo | Novartis | ||
200 mg with Carbidopa 31.25 mg (of anhydrous carbidopa) and Levodopa 125 mg | Stalevo | Novartis | ||
200 mg with Carbidopa 37.5 mg (of anhydrous carbidopa) and Levodopa 150 mg | Stalevo | Novartis | ||
200 mg with Carbidopa 50 mg (of anhydrous carbidopa) and Levodopa 200 mg | Stalevo | Novartis |
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Comtan 200MG Tablets (NOVARTIS): 30/$112.99 or 90/$310.97
Stalevo 100 25-100-200MG Tablets (NOVARTIS): 90/$318 or 270/$898.92
Stalevo 150 37.5-150-200MG Tablets (NOVARTIS): 30/$113.99 or 90/$334.97
Stalevo 200 50-200-200MG Tablets (NOVARTIS): 100/$363.99 or 300/$1043.97
Stalevo 50 12.5-50-200MG Tablets (NOVARTIS): 30/$110.98 or 90/$317.97
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions February 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
References
1. Novartis Pharmaceuticals Corporation. Comtan (entacapone) tablets prescribing information. East Hanover, NJ; 2009 Mar.
2. LeWitt PA. New drugs for the treatment of Parkinson’s disease. Pharmacotherapy. 2000; 20:26S-32S.
3. Holm KJ, Spencer CM. Entacapone: a review of its use in Parkinson’s disease. Drugs. 1999; 58:159-77.
4. Anon. Entacapone for Parkinson’s disease. Med Lett Drugs Ther. 2000; 42:7-8.
5. Rinne UK, Larsen JP, Siden A et al. Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Neurology. 1998; 51:1309-14.
6. Parkinson Study Group. Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Ann Neurol. 1997; 42:747-55.
7. Novartis, East Hanover, NJ: Personal communication.
8. Novartis. Stalevo 50, Stalevo 75, Stalevo 100, Stalevo 125, Stalevo 150, Stalevo 200 (carbidopa, levodopa, and entacapone) tablets prescribing information. East Hanover, NJ; 2009 Mar.
9. Mylan Bertek Pharmaceuticals Inc. Apokyn (apomorphine hydrochloride) injection prescribing information. Research Triangle Park, NC; 2004 Apr.
10. van der Geest R, van Laar T, Kruger PP et al. Pharmacokinetics, enantiomer interconversion, and metabolism of R-apomorphine in patients with idiopathic Parkinson’s disease. Clin Neuropharmacol. 1998; 21:159-68. [PubMed 9617507]
11. Food and Drug Administration. FDA drug safety communication: ongoing safety review of Stalevo (entacapone/carbidopa/levodopa) and possible development of prostate cancer. Rockville, MD; 2010 Mar 31. From FDA website ().
12. Food and Drug Administration. FDA drug safety communication: ongoing safety review of Stalevo and possible increased cardiovascular risk. Rockville, MD; 2010 Aug 20. From FDA website ().
13. Stocchi F, Rascol O, Kieburtz K et al. Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study. Ann Neurol. 2010; 68:18-27. [PubMed 20582993]
a. Heikkinen H, Saraheimo M, Antila S et al. Pharmacokinetics of entacapone, a peripherally acting catechol-O-methyltransferase inhibitor, in man. A study using a stable isotope technique. Eur J Clin Pharmacol. 2001; 56: 821-6. [PubMed 11294372]
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